Conditions: Achondroplasia
Keywords: Achondroplasia Dwarfism Bone Diseases Bone Diseases, Developmental ACH Natriuretic Peptide, C-Type Musculoskeletal Diseases Natriuretic Agents Physiological Effects of Drugs Skeletal Dysplasias Genetic Diseases, Inborn Osteochondrodysplasias
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 121
Healthy volunteers: no

Brief summary:
The intent and design of this Phase 3 study is to assess BMN 111 as a therapeutic option for the treatment of children with Achondroplasia.

Detailed description:
This is a Phase 3 randomized, placebo-controlled, double-blind multicenter study with approximately 110 subjects, aged 5 to \< 18 years old. Subjects with documented Achondroplasia confirmed by genetic testing will have been enrolled in Study 111-901 for at least a 6-month period immediately before entering into the 111-301 study. Eligible subjects will be randomly assigned to one of two treatment groups: placebo or BMN 111 at 15 μg/kg. The route of administration is subcutaneous injection and the frequency is daily.

Arms:
arm 1: Daily subcutaneous injection of 15 micrograms per kilogram BMN111 arm 2: Daily subcutaneous injection of placebo

Interventions: intervention 1: BMN 111 intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous injection of 15 μg/kg of BMN 111 daily intervention 2: Subcutaneous injection of 15 μg/kg of placebo daily

Protocol document:
Prot_000.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title: A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to 
Evaluate the Efficacy and Safety of BMN 111 in Children with Achondroplasia 
 
NCT Number: NCT03197766 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 01 February 2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Proprietary and Confidential
16
APPENDICES
16.1
Study Information
16.1.1 Protocol and Protocol Amendments
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CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter 
Study to Evaluate the Efficacy and Safety of BMN 111 in Children with 
Achondroplasia 
Protocol Number:
111-301
Active Investigational Product:
BMN 111 (modified rhCNP)
IND Number:
111299 
European Union Drug Regulating 
Authorities Clinical Trials 
(EudraCT) Number:
2015-003836-11
Indication:
Achondroplasia 
Sponsor:
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
Development Phase:
Phase 3
Sponsor's Responsible Medical 
Monitor:
, MD 
 
BioMarin UK LTD
10 Bloomsbury Way
London WC1A 2SL
Treatment Duration:
52 weeks 
Duration of Subject Participation:
60 weeks
Dose:
BMN 111 15 μg/kg or placebo daily
Study Population:
Children with achondroplasia 
Date of Original Protocol:
1 September 2016
Date of Amendment 1
28 November 2016
Date of Amendment 2 
27 April 2017
Date of Amendment 3
05 January 2018
Date of Amendment 4
01 February 2019
Property of BioMarin
CONFIDENTIAL
May not be divulged, published, or otherwise disclosed to others without prior written approval from 
BioMarin.
This study will be conducted according to the principles of Good Clinical Practice as described in the U.S. 
Code of Federal Regulations and the International Conference on Harmonisation Guidelines, including the 
archiving of essential documents.
BioMarin is a registered trademark of BioMarin Pharmaceutical Inc.
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01 February 2019
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY
Amendment: 4
Date: 01 February 2019
RATIONALE AND SUMMARY OF MAJOR CHANGES
This protocol is being revised to make the following changes:
1. The following exploratory objectives have been moved to secondary 
x
Evaluation of change from baseline in body proportion ratios of the extremities [§8.0, 
Synopsis, and additional appropriate sections]. 
x
Evaluation of the effect of BMN 111 on bone morphology/quality by X-ray and dual 
X-ray absorptiometry (DXA) [§8.0 and additional appropriate sections]. 
x
Evaluate potential changes in health-related quality of life (HRQoL) and functional 
independence as measured by quality of life questionnaires [§8.0 and additional 
appropriate sections]. 
Rationale: Due to the importance of clinical, morbidity, and HRQoL outcomes in 
achondroplasia, all clinical outcome endpoints (with the exception of optional 
assessments) have been moved from exploratory to secondary. 
2. Description of contraception in the study inclusion criteria (§9.3.1 and additional 
appropriate sections) and birth control during and after the study (§9.3.3) have 
been updated. 
Rationale: To provide clarity on requirements for the use of highly effective methods 
used in female participants and acceptable methods in male participants, and to define 
true abstinence to clarify when it is considered an acceptable method of 
contraception. This is in line with the Clinical Trial Facilitation Group 
“Recommendations related to contraception and pregnancy testing in clinical trials.”
3. Duration of Subject Participation updated (§9.3.6 and additional appropriate 
sections) to 4-week safety follow-up after Week 52.  
Rationale: Follow-up after the study has been extended to ensure adequate passage of 
time before the final safety follow-up so that potentially drug-related AEs should 
have already occurred
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01 February 2019
4. Primary and secondary efficacy variables separated so that new secondary 
variables are incorporated (§9.12.2 and additional appropriate sections).
Rationale: This change made to support Rationale 1. 
5. Move selected exploratory objectives to be new secondary objectives (Synopsis, 
§9.12.3, and additional appropriate sections). 
Rationale: This change made to support Rationale 1. 
6. Exploratory efficacy variables deleted from §9.12.4 and moved to secondary 
efficacy variables (§9.12.3). 
Rationale: This change made to support Rationale 1.
7. Change medical monitor from 
 
 MD, PhD to 
, MD. 
8. Replace “18 years of age” with “age of majority” (§5.3, §12 and additional 
appropriate sections).
Rationale: The age of majority varies by country.
9. Inserted “In Japan, subject enrollment will be staggered initially, with a 
minimum of a 2-week window between the first 4 subjects enrolled” in Study 
Design and Plan in Synopsis and §9.1. 
Rationale: This measure was taken in Japan and implemented in a country-specific 
protocol given the limited exposure experience of Japanese subjects to BMN 111 at 
the time of the 111-301 study. The sponsor has now consolidated into one global 
protocol. 
10. Removed “plasma DNA” in §9.12.4.4. 
Rationale: DNA is not obtained from plasma
11. Administrative changes have been made throughout the amended protocol for 
consistency, accuracy, and clarity.
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01 February 2019
2
SYNOPSIS
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
TITLE OF STUDY: 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the 
Efficacy and Safety of BMN 111 in Children with Achondroplasia 
PROTOCOL NUMBER:
111-301
STUDY SITES:
Approximately 33 clinical centers worldwide
PHASE OF DEVELOPMENT:
Phase 3
STUDY RATIONALE:
Achondroplasia (ACH), the most common form of disproportionate short stature or dwarfism, is an 
autosomal dominant genetic skeletal disorder caused by a gain-of-function mutation in the 
fibroblast growth factor receptor-3 gene (FGFR3), a negative regulator of endochondral bone 
formation. Due to this FGFR3 mutation, there is exaggerated negative regulation on endochondral 
ossification, which results in ACH (Laederich, 2010).
The use of modified recombinant C-type natriuretic peptide (rhCNP) as a potential therapy for the 
treatment of ACH is based on the mechanism of action of C-type natriuretic peptide (CNP). CNP 
and its receptor, NPR-B, are key regulators of skeletal growth. CNP binding to its receptor, 
natriuretic peptide receptor-B (NPR-B), acts as a key regulator of longitudinal bone growth by 
down-regulating the mitogen-activated protein kinase (MAPK) pathway. CNP-mediated activation 
of NPR-B results in the rescue of the dwarfism phenotype of mice with a FGFR3 gain-of-function 
mutation (Yasoda, 2004; Yasoda 2009). The pharmacological activity of BMN 111 was explored 
in two mouse models of ACH, a severe, Fgfr3Y367C/+ model (Lorget, 2012,), and a mild [Ach] /+ 
model. Partial or complete reversion of the ACH phenotype was observed in these mouse models 
after BMN 111 administration. Additionally, in wild-type mice, and normal rats and monkeys, 
BMN 111 administration resulted in growth plate expansion and dose-dependent skeletal growth at 
hemodynamically-tolerated dose levels (Wendt, 2015,). Therefore, administration of CNP has been 
proposed as a therapeutic approach for ACH.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
BioMarin has engineered a CNP analog (BMN 111) that has a longer half-life than endogenous 
CNP, thereby allowing daily subcutaneous (SC) administration. Similar to CNP, BMN 111 
activates NPR-B signaling with subsequent inhibition of FGFR3 downstream signaling, leading to 
the promotion of chondrocyte proliferation and differentiation and subsequent increased 
endochondral bone formation. BMN 111 administration has been shown to promote endochondral 
bone formation at hemodynamically tolerated dose levels in both normal animals and mouse 
models of ACH reported (refer to current Investigators Brochure for additional information).
Human studies to date have demonstrated that BMN 111 is safe and well-tolerated at doses that 
result in improvements in growth velocity approaching that of children of average stature.
Study 111-101 was a Phase 1 double-blind, placebo-controlled study to assess the safety and 
tolerability of BMN 111 in healthy adult male volunteers without ACH. Part 1 examined a series of 
single subcutaneous doses (5 μg/kg, 10 μg/kg and 15 μg/kg), and Part 2 included 10 days of either 
fixed dosing or dose escalation (0.5 μg/kg to 8 μg/kg). BMN 111 was generally well tolerated at all 
doses. As expected, mild, transient, self-limited hypotension was reported (refer to current 
Investigators Brochure for additional information). BMN 111 demonstrated dose-related linear 
increases in exposure by maximum observed plasma concentration (Cmax) (from 2.5 μg/kg to 
15 μg/kg) in healthy volunteers; plasma elimination half-life (t1/2) ranged from 30.7 to 140 minutes.
Study 111-202 was a Phase 2, open-label, sequential cohort, dose escalation study that assesses 
daily SC BMN 111 in pediatric subjects with ACH, starting with a dose of 2.5 μg/kg and escalating 
through additional dose cohorts up to 30 μg/kg. The primary objective of Study 111-202 was to 
evaluate the safety and tolerability of BMN 111 administered for 6 months and up to 24 months; 
the secondary objectives were to determine change from baseline in annualized growth velocity 
(AGV), growth parameters, body proportions, and evaluate the dose-exposure and pharmacokinetic 
(PK) profiles of BMN 111 in children with ACH. 
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that treatment 
with BMN 111 for 6 months at the doses of 2.5, 7.5, 15, and 30 μg/kg was generally well tolerated 
at all dose levels (refer to current Investigators Brochure for specific details).
Analysis of efficacy data from the 6-month initial phase of Study 111-202 demonstrated a positive 
dose-dependent response in mean change from baseline AGV at doses ranging from 2.5-15 μg/kg 
daily. Subjects treated with 30 μg/kg daily also showed similar improvement in AGV after 6 
months compared with subjects treated with 15 μg/kg daily. Safety data for the 30-μg/kg daily 
dose was also similar to the 15-μg/kg daily dose. Given that no clinically significant difference 
could be identified between the 15-μg/kg and 30-μg/kg daily dose in the Phase 2, 6-month safety 
and efficacy data, the lower of the two doses has been chosen for this Phase 3 study.
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Proprietary and Confidential
01 February 2019
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Study 111-301 is designed to further characterize and confirm efficacy and safety of BMN 111 at 
15 μg/kg for 52 weeks. This 60-week study (up to 4 weeks of screening, 52 weeks of treatment 
with an additional 4 weeks of safety follow up) will allow for assessment of the effect of daily 
BMN 111 administration on change from baseline in AGV, height, and body proportions in
subjects treated with BMN 111 compared with control subjects in the placebo group, as well as 
further characterize safety and tolerability of BMN 111 in children with ACH. Additional 
endpoints will also be examined to determine the effect of BMN 111 on bone physiology and to 
assess quality of life and daily function of study subjects.
OBJECTIVES: 
The primary objective of the study is to:
x
Evaluate change from baseline in annualized growth velocity at 52 weeks in subjects 
treated with BMN 111 compared with control subjects in the placebo group.
The secondary objectives of the study are to:
x
Evaluate change from baseline in height Z-score in subjects treated with BMN 111 
compared with control subjects in the placebo group at 52 weeks. 
x
Evaluate change from baseline in upper:lower segment body ratio in subjects treated with 
BMN 111 compared with control subjects in the placebo group at 52 weeks.
x
Evaluate change from baseline in body proportion ratios of the extremities.  
x
Evaluate effect of BMN 111 on bone morphology/quality by X-ray and dual X-ray 
absorptiometry (DXA).
x
Evaluate potential changes in health-related quality of life (HRQoL) as measured by the 
Quality of Life in Short Stature Youth (QoLISSY) and the Pediatric Quality of Life 
Inventory (PedsQL) questionnaires.
x
Evaluate potential changes in functional independence as measured by the Functional 
Independence Measure (WeeFIM) clinician-reported outcome.  
x
Evaluate safety and tolerability of BMN 111 in children with ACH.
x
Evaluate the PK of BMN 111.
x
Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy 
measures.
x
Evaluate change from baseline in bone metabolism biomarkers.
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01 February 2019
NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
The exploratory objectives of the study are to:
x
Evaluate sleep study scores by polysomnography in a subset of subjects.
x
Evaluate biomarkers of BMN 111 activity.
x
Evaluate genomic biomarkers.
STUDY DESIGN AND PLAN: 
This is a Phase 3 randomized, double-blind, placebo-controlled, multicenter study to evaluate the
effect of BMN 111 on growth velocity in children with ACH. Subjects who are 5 to < 18 years old, 
with documented ACH confirmed by genetic testing will have been enrolled in Study 111-901 for 
at least a 6-month period immediately before study entry, and meet all study eligibility criteria will 
participate. At least 110 eligible subjects will be stratified based on sex and Tanner stage (Stage 1, 
and > Stage 1, with no more than 20% of subjects > Tanner Stage 1) at Screening, and randomly 
assigned in a 1:1 ratio to one of two treatment groups: placebo or BMN 111 at 15 μg/kg/day. To 
achieve gender balance, approximately 50% of each gender will be enrolled, with neither to exceed 
55%. In Japan, subject enrollment will be staggered initially, with a minimum of a 2-week window 
between the first 4 subjects enrolled. 
For both placebo and BMN 111, the route of administration is subcutaneous injection and the 
frequency is daily. Approximately 33 clinical centers worldwide will participate in the study.  
Safety monitoring will be conducted for all subjects randomized to BMN 111 or placebo after the 
first dose of BMN 111 or placebo is received and over the duration of the study. This will include a 
minimum of 2 hours post-dose observation on the first 3 days of dosing (and 30 minutes for all 
other days of dose administration) in conjunction with caregiver training for BMN 111 or placebo 
administration and adverse event (AE) documentation/reporting. It is generally expected that after 
subjects are tolerating BMN 111 or placebo well and specified criteria have been met (refer to
Study Reference Manual), caregivers will begin administering BMN 111 or placebo at home. If the 
caregiver is unable or unavailable to administer BMN 111 or placebo, home health care may be 
provided. Contact by a study staff member to the caregiver will be required every 4 weeks 
(± 10 days) to all study subjects after the Week 6 visit when there are no study visits or contact in 
the preceding 4 weeks. During these contacts, study staff will ask about dose administration and 
seek information on AEs and SAEs by specific questioning. Information on all AEs and serious 
adverse events (SAEs) should be recorded in the subject’s medical record and on the AE eCRF.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
After subjects have completed the treatment period of the study, those in both treatment and 
control groups may be eligible to receive BMN 111 in the extension study 111-302, to assess safety 
and efficacy of BMN 111 over a longer time period. Subjects will have the option to enroll in 
111-302 after the Week 52/Study Completion Visit. Week 52 assessments will serve as Baseline 
assessments for entry to study 111-302 if the visit occurs on the same day or within 2 weeks. 
Subjects who enroll into 111-302 more than 2 weeks after the 111-301 Week 52 visit will have a 
separate Baseline visit; the same assessments as those performed at Week 52 will be repeated at 
that time.
Data Monitoring Committee
In addition to safety monitoring by BioMarin personnel, an independent data monitoring 
committee (DMC) will review and provide input on the safety data collected in the study. DMC 
data review will occur at regular time periods during the course of the study (or ad hoc, if 
indicated) as outlined in a separate DMC charter.
NUMBER OF SUBJECTS PLANNED: 
At least 110 subjects with ACH, as documented by clinical grounds and genetic testing.
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION: 
Individuals eligible to participate in this study must meet all of the following inclusion criteria:
1.
Parent(s) or guardian(s) are willing and able to provide written, signed informed consent
after the nature of the study has been explained and prior to performance of any research-
related procedure. Also, subjects under the age of majority are willing and able to provide 
written assent (if required by local regulations or the IRB/EC) after the nature of the study 
has been explained and prior to performance of any research-related procedure. Subjects 
who reach the age of 18 years while the study is ongoing will be asked to provide their 
own written consent.
2.
5 to < 18 years old at study entry.
3.
Have ACH, documented by clinical grounds and confirmed by genetic testing.
4.
Have at least a 6-month period of pretreatment growth assessments, including standing 
height, and are currently active participants in 111-901.
5.
)HPDOHV\HDUVROGRUZKRKave begun menses must have a negative pregnancy test at 
the Screening Visit and be willing to have additional pregnancy tests during the study.  
6.
If sexually active, willing to use contraception as specified in Section 9.3.3
7.
Are ambulatory and able to stand without assistance. 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
8.
Are willing and able to perform all study procedures.
9.
Caregivers are willing to administer daily injections to the subjects and complete the 
required training.
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study:
1.
Have hypochondroplasia or short stature condition other than ACH (eg, trisomy 21, 
pseudoachondroplasia).
2.
Have any of the following:  
o
Hypothyroidism or hyperthyroidism.
o
Insulin-requiring diabetes mellitus. 
o
Autoimmune inflammatory disease (including celiac disease, lupus (SLE), 
juvenile dermatomyositis, scleroderma, and others).
o
Inflammatory bowel disease.  
o
Autonomic neuropathy. 
3.
Have a history of any of the following:
o
Renal insufficiency defined as serum creatinine > 2 mg/dl.
o
Chronic anemia.
o
Baseline systolic blood pressure (BP) < 70 millimeters of mercury (mm Hg) or 
recurrent symptomatic hypotension (defined as episodes of low BP generally 
accompanied by symptoms ie, dizziness, fainting) or recurrent symptomatic 
orthostatic hypotension.
o
Cardiac or vascular disease, including the following:

Cardiac dysfunction (abnormal echocardiogram) at Screening Visit. 

Hypertrophic cardiomyopathy.

Pulmonary hypertension.

Congenital heart disease.

Cerebrovascular disease.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:

Aortic insufficiency or other clinically significant valvular 
dysfunction.

Clinically significant atrial or ventricular arrhythmias.
4.
Have a clinically significant finding or arrhythmia on screening electrocardiogram (ECG) 
that indicates abnormal cardiac function or conduction or QTc-F > 450 msec.
5.
Have an unstable condition likely to require surgical intervention during the study 
(including progressive cervical medullary compression or severe untreated sleep apnea).
6.
Evidence of decreased growth velocity (AGV < 1.5 cm/year) as assessed over a period of 
at least 6 months or of growth plate closure (proximal tibia, distal femur) through bilateral 
lower extremity X-rays including both AP and lateral views.
7.
Documented Vitamin D deficiency (concentration of blood 25-hydroxy-vitamin D 
<12 ng/mL or <30 nmol/L).
8.
Require any investigational agent prior to completion of study period.
9.
Have received another investigational product or investigational medical device within 
6 months before the Screening Visit. 
10. Have used any investigational product or investigational medical device for the treatment 
of ACH or short stature at any time, including BMN 111. 
11. Current therapy with antihypertensive medications, angiotensin-converting enzyme (ACE) 
inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, calcium-channel 
blockers, cardiac glycosides, systemic anticholinergic agents, GnRH agonists, any 
medication that may impair or enhance compensatory tachycardia, diuretics, or other drugs 
known to alter renal or tubular function (Table 9.3.2.1).
12. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic 
steroids in the previous 6 months or treatment greater than 6 months at any time. 
13. Have had > 1 month treatment with oral corticosteroids (low-dose ongoing inhaled steroid 
for asthma, or intranasal steroids, are acceptable) in the previous 12 months. 
14. Planned or expected to have limb-lengthening surgery during the study period. Subjects 
with previous limb-lengthening surgery may enroll if surgery occurred at least 18 months 
prior to screening and healing is complete without sequelae.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
15. Planned or expected bone-related surgery (ie, surgery involving disruption of bone cortex, 
excluding tooth extraction), during the study period. Subjects with previous bone-related 
surgery may enroll if surgery occurred at least 6 months prior to screening and healing is 
complete without sequelae.
16. Have had a fracture of the long bones or spine within 6 months prior to screening. 
17. Pregnant or breastfeeding at the Screening Visit or planning to become pregnant (self or 
partner) at any time during the study. 
18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at least 
3×upper limit of normal (ULN) or total bilirubin at least 2×ULN (except for subjects with 
known history of Gilbert’s disease).
19. History of severe untreated sleep apnea. 
20. Have had new initiation of sleep apnea treatment (eg, continuous positive airway pressure 
[CPAP] or sleep apnea-mitigating surgery) in the previous 2 months prior to screening. 
21. Have current malignancy, history of malignancy, or currently under work-up for suspected 
malignancy.
22. Have known hypersensitivity to BMN 111 or its excipients.
23. Have a history of hip surgery or hip dysplasia atypical for achondroplasia subjects. 
24. Have clinically significant hip injury in the 30 days prior to screening.
25. History of slipped capital femoral epiphysis or avascular necrosis of the femoral head. 
26. Are unable to lie flat when in prone position (needed for hip exam). 
27. Have abnormal findings on baseline clinical hip exam or imaging assessments that are 
determined to be clinically significant as determined by the investigator.
28. Concurrent disease or condition that, in the view of the investigator, would interfere with 
study participation or safety evaluations, for any reason.  
29. 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.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN: 
For subjects randomized to BMN 111, the clinical drug product will be supplied in sterile, single-
dose, Type I glass vials with coated stopper and flip-off aluminum cap. BMN 111 drug product is 
supplied as 0.8-mg or 2-mg lyophilized, preservative-free, white to yellow powder for 
reconstitution with commercially-sourced sterile water for injection (WFI). The reconstituted 
solution is colorless to yellow and contains 0.8 mg/mL to 2 mg/ml of BMN 111, as well as citric 
acid, sodium citrate, trehalose, mannitol, methionine, polysorbate 80, and sterile WFI. The target 
pH of the reconstituted solution is 5.5. 
All reconstitution and dose preparation steps should be performed as indicated in the Study Drug 
Injection Guide and Injection instruction media. 
BMN 111 will be administered as a single SC daily dose of 15 μg/kg. BMN 111 will be 
administered as a single SC injection given daily at approximately the same time each day 
whenever possible. Subjects will be observed for 2 hours after the injection for Days 1 to 3, and 30 
minutes for all other dosing administration days.
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN: 
BMN 111 placebo lyophilized product will be supplied in sterile, single-dose, Type I glass vials 
with coated stopper and flip-off aluminum cap. The placebo is designed to be comparable in 
appearance to the drug product and contains all of the components of the drug product except the 
drug substance. 
All reconstitution and dose preparation steps should be performed as indicated in the Study Drug 
Injection Guide and Injection instruction media.
Placebo will be administered as a single SC injection given daily at approximately the same time 
each day whenever possible. Subjects should be observed for 2 hours after the injection for Days 1 
to 3, and 30 minutes for all other dosing administration days.  
DURATION OF TREATMENT: 
52 weeks
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CRITERIA FOR EVALUATION: 
Primary Efficacy: 
Primary efficacy will be assessed by change from baseline in height growth velocity (annualized to 
cm/yr).
Safety:
Safety will be evaluated by assessment of AEs, SAEs, laboratory test results (urinalysis, chemistry, 
hematology), changes in vital signs, physical examination, ECG, X-ray/DXA assessments of bone 
morphology and quality, clinical hip assessment, anti-BMN 111 immunogenicity assessments; 
salivary cortisol, serum prolactin, and follicle stimulating hormone (FSH)/luteinizing hormone 
(LH) levels (FSH/LH will be monitored for all subjects >8 years of age, and for subjects at Tanner 
stage 2, whichever is earlier); and cognitive assessment with the Childhood Behavioral Checklist 
(CBCL). Additional assessments will be conducted to evaluate changes from baseline in bone 
metabolism.
Pharmacokinetics:
PK sampling will be carried out over the 12-month study period in subjects randomized to 
BMN 111 or placebo. If supported by the data, the PK variables to be calculated for subjects 
randomized to BMN 111 will include: 
x
Area under the plasma concentration-time curve from time 0 to infinity (AUC0-).
x
Area under the plasma concentration-time curve from time 0 to the time of last measurable 
concentration (AUC0-t).
x
Maximum observed plasma concentration (Cmax).
x
Time to reach Cmax (Tmax).
x
Elimination half-life (t1/2).
x
Apparent clearance (CL/F).
x
Apparent volume of distribution (Vz/F).
All PK variables will be estimated by non-compartmental analysis.
Secondary:
Secondary assessments will include change from baseline in growth parameters (height), body 
proportions of the upper and lower segments, and proportions of the extremities by anthropometry. 
Growth parameters will be assessed by height Z-scores. Body proportions will be assessed by 
anthropometric measurements and measurement ratios. Anthropometric measurements may include 
but are not limited to standing height; sitting height; weight; head circumference; upper and lower 
arm length; leg length; and arm span. Measurement ratios may include, but are not limited to, 
upper:lower body segment ratio, upper arm:forearm length ratio, upper leg:lower leg length ratio, 
and arm span:standing height ratio. Further details are provided in the Study 111-301
Anthropometric Measurement Guidelines.
Health-related quality of life and functional independence will be assessed using the QoLISSY, 
PedsQL, and WeeFIM (reference Training Materials for specifics).
Exploratory:
Polysomnography will be conducted to evaluate sleep apnea in a subset of subjects. Additional 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
exploratory assessments will be conducted to evaluate changes from baseline in BMN 111 activity 
biomarkers and optional genomic biomarkers will be evaluated.
STATISTICAL METHODS: 
Sample Size Determination:
With 55 subjects planned in each of the two randomized groups (one BMN 111 group and one 
placebo group), the power to detect a difference of 1.75 cm/year between the BMN 111 group and 
the placebo group in change from baseline in AGV at 12 months is approximately 90%, assuming 
that the pooled standard deviation of the change from baseline in AGV is 2.80, using a two-sided 
two-sample t-test at a 0.05 significance level. The power calculation is based on data from Study 
111-202 (a phase 2, open-label, sequential cohort dose-escalation study) and Study 111-901 (a 
natural history study for pediatric subjects with achondroplasia). 
Efficacy Analysis: 
Efficacy analysis will be carried out for the 52-week (12-month) period. Efficacy analysis will be 
based on all randomized subjects who receive at least one dose of double-blinded BMN 111 or 
placebo in this study.
The primary efficacy endpoint is the change from baseline in AGV at the 12-month time point 
based on standing height measures. The details of the derivation for AGV are provided in 
Section 14.2.1. The AGV and its change from baseline at each scheduled post-treatment visit will 
be summarized using descriptive statistics (mean, standard deviation [SD], median, minimum, and 
maximum) per group. The primary estimand is the difference in mean change from baseline in 
AGV at the 12-month time point between the BMN 111 group and the placebo group. The 
estimand is defined on all randomized subjects who received at least one dose of double-blinded 
BMN 111 or placebo. 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949 
NAME OF FINISHED PRODUCT:
BMN 111 
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume: 
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
Subjects who discontinue from the study drug will be encouraged to remain in the study, and their 
non-missing height measurements will continue to be used in calculating the AGV and to be
included in the analysis per intend to treat principle. In the event that missing data does occur 
despite all efforts, missing standing height will be imputed based on multiple imputation (MI) with
pattern-mixture models (Little 1993; Molenberghs 2007,) implemented in Proc MI of SAS where
the missing, unobserved observations of the standing height are assumed to follow missing not at
random (MNAR) mechanism. For each imputation, the standing heights collected from the
subjects in the same randomization group who also discontinue treatment prematurely
(but remain in the study), referred to as off-treatment data, will be used as the reference data for
MI. Ten (10) sets of imputations of the missing standing heights will be constructed from MI and
the AGV at the 12-month time point will be calculated based on these 10 sets of data. For each 
subject whose value is imputed, the 10 imputed values will be provided in a data listing that will be
included in the appendix of the CSR. 
The primary null hypothesis of no difference between the BMN 111 group and the placebo group 
in the mean change from baseline in AGV at the 12-month time point will be tested based on an 
analysis of covariance (ANCOVA) model, with fixed-effect terms including treatment group, sex, 
and Tanner stage, and age and the baseline AGV as covariates. The above-mentioned ANCOVA 
model will be applied to the 10 imputed data sets from MI. The analysis results based on the 
10 imputed datasets will be summarized using Proc MIANALIZE in SAS.
The key secondary efficacy endpoints are the change from baseline in height Z-score, and the 
change from baseline in upper:lower body segment ratio. The estimand of the key secondary
efficacy endpoints is the difference in mean change from baseline in the corresponding endpoint at
the 12-month time point between the BMN 111 group and the placebo group (all randomized 
subjects who received at least one dose of double-blinded BMN 111 or placebo). The measurement 
of standing height at each scheduled visit will be converted to age-and sex-appropriate standard 
score, also referred to as Z-score, by comparison with normal reference standards (not ACH). The 
height Z-score and its change from baseline will be summarized using descriptive statistics. Any
missing observations will be imputed based on MI with pattern-mixture models described above. 
The null hypothesis of no difference between the BMN 111 group and the placebo group in the
mean change from baseline in the height Z-score at the 12-month time point will be tested based on 
10 imputed data sets using an analysis of covariance (ANCOVA) model, with fixed-effect terms 
including treatment group, sex, and Tanner stage, and age and the baseline Z-score as covariates.
The analysis results based on the 10 imputed datasets will be summarized using Proc MIANALIZE
in SAS. The change from baseline in upper:lower body segment ratio at the 12-month time point 
will be similarly summarized and tested.
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
The overall type I family-wise error rate for testing the primary and secondary efficacy endpoints 
will be controlled at the 0.05 significance level using the following 3-step serial gatekeeping 
multiple comparisons procedure (MCP). Following this MCP, advancement to the next step will 
only occur if the null hypotheses within a step and the previous step(s) are all rejected at the 
significance level of 0.05 in favor of BMN 111. If any null hypotheses within a step is not rejected 
or is rejected but not in favor of BMN 111, the hypothesis tests corresponding to all subsequent 
steps will not be considered statistically significant. All hypothesis tests will be two-sided. 
1.
The first step will be the test comparing the BMN 111 group to the placebo group for the 
primary efficacy endpoint, the change from baseline in AGV at 12-month time point. If the 
null hypothesis is not rejected (ie, p-value > 0.05) or is rejected but not in favor of 
BMN 111, all subsequent statistical tests will not be considered statistically significant. 
The study is considered positive if the primary test is significant in favor of BMN 111. 
2.
The second step will be the test comparing the BMN 111 group to the placebo group for 
the secondary efficacy endpoint, the change from baseline in height Z-score at 12-month 
time point. If the null hypothesis is not rejected (ie, p-value > 0.05) or is rejected but not in 
favor of BMN 111, the subsequent statistical test will not be considered statistically 
significant. 
3.
The third step will be the test comparing the BMN 111 group to the placebo group for the 
secondary efficacy endpoint, the change from baseline in upper:lower body segment ratio 
at 12-month time point at a significance level of 0.05. 
Additional secondary efficacy analyses will also include change from baseline in body proportions 
of extremities, and HRQoL and functional independence assessments. 
Change in body proportions of extremities will be assessed by anthropometry. 
To assess the robustness of the primary analysis result, sensitivity analyses such as the following 
will be performed:
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Mixed Model with Repeated Measures (MMRM)
The primary null hypothesis of no difference between the BMN 111 group and the placebo group 
in the mean change from baseline in AGV at the 12-month time point will be tested based on all 
available AGV assessments from all scheduled visits using a mixed model with repeated measures 
(MMRM), with fixed-effect terms including treatment group, visit, sex, Tanner stage, and 
interaction of treatment group and visit, and age and the baseline AGV as covariates, repeated over 
visits. 
MI Based on Missing At Random (MAR) Assumption
The sensitivity analyses will be based on the MI technique as proposed by Little and Rubin (1987)
implemented in PROC MI of SAS where the missing, unobserved observations of the response 
variable are assumed to follow MAR mechanism. The MI procedure will be directly applied to 
standing height and AGV will be calculated based on imputed height. The ANCOVA model 
described in the primary analysis will be performed separately for each imputation dataset and a 
summary overall imputed samples will be provided for each analysis.
Random Coefficients Model
The mean change from baseline in height at 12-month time point will be estimated for both the 
treatment group and the placebo group based on a MMRM, with fixed-effect terms including 
treatment group, visit, sex, Tanner stage, and age and the baseline height as covariates, and 
random-effect terms of the intercept and the subject×visit interaction. For each randomized group, 
an AGV at 12-month time point will be defined as the mean change from baseline in height at 
12-month from the MMRM model above.  
ANCOVA on Completers
In this sensitivity analysis, the estimand will be the difference of the means of the change from 
baseline in AGV at 12-month observed from subjects who have non-missing observation at 
12-month between the two randomized groups. The LS means of the change from baseline in AGV 
at 12-month will be estimated for both the randomized groups based on the ANCOVA model 
described in the primary analysis. In this analysis, only subjects with observed AGV change from 
baseline at 12-month will be included. No extrapolation or imputation will be performed for 
missing 12-month or Day 1 standing height measurements. 
Similar sensitivity analyses may also be performed on secondary efficacy endpoints. Subgroup 
analyses on the efficacy endpoints based on Tanner stage or age groups may also be performed. 
By-subject listings will also be provided for efficacy endpoints. Detailed statistical methods will be 
provided in the SAP.
Safety Analysis:
All randomized subjects who receive at least one dose of double-blinded BMN 111 or placebo will 
be included in the study safety analysis. The safety analysis will be descriptive. 
All AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA) to assign system organ class and preferred term classification to event and 
disease, based on the original terms entered on the CRF. The incidence of AEs will be summarized 
by system organ class, preferred term, relationship to study treatment as assessed by investigator, 
and severity. All AEs, including SAEs and AEs that lead to permanent discontinuation from the 
study and from the study treatment, will be listed.
All other safety measures including X-ray/DXA assessments of bone morphology, quality, and 
growth of the extremities and spine (X-rays only), laboratory tests, CBCL assessments, vital signs, 
physical examination, ECG, clinical hip assessment, anti-BMN 111 immunogenicity, and bone 
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NAME OF COMPANY
BioMarin Pharmaceutical Inc.
105 Digital Drive
Novato, CA 94949
NAME OF FINISHED PRODUCT:
BMN 111
NAME OF ACTIVE INGREDIENT:
Modified rhCNP
SUMMARY TABLE
Referring to Part of the 
Dossier:
Volume:  
Page: 
Reference: 
FOR NATIONAL 
AUTHORITY USE 
ONLY:
metabolism biomarkers, will also be summarized descriptively by group, as appropriate. 
By-subject listings will be provided for these safety endpoints. 
Pharmacokinetic Analysis: 
In subjects randomized to the active treatment arm, PK parameters generated over the course of the 
study will be evaluated and summarized with descriptive statistical measures (mean, standard 
deviation, percentage of coefficient of variation [CV%], minimum, median and maximum). 
Correlative analyses of some of the PK parameters with efficacy, safety and immunogenicity 
measures may be conducted.
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3
TABLE OF CONTENTS
1    TITLE PAGE………………………………………………………………………………1 
CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY............................................2 
2 SYNOPSIS...........................................................................................................................4 
3 TABLE OF CONTENTS...................................................................................................19 
4 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................26 
5 ETHICS..............................................................................................................................30 
5.1 Institutional Review Board or Independent Ethics Committee ................................30 
5.2 Ethical Conduct of Study..........................................................................................31 
5.3 Subject Information and Informed Consent..............................................................31 
6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................33 
7 INTRODUCTION .............................................................................................................34 
7.1 Nonclinical Studies ...................................................................................................35 
7.2 Previous Clinical Studies ..........................................................................................36 
7.2.1 
Study 111-101 .............................................................................................36 
7.2.2 
Study 111-202 .............................................................................................37 
7.3 Ongoing Clinical Studies ..........................................................................................38 
7.3.1 
Study 111-205 .............................................................................................38 
7.4 Study Rationale.........................................................................................................38 
7.5 Summary of Overall Risks and Benefits...................................................................39 
7.5.1 
Summary of Risks from Nonclinical Studies..............................................39 
7.5.2 
Summary of Risks from Clinical Studies....................................................40 
7.5.2.1 
Study 111-101..............................................................................40 
7.5.2.2 
Study 111-202..............................................................................40 
7.5.3 
Summary of Potential Benefits from Clinical Studies ................................41 
8 STUDY OBJECTIVES......................................................................................................42 
9 INVESTIGATIONAL PLAN............................................................................................43 
9.1 Overall Study Design and Plan.................................................................................43 
9.2 Discussion of Study Design, Including Choice of Control Group ............................52 
9.3 Selection of Study Population ...................................................................................52 
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9.3.1 
Inclusion Criteria.........................................................................................53 
9.3.2 
Exclusion Criteria........................................................................................53 
9.3.3 
Use of Birth Control During and After Study Participation ........................56 
9.3.4 
Removal of Subjects from Treatment or Assessment .................................57 
9.3.5 
Subject Identification ..................................................................................59 
9.3.6 
Duration of Subject Participation................................................................59 
9.4 Treatments.................................................................................................................59 
9.4.1 
Treatments Administered ............................................................................59 
9.4.1.1 
BMN 111 .....................................................................................60 
9.4.1.2 
Placebo.........................................................................................60 
9.4.2 
Identity of BMN 111 ...................................................................................60 
9.4.2.1 
Product Characteristics and Labeling ..........................................61 
9.4.3 
Storage.........................................................................................................61 
9.4.4 
Directions for Administration .....................................................................62 
9.4.5 
Method of Assigning Subjects to Treatment Groups..................................63 
9.4.6 
Selection of Dose and Dosing Schedule Used in the Study........................63 
9.4.7 
Blinding .......................................................................................................63 
9.4.8 
Prior and Concomitant Medications............................................................64 
9.4.9 
Treatment Compliance ................................................................................64 
9.5 Investigational Product Accountability (BMN 111 or Placebo)...............................64 
9.5.1 
Return and Disposition of Clinical Supplies...............................................64 
9.6 Dietary or Other Protocol Restrictions......................................................................65 
9.7 Demographic Data and Medical History ..................................................................65 
9.8 Biological Parental Standing Height.........................................................................65 
9.9 Physical Examination Findings.................................................................................66 
9.10 Tanner Stage of Pubertal Development ....................................................................66 
9.11 Echocardiogram ........................................................................................................66 
9.12 Efficacy and Safety Variables...................................................................................66 
9.12.1 Efficacy and Safety Measurements Assessed .............................................66 
9.12.2 Primary Efficacy Variable...........................................................................66 
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9.12.3 Secondary Efficacy Variables .....................................................................67 
9.12.3.1 
Height...........................................................................................67 
9.12.3.2 
Body Proportion Ratio of Upper to Lower Segment ...................67 
9.12.3.3 
Body Proportion Ratios of the Extremities..................................67 
9.12.3.4 
Health-related Quality of Life and Functional 
Independence Measure.................................................................67 
9.12.4 Exploratory Efficacy Variables...................................................................68 
9.12.4.1 
Sleep Sub-Study...........................................................................68 
9.12.4.2 
BMN 111 Activity Biomarkers....................................................69 
9.12.4.3 
Biomarker Research Sample Analyses ........................................69 
9.12.4.4 
Genomic Biomarker Analysis......................................................69 
9.12.5 Pharmacokinetics Variables ........................................................................69 
9.12.6 Safety Variables ..........................................................................................70 
9.12.6.1 
Adverse Events ............................................................................70 
9.12.6.2 
Procedures During the Study .......................................................70 
9.12.6.3 
Bone Morphology, Bone Mineral Density, Bone Mineral 
Content and Bone Age.................................................................71 
9.12.6.4 
Imaging Assessment Procedures (per Schedule of Events).........71 
9.12.6.5 
Clinical Laboratory Assessments.................................................71 
9.12.6.6 
Other Laboratory Assessments ....................................................73 
9.12.6.7 
Child Behavior Checklist.............................................................73 
9.12.6.8 
Bone Metabolism Biomarkers .....................................................73 
9.12.6.9 
Vital Signs, Physical Examinations and Other 
Observations Related to Safety....................................................74 
9.12.6.10 Mitigating the Risk of Potential Hypotension .............................75 
9.12.6.11 Electrocardiography.....................................................................76 
9.12.6.12 Hip Clinical Assessment..............................................................76 
9.12.6.13 Pregnancy Testing........................................................................76 
9.12.6.14 Pediatric Blood Volume...............................................................77 
9.12.6.15 Anti- BMN 111 Immunogenicity Assessments...........................77 
9.12.6.16 Ad Hoc Safety Assessments ........................................................78 
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9.12.6.17 HPA Axis Assessments................................................................78 
9.12.6.18 Unscheduled Safety Visits...........................................................79 
9.12.6.19 Medical Photography...................................................................79 
10 REPORTING ADVERSE EVENTS .................................................................................80 
10.1 Safety Parameters and Definitions............................................................................80 
10.1.1 Adverse Events............................................................................................80 
10.1.2 Serious Adverse Events...............................................................................80 
10.1.3 Events of Special Interest..............................................................................81 
10.2 Methods and Timing for Capturing and Assessing Safety Parameters.....................81 
10.2.1 Adverse Event Reporting Period .................................................................81 
10.2.2 Eliciting Adverse Events.............................................................................81 
10.2.3 Assessment of Seriousness, Severity, and Causality ...................................81 
10.2.3.1 
Seriousness...................................................................................82 
10.2.3.2 
Severity ........................................................................................82 
10.2.3.3 
Causality ......................................................................................82 
10.3 Procedures for Recording Adverse Events ...............................................................84 
10.3.1 Recording Adverse Events on an eCRF......................................................84 
10.3.1.1 
Diagnosis versus Signs and Symptoms........................................84 
10.3.1.2 
Adverse Events Occurring Secondary to Other Events...............84 
10.3.1.3 
Persistent or Recurrent Adverse Events.......................................84 
10.3.1.4 
Hypotension.................................................................................85 
10.3.1.5 
Injection Site Reactions ...............................................................85 
10.3.1.6 
Abnormal Laboratory Values ......................................................85 
10.3.1.7 
Pre-existing Conditions................................................................86 
10.3.1.8 
General Physical Examination Findings......................................86 
10.3.1.9 
Hospitalization, Prolonged Hospitalization, or Surgery ..............87 
10.3.1.10 Deaths ..........................................................................................87 
10.3.1.11 Pregnancy.....................................................................................87 
10.4 Reporting Requirements ...........................................................................................88 
10.4.1 Expedited Reporting Requirements.............................................................88 
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10.4.2 IRB/EC Reporting Requirements................................................................88 
10.5 Follow-up of Subjects after Adverse Events.............................................................89 
10.6 Post-Study Adverse Events.......................................................................................89 
10.7 Urgent Safety Measures............................................................................................89 
10.8 BioMarin Pharmacovigilance Contact Information..................................................90 
11 APPROPRIATENESS OF MEASUREMENTS...............................................................91 
12 STUDY PROCEDURES ...................................................................................................92 
12.1 Screening Visit (Day -30 to Day -1).........................................................................92 
12.2 Treatment Visits........................................................................................................93 
12.2.1 Day 1 (no visit window)..............................................................................93 
12.2.2 Day 2 (no visit window)..............................................................................94 
12.2.3 Day 3 (no visit window)..............................................................................94 
12.2.4 Day 10 (± 1 day)..........................................................................................94 
12.2.5 Week 6 (± 7 days) .......................................................................................95 
12.2.6 Week 13 (± 7 days) .....................................................................................95 
12.2.7 Week 26 (± 7 days) .....................................................................................96 
12.2.8 Week 39 (± 7 days) .....................................................................................97 
12.2.9 Week 52 (± 7 days) .....................................................................................98 
12.3 Week 56 (± 7 Days) Safety Follow-Up Visit............................................................99 
12.4 Early Termination ...................................................................................................100 
12.5 Contact for Study Follow-up...................................................................................101 
13 DATA QUALITY ASSURANCE...................................................................................102 
14 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE................103 
14.1 Statistical and Analytical Plans...............................................................................103 
14.1.1 Interim Analyses........................................................................................103 
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data........103 
14.2 Efficacy Analysis ....................................................................................................103 
14.2.1 Primary Efficacy Analysis.........................................................................103 
14.2.2 Secondary Efficacy Analyses....................................................................105 
14.2.3 Controlling for Multiplicity.......................................................................106 
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14.2.4 Sensitivity Analyses ..................................................................................106 
14.2.5 Exploratory Analyses ................................................................................107 
14.3 Pharmacokinetic Analyses......................................................................................107 
14.4 Safety Analysis .......................................................................................................108 
14.5 Immunogenicity Analysis .......................................................................................108 
14.6 Determination of Sample Size ................................................................................109 
14.7 Analysis Populations...............................................................................................109 
14.7.1 Efficacy Population ...................................................................................109 
14.7.2 Safety Population ......................................................................................109 
14.7.3 PK Population ............................................................................................109 
14.8 Changes in the Conduct of the Study or Planned Analyses....................................109 
15 DATA MONITORING COMMITTEE...........................................................................111 
16 COMPENSATION AND INSURANCE.........................................................................112 
17 CASE REPORT FORMS AND SOURCE DOCUMENTS............................................113 
18 STUDY MONITORING AND AUDITING ...................................................................115 
19 RETENTION OF RECORDS..........................................................................................116 
20 USE OF INFORMATION AND PUBLICATION..........................................................117 
21 REFERENCES ................................................................................................................118 
22 INVESTIGATOR RESPONSIBILITIES........................................................................121 
22.1 Conduct of Study and Protection of Human Subjects.............................................121 
23 SIGNATURE PAGE .......................................................................................................122 
24 PROTOCOL AMENDMENT TEXT REVISIONS ........................................................123 
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LIST OF TABLES
Table 9.1.1:  Schedule of Events for Subjects Randomized to Daily Investigational 
BMN 111 or Placebo Injections ....................................................................45 
Table 9.3.2.1:  Current Chronic Therapy with Restricted Medications...................................56 
Table 9.12.6.3.1:  Clinical Laboratory Tests ...........................................................................72 
Table 9.12.6.4.1:  Biomarkers and Anti-BMN 111 Antibodies...............................................73 
Table 9.12.6.6.1.1:  Vital Sign Assessment Frequency ...........................................................75 
Table 10.2.3.2.1:  Adverse Event Grading (Severity) Scale....................................................82 
Table 10.2.3.3.1:  Causality Attribution Guidance..................................................................83 
LIST OF FIGURES
Figure 9.1.1:  111-301 Study Design.......................................................................................43 
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
μg/kg
microgram/kilogram
ACE
angiotensin-converting enzyme
Ach
Fgfr3G380R achondroplasia mouse model
ACH
achondroplasia
ADL
Activity of Daily Living
AE
adverse event
AGV
annualized growth velocity
ALT
alanine aminotransaminase
ANCOVA
analysis of covariance
ANP
atrial natriuretic peptide
AP
anterior-posterior
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve 
BMC
bone mineral content
BMD 
bone mineral density
BNP
B-type Natriuretic Peptide
BP
blood pressure
BPV
BioMarin pharmacovigilance
°C
degree Celsius
CBCL
Child Behavior Checklist 
CFR
Code of Federal Regulations
cGMP
cyclic guanosine monophosphate
CL/F
Apparent clearance
Cmax
maximum observed plasma concentration
CNP 
C-type natriuretic peptide
CNP-53
C-type natriuretic peptide (53 amino acids in length)
CPAP
continuous positive airway pressure
CRA
clinical research associate
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CV
cardiovascular
CV%
percentage of coefficient of variation
DBP
diastolic blood pressure
DMC
DXA
data monitoring committee
dual X-ray absorptiometry
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ECHO
echocardiogram
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EOSI
Event(s) of special interest
ERK
extracellular signal-regulated kinase
EU
European Union
FDA
Food and Drug Administration
FGF
fibroblast growth factor
FSH
follicle stimulating hormone
G380R
substitution in the transmembrane domain of the FGFR3 receptor at position 380
GCP
good clinical practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
HPA
hypothalamic pituitary adrenal
HR
heart rate
HRQoL
health-related quality of life
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IgE
immunoglobulin E
IP
investigational product
IRB
institutional review board
ISR
injection site reaction
IUD
intrauterine device
LH
luteinizing hormone
LS
least squares
LV
left ventricular
MAPK
mitogen-activated protein kinase
MAR
missing at random
MCP
multiple comparisons procedure
mg
milligram
MI
multiple imputation
mL
milliliter
msec
millisecond
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model with repeated measures
MNAR
missing not at random
NAb
neutralizing antibodies
NCI
National Cancer Institute
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NEP
neutral endopeptidase
NP
natriuretic peptide
NPR-B
natriuretic peptide receptor type B
PA
posterior-anterior
PedsQL
Pediatric Quality of Life Inventory
PI
Principal Investigator
PK
pharmacokinetics
PRO
patient-reported outcome
REB
research ethics board
QoL
quality of life
QoLISSY
Quality of Life in Short Stature Youth
QT
a measure of the time between the start of the Q wave and the end of the T wave 
QTc-F
Fridericia’s corrected QT interval
rhCNP 
recombinant C-type natriuretic peptide
SAEs
serious adverse events
SAP
statistical analysis plan
SBP
systolic blood pressure
SC
subcutaneous
SD
standard deviation
SDV
source document verification
SUSAR
suspected unexpected serious adverse reactions
t1/2
elimination half-life
TAb
total antibody
Tmax
time to reach Cmax
ULN
upper limit of normal
US
United States
USA
United States of America
Vz/F
Apparent volume of distribution
WeeFIM
Functional independence measure for children
WFI
water for injection
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Definition of Terms: 
Investigational Product (IP):
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use” 
(from International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline: 
Guideline for Good Clinical Practice E6 [ICH E6]).  
The terms “IP” and “study drug” may be used interchangeably in the protocol. 
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5
ETHICS
BioMarin Pharmaceutical Inc. (hereafter referred to as BioMarin or the Sponsor) conducts its 
studies according to the highest ethical and scientific standards. The following sections 
articulate standards to which investigators will be held accountable, as well as matters of 
compliance to document adherence to such standards. 
5.1
Institutional Review Board or Independent Ethics Committee
Investigators are expected to interact with independent ethics committees (IECs) promptly, as 
required, during the course of the study. This includes, but is not limited to, providing 
appropriate documentation to support study initiation and maintaining appropriate flow of 
safety and other information during the course of the study and for study close-out activities. 
BioMarin (or designee) will assist investigators with access to timely and accurate 
information and with assurance of prompt resolution of any queries.
Prior to initiating the study, the investigator will obtain written confirmation that the 
institutional review board (IRB), IEC, or research ethic board (REB) is properly constituted 
and compliant with International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) 
requirements, applicable laws and local regulations. A copy of the confirmation from the 
IRB/IEC/REB will be provided to BioMarin Pharmaceutical Inc. (BioMarin) or its designee. 
The investigator will provide the IRB/IEC/REB with all appropriate material, including, but 
not limited to, the protocol, Investigator’s Brochure, Informed Consent Form (ICF) including 
compensation procedures, and any other written information provided to the subjects, 
including all ICFs translated to the native language of the clinical site or to the language of 
the intended subject, if the subject speaks a language other than the native language. 
The study will not be initiated and Investigational Product (IP) supplies will not be shipped 
to the site until appropriate documents from the IRB/IEC/REB confirming unconditional 
approval of the protocol, the ICF and all subject recruitment materials are obtained in writing 
by the investigator and copies are received at BioMarin or its designee. The approval 
document should refer to the study by protocol title and BioMarin protocol number (if 
possible), identify the documents reviewed, and include the date of the review and approval. 
BioMarin will ensure that the appropriate reports on the progress of the study are made to the 
IRB/IEC/REB and BioMarin by the investigator in accordance with applicable guidance 
documents and governmental regulations.
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5.2
Ethical Conduct of Study
It is expected that investigators understand and comply with the protocol. This includes, but 
is not limited to: establishing and meeting enrollment commitments, providing eligible 
subjects for study enrollment; adhering to diagnostic or other procedures as specified in the 
protocol; and assuring appropriate compliance with study treatment administration and 
accountability.
This study will be conducted in accordance with the following:
x
European Clinical Trial Directive 2001/20/EC and Good Clinical Practice Directive 
2005/28/EC, for studies conducted within any European country.
x
United States Code of Federal Regulations (CFR) sections that address clinical 
research studies, and/or other national and local regulations, as applicable.
x
ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 (R2) 
(ICH E6 R2).
x
The ethical principles established by the Declaration of Helsinki.
Specifically, this study is based on adequately performed laboratory and animal 
experimentation, and previous clinical data as well. The study will be conducted under a 
protocol reviewed and approved by an IRB/IEC/REB and will be conducted by scientifically 
and medically qualified persons. The benefits of the study are in proportion to the risks. 
The rights and welfare of the subjects will be respected and the investigators conducting the 
study do not find the hazards to outweigh the potential benefits. Each subject, or his/her 
legally authorized representative will provide written, informed consent before any 
study-related tests or evaluations are performed.
5.3
Subject Information and Informed Consent
A properly written and executed informed consent form (ICF), in compliance with the
Declaration of Helsinki, ICH E6 R2 (Section 4.8), United States Code of Federal Regulations 
(CFR) 21 CFR §50 and other applicable local regulations, will be obtained for each subject 
prior to entering the subject into the study. The investigator will prepare the ICF and provide 
the documents to BioMarin for approval prior to submission to the IRB/IEC/REB approval. 
BioMarin and the IRB/IEC/REB must approve the documents before they are implemented. 
A copy of the approved ICF (minor assent form and parental ICF for studies involving 
minors), and if applicable, a copy of the approved subject information sheet and all ICFs 
translated to a language other than the native language of the clinical site must also be 
received by BioMarin or designee prior to any study-specific procedures being performed.
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Subjects under the age of majority will provide written assent (if required), and his/her 
legally authorized representative (parent or legal guardian) will provide written informed 
consent for such subjects. The investigator will provide copies of the signed ICF to each 
subject (or the legally authorized representative of the subject) and will maintain the original 
in the record file of the subject. 
During administration of informed consent, expectations regarding participation in the study 
should be made clear to subjects. Subjects who are not willing and/or are not able to comply 
with all aspects of the study should not be encouraged to participate.
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6
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
Prior to beginning the study, the investigator at each site must provide to BioMarin or 
designee, a fully executed and signed United States (US) Food and Drug Administration 
(FDA) Form FDA 1572 and a Financial Disclosure Form. All sub-investigators must be 
listed on Form FDA 1572. Financial Disclosure Forms must also be completed for all sub-
investigators listed on the Form FDA 1572 who will be directly involved in the treatment or 
evaluation of subjects in this study.
The study will be administered by and monitored by employees or representatives of 
BioMarin. Clinical Research Associates (CRAs) or trained designees will monitor each site 
on a periodic basis and perform verification of source documentation for each subject as well 
as other required review processes. BioMarin’s Pharmacovigilance Department (or designee) 
will be responsible for the timely reporting of SAEs to appropriate regulatory authorities as 
required.
In multicenter studies, a Coordinating Investigator will be identified who will be responsible 
for study oversight. The Coordinating Investigator will read the clinical study report (CSR) 
and confirm that it accurately describes the conduct and results of the study, to the best of his 
or her knowledge. The Coordinating Investigator will be chosen on the basis of active 
participation in the study, ability to interpret data, and willingness to review and sign the 
report in a specified timeframe. The identity of the Coordinating Investigator and a list of all 
investigators participating in the study will be provided in the CSR.
Clinical laboratory evaluations will be performed at central laboratories unless use of a local 
laboratory is clinically indicated in order to have expedited results. Assessment of 
pharmacokinetics (PK) and biomarkers will be conducted by BioMarin (or designee). 
Additional details and requirements will be provided in the Study Laboratory Manual. 
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7
INTRODUCTION
BMN 111 is a proposed pharmacologic therapeutic option for achondroplasia (ACH), the 
most common form of dwarfism. 
ACH is a rare disease with a prevalence of 1/25000 in the US (Wynn, 2007). The average 
adult heights for men and women with ACH are 131 cm and 124 cm, respectively (Genetics
Home Reference, 2012). Characteristic features include long and narrow trunk, a large head
with frontal bossing, hypoplasia of the mid-face, bowed legs and stenosis of the foramen and 
spinal canals that can be life-threatening. Foramen magnum stenosis can lead to 
cervicomedullary compression in infants with complications including hydrocephalus, 
hypotonia, respiratory insufficiency, apnea, cyanotic episodes, feeding problems, 
quadriparesis, and sudden death.  
There is no approved pharmacological therapy for achondroplasia in the United States of
America (USA) or European Union (EU). Current treatments for achondroplasia are focused
on neurosurgical interventions for foramen magnum stenosis or lumbar stenosis, 
thoracolumbar braces to help ameliorate the kyphosis, or limb lengthening requiring multiple
operations over 2 to 3 years (Shirley, 2009); Horton 2007).
ACH is caused by a gain-of-function mutation in fibroblast growth factor (FGF) R3, a 
negative regulator of chondrocyte proliferation and differentiation. The most common 
mutation (98%) in ACH patients is a G380R substitution in the transmembrane domain of 
FGFR3. The majority of new cases (80%) originate from parents of average stature.   
The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) 
pathway mediates part of FGFR3 inhibition of chondrocyte proliferation and differentiation 
(Foldynova-Trantirkova, 2012,). The ERK MAPK pathway is modulated by CNP, a positive 
regulator of chondrocyte proliferation and differentiation. Binding of CNP to the Natriuretic 
Peptide-Receptor B (NPR-B) antagonizes FGFR3 downstream signaling by inhibiting the 
MAPK (ERK1/2) pathway at the level of RAF-1 (Krejci, 2005,); (Yasoda, 2004,); (Yasoda, 
2009,);(Pejchalova, 2007). This crosstalk was demonstrated in a mouse model of FGFR3-
related chondrodysplasia (Yasoda, 2004,);(Yasoda, 2009,). The dwarfism phenotype of mice 
harboring the FGFR3G380R mutation was rescued by expression of C-type natriuretic 
peptide (CNP) in cartilage or by the continuous administration of CNP (infusion). 
CNP is a member of the natriuretic peptide (NP) family that includes Atrial Natriuretic 
Peptide (ANP) and B-type Natriuretic Peptide (BNP). These peptides are structurally related 
but are distinct paracrine/autocrine (CNP) or endocrine (ANP and BNP) factors that regulate 
the cardiovascular (CV), skeletal, nervous, reproductive and other systems. Synthetic analogs 
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of ANP (anaritide and carperitide) and BNP (nesiritide) have been investigated as potential 
therapies for the treatment of decompensated heart failure and cardiovascular-related 
diseases.
BMN 111 is a 39-amino acid CNP analogue harboring the 37 amino acids of the human 
CNP53 C-terminal sequence and modified by the addition of two amino acids (Pro-Gly) on 
the N-terminus. It is a recombinant human peptide fused to human transcription factor (TAF) 
and expressed as an inclusion body in E. coli. BMN 111 is liberated and solubilized from the 
TAF-fusion protein by formic acid cleavage, and purified by column chromatography (Long, 
2012,). BMN 111 was designed to 1) mimic CNP activities in terms of receptor binding and 
pharmacological activity and 2) be resistant to neutral endopeptidase (NEP) digestion in 
order to have an extended half-life in comparison to CNP that is presumed to increase 
exposure to the target growth plate (Wendt, 2015,).  
A comprehensive review of BMN 111 is contained in the current version of the Investigator’s 
Brochure supplied by BioMarin. Investigators are required to review the Investigator’s 
Brochure prior to initiating this study.
7.1
Nonclinical Studies
The pharmacological activity of BMN 111 was explored in two mouse models of ACH, a 
severe, Fgfr3Y367C/+ model (Lorget, 2012,), and a mild [Ach] /+ model. Partial or complete 
reversion of the ACH phenotype was observed in these mouse models after BMN 111
administration. Additionally, in wild-type mice, and normal rats and monkeys, BMN 111 
administration resulted in growth plate expansion and dose-dependent skeletal growth at 
hemodynamically tolerated dose levels (Wendt, 2015,).
BMN 111-related adverse findings in nonclinical species (mice, rats, cynomolgus monkeys) 
were limited to the known mechanism of action of CNP on the growth plate and vasculature. 
Reversible subcutaneous injection site reactions were reported, including injection site 
discoloration and microscopic findings of perivascular mononuclear cell infiltrates that were 
seen with slightly higher incidence and severity in BMN 111-treated rats and monkeys 
compared to the vehicle control. Adverse skeletal changes associated with exaggerated 
growth were seen in normal nonclinical species with open growth plates, and were dose-,
exposure- and time-dependent. 
 
 
 
 
. Additional detailed information 
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about nonclinical studies of BMN 111 is provided in the current version of the Investigator’s 
Brochure supplied by BioMarin.   
7.2
Previous Clinical Studies
7.2.1
Study 111-101
Study 111-101, “A Phase 1, Two Part, Double Blind, Placebo-Controlled Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of BMN 111 
Administered to Healthy Adult Volunteers,” was a first-in-human study conducted in 2 parts 
to allow for assessment of the safety, tolerability, and PK of BMN 111 administered as a 
single dose and as a multiple dose to healthy adult male volunteers.
Doses ranging from 5.0 μg/kg to 15.0 μg/kg were administered as a single SC dose; doses 
ranging from 0.5 μg/kg to 8.0 μg/kg were administered daily in the multiple ascending dose 
segment of the study. As expected, mild, transient, self-limited hypotension occurred. 
The majority of these cases were asymptomatic and observed upon assumption of an upright 
posture following recumbence. Hypotension events were reported in the BMN 111 treatment 
groups with higher frequency compared with placebo. All events were judged to be mild in 
severity and resolved spontaneously without an intervention. These events occurred across 
dose ranges. Due to the limited number of events at each dose, it is unclear if symptomatic
hypotension is dose related. No dose limiting toxicities were identified outside of these 
cardiovascular findings. The only AEs occurring in more than one subject receiving 
BMN 111 were orthostatic hypotension, contact dermatitis, and back pain, and injection site 
reactions. Most AEs in the study were of mild severity, and no SAEs were reported. 
There were no AEs that led to premature discontinuation of study drug.  
The PK parameters for BMN 111 were obtained from Part 1 of the study and from the first
dose on Day 1 of the multiple dose study in Part 2. 
 
 
 
 
 
 
 
 
 
 
 
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.
7.2.2
Study 111-202
Study 111-202 was a Phase 2, open-label, sequential cohort, dose escalation study that 
assesses daily SC administration of BMN 111 in pediatric subjects with ACH. The primary 
objective of Study 111-202 was to evaluate the safety and tolerability of BMN 111 
administered for 6 months and up to 24 months; the secondary objectives were to determine 
change from baseline in annualized growth velocity (AGV), growth parameters, body 
proportions, and evaluate the dose-exposure and PK profiles of BMN 111 in children with 
ACH. 
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that 
treatment with BMN 111 for 6 months at dose cohorts of 2.5, 7.5, 15, and 30 μg/kg 
(Cohorts 1 to 4, respectively) was generally well tolerated. The most common AEs were mild 
injection site reactions, pyrexia, asymptomatic hypotension, headache, and nasopharyngitis. 
For a detailed summary of risks, please refer to the current version of the Investigator’s 
Brochure supplied by BioMarin.  
Analysis of efficacy data from the 6-month initial phase of Study 111-202 demonstrated that 
the mean (standard deviation) change from baseline AGV when BMN 111 is administered at 
2.5, 7.5, 15, and 30 μg/kg subcutaneously daily for 6 months is -0.37 (1.592), 1.28 (1.439), 
2.01 (1.999), and 2.08 (2.137) cm/year, respectively. Thus, a positive dose-dependent 
response was observed in change from baseline AGV at doses ranging from 2.5-15 μg/kg 
daily.  
In regards to 12-month data, subjects in Cohort 3 completed 12 months on a stable daily dose 
of 15 μg/kg and positive change from baseline in AGV was observed in subjects in Cohort 3. 
Subjects treated with 30 μg/kg daily also showed similar improvement in mean AGV after 
6 months and their mean changes from baseline in AGV were similar to subjects treated with 
15 μg/kg daily. Safety data for the 30 μg/kg daily dose was also similar to the 15 μg/kg daily 
dose. Thus, no clinically significant difference could be identified between the 15 μg/kg and 
30 μg/kg daily dose in the Phase 2, 6-month safety and efficacy data.
Single-dose PK data from Day 1 showed BMN 111 was rapidly absorbed (median Tmax
between 5.00 and 16.0 minutes) and rapidly cleared from plasma (mean t1/2 ranging from 
24.4 to 27.0 minutes).   
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There was no evidence of accumulation with multiple daily dosing, and all pre-dose PK 
samples were below the limit of quantitation, consistent with the short half-life relative to the 
daily dosing regimen. Overall, exposure following multiple dosing was similar to exposure 
following single doses, and remained consistent through 24 months, indicating no apparent 
time-dependence in PK through 24 months of treatment. 
Further details regarding results from the 111-202 study can be found in the current version 
of the Investigator’s Brochure.
7.3
Ongoing Clinical Studies
7.3.1
Study 111-205
Study 111-205 is an ongoing open-label, Phase 2 extension study to assess long-term safety, 
tolerability, and efficacy of BMN 111 in children with ACH. Subjects continue receiving the 
same stable dose of BMN 111 received upon completion of the 111-202 study (up to 
30 μg/kg daily). This 5-year study allows for long-term assessment of the effect of daily 
BMN 111 administration on safety, tolerability, growth velocity, height, and body 
proportions in subject completing 2 years of BMN 111 treatment in Study 111-202 (7 years 
total BMN 111 treatment duration). Additional exploratory endpoints are being examined to 
determine long-term effects of BMN 111 on bone physiology and the medical complications 
of ACH.
7.4
Study Rationale
BioMarin has engineered a CNP analog (BMN 111) that has a longer half-life than 
endogenous CNP, thereby allowing daily subcutaneous (SC) administration. Similar to CNP, 
BMN 111 activates NPR-B signaling with subsequent inhibition of FGFR3 downstream 
signaling, leading to the promotion of chondrocyte proliferation and differentiation and 
subsequent increased endochondral bone formation. BMN 111 administration has been 
shown to promote endochondral bone formation at hemodynamically tolerated dose levels in 
both normal animals and mouse models of ACH reported (refer to current Investigators 
Brochure for additional information).
Human studies to date have also demonstrated that BMN 111 is safe and well tolerated at 
doses that result in improvements in growth velocity approaching that of children of average 
stature.
Analysis of safety data from the Study 111-202 showed that treatment with BMN 111 was 
generally well tolerated at all dose levels (refer to current Investigators Brochure for specific 
details). 
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Analysis of efficacy data from Study 111-202 demonstrated that that subjects given 
BMN 111 at the dose of 15 μg/kg daily had a clinically significant improvement in AGV, 
with approximately ~50% increase over baseline seen with treatment for 6 months which was 
sustained after continued treatment for 12 months.   
Subjects treated with 30 μg/kg daily also showed similar improvement in mean AGV after 
6 months and their mean changes from baseline in AVG were similar to subjects treated with 
15 μg/kg daily. Safety data for the 30-μg/kg daily dose was also similar to the 15-μg/kg daily 
dose. Given that no clinically significant difference could be identified between the 15 μg/kg 
and 30 μg/kg daily dose in the Phase 2, 6-month safety and efficacy data, the lower of the 
two doses has been chosen for this Phase 3 study. 
Study 111-301 is designed to further characterize and confirm efficacy and safety of 
BMN 111 at a dose of 15 μg/kg for 52 weeks in a placebo-controlled study. This 60-week 
study (up to 4 weeks of screening, 52 weeks of treatment with an additional 4 weeks of safety 
follow up) will allow for assessment of the effect of daily BMN 111 administration on 
growth velocity, growth (height), and body proportions (lower:upper segments) in subjects 
treated with BMN 111 compared with the placebo group, as well as further characterize 
safety and tolerability of BMN 111 in children with ACH. Additional endpoints will also be 
examined. Secondary endpoints to determine the effects of BMN 111 include evaluation of 
change from baseline in body proportions of the extremities by anthropometry, bone 
physiology (including changes in bone morphology, quality, and growth via X-rays and dual 
X-ray absorptiometry (DXA) of the extremities and spine). Other secondary endpoints 
assessing quality of life and daily function of study subjects include health-related quality of
life (HRQoL) and functional independence assessments. These endpoints include 
administration of the Pediatric Quality of Life Inventory (PedsQL), Quality of Life in Short 
Stature Youth (QoLISSY), and Functional Independence Measure (WeeFIM) assessments. 
The Child Behavior Checklist (CBCL) will also be administered. Additional exploratory 
endpoints include polysomnography to evaluate sleep apnea, BMN 111 activity biomarkers, 
and genomic biomarkers. Subjects who are in the control arm of the study who have been
receiving placebo may be eligible to receive active treatment after they have completed the 
treatment period of the study.
7.5
Summary of Overall Risks and Benefits
7.5.1
Summary of Risks from Nonclinical Studies
 
 
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7.5.2
Summary of Risks from Clinical Studies
7.5.2.1
Study 111-101
Based on review of the first-in-human Phase 1 study of BMN 111 in healthy adult volunteers, 
Study 111-101, BMN 111 administered SC daily was well tolerated with doses ranging from 
0.5 μg/kg to 15 μg/kg. All AEs were of mild severity, and no SAEs were reported. The most 
common AE was mild, transient, self-limited orthostatic hypotension, of which the majority 
of cases were asymptomatic and observed only upon assumption of an upright posture 
following recumbence. No dose-limiting toxicities were identified outside of these CV 
findings.
7.5.2.2
Study 111-202
Analysis of safety data from the 6-month initial phase of Study 111-202 showed that 
treatment with BMN 111 for 6 months at doses of 2.5, 7.5, 15, and 30 μg/kg was generally 
well tolerated. In addition BMN 111 at 15 μg/kg was well tolerated for over 12 months with 
no new safety concerns identified. 
Based on review of data from the Phase 2 clinical trial, injection site reactions and 
hypotension have been identified as risks associated with BMN 111 injections. 
Hypersensitivity reactions including development of BMN 111 antibodies are potential risks 
associated with BMN 111 injections. For a detailed summary of risks, please refer to the 
current version of the Investigator’s Brochure supplied by BioMarin. 
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7.5.3
Summary of Potential Benefits from Clinical Studies
For children with ACH who will receive BMN 111 as part of Study 111-301, potential 
benefits may include improvement of AGV rates such that their increase in growth velocity 
may approach that of children of average stature. Additional potential benefits may include 
improvement of the disproportionate growth as well as improvement in quality of life, 
activities of daily living, and medical complications of ACH. For example, improvement in 
height could have an impact on daily activity performance.
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8
STUDY OBJECTIVES
The primary objective of the study is to:
x
Evaluate change from baseline in annualized growth velocity at 52 weeks in subjects 
treated with BMN 111 compared with control subjects in the placebo group.  
The secondary objectives of the study are to:
x
Evaluate change from baseline in height Z-score in subjects treated with BMN 111 
compared with control subjects in the placebo group at 52 weeks.
x
Evaluate change from baseline in upper:lower segment body ratio in subjects treated 
with BMN 111 compared with control subjects in the placebo group at 52 weeks.
x
Evaluate change from baseline in body proportion ratios of the extremities. 
x
Evaluate effect of BMN 111 on bone morphology/quality by X-ray and DXA.
x
Evaluate potential changes in HRQoL as measured by the QoLISSY and PedsQL 
questionnaires. 
x
Evaluate potential changes in functional independence as measured by the WeeFIM 
clinician-reported outcome.
x
Evaluate safety and tolerability of BMN 111 in children with ACH.
x
Evaluate the pharmacokinetics of BMN 111. 
x
Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy 
measures.
x
Evaluate change from baseline in bone metabolism biomarkers.
The exploratory objectives of the study are to:
x
Evaluate sleep study scores by polysomnography in a subset of subjects.
x
Evaluate biomarkers of BMN 111 activity.
x
Evaluate genomic biomarkers.
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan 
This is a Phase 3 randomized, placebo-controlled, double-blind multicenter study to evaluate 
the effect of BMN 111 on growth in children with ACH. Subjects who are 5 to < 18 years old 
with documented ACH confirmed by genetic testing will have been enrolled in Study 
111-901 for at least a 6-month period immediately before study entry, and meet all study 
eligibility criteria will participate. At least 110 eligible subjects will be stratified based on sex 
and Tanner Stage (Stage 1, and > Stage 1) (with no greater than 20% of subjects > Tanner 
Stage 1), and randomly assigned in a 1:1 ratio to one of two treatment groups: placebo or 
BMN 111 at 15 μg/kg. To achieve gender balance, approximately 50% of each gender will 
be enrolled, with neither to exceed 55%. In Japan, subject enrollment will be staggered 
initially, with a minimum of a 2-week window between the first 4 subjects enrolled.
For placebo and BMN 111, the route of administration is subcutaneous injection and the 
frequency is daily. Approximately 33 clinical centers worldwide will participate in the study.
The 111-301 study design is presented below in Figure 9.1.1.
Figure 9.1.1:  111-301 Study Design
BMN 111 or placebo will be administered as a single subcutaneous dose of 15 μg/kg given 
daily for 52 weeks. The control group will receive subcutaneous injections with placebo daily 
for 52 weeks.
Safety monitoring will be conducted for all subjects randomized to BMN 111 or placebo 
after the first dose is received and over the duration of the study. This will include a 
minimum of 2 hours post-dose observation on the first 3 days of dosing and 30 minutes on all 
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other days of dose administration, in conjunction with caregiver training for BMN 111 or 
placebo administration and AE documentation/reporting. It is generally expected that after 
subjects are tolerating BMN 111 or placebo well and specified criteria have been met, 
caregivers will begin administering BMN 111 or placebo. If the caregiver is unable or 
unavailable to administer BMN 111 or placebo, home health care may be provided. Contact 
by a study staff member to the caregiver will be required every 4 weeks (± 10 days) to all 
study subjects after the Week 6 visit when there are no study visits or contact in the 
preceding 4 weeks. During these contacts, study staff will ask the caregiver about dose 
administration and seek information on adverse events (AEs) and serious AEs (SAEs) by 
specific questioning. Information on all AEs and SAEs should be recorded in the subject’s 
medical record and on the AE electronic case report form (eCRF).
After the study is completed, subjects in both treatment and control groups will be eligible to 
receive BMN 111 in 111-302, to assess safety and efficacy of BMN 111 over the longer 
term. Subjects will have the option to enroll in 111-302 after the Week 52/Study Completion 
Visit. Week 52 assessments will serve as Baseline assessments for entry to study 111-302 if 
the visit occurs on the same day or within 2 weeks. Subjects who enroll into 111-302 more 
than 2 weeks after the 111-301 Week 52 visit will have a separate Baseline visit; the same 
assessments as those performed at Week 52 will be repeated at that time.
Data Monitoring Committee
In addition to safety monitoring by BioMarin personnel, an independent data monitoring 
committee (DMC) will act as an advisory body to BioMarin and provide input on the safety 
data collected in the study. DMC data review will occur at regular time periods during the 
study (or ad hoc, if indicated). Membership, roles, and responsibilities of the DMC will be 
outlined in a separate DMC charter.
Assessments
For a discussion of efficacy assessments, see Section 9.12.2, 9.12.3, and 9.12.4; exploratory 
assessments, Section 9.12.4; safety assessments, Section 9.12.6; and PK variables, Section 
9.12.5.
A summary of events and assessments are provided by visit in Table 9.1.1.
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Table 9.1.1:  Schedule of Events for Subjects Randomized to Daily Investigational BMN 111 or Placebo Injections  
Procedure
Screening 
Day -30 
to Day -1b
Day 
1
Day 
2
Day 
3
Day 10 
± 1
Daya
Week 6
±7 Days
Week 13
± 7 Days
Week 26
± 7 Days 
Week 39
± 7 Days
Week 52
± 7 Days
Safety 
Follow-up
Week 56
±7 Daysdd
Early 
Term
Informed consent
X
Medical historyc
X
Parental heightd
X
Diagnostic genetic testing 
(if needed)e
X
Physical examinationf
X
X
X
X
X
X
X
X
X
X
Tanner Stage of Pubertal 
Development
X
X
X
X
Menstrual history in female 
subjects (if applicable)
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testg
X
X
X
X
X
X
X
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
X
X
X
Anthropometric measurementsi
X
X
X
X
X
X
Xi
Weight
X
X
X
X
X
X
X
X
X
X
HRQoL (PedsQL, QoLISSY), 
WeeFIM, and CBCLj
X
X
X
Hip imaging via pelvis X-ray 
(AP view)
X
Hip clinical assessmentk
X
X
X
X
Sleep sub-study (optional)l
Xl
Xl
Xl
ECGm
X
X
X
X
X
X
X
X
X
Echocardiogram
X
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Procedure
Screening 
Day -30 
to Day -1b
Day 
1
Day 
2
Day 
3
Day 10 
± 1
Daya
Week 6
±7 Days
Week 13
± 7 Days
Week 26
± 7 Days 
Week 39
± 7 Days
Week 52
± 7 Days
Safety 
Follow-up
Week 56
±7 Daysdd
Early 
Term
Clinical labs (hematology, 
chemistry, and urinalysis)n
X
X
X
X
X
X
X
X
X
X
Thyroid function tests
X
X
X
Vitamin D, 25-hydroxy
X
X
X
X
Salivary cortisol
X
X
X
X
Serum prolactin
X
X
X
X
FSH/LHo
X
X
X
X
Anti-BMN 111 
immunogenicityp
X
X
X
X
X
X
X
Bone metabolism blood 
biomarkersq
X
X
X
X
X
X
X
Bone metabolism urine 
biomarkersr
X
X
X
X
X
X
X
BMN 111 activity urine 
biomarkers (cGMP)s
X
X
X
X
X
X
Urine chemistrys
X
X
X
X
X
X
Genomic biomarkers (optional)
X
X
PKt
X
(full)
X
(partial)
X
(full)
X
(partial)
X
(full)
DXA (BMD and BMC of 
whole body less head, spine)u
X
X
X
Xu
Left hand and wrist X-ray (PA 
view)v
X
X
X
Xv
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Procedure
Screening 
Day -30 
to Day -1b
Day 
1
Day 
2
Day 
3
Day 10 
± 1
Daya
Week 6
±7 Days
Week 13
± 7 Days
Week 26
± 7 Days 
Week 39
± 7 Days
Week 52
± 7 Days
Safety 
Follow-up
Week 56
±7 Daysdd
Early 
Term
Bilateral lower extremity 
X-rays including AP and lateral 
viewsv
X
X
X
(Bilateral 
whole leg, 
AP only)
Xw
Lumbar spine X-rays (AP and 
lateral views)w
X
X
Xw
Injection site photos (optional)x
X
X
X
Xx
Concomitant medicationsy
X
X
X
X
X
X
X
X
X
X
X
X
BMN 111 or placebo 
administrationz
X
X
X
X
X
X
X
X
X
BMN 111 or placebo 
accountability
X
X
X
X
X
X
X
X
X
X
Adverse eventsaa
X
X
X
X
X
X
X
X
X
X
X
X
Capture procedures/
interventions/surgeriesbb
X
X
X
X
X
X
X
X
X
X
X
Contact for Study Follow Upcc
Required every 4 weeks (± 10 days) after the Week 6 visit when there are no study visits or contact in the preceding 4 weeksdd
NOTE: ALL BLOOD AND URINE LABORATORY ASSESSMENTS ARE PRE-DOSE EXCEPT WHEN SPECIFIED. OTHER ASSESSMENTS CAN BE CONDUCTED EITHER 
PRE-DOSE OR POST-DOSE UNLESS OTHERWISE SPECIFIED.
a. Day 10 visit has a ± 1-day window; all subsequent visits have a ±7-day window. 
b. If both visits are on the same day, the 111-901 procedures that can be used as the 111-301 screening data are outlined in the Study Reference Manual.
c. Demographics, medical history, including ACH-related history, should include all major illnesses, diagnoses, and surgeries that the subject has ever had; including any prior or 
existing medical conditions that might interfere with study participation or safety.
d. Standing height of the subject’s biological parents may be assessed (optional) via height measurement or stated height. Height measurement can be done at any point in the 
study. Prior to the measurement being taken, each parent is required to complete an ICF specific to parent height assessment. The ICF will be signed prior to the 
assessment, which can be done at any point in the study. If the biological parent is not available during the course of the study to take his/her standing height, if consented, 
the biological parent can provide his/her stated height.  
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e. If subjects had previous genetic testing, subjects must have either a written letter by the physician confirming genetic testing, including the specific mutation required for Study 
111-301 include the identification of FGFR3 mutation (G346E, G375C, G380R, or “other”) OR a lab report from a certified laboratory with the study specific mutation 
documented.
f.
Complete physical exam includes all major body systems. 
g. Pregnancy test will be conducted at each indicated visit for female subjects who have begun menses or are 10 years of age and older. Either urine or serum test may be used. 
Serum pregnancy tests will be performed in the event that urine pregnancy test results are positive or equivocal (indeterminate).
h. All treatment visits have pre- and post-dose vital sign assessments. Left brachial arm should be the first method of assessment considered, and the same site should be used for 
blood pressure measurement in each subject throughout the study. 
x
Pre-Dose vital sign assessments: Vital signs at pre-dose include: body temperature in degrees Celsius (°C), heart rate, BP, and respiratory rate
o
Pre-dose vital signs should always be taken and recorded prior to pre-dose blood draw.
x
Post-dose vital sign assessments: Vital signs at post dose include heart rate and BP
o
Vital signs should be taken prior to blood draws.
o
When blood samples and BP assessments are scheduled at the same time or within the same time window, BP should be measured before blood 
samples are drawn.
o
If a BP measurement must be taken after a blood draw, ensure adequate analgesia for the blood draw and at least 5 minutes before measuring BP.
o
Vital signs may be monitored more frequently or for longer duration post-dose as clinically indicated.
x
Hypotensive Event:
x
If a subject has symptoms potentially consistent with hypotension or a decrease in systolic BP of 20 mm Hg or more from pre-dose systolic BP, blood pressure and 
heart rate (BP/HR) should be measured and recorded approximately every 15 minutes for the first hour and every 30 minutes thereafter until the systolic BP returns to 
pre-dose systolic BP (or within the normal range for this subject as defined by PI) and symptoms (if present) resolve.
NOTE: If the hypotension resolves within the first hour and returns to the normal range, additional BP monitoring as described above is not required. Detailed guidance for blood 
pressure assessments is provided in the most recent Blood Pressure Instrument and Technique Guidelines. 
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Vital Sign Assessment Frequency
Screening
After at least 5 min of rest, subject’s BP is taken in sitting position. Then the subject will 
stand and BP will be taken again at approximately 1 and 3 minutes after standing.  
All other visits
After at least 5 min of rest, subject’s BP is taken 1 time in sitting position.
Assessment Frequency post- dose
Dosing Visits
0-1 hr post-dose
1-2 hr post-dose
Days 1
Day 2 -3
Q15 min (± 5 min)
Q30 min (± 5 min)
Q 30 min (± 5 min)
Q30 min (± 5 min)
All other dosing visits: vital sign 
measurements are taken once per 
time point in a sitting position 
after at least 5 minutes of rest.
Q30 min (± 5 min);
for 1 hour
Note: Please reference the Blood Pressure Instrument and Technique Guidelines document for additional information on blood pressure measurement requirements.
i.
Growth measures should be collected at approximately the same time each visit (± 2 hr from the time when the first measurement assessment was taken at Screening) by a 
study staff member, preferably the same person throughout the study, who has been trained by a BioMarin representative. Anthropometric measurements may include but 
are not limited to standing height; sitting height; weight; head circumference; upper and lower arm length; leg length; and arm span (See Anthropometric Measurement 
Guidelines). Anthropometric measurements will be taken three times in a row with the exception of weight, which is taken once. Anthropometric measurements will be 
taken at the early termination visit only if subject discontinues after Week 6 and > 2 weeks since previous anthropometric measurement assessment.
j.
Reference the study-specific HRQoL and WeeFIM guidance documents. NOTE: for the Child Behavior Checklist (CBCL), no data will be collected from the language 
scale, as it is supplemental and not required to calculate any of the behavior measures.
k. Hip clinical assessment: this assessment will include medical history of the hip and physical exam (including observation of gait when possible) to determine changes in 
hip function or pain with hip (active and passive range of motion, when possible). Changes from baseline may trigger further evaluation based on the investigator’s clinical 
assessment. 
l.
If sleep study results in a poor recording or is uninterpretable, the subject may need to repeat the assessment. Sleep study occurs at the early termination visit only if early 
termination visit occurs after Week 26 and subject has had a previous sleep study during the trial, ie, has entered the substudy. 
m. A standard 12 lead ECG will include heart rate, rhythm, intervals, axis, conduction defects, and anatomic abnormalities. All ECGs will be performed in triplicate at the 
visits indicated in the Schedule of Events (Table 9.1.1). ECGs will be performed post-dose on study day visits at which a dose is given; in addition, on Day 1, ECGs will be 
performed pre-dose. On days when PK samples are being drawn, ECGs should be performed within a 5-minute window prior to 30-minute PK assessment
n. Clinical labs (hematology, chemistry, and urinalysis) are all pre-dose collections.  
o. FSH/LH will be monitored for all subjects >8 years of age, and for subjects at Tanner stage 2 (whichever is earlier).
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p. Immunogenicity: Total and neutralizing anti-BMN 111 antibody samples (serum) will be drawn pre-dose on Day 1, Weeks 13, 26, 39, 52, and Safety Follow-Up or Early 
Termination visit as listed in the SOE. NAb testing and TAb testing for cross-reactivity with endogenous CNP, ANP or BNP will be performed only on Baseline and TAb 
positive samples. Blood (serum) samples for testing Total immunoglobulin E (IgE) and drug-specific IgE will be drawn on Day 1 and in the event of a Grade 3 or 
significant hypersensitivity adverse event, or at investigator or Sponsor discretion. The drug-specific IgE sample should be drawn at least 8 hr after the event start time or 
before the next dose. A sample for total IgE and serum tryptase should be drawn within 1 hour of the start of the event when possible or during the unscheduled safety visit. 
q. Bone metabolism blood biomarker samples will be collected pre-dose on the indicated visits. 
r. Bone metabolism urine biomarker samples will be collected as soon as possible upon arrival at the clinic. Each sample will be tested for biomarker concentration and 
creatinine concentration for normalization.  
s. BMN 111 activity urine biomarker and urine chemistry samples will be collected pre-dose, and 1, 2, and 4 hr post-dose on the indicated visits (± 20 minutes for all urine 
sample time points). Each collection will be tested for biomarker concentration and urine creatinine concentration for normalization.
t.
Full PK samples are collected pre-dose and at 5 (± 2 min), 15 (± 2 min), 30 (± 5 min), 45(± 5 min), 60 (± 5 min), 90 (± 5 min), 120 (± 5 min) minutes post dose at Day 1, 
Week 26, and Week 52 visits. Partial PK samples are collected pre-dose and at 15 (± 2 min), 30 (± 5 min), and 60 (± 5 min) minutes post-dose at Week 13 and Week 39 
visits.
u. DXA at early termination visit only if subject discontinues after 9 months to reduce unnecessary radiation exposure (unless additional X-rays are recommended by 
investigator, BioMarin, or DMC).
v. Left hand and wrist X-ray (PA view), and bilateral X-ray of lower extremity (AP/lateral views) including distal femoral growth plate and proximal tibia growth plate. 
Week 52 X-ray is bilateral whole leg, AP only. X-rays are obtained at the early termination visit only if subject discontinues after 9 months to reduce unnecessary radiation 
exposure (unless additional procedure is recommended by investigator, BioMarin, or DMC). For PA of hand and wrist X-ray, the left-sided extremities should be first sites 
of assessment considered, and the same sites should be used for measurement in each subject throughout the study.
w. Lateral and AP lumbar spine X-rays at early termination visit only if subject discontinues after 9 months to reduce unnecessary radiation exposure (unless additional 
X-rays are recommended by investigator, BioMarin, or DMC). 
x. Injection site photos are optional, but sites are strongly encouraged to take photos on Day 1, Week 26, Week 52, and Early Term Visit. During a scheduled visit, photos of 
the injection site will be taken in either of these two situations: 1) If an injection site reaction (ISR) occurs, photos will be taken for each ISR when it becomes apparent (or 
at onset), at most severe, and then post resolution. The time of the post-resolution photo may not be the same as the time the AE resolved, and this is expected. If the visit 
has ended and the ISR has not resolved, the subject is not expected to remain on site until ISR resolves. If the ISR is ongoing at the end of the visit, record as an ongoing 
AE. 2) If the subject has not had an ISR by the end of the study visit, a photo will still be taken of the injection site used on that day. In between visits, if an ISR worsens or 
changes in pattern, then the subject should have an unscheduled site visit. During the visit photos of the injection site with the ISR should be taken. Also, injection sites 
may be photographed if there is a new ISR or at any other time at the discretion/medical judgment of the investigator or as recommended by the sponsor. 
y. All medications (prescription, over-the-counter and herbal) and nutritional supplements taken 30 days prior to Screening and throughout the study should be documented.
z. The same injection site should not be used 2 days in a row, and should be rotated between the four injection sites bilaterally (upper thigh, upper back of arm, abdomen or 
buttocks).
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aa. After written informed consent but before study treatment initiation, only SAEs associated with protocol-imposed interventions will be recorded. After study drug 
initiation, all AEs and SAEs will be recorded until 4 weeks after either the last administration of study drug or the Early Termination visit. In the event of pregnancy the 
reporting period will be 12 weeks after either the last administration of study drug or the Early Termination visit. If a subject is discontinued from the study prematurely, 
AEs and SAEs will be recorded at the Early Termination visit. 
bb. All procedures/interventions/surgeries will be recorded after informed consent is obtained and after the first administration of study drug, until 4 weeks after either the last 
administration of study drug or the Early Termination visit. If a subject is discontinued from the study prematurely, all procedures/interventions/surgeries will be recorded 
at the Early Termination visit.
cc. Contact by a study staff member to the caregiver will be required after the Week 6 visit every 4 weeks (±10 days) when there are no study visits or contact in the preceding 
4 weeks. During these contacts, study staff will ask about dose administration and seek information on AEs and SAEs by specific questioning. Information on all AEs and 
SAEs should be recorded in the subject’s medical record and on the AE eCRF.
dd. The 4-week safety follow up visit will be waived for subjects who enter BMN 111 study 111-302 within the 2-week period following last dose of study drug. If sponsor
discontinues development program at any time, a 4-week safety follow-up visit should occur.
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9.2
Discussion of Study Design, Including Choice of Control Group
The intent and design of this Phase 3 study is to assess BMN 111 as a therapeutic option for 
the treatment of children with ACH. The age range of enrollment of children with ACH has 
been chosen to be 5 to < 18 years old for this study. Identification of efficacy at this age 
range is congruent with mechanism of action of BMN 111, because BMN 111 is expected to 
act at open epiphyseal growth plates. Therefore, to have a potential therapeutic benefit for 
subjects with ACH, treatment is expected to be required prior to epiphyseal growth plate 
closure. The exact chronological age at which growth plates completely fuse is variable but is 
thought to occur sometime in late adolescence, hence the upper limit of the age range for 
subjects to be enrolled in this study is < 18 years old.  
To achieve gender balance, approximately 50% of each gender will be enrolled, with neither 
to exceed 55%.
In terms of the study design, a randomized double-blind placebo control will be used to 
mitigate the risk of selection bias and any potential bias in data collection and study conduct. 
Additionally, this design provides a framework for interpretation of any endpoints with a 
subjective component, eg, HRQoL and functional independence questionnaires and any 
subjective assessment of safety.
9.3
Selection of Study Population
Subjects 5 to < 18 years old who have documented ACH, as documented by clinical grounds 
and confirmed by genetic testing, were selected to participate in this study. Additional 
criteria for participation in the study are provided in Sections 9.3.1and 9.3.2.
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9.3.1
Inclusion Criteria
Individuals eligible to participate in this study must meet all of the following criteria:
1. Parent(s) or guardian(s) are willing and able to provide written, signed informed 
consent after the nature of the study has been explained and prior to performance of 
any research-related procedure. Also, subjects under the age of majority are willing 
and able to provide written assent (if required by local regulations or the 
IRB/IEC/REB) after the nature of the study has been explained and prior to 
performance of any research-related procedure. Subjects who reach the age of 
majority while the study is ongoing will be asked to provide their own written 
consent.
2. 5 to < 18 years old at study entry.
3. Have ACH, documented by clinical grounds and confirmed by genetic testing. 
4. Have at least a 6-month period of pretreatment growth assessments, including 
standing height, and are currently active participants in 111-901. 
5. )HPDOHV\HDUVROGRUZKRKDYHEHJXQPHQVHVPXVWKDYHDQHJDWLYHSUHJQDQF\
test at the Screening Visit and be willing to have additional pregnancy tests during the 
study.   
6. If sexually active, willing to use contraception as specified in Section 9.3.3.
7. Are ambulatory and able to stand without assistance.  
8. Are willing and able to perform all study procedures.  
9. Caregivers are willing to administer daily injections to the subjects and complete the 
required training. 
9.3.2
Exclusion Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. Have hypochondroplasia or short stature condition other than ACH (eg, trisomy 21, 
pseudoachondroplasia). 
2. Have any of the following: 
o
Hypothyroidism or hyperthyroidism.
o
Insulin-requiring diabetes mellitus. 
o
Autoimmune inflammatory disease (including celiac disease, lupus (SLE),
juvenile dermatomyositis, scleroderma, and others). 
o
Inflammatory bowel disease. 
o
Autonomic neuropathy. 
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3. Have a history of any of the following:
o
Renal insufficiency defined as serum creatinine > 2 mg/dl.
o
Chronic anemia.
o
Baseline systolic blood pressure (BP) < 70 millimeters of mercury (mm 
Hg) or recurrent symptomatic hypotension (defined as episodes of low BP 
generally accompanied by symptoms ie, dizziness, fainting) or recurrent 
symptomatic orthostatic hypotension.
o
Cardiac or vascular disease, including the following:

Cardiac dysfunction (abnormal echocardiogram [ECHO] including 
abnormal left ventricle [LV] mass) at Screening Visit. 

Hypertrophic cardiomyopathy.

Pulmonary hypertension. 

Congenital heart disease. 

Cerebrovascular disease.

Aortic insufficiency or other clinically significant valvular 
dysfunction. 

Clinically significant atrial or ventricular arrhythmias.
4. Have a clinically significant finding or arrhythmia on screening electrocardiogram 
(ECG) that indicates abnormal cardiac function or conduction or Fridericias corrected 
QT interval (QTc-F) > 450 msec. 
5. Have an unstable condition likely to require surgical intervention during the study 
(including progressive cervical medullary compression or severe untreated sleep 
apnea).
6. Evidence of decreased growth velocity (AGV < 1.5 cm/year) as assessed over a 
period of at least 6 months or of growth plate closure (proximal tibia, distal femur) 
through bilateral lower extremity X-rays including both AP and lateral views. 
7. Documented Vitamin D deficiency (concentration of blood 25-hydroxy-vitamin 
D<12 ng/mL or<30 nmol/L).
8. Require any investigational agent prior to completion of study period.
9. Have received another investigational product or investigational medical device 
within 6 months before the Screening Visit.  
10. Have used any other investigational product or investigational medical device for the 
treatment of ACH or short stature at any time, including BMN 111.
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11. 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, GnRH 
agonists, any medication that may impair or enhance compensatory tachycardia, 
diuretics, or other drugs known to alter renal or tubular function (Table 9.3.2.1). 
12. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or 
anabolic steroids in the previous 6 months or treatment greater than 6 months at any 
time.
13. Have had > 1 month treatment with oral corticosteroids (low-dose ongoing inhaled 
steroid for asthma, or intranasal steroids, are acceptable) in the previous 12 months. 
14. Planned or expected to have limb-lengthening surgery during the study period. 
Subjects with previous limb-lengthening surgery may enroll if surgery occurred at 
least 18 months prior to screening and healing is complete without sequelae.  
15. Planned or expected bone-related surgery (ie. surgery involving disruption of bone 
cortex, excluding tooth extraction), during the study period. Subjects with previous 
bone-related surgery may enroll if surgery occurred at least 6 months prior to 
screening and healing is complete without sequelae.  
16.  Have had a fracture of the long bones or spine within 6 months prior to screening. 
17. Pregnant or breastfeeding at the Screening Visit or planning to become pregnant (self 
or partner) at any time during the study.
18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at least 
3×upper limits of normal (ULN) or total bilirubin at least 2×ULN (except for
subjects with known history of Gilbert’s disease).
19. History of severe untreated sleep apnea.
20. Have had new initiation of sleep apnea treatment (eg, continuous positive airway 
pressure [CPAP] or sleep apnea-mitigating surgery) in the previous 2 months prior to 
screening.
21. Have current malignancy, history of malignancy, or currently under work-up for
suspected malignancy.
22. Have known hypersensitivity to BMN 111 or its excipients.
23. Have a history of hip surgery or hip dysplasia atypical for achondroplastic subjects.
24. Have clinically significant hip injury in the 30 days prior to screening.
25. History of slipped capital femoral epiphysis or avascular necrosis of the femoral head. 
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26. Are unable to lie flat when in prone position (needed for hip exam).
27. Have abnormal findings on baseline clinical hip exam or imaging assessments that are 
determined to be clinically significant as determined by the investigator.
28. Concurrent disease or condition that, in the view of the investigator, would interfere 
with study participation or safety evaluations, for any reason. 
29. 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.
Table 9.3.2.1:  Current Chronic Therapy with Restricted Medications 
Restricted Medications
x
Antihypertensive medications
x
Angiotensin-converting enzyme (ACE) inhibitors
x
Angiotensin II receptor blockers
x
Diuretics
x
Beta-blockers
x
Calcium-channel blockers
x
Cardiac glycosides
x
Systemic anticholinergic agents
x
GnRH agonists
x
Any medication that may impair or enhance compensatory tachycardia, diuretics, or 
other drugs known to alter renal or tubular function
x
Any medication that in the investigator’s judgment, may compromise the safety or 
ability of the subject to participate in the clinical trial
9.3.3
Use of Birth Control During and After Study Participation
Female subjects who choose to be sexually active must agree to use a highly effective 
method of birth control during the study and for 30 days after taking the last dose of study 
drug. This includes combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal); intrauterine device 
(IUD); or intrauterine hormone-releasing systems.  
Male subjects must use a double-barrier method of contraception during the study and for 3 
months after taking the last dose of study drug. This includes a combination of male condom 
with either cap, diaphragm, or sponge with spermicide, which is considered an acceptable but 
not highly effective method. True abstinence from having heterosexual intercourse during the 
entire period of risk associated with study treatments can be used as an acceptable method of 
contraception if considered preferred and usual lifestyle of the participant. Periodic 
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abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of period at risk, and withdrawal are not acceptable methods of 
contraception. 
9.3.4
Removal of Subjects from Treatment or Assessment
Subjects (or their legally authorized representative) may withdraw their consent to participate 
in the study at any time without prejudice. The investigator must withdraw from the study 
any subject who requests to be withdrawn. A subject’s participation in the study may be 
discontinued at any time at the discretion of the investigator and in accordance with his/her 
clinical judgment. When possible, the tests and evaluations listed for the termination visit 
should be carried out. BioMarin must be notified of all subject withdrawals as soon as 
possible. 
Investigators may discontinue administration of BMN 111 or placebo at any time. Reasons 
for which the investigator or BioMarin will withdraw a subject from study treatment include, 
but are not limited to, the following: 
1. Evidence of both (1) growth plate fusion as assessed by radiographic imaging of 
distal femur and proximal tibial and (2) decreased AGV (AGV < 1.5 cm/yr) as 
assessed over a period of at least 6 months. In case of discordant imaging and AGV, 
subject continuation will be discussed with BioMarin Medical Monitor, Principal 
Investigator and the DMC.  
2. Subject experiences a serious or intolerable AE due to BMN 111 as determined by the 
investigator or sponsor.
3. Subject requires medication or medical procedure prohibited by the protocol. 
4. Subject does not adhere to study requirements specified in the protocol.
5. Subject is lost to follow-up.
6. Subject becomes pregnant (refer to Section 10.3.1.11 for details on the reporting 
procedures to follow in the event of pregnancy).
If a subject fails to return for scheduled visits, documented effort must be made to determine 
the reason. If the subject’s caregiver cannot be reached by telephone, a certified letter should 
be sent to the subject (or the subject’s legally authorized representative, if appropriate) 
requesting that he or she contact the investigator. A copy of this letter and any response 
should be kept in the subject study records. If the subject cannot be contacted or does not 
respond, the subject will be considered lost to follow-up.
The investigator (or designee) must explain to each subject before enrollment into the study 
that the subject’s protected health information obtained during the study may be shared with 
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BioMarin, regulatory agencies, and the IRB/IEC/REB. It is the investigator’s (or designee’s) 
responsibility to obtain written permission to use protected health information per 
country-specific regulations, such as the Health Insurance Portability and Accountability Act
of 1996 (HIPAA) in the USA, from each subject (or the subject’s legally authorized 
representative). If permission to use protected health information is withdrawn by the subject, 
it is the responsibility of the investigator to obtain a written request from the subject to ensure 
that no further data will be collected from the subject. The subject will then be removed from 
the study. 
It is a priority of the study to maximize study subject retention and adherence to study-
specific procedures. The completeness of the study data may affect the integrity and accuracy 
of the study results. Therefore, subjects who discontinue study treatment should be 
encouraged to continue to undergo as many of the protocol-specified procedures and 
assessments as possible for the remainder of the study, as long as such continued 
participation does not detrimentally affect the health, safety, or welfare of the subject and 
consent remains in place. It is important that following treatment discontinuation the original 
visit schedule is strictly adhered to.
For subjects who discontinue BMN 111 or placebo but remain in the study, PK and 
BMN 111 activity assessments will be waived completely; vital signs and clinical 
labs/biomarkers will be obtained only once at each visit subsequent to BMN 111 or placebo 
discontinuation. Pre-and post-dose designations will not apply as the subject has discontinued 
dosing and vital sign and clinical lab/biomarkers assessments previously designated as “post-
dose” will be waived. All other assessments at each visit should be completed if possible and 
the subject is willing. Data from the study procedures and assessments may be used to further 
characterize the natural progression of ACH. 
BioMarin reserves the right to discontinue the study at any time. Premature termination of 
the study may occur because of regulatory authority decision, a change in the opinion of the 
IRB/IEC/REB, clinical or safety reasons, or at the discretion of the Sponsor. The Sponsor 
reserves the right to discontinue the development of BMN 111 at any time, or to discontinue 
participation by an individual investigator or site for poor enrollment or noncompliance. Any 
decision to terminate the study will be promptly communicated to investigators, regulatory 
authorities, and IRB/IEC/REB. The investigator is responsible for communicating any 
decision to terminate a study to hospital staff involved in the conduct of the study and the 
participating subjects (and their families).
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9.3.5
Subject Identification 
Each subject will be assigned a unique subject identifier. This unique identifier will be on all 
eCRF pages.
9.3.6
Duration of Subject Participation
The planned duration of subject participation in this study is approximately 60 weeks, 
including up to 4 weeks of screening. After screening, subjects randomized to BMN 111 or 
placebo will receive study treatment daily for 52 weeks. Following completion of 52 weeks, 
subjects will be followed for safety for an additional 4 weeks. After the Phase 3 study has 
been completed, subjects in both the BMN 111 treatment arm and the control arm of the 
study may be eligible to receive BMN 111 over the longer term. If the sponsor discontinues 
development program at any time, a 4-week safety follow-up visit should occur.  
Subjects who are not eligible to receive BMN 111 in a separate study will return at Week 56 
for the Safety Follow-Up visit to assess for any AEs that may have occurred following 
completion of dosing.
Follow-up assessments and procedures should be performed as outlined in the Study 111-301
Schedule of Events (Table 9.1.1). 
Subjects who discontinue from study treatment will be asked to complete study assessments 
and procedures for the remainder of the study. If subjects discontinue from study treatment
and decline to participate for the remainder of the study, they will be asked to return for a 
final follow-up visit 4 weeks after their last study visit, and the agreement should be 
documented.
Subjects will participate in the study until completion or until one of the following occurs: 
the subject withdraws consent and discontinues from the study, the subject is discontinued 
from the study at the discretion of the investigator or BioMarin (upon consultation and in 
agreement with the investigator) or the study is terminated.
9.4
Treatments
9.4.1
Treatments Administered
BioMarin and/or its designee will provide the study site with a supply of IP sufficient for the 
completion of the study.
Subjects will be randomized to BMN 111 at a daily dose of 15 μg/kg or placebo for the 
duration of the study. The normal dosing schedule is a single daily subcutaneous injection 
given 7 days a week.
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If a recent acute illness associated with volume depletion (eg, nausea, vomiting, diarrhea) has 
not completely resolved prior to the first dose of BMN 111 or placebo, the dosing will be 
delayed until hydration status has improved (up to the maximum period allowed for the visit 
window).
9.4.1.1
BMN 111 
During the study, BMN 111 will be administered as a single 15 μg/kg SC injection given 
daily at approximately the same time each day whenever possible. The same injection site 
should not be used 2 days in a row, and should be rotated between the four injection sites 
(upper thigh, upper back of arm, abdomen or buttocks). Doses may be administered in any of 
the common SC areas (upper arm, thigh, abdomen, buttocks). Following administration of 
each dose, subjects will be observed for at least 2 hours after the injection for Days 1 to 3, 
and 30 minutes for all other days of dose administration (longer if clinically indicated) either 
in the clinic by study personnel, by a home health nurse, or by a parent/caregiver. 
Instructions for home administration of BMN 111 for subjects who qualify for 
parent/caregiver administration are provided in the Study Drug Injection Guide and Injection 
media.
9.4.1.2
Placebo
During the study, placebo will be administered as a single SC injection given daily at 
approximately the same time each day whenever possible. The same injection site should not 
be used 2 days in a row, and should be rotated between the four injection sites (upper thigh, 
upper back of arm, abdomen or buttocks). Doses may be administered in any of the common 
SC areas (upper arm, thigh, abdomen, buttocks). Following administration of each dose, 
subjects will be observed for at least 2 hours after the injection for Days 1 to 3, and 
30 minutes for all other days of dose administration (longer if clinically indicated) either in 
the clinic by study personnel, by a home health nurse, or by a parent/caregiver. Instructions 
for home administration of placebo for subjects who qualify for parent/caregiver 
administration are provided in the Study Drug Injection Guide and Injection media.  
9.4.2
Identity of BMN 111 
BMN 111 is cloned into the pJexpress401 vector, expressed in E. coli and then purified. 
The drug substance is a modified CNP peptide that retains wild-type activity and specificity. 
The modified CNP sequence is:
PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
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The amino acid sequence is an analogue of the naturally occurring tissue-expressed form of 
C-type natriuretic peptide (CNP-53). BMN 111 is a recombinant 39 amino acid peptide that 
includes the 37 C-terminal amino acids of the human CNP-53 sequence, and is engineered to 
include two additional amino acids (Pro-Gly) on the N-terminus, which renders the peptide 
more resistant to degradation. It is a cyclic peptide formed by an intramolecular disulfide 
bond. The molecular weight of the purified product is 4.1 kDa.
9.4.2.1
Product Characteristics and Labeling
The clinical drug product will be supplied in sterile, single-dose, Type I glass vials with 
coated stopper and flip-off aluminum cap. BMN 111 drug product is supplied as a 0.8-mg, or 
2-mg lyophilized, preservative-free, white to yellow powder for reconstitution with 
commercially sourced sterile water for injection (WFI). The reconstituted solution is 
colorless to yellow and contains 0.8 mg/mL to 2 mg/ml of BMN 111, as well as citric acid, 
sodium citrate, trehalose, mannitol, methionine, polysorbate 80, and sterile WFI. The target 
pH of the reconstituted solution is 5.5. Sterile water for injection will be commercially 
sourced for reconstitution. All reconstitution and dose preparation steps should be performed 
as indicated in the Study Drug Injection Guide and Injection media. 
BMN 111-placebo lyophilized product will be supplied in sterile, single-dose, Type I glass 
vials with coated stopper and flip-off aluminum cap. The placebo is designed to be 
comparable in appearance to the drug product and contains all of the components of the drug 
product including commercially sourced sterile WFI except the drug substance.
The BMN 111 or placebo kit label includes the following information: the contents, 
directions, lot number, quantity, subject ID, vial ID, investigator, the required storage 
conditions, a precautionary statement, the expiry date, the study number, and BioMarin 
Pharmaceutical name and location. This may vary based on country requirements. 
9.4.3
Storage
At the study site, all IP must be stored under the conditions specified in the Investigator’s 
Brochure in a secure area accessible only to the designated pharmacists and clinical site 
personnel. All IP must be stored and inventoried and the inventories must be carefully and 
accurately documented according to applicable state, federal and local regulations, ICH good
clinical practice (GCP), and study procedures. 
Specific information for storage and return of BMN 111 or placebo is provided in the 
Pharmacy Manual, Study Drug Injection Guide, and Injection media.
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9.4.4
Directions for Administration
Refer to the Study Drug Injection Guide for complete BMN 111 or placebo preparation 
instructions.  
The injection will be administered as a daily dose of BMN 111 15 μg/kg or placebo given as 
a single subcutaneous injection. The dose should be given at approximately the same time 
every day whenever possible. Following administration of each dose, subjects will be 
observed for at least 2 hours after the injection for Days 1 to 3, and 30 minutes for all other 
dose administration days. Subjects should have adequate food intake prior to dosing. In the 
hour prior to injection, all subjects should have attempted to drink approximately 
8-10 ounces or 240-300 mL of fluid (eg, water, milk, juice, etc).
Caregivers will administer BMN 111 or placebo at home once approved by the investigator 
and adequate training is demonstrated. Instructions on how to complete and document the 
training can be found in the Study Reference Manual. A caregiver will be eligible to 
administer BMN 111 or placebo if he or she meets all of the following criteria:
x
The subject has been on a stable dosing regimen for a minimum of 3 days 
x
PI has approved administration of BMN 111 or placebo by the caregiver
x
The caregiver has completed the Administration Training conducted by qualified 
study site personnel and has been observed by the study site personnel to be able to 
adequately prepare the proper dose and perform the injections safely
For dosing between planned clinic visits prior to caregiver approval, a home health nurse 
may administer BMN 111 or placebo, or subjects may be administered BMN 111 or placebo 
in the clinic by study staff or trained caregiver.  
A subject’s suitability for continued at-home drug administration will be evaluated by the 
investigator and the Sponsor’s Medical Monitor if a subject experiences a Common
Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher AE that is considered 
possibly or probably drug-related, and/or a hypersensitivity reaction during the study.  
Contact by a study staff member to the caregiver will be required after the Week 6 visit every 
4 weeks (± 10 days) when there are no study visits or contact in the preceding 4 weeks. 
During these contacts, study staff will ask the caregiver about dose administration and seek 
information on AEs and SAEs by specific questioning. Information on all AEs and SAEs 
should be recorded in the subject’s medical record and on the AE eCRF.  
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The investigator or the Sponsor’s Medical Monitor may request that BMN 111 or placebo 
administration by the caregiver be halted at any time and that injections be administered by 
study site personnel or a home health nurse.
9.4.5
Method of Assigning Subjects to Treatment Groups
Subjects will be randomized in a 1:1 ratio, ie, injection with placebo: 15 μg/kg of BMN 111, 
using an interactive voice/web response system. The randomization will be based on Tanner 
Stage (Stage 1, or > Stage 1) and sex. 
An independent third party vendor will develop the randomization schedule so that BioMarin 
and site personnel are blinded to treatment assignments. 
9.4.6
Selection of Dose and Dosing Schedule Used in the Study
 
 
 
 
 
 
 
 
 
 
Thus to further confirm the potential improvement in growth using BMN 111 through a 
larger placebo-cRQWUROOHG3KDVHVWXG\WKHȝJNJGRVHKDVEHHQVHOHFWHG
9.4.7
Blinding
An independent third-party vendor will develop the randomization schedule so that BioMarin 
and site personnel will not know treatment assignments. BMN 111 or placebo will be labeled 
with the study number and a unique identification number. Subjects and the participating site 
members will be blinded to the two study treatments (15 μg/kg BMN 111 or placebo).
The investigator and other members of site staff involved with the study will remain blinded 
to the treatment randomization code during the assembly procedure. In the event of a medical 
emergency, the investigator may contact the Sponsor’s Medical Monitor or other authorized 
BioMarin representative to discuss the necessity of unblinding the subject’s treatment 
assignment. The blinded treatment assignments will be directly accessible to the investigator 
should a subject need to be unblinded in an emergency. If unblinding occurs, the investigator 
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or study pharmacist must record the reason for unblinding, as well as the date and time of the 
event. Corresponding information will be recorded on the eCRF by the investigator. 
9.4.8
Prior and Concomitant Medications
All medications (prescription, over-the-counter and herbal), and nutritional supplements 30 
days prior to screening and throughout the study will be recorded on the designated eCRF. 
The investigator may prescribe additional medications during the study, as long as the 
prescribed medication is not prohibited by the protocol. In the event of an emergency, any 
needed medications may be prescribed without prior approval, but the Sponsor’s Medical 
Monitor must be notified of the use of any contraindicated medications immediately 
thereafter. Any concomitant medications added or discontinued during the study should be 
recorded on the eCRF. Concomitant medication information will be collected at the time 
points indicated in the Schedule of Events (Table 9.1.1). Restricted medications are listed in 
Table 9.3.2.1.
9.4.9
Treatment Compliance
Subjects will be instructed to return all used and unused BMN 111 or placebo kits at each 
study visit. Subject compliance with the dosing regimen will be assessed by reconciliation of 
the used and unused vials. The quantity dispensed, returned, used, lost, etc must be recorded 
on the dispensing log provided for the study.
The date, time, and volume of each dose of BMN 111 or placebo administered to each 
subject must be recorded. These data will be used to assess treatment compliance. 
9.5
Investigational Product Accountability (BMN 111 or Placebo)
The investigator or designee is responsible for maintaining accurate records (including dates 
and quantities) of IP(s) received, subjects to whom IP is dispensed (subject-by-subject kit 
specific accounting), and IP lost or accidentally or deliberately destroyed. The investigator or 
designee must retain all unused or expired study supplies until the study monitor (on-site 
CRA) has confirmed the accountability data.
9.5.1
Return and Disposition of Clinical Supplies
Unused BMN 111 or placebo must be kept in a secure location for accountability and 
reconciliation by the study monitor. The investigator or designee must provide an 
explanation for any destroyed or missing BMN 111 or placebo kits/vials.  
Unused BMN 111 or placebo may be destroyed on site, per the site’s standard operating 
procedures, but only after BioMarin has granted approval for destruction. The study monitor 
must account for all BMN 111 or placebo kits/vials in a formal reconciliation process prior to 
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destruction. The site must document all BMN 111 or placebo destroyed on site, and 
documentation must be provided to BioMarin and retained in the investigator study files. If a 
site is unable to destroy BMN 111 or placebo appropriately, the site can, upon request, return 
unused BMN 111 or placebo to the BioMarin contracted facility. The return of all BMN 111 
or placebo kits/vials must also be documented and accounted for per instructions provided by 
BioMarin.
All BMN 111 or placebo and related materials should be stored, inventoried, reconciled, and 
destroyed or returned according to applicable state and federal regulations and study 
procedures.
Caregivers of subjects who qualify for home administration of study BMN 111 or placebo 
will be provided with instructions for returning used and unused kits and the proper disposal 
of any ancillary supplies. 
9.6
Dietary or Other Protocol Restrictions
BMN 111 will be administered as a single daily dose of 15 μg/kg SC injection given daily at 
approximately the same time each day whenever possible. Placebo will be administered as a 
single SC injection given daily at approximately the same time each day whenever possible. 
Following administration of each dose, subjects will be observed for at least 2 hours after the 
injection for observation for Days 1 to 3, and 30 minutes for all other days of dose 
administration. 
Subjects should have an adequate food intake. In the hour prior to injection, all subjects 
should have attempted to drink approximately 8-10 ounces or 240-300 mL of fluid 
(eg, water, milk, juice).
9.7
Demographic Data and Medical History 
Demographic data and a detailed medical history will be obtained at Screening. This medical 
history should elicit all major illnesses, diagnoses, and surgeries that the subject has ever had; 
any prior or existing medical conditions that might interfere with study participation or 
safety; and evaluation for knee, thigh, hip or groin pain, or change in gait/activity.  
9.8
Biological Parental Standing Height
Standing height of the subject’s biological parents will be assessed via height measurement 
or stated height. Height measurement can be done at any point in the study. Prior to the 
measurement being taken, each parent is required to complete an ICF specific to parent 
height assessment. The ICF will be signed prior to the assessment, which can be done at any 
point in the study. If the biological parent is not available during the course of the study to 
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take his/her standing height, if consented, the biological parent can provide his/her stated 
height. 
9.9
Physical Examination Findings
Physical examination will include assessment of general appearance; CV; dermatologic; 
head, eyes, ears, nose, and throat; lymphatic; respiratory; gastrointestinal (GI); 
musculoskeletal; and neurological/psychological and genitourinary. Other body systems may 
be examined. Screening results will be the baseline values and clinically significant changes 
from baseline will be recorded as an AE or SAE and study drug related or unrelated when 
appropriate based on the investigator’s clinical judgment.
9.10
Tanner Stage of Pubertal Development
Tanner stage of Pubertal Development will also be assessed by the investigator (MD) or sub-
investigator (MD) when indicated on the Schedule of Events (Table 9.1.1). The Tanner stage 
assessment document is included in the Study Reference Manual.   
9.11
Echocardiogram
Cardiac anatomy and function will be evaluated by a standard 2-dimensional Doppler 
echocardiogram by a cardiologist. Echocardiograms will be performed at screening and 
provide information regarding cardiac anatomy and function prior to enrollment in the study.
9.12
Efficacy and Safety Variables
9.12.1 Efficacy and Safety Measurements Assessed
Table 9.1.1 describes the timing of required evaluations in subjects who are randomized to 
receive BMN 111 or placebo. 
9.12.2 Primary Efficacy Variable
The primary efficacy endpoint is change from baseline in height growth velocity (annualized 
to cm/yr).  
Growth measures may be collected approximately the same time each visit (± 2 hr from the 
time when the first measurement assessment was taken at Screening) by a study staff 
member, preferably the same person throughout the study, who has been trained by a 
BioMarin representative. Standardized measuring equipment and detailed measurement 
techniques are detailed in the Anthropometric Measurement Guidelines. 
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9.12.3 Secondary Efficacy Variables
Secondary efficacy endpoints include absolute height Z-score, upper:lower segment body 
ratio, body proportion ratios of the extremities, HRQoL (QoLISSY, PedsQL) questionnaires,
and assessment of functional independence (WeeFIM).  
Weight will be measured at Screening and at study visits as indicated on the Schedule of 
Events (Table 9.1.1). Standardized measuring equipment and detailed measurement 
techniques are detailed in the Anthropometric Measurement Guidelines
9.12.3.1
Height
Change from baseline in height will be evaluated using height Z-scores. Growth measures 
may be collected approximately the same time each visit (± 2 hr from the time when the first 
measurement assessment was taken at Screening) by a study staff member, preferably the 
same person throughout the study, who has been trained by a BioMarin representative.
9.12.3.2
Body Proportion Ratio of Upper to Lower Segment
Change from baseline in the ratio of the upper to lower body segments will be evaluated 
using anthropometric measurements and measurement ratios. Measurements not taken in the 
midsagittal plane should be taken on the right side of the body when possible. 
Standardized measuring equipment and detailed measurement techniques are detailed in the 
Anthropometric Measurement Guidelines.  
9.12.3.3
Body Proportion Ratios of the Extremities
Change from baseline in body proportion ratios of the extremities will be evaluated using 
anthropometric measurements and measurement ratios. Measurements not taken in the 
midsagittal plane should be taken on the right side of the body when possible. 
Body proportion measurements of the extremities may include, but are not limited to, upper 
arm:forearm length ratio, upper leg:lower leg length ratio, and armspan:standing height ratio.
Standardized measuring equipment and detailed measurement techniques are detailed in the 
Anthropometric Measurement Guidelines. 
9.12.3.4
Health-related Quality of Life and Functional Independence Measure
HRQoL questionnaires will be administered to assess the health-related quality of life of 
study subjects. The Functional independence measure (WeeFIM) will be used in study 
subjects to assess functional independence. HRQoL and functional independence will be 
assessed at the time points indicated in the Schedules of Events (Table 9.1.1). These 
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assessments will be implemented in those countries where country-specific versions are 
available.  
9.12.3.4.1 Pediatric Quality of Life Inventory 
The PedsQL measurement model was designed to measure health-related quality of life 
(QoL) in children and adolescents. It is a generic tool that includes measurement of physical, 
emotional, social, and school functioning, and has both child self-report and parent-report 
versions. 
9.12.3.4.2 Quality of Life in Short Stature Youth
The QoLISSY questionnaire is a disease-specific patient-reported outcome (PRO) tool 
consisting of questions across seven domains (Physical QoL, Social QoL, Emotional QoL, 
Coping, Beliefs about Height, Future and Effects on Parents) and has both child self-report 
and parent-report versions.
9.12.3.4.3 Functional Independence Measure
The WeeFIM instrument is an assessment tool that measures functional performance across
three domains (self-care, mobility and cognition) (Ireland, 2011; Ireland, 2012).
The WeeFIM instrument has been used in previous research in children with ACH, and has 
identified ongoing limitations in functional performance across these domains extending 
beyond the age of 7 years (Ireland, 2011). Because the WeeFIM considers the child’s 
performance from a caregiver’s perspective (Ireland, 2012), this tool in turn gives an 
indication of “burden of care” for families and caregivers of children with ACH.
9.12.4 Exploratory Efficacy Variables
9.12.4.1
Sleep Sub-Study
Given that sleep apnea is a finding in children with ACH (Waters, 1993,) and has 
implications on functional and health outcomes, an optional sleep sub-study will be 
performed in a limited number of qualified sleep centers for a subset of subjects. A sleep 
testing device will be used to assess the presence and severity of sleep-disordered breathing 
by measurement of blood oxygen saturation, pulse rate, and airflow during overnight 
monitoring. Assessment of episodes of sleep apnea will include, but may not be limited to, 
the number of episodes of apnea and hypopnea per hour (Apnea/Hypopnea Index). 
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9.12.4.2
BMN 111 Activity Biomarkers
Biomarkers may include but are not limited to assessment of changes in bone and collagen 
metabolism and BMN 111 bioactivity. BioMarin or designee will perform analysis, and 
samples may also be used for assay development.   
Samples for blood and/or urine biomarkers will be collected at the time points presented in 
the Schedule of Events (Table 9.1.1). Refer to the Study Laboratory Manual for instructions 
regarding obtaining and shipping samples. The sample type will also be included in the Study 
Laboratory Manual.
9.12.4.3
Biomarker Research Sample Analyses
All samples collected in this study may be used for exploratory biomarker research once the 
primary use has been completed.
For each portion of the blood and urine samples reserved for protocol-specified analyses, 
there may be multiple sample aliquots. Once samples have been successfully analyzed during 
the study, unused sample portions may be used during the study for assay development or 
other purposes stated in this section. 
9.12.4.4
Genomic Biomarker Analysis
While the inherited FGFR3 mutations associated with achondroplasia are well characterized, 
disease phenotype in monogeneic diseases is often modified by variants in other genes. To 
identify and study genetic variants that may modify achondroplasia, a whole blood sample 
will be collected. Exploratory genomics will include, but are not limited to NPR-B, BRAF, 
and other genes associated with CNP signaling. Exploratory genomic analysis may inform 
understanding of the BMN 111 mechanism of action in achondroplasia. Exploratory 
genomics will not be conducted without express consent from the subject and his/her legally 
authorized representative (parent or legal guardian).   
9.12.5 Pharmacokinetics Variables
Full PK samples are collected pre-dose and at 5 (± 2 min), 15 (± 2 min), 30 (± 5 min), 
45 (± 5 min), 60 (± 5 min), 90 (± 5 min), 120 (± 5 min) minutes post dose at Day 1, Week 26, 
and Week 52 visits. Partial PK samples are collected pre-dose and at 15 (± 2 min), 
30 (± 5 min), and 60 (± 5 min) minutes post dose at Week 13 and Week 39 visits.
Whenever possible, the following PK parameters for subjects randomized to the BMN 111 
treatment group will be estimated by non-compartmental analysis:
x
Area under the plasma concentration-time curve from time 0 to infinity (AUC0-).
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x
Area under the plasma concentration-time curve from time 0 to the time of last 
measurable concentration (AUC0-t).
x
Cmax.
x
Tmax.
x
Elimination half-life (t1/2).
x
Apparent clearance (CL/F).
x
Apparent volume of distribution (Vz/F).
Refer to the Study Laboratory Manual for additional instructions regarding obtaining and 
shipping samples. BioMarin will perform sample analysis, and samples may also be used for 
assay development.  
9.12.6 Safety Variables 
Safety will be evaluated by the incidence of AEs, SAEs, and clinically significant changes in 
vital signs, physical examination, ECG, X-ray/DXA assessments of bone morphology, 
quality, and growth of the extremities and spine (X-rays only), laboratory test results 
(urinalysis, chemistry, hematology), and CBCL assessments. Imaging (X-ray/DXA 
assessments), hip monitoring, biomarker, immunogenicity, salivary cortisol, serum prolactin, 
follicle stimulating (FSH)/luteinizing hormone (LH) levels, and physical measurement data 
will be utilized for safety-related reviews and analysis. FSH/LH will be monitored for all 
subjects > 8 years of age, and for subjects at Tanner stage 2 (whichever is earlier). Additional 
assessments will be conducted to evaluate changes from baseline in bone metabolism. 
9.12.6.1
Adverse Events
The occurrence of AEs will be assessed continuously from the time the subject receives study 
drug. The determination, evaluation and reporting of AEs will be performed as outlined in 
Section 10. Assessments of AEs will occur at the time points shown in the Schedule of 
Events Table 9.1.1). Additionally, contact by a study staff member to the caregiver will be 
required approximately every 4 weeks (+/- 10 days) after the Week 6 visit when there are no 
study visits or contact within in the preceding 4 weeks. During these contacts, study staff will 
ask the caregiver about dose administration and seek information on AEs and SAEs by 
specific questioning. Information on all AEs and SAEs should be recorded in the subject’s 
medical record and on the AE eCRF.  
9.12.6.2
Procedures During the Study
All procedures/intervention/surgery will be recorded after informed consent is obtained and 
after the first administration of study drug, until 4 weeks after either the last administration of 
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study drug or the Early Termination visit. If a subject is discontinued from the study 
prematurely, all procedures/intervention/surgery will be recorded at the Early Termination 
visit.
9.12.6.3
Bone Morphology, Bone Mineral Density, Bone Mineral Content and Bone 
Age
The effect of BMN 111 on bone morphology and pathology will be assessed by X-ray and 
bone mineral density (BMD) and bone mineral content (BMC) by DXA. Bone growth and 
age will be assessed by the means of X-rays of wrist/hand. 
9.12.6.4
Imaging Assessment Procedures (per Schedule of Events)
Imaging assessment procedures for all visits must be performed using the same instruments.
x
Left hand and wrist X-ray, posterior-anterior (PA) view, to assess bone age (Greulich, 
1971,; Tanner, 1975,).
x
Bilateral X-rays of lower extremity (anterior-posterior [AP] and lateral views) to 
assess growth plates. 
x
Hip imaging via pelvis X-ray to identify hip pathology if clinically indicated by 
clinical hip assessment.
x
Lumbar spine X-rays to measure changes from baseline in bone morphology and 
pathology.  
x
DXA scan (whole body less head, spine) to assess bone mineral density (BMD) and 
bone mineral content (BMC). 
Additional imaging may be conducted should there be any issues or concerns with the 
subject’s imaging assessments; one example is a situation in which the lower extremity 
X-rays are not sufficient to determine whether the subject’s distal, femoral, and proximal 
tibia growth plates are closed. Imaging assessments will be collected and interpreted by a 
central reader. If clinically significant abnormalities are noted, the investigator or designee is 
required to assess whether it is appropriate to report an AE and if the subject should continue 
in the study. Refer to the vendor Imaging Guidelines for detailed imaging assessment 
requirements and procedures.
9.12.6.5
Clinical Laboratory Assessments
Specific visits for obtaining clinical laboratory assessment samples are provided in the 
Schedule of Events (Table 9.1.1). The scheduled clinical laboratory tests are listed in 
Table 9.12.6.5.1. Refer to the Study Laboratory Manual for instructions on obtaining and 
shipping samples.
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Any test results may be repeated at the discretion of the investigator or sponsor.
The investigator should assess all test results, in addition to signing, dating, and including a 
comment on the laboratory report whether or not any abnormal result is clinically significant. 
Please refer to Section 10.3.1.6 for further guidance on reporting abnormal test results as an 
adverse event.
If there is an abnormal test result determined to be clinically significant by the investigator it 
should be repeated (at the investigator’s discretion) until the cause of the abnormality is 
determined, the value returns to baseline or to within normal limits, or the investigator 
determines that the abnormal value is no longer clinically significant.
Table 9.12.6.5.1:  Clinical Laboratory Tests
Blood Chemistry
Hematology
Urinalysis
Albumin
Hemoglobin
Appearance
Alkaline phosphatase, total
Hematocrit
Color
ALT (SGPT)
WBC count
pH
AST (SGOT)
RBC count
Specific gravity
Direct bilirubin
Platelet count
Ketones
Total bilirubin
Differential cell count
Protein
BUN
Glucose
Calcium
Bilirubin
Chloride
Nitrite
Potassium
Urobilinogen
Sodium
Hemoglobin
Glucose
Bicarbonate
Urine Chemistry 
Urine creatinine
Urine sodium
Urine potassium
LDH
Phosphorus
Total protein
25-hydroxy Vitamin D
Creatinine
Thyroid function (TSH, FT4; if either 
TSH and FT4 are abnormal then T3 
may be measured in addition)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; cGMP, cyclic guanosine 
monophosphate; FT4, free thyroxine; LDH, lactate dehydrogenase; RBC, red blood cell; SGOT, serum glutamic-oxaloacetic 
transaminase; SGPT, serum glutamic-pyruvic transaminase; T3, triiodothyronine; TSH, thyroid stimulating hormone; WBC, 
white blood cell.
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9.12.6.6
Other Laboratory Assessments 
Subjects will be asked to provide blood and urine at the times indicated in the Schedule of 
Events (Table 9.1.1). Blood volume for testing has been reduced to the minimum necessary 
for adequate evaluation of efficacy and safety of BMN 111. 
For subjects who have not previously had genetic testing confirming diagnosis of ACH, 
molecular genetic diagnosis to identify the FGFR3 mutation (G346E, G375C, G380R, or 
“other”) will be performed. If subjects had previous genetic testing, subjects must have either 
a written letter by the physician confirming genetic testing, including the specific mutation, 
or a lab report from a certified laboratory with the study specific mutation documented. 
Scheduled biomarker and anti-BMN 111 antibodies collections are listed in Table 9.12.6.6.1.
Table 9.12.6.6.1:  Biomarkers and Anti-BMN 111 Antibodies 
Blood Special Chemistry
Urine Biomarkers
Bone metabolism biomarkers
Bone metabolism urine biomarkers
Genomic biomarkers
BMN 111 pharmacodynamics biomarkers (cGMP)
Anti-BMN 111 antibodies
9.12.6.7
Child Behavior Checklist 
The CBCL 1.5 - 5 and the CBCL 6 - 18 comprise questions addressing symptoms related to 
mood, behavior issues, and sleep disturbance. It is completed by the parent or primary 
caregiver. The CBCL 1.5 - 5 years old should be used in children aged 5 to < 6 years old. 
The CBCL 6 - 18 years old should be used in children aged 6 up to 18 years old. No data will 
be collected from the language scale, as it is supplemental and not required to calculate any 
of the behavior measures. 
The form requires approximately 15 minutes to complete. The checklist yields scores in the 
following areas: reactivity, anxiety, depression, somatic complaints, withdrawal, sleep 
problems, attention problems, and aggressive behavior.  
The CBCL assessment will be implemented in those countries where country-specific 
versions are available.
9.12.6.8
Bone Metabolism Biomarkers
Bone metabolism biomarkers will be collected to assess changes in bone metabolism. 
BioMarin or designee will perform analysis, and samples may also be used for assay 
development.  
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Samples for bone metabolism biomarkers will be collected at the time points presented in the 
Schedule of Events (Table 9.1.1). Refer to the Study Laboratory Manual for instructions 
regarding obtaining and shipping samples. The sample type will also be included in the Study 
Laboratory Manual.
9.12.6.9
Vital Signs, Physical Examinations and Other Observations Related to Safety 
9.12.6.9.1 Vital Signs
Vital signs assessed pre-dose will include seated systolic blood pressure (SBP) and diastolic 
blood pressure (DBP) measured in mm Hg, heart rate in beats per minute, respiration rate in 
breaths per minute, and temperature in degrees Celsius (°C). All treatment visits have 
pre-dose vital sign assessments. Post-dose measurements include heart rate and BP. For all 
dosing visits, assessment frequency is detailed in Table 9.12.6.9.1.1 (see Schedule of Events, 
Table 9.1.1).
At Screening, after at least 5 minutes of rest, subject’s BP is taken in sitting position. Then 
the subject will stand and BP will be taken again at approximately 1 and 3 minutes after 
standing. At other visits, vital sign measurements are taken once per time point in a sitting 
position after at least 5 minutes of rest. Heart rate should be taken at each time point that BP 
is measured. When blood samples and BP assessments are scheduled at the same time or 
within the same time window, BP should be measured before blood samples are drawn. If a
BP measurement must be taken after a blood draw, ensure adequate analgesia for the blood 
draw and wait several minutes before measuring BP. Pre-dose vital signs should always be 
taken and recorded prior to pre-dose blood draw. Vital signs may be monitored more 
frequently or for longer duration post-dose as clinically indicated.  
If a subject has symptoms potentially consistent with hypotension or a decrease in SBP of 20 
mm Hg or more from pre-dose SBP, blood pressure and heart rate (HR) should be measured
and recorded approximately every 15 minutes for the first hour and every 30 minutes
thereafter until the systolic BP returns to pre-dose systolic BP (or within the normal range for 
this subject as defined by PI) and symptoms (if present) resolve. If the hypotension resolves 
within the first hour and returns to the normal range, additional BP monitoring as described 
above is not required. Detailed guidance for blood pressure measurements is provided in the 
Blood Pressure Instrument and Technique Guidelines.
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Table 9.12.6.9.1.1: Vital Sign Assessment Frequency 
Vital Sign Assessment Frequency Pre-Dose
Screening
After at least 5 min of rest, subject’s BP is taken in sitting position. Then 
the subject will stand and BP will be taken again at approximately 1 and 3 
minutes after standing.
All other visits
After at least 5 min of rest, subject’s BP is taken 1 time in sitting position
Assessment Frequency Post-Dose
Dosing Visits
0-1 hr post-dose
1-2 hr. post-dose
Days 1
Day 2 -3
Q15 min (± 5 min)
Q30 min (± 5 min)
Q 30 min (± 5 min)
Q30 min (± 5 min)
All other dosing visits: vital 
sign measurements are taken 
once per time point in a sitting 
position after at least 5 minutes 
of rest.
Q 30 min (± 5 min);
for 1 hour
9.12.6.10 Mitigating the Risk of Potential Hypotension 
Study personnel and caregivers should be made aware of the potential risk of hypotension 
with BMN 111 administration. Subjects must be well hydrated and at a minimum eat a light 
snack prior to administration of BMN 111 or placebo. In the hour prior to injection, all 
subjects should have attempted to drink approximately 8-10 ounces or 240-300 mL of fluid 
(eg, water, milk, juice). If a recent acute illness associated with volume depletion (eg, nausea, 
vomiting, diarrhea) has not completely resolved prior to the first dose of BMN 111 or 
placebo, BMN 111 or placebo dosing may be delayed until hydration status has improved (up 
to the maximum period allowed for the screening window).
Caregivers should be trained to observe and recognize the symptoms of dehydration 
(eg, from fever, vomiting, diarrhea) and contact the investigator prior to BMN 111 or placebo 
administration if dehydration is suspected. Site personnel and caregivers should be trained to 
identify the symptoms of hypotension and, if they occur, should implement first-aid
strategies at the discretion of the investigator such as having the subject lie down supine, 
elevating the lower extremities, and administering fluids. For guidelines on how to report 
adverse events associated with hypotension, refer to Section 10.
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9.12.6.11 Electrocardiography
A standard 12-lead ECG will include heart rate, rhythm, intervals, axis, conduction defects, 
and anatomic abnormalities. All ECGs will be performed in triplicate at the visits indicated in 
the Schedule of Events (Table 9.1.1). ECGs will be performed post-dose on study day visits 
at which a dose is given; in addition, on Day 1, ECGs will be performed pre-dose. On days 
when PK samples are being drawn, ECGs should be performed within a 5-minute window 
prior to 30-minute PK assessment.  
9.12.6.12 Hip Clinical Assessment
The hip clinical assessment should be completed by an appropriately qualified health care 
professional at the time points indicated in the Schedule of Events (Table 9.1.1). Medical 
history will be obtained to evaluate for hip, thigh, or knee pain, or change in gait. The 
physical exam (including observation of gait when possible) identifies and evaluates any 
changes in hip function or pain with assessment of active and passive range of motion. 
Changes from baseline may trigger further evaluation based on the investigator’s clinical 
assessment, which may include hip imaging and/or orthopedic consultation. If findings on 
clinical hip exam are determined to be clinically significant by the investigator and in
consultation with Sponsor’s Medical Monitor and orthopedic specialist (if needed), the DMC 
will be notified of AEs resulting from clinically significant abnormal hip monitoring 
assessments. DMC may provide recommendations as to if/when BMN 111 or placebo 
treatment should be temporarily or permanently discontinued.  
9.12.6.13 Pregnancy Testing
)HPDOHVXEMHFWVZKRKDYHEHJXQPHQVHVRUDUH 10 years old will have a urine or serum 
pregnancy test at the time points specified in the Schedule of Events (Table 9.1.1). Start date 
of menses will be captured. Female subjects with a positive pregnancy test at any time will 
be withdrawn from BMN 111 or placebo treatment. 
Serum pregnancy tests will be performed in the event that urine pregnancy test results are 
positive or equivocal (indeterminate). 
Refer to Section 10.3.1.11 for details on the reporting procedures to follow in the event of 
pregnancy. 
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9.12.6.14 Pediatric Blood Volume
Clinical labs and immunogenicity samples are necessary to perform to adequate safety 
assessment in this study. The objectives of testing pharmacodynamics biomarkers are to 
demonstrate biologic activity of BMN 111 and to understand the impact of immune 
responses on drug activity; and for exploratory blood biomarkers, to investigate the effects of 
treatment on changes in bone metabolism and endogenous CNP production. 
To minimize blood collection volumes, assay technologies were chosen that are capable of 
sensitively detecting analytes using the lowest possible volume of blood for analysis. 
Additionally, assays capable of detecting analytes in urine rather than blood have been 
selected where possible. Blood volume for testing has been reduced to the minimum 
necessary for adequate evaluation of efficacy and safety of BMN 111.
9.12.6.15 Anti- BMN 111 Immunogenicity Assessments
Subjects randomized to receive BMN 111 or placebo will undergo immunogenicity testing. 
Blood (serum) samples for immunogenicity assessments will be collected at the time points 
indicated in the Schedule of Events (Table 9.1.1) and testing performed using validated 
assays. Neutralizing antibody (NAb) testing will be performed on Baseline and TAb positive 
samples. 
Scheduled samples will be tested in one or more of the following assessments:
x
Anti- BMN 111 total antibody (TAb).
x
Anti-BMN 111 antibody cross-reactivity with endogenous CNP, ANP, and 
BNP (TAb).
x
Anti- BMN 111 Nab.
Testing for the presence of cross-reactive antibodies that bind to endogenous CNP, ANP, or 
BNP and for the presence of BMN 111 NAbs will be performed on baseline samples and 
anti- BMN 111 TAb-positive samples. Baseline NAb sample and cross-reactive TAb sample 
testing will be done at any time prior to the end of study.
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9.12.6.16 Ad Hoc Safety Assessments
Samples for total immunoglobulin E (IgE) and drug-specific IgE testing will be drawn on 
Day 1 and in the event of a significant hypersensitivity AE, or at the discretion of the 
investigator and/or BioMarin. A significant hypersensitivity AE is defined as an event that is 
grade 3 or higher, requires temporary or permanent cessation of BMN 111, or is determined 
to be significant at the discretion of investigator and/or BioMarin (excluding reactions that 
are solely a localized injection site reaction). If a hypersensitivity AE occurs, an unscheduled 
safety visit should occur no later than 48 hours of the start of the reaction, including 
inspection of the injection site and clinical laboratory tests. 
Blood (serum) samples should be collected and tested in one or more of the following 
assessments:
x
Drug-specific IgE
x
Total IgE
x
Serum tryptase
If feasible, a sample for drug-specific IgE should be drawn no sooner than 8 hours after the 
event start time or before the next dose. A sample for total IgE and serum tryptase should 
also be drawn within 1 hour of the start of the event when possible or during the unscheduled 
safety visit. 
A localized injection site reaction is defined as skin signs or symptoms restricted to one 
affected primary location, ie, hives, wheals, or swelling or an area of erythema, redness, 
induration, pain, or itching at or near the site of injection. Management of such localized 
reactions should be determined by the investigator’s clinical judgment in consultation with 
the Sponsor’s Medical Monitor (if warranted).
9.12.6.17 HPA Axis Assessments
To address potential effects of BMN 111 on activation of the hypothalamic pituitary adrenal 
(HPA) axis, assessment of salivary cortisol, serum prolactin levels, and FSH / LH will be 
analyzed at the time points indicated in the Schedule of Events (Table 9.1.1). FSH / LH will 
be done for all subjects > 8 years old or Tanner Stage 2 (whichever is earlier). These tests 
will be done at Baseline, Week 26, and Week 52. 
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9.12.6.18 Unscheduled Safety Visits
Unforeseen circumstances may arise in which an unscheduled visit may be needed. In such a 
case, the procedures performed at the unscheduled visit will be completed on a case-by-case 
basis.
9.12.6.19 Medical Photography
Injection site photos are optional, but sites are strongly encouraged to take photos on Day 1, 
Week 26, Week 52, and Early Termination visit. During a scheduled visit, if photos are being 
planned, photos of the injection site will be taken in either of these two situations: 1) If an 
injection site reaction (ISR) occurs, photos will be taken for each ISR when it becomes 
apparent (or at onset), at most severe, and then post resolution. The time of the post-
resolution photo may not be the same as the time the AE resolved, and this is expected. If the 
visit has ended and the ISR has not resolved, the subject is not expected to remain on site 
until ISR resolves. If the ISR is ongoing at the end of the visit, record as an ongoing AE. 2) If 
the subject has not had an ISR by the end of the study visit, a photo will still be taken of the 
injection site used on that day. The site is instructed to document the absence of an ISR on 
the injection administration eCRF. In between visits, if an ISR worsens or changes in pattern, 
then the subject should have an unscheduled site visit. During the visit, photos of the 
injection site with the ISR may be taken. Also, injection sites may be photographed if there is 
a new ISR or at any other time at the discretion/medical judgment of the investigator or as 
recommended by the sponsor. 
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10
REPORTING ADVERSE EVENTS
10.1
Safety Parameters and Definitions
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables; 
measurement of protocol-specified vital signs; and other protocol-defined events of special 
interest that are deemed critical to the safety evaluation of the study drug.
10.1.1 Adverse Events
For this protocol, a reportable AE is any untoward medical occurrence (eg, sign, symptom, 
illness, disease or injury) in a subject administered the study-drug or other protocol-imposed 
intervention, regardless of attribution. This includes the following:
x
AEs not previously observed in the subject that emerge during the course of the 
study.
x
Pre-existing medical conditions judged by the investigator to have worsened in 
severity or frequency or changed in character during the study.
x
Complications that occur as a result of non-drug protocol-imposed interventions 
(eg, AEs related to screening procedures, medication washout, or no-treatment 
run-in).
An adverse drug reaction is any AE for which there is a reasonable possibility that the study 
drug caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the study-drug and the AE.
10.1.2 Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose meets one or more of the 
following criteria:
x
Is fatal.
x
Is life threatening 
Note: Life-threatening refers to an event that places the subject at immediate risk of 
death. This definition does not include a reaction that, had it occurred in a more 
severe form, might have caused death.
x
Requires or prolongs inpatient hospitalization.  
x
Results in persistent or significant disability or incapacity.
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x
Is a congenital anomaly or birth defect in the child or fetus of a subject exposed to IP 
prior to conception or during pregnancy.
x
Is an important medical event or reaction – that, based on medical judgment, may 
jeopardize the subject or require intervention to prevent one of the above 
consequences (eg, anaphylaxis).
All adverse events that do not meet any of the criteria for SAEs should be regarded as 
non-serious AEs.
10.1.3 Events of Special Interest
The following events of special interest (EOSI) need to be reported to the Sponsor within 
24 hours of site awareness, irrespective of seriousness, severity or causality: 
x
Fracture
x
Slipped capital femoral epiphysis
x
Avascular necrosis or osteonecrosis
10.2
Methods and Timing for Capturing and Assessing Safety Parameters
10.2.1 Adverse Event Reporting Period
The study AE reporting period is as follows: after informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported. After informed consent is obtained and the first administration of study drug, all 
non-serious AEs and SAEs reporting period begins and continues until 4 weeks following 
either the last administration of study drug or the Early Termination visit, whichever is 
longer (refer to Section 12.4). The criteria for determining, and the reporting of, SAEs is 
provided in Section 10.1.2.
10.2.2 Eliciting Adverse Events
Investigators will seek information on AEs and SAEs at each subject contact by specific 
questioning and, as appropriate, by examination. Information on all AEs and SAEs should be
recorded in the subject’s medical record and on the AE eCRF.
10.2.3 Assessment of Seriousness, Severity, and Causality 
The investigator responsible for the care of the subject or qualified medical designee will 
assess AEs for severity, relationship to study drug, and seriousness (refer to Section 10.1.2
for SAE definitions). These assessments must be made by a study clinician with the training 
and authority to make a diagnosis (eg, MD/DO, physician’s assistant, nurse practitioner, or
DDS).
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10.2.3.1
Seriousness
The investigator will assess if an AE should be classified as “serious” based on the 
seriousness criteria enumerated in Section 10.1.2. Seriousness serves as a guide for defining 
regulatory reporting obligations.
10.2.3.2
Severity
Severity (as in mild, moderate, or severe headache) is not equivalent to seriousness, which is 
based on subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning. The severity of each will be assessed using the 
defined categories in Table 10.2.3.2.1.
The investigator will determine the severity of each AE and SAE [and EOSI, if applicable] 
using the National Cancer Institute (NCI) CTCAE v4. Adverse events that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading 
used in the CTCAE v4 as stated below.
Table 10.2.3.2.1: Adverse Event Grading (Severity) Scale
Grade
Description
1
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
2
Moderate: minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLa
3
Severe or medically significant but not immediately life-threatening: hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADLb
4
Life threatening consequences; urgent intervention indicated
Grade 4 and 5 AEs 
should always be 
reported as SAEs
5
Death related to AE
a Instrumental ADL refers to the following examples: preparing meals, shopping for groceries or clothes, using the 
telephone, managing money.
b Self-care ADL refer to the following examples: bathing, dressing and undressing, feeding oneself, using the toilet, 
taking medications, not bedridden.
10.2.3.3
Causality 
The investigator will determine the relationship of an AE to the study drug and will record it 
on the source documents and AE CRF. To ensure consistency of causality assessments, 
investigators should apply the guidance in Table 10.2.3.3.1.
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Table 10.2.3.3.1: Causality Attribution Guidance
Relationship
Description
Not Related
x
Exposure to the IP has not occurred
OR
x
The administration of the IP and the occurrence of the AE are not 
reasonably related in time
OR
x
The AE is considered likely to be related to an etiology other than the 
use of the IP; that is, there are no facts, evidence, or arguments to 
suggest a causal relationship to the IP.
Related
x
The administration of the IP and the occurrence of the AE are 
reasonably related in time
AND
x
The AE could possibly be explained by factors or causes other than 
exposure to the IP
OR
x
The administration of IP and the occurrence of the AE are reasonably 
related in time 
AND
x
The AE is more likely explained by exposure to the IP than by other 
factors or causes.
Factors suggestive of a causal relationship could include (but are not limited to):
x
Plausible temporal relationship.
x
Absence of alternative explanations.
x
Rarity of event in a given subject or disease state.
x
Absence of event prior to study drug exposure.
x
Consistency with study product pharmacology.
x
Known relationship to underlying mechanism of study drug action.
x
Similarity to adverse reactions seen with related drug products.
x
Abatement of AE with discontinuation of study drug, and/or recurrence of AE with 
reintroduction of study drug.
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The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process. Regardless of the investigator’s assessment of causality for 
individual AE reports, the Sponsor will promptly evaluate all reported SAEs against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to investigators and applicable regulatory authorities. 
10.3
Procedures for Recording Adverse Events 
10.3.1 Recording Adverse Events on an eCRF
Investigators should use precise medical terminology when recording AEs or SAEs on an 
eCRF. Avoid colloquialisms and abbreviations.
Record only one diagnosis, sign, or symptom per event field on the AE eCRF (eg, nausea and 
vomiting should not be recorded in the same entry, but as 2 separate entries).
In order to classify AEs and diseases, preferred terms will be assigned by the Sponsor to the 
original terms entered on the eCRF, using Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.
10.3.1.1
Diagnosis versus Signs and Symptoms
Using accepted medical terminology, enter the diagnosis (if known). If not known, enter the 
most medically significant sign(s) and/or symptom(s). If a diagnosis subsequently becomes 
available, then this diagnosis should be entered on the AE form, replacing the original entries 
where appropriate.
10.3.1.2
Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (eg, cascade events) should be identified 
by their primary cause. For example, if severe diarrhea is known to have resulted in 
dehydration, it is sufficient to record only diarrhea as an AE or SAE on the eCRF. However, 
medically important events that may be linked and/or separated in time should be recorded as 
independent events on the eCRF. For example, if severe hemorrhage leads to renal failure, 
both events should be recorded separately on the eCRF. 
10.3.1.3
Persistent or Recurrent Adverse Events
A persistent AE is one that extends continuously, without resolution, between subject 
evaluation time points. Such an event should be recorded only once on the eCRF unless its 
severity increases or decreases (in which case it should be recorded again on the AE eCRF).
A recurrent AE is one that occurs and resolves between subject evaluation time points, but 
then subsequently recurs. Each recurrence of the AE should be recorded on the AE eCRF. 
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10.3.1.4
Hypotension
If an asymptomatic drop in blood pressure meets the protocol definition of AE per clinical 
judgment of the reporter, report the event as “blood pressure decreased.” If the drop in blood 
pressure is associated with signs or symptoms, complete the symptomatic hypotension eCRF 
and use the following guidance to report the corresponding AE eCRF: If a unifying diagnosis 
is available to explain the event of hypotension, report the diagnosis as an AE and capture 
signs and symptoms on the symptomatic hypotension eCRF page. If no other unifying 
diagnosis is available, report “hypotension” as the event and capture signs and symptoms on 
the symptomatic hypotension eCRF page. 
10.3.1.5
Injection Site Reactions
If an injection site reaction is associated with a single sign or symptom, report the event on 
AE eCRF page (eg, redness at injection site, AE is injection site redness). If the injection site 
reaction is associated with multiple signs or symptoms, report injection site reaction as the
adverse event on the AE page, and individual signs and symptoms will be reported on the 
ISR eCRF page (eg, if the subject experiences redness and induration, report “Injection site 
reaction” on the AE page, and in the corresponding Injection eCRF page, report erythema 
and induration).
10.3.1.6
Abnormal Laboratory Values
A data transfer file from the central laboratory will provide laboratory test results.
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, 
in addition to being recorded as an AE in the eCRF.
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A clinical laboratory abnormality should be documented as AE if it is not otherwise refuted 
by a repeat test to confirm the abnormality and any one or more of the following conditions 
are met:
x
Accompanied by clinical symptoms.
x
Leading to a change in study medication (eg, interruption or permanent 
discontinuation).  
x
Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment).
x
The abnormality suggests a disease and/or organ toxicity.
x
The abnormality is of a degree that requires active management (eg, discontinuation 
of study drug, more frequent follow-up assessments, further diagnostic investigation).
This applies to any protocol and non-protocol specified safety and efficacy laboratory result 
from tests performed after the first dose of study medication that falls outside the laboratory 
reference range and meets the clinical significance criteria.
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range but that does not meet the clinical significance criteria (these will be 
analyzed and reported as laboratory abnormalities), those that are considered AEs of the type 
explicitly exempted by the protocol, or those which are a result of an AE that has already 
been reported.
10.3.1.7
Pre-existing Conditions
A pre-existing condition is one that is present at the screening visit. Such conditions should 
be recorded as medical history on the appropriate eCRF. 
A pre-existing condition should be recorded as an AE or SAE during the study only if the 
frequency, intensity, or character of the condition worsens during the study period. It is 
important to convey the concept that a pre-existing condition has changed by including 
applicable language in the verbatim description of the event (eg, more frequent headaches).
10.3.1.8
General Physical Examination Findings
At screening, any clinically significant abnormality should be recorded as a pre-existing 
condition (refer to Section 10.3.1.7). During the study, any new clinically significant findings 
and/or abnormalities discovered on physical examination that meet the definition of an AE 
(or an SAE) must be recorded and document as an AE or SAE on the AE eCRF. 
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10.3.1.9
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol (refer to 
Section 10.1.2).
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE. These scenarios include planned hospitalizations or prolonged 
hospitalizations to:
x
Perform a protocol-mandated procedure.
x
Undergo a diagnostic or elective surgical procedure planned prior to study enrollment 
or for a pre-existing medical condition that has not changed.
x
Receive scheduled therapy (study drug or otherwise) for the study indication. 
10.3.1.10 Deaths
All deaths that occur during the AE reporting period (refer to Section 10.2.1), regardless of 
attribution, will be recorded on the AE eCRF and expeditiously reported to the Sponsor as an 
SAE.
When recording a death, the event or condition that caused or contributed to the fatal 
outcome should be recorded as the single medical concept on the eCRF. If the cause of death 
is unknown and cannot be ascertained at the time of reporting, record “Unexplained Death” 
or “Death of Unknown Cause” on the eCRF. If the death is attributed to progression of the 
disease or condition being studied, record progression of achondroplasia as the SAE term on 
the eCRF.
10.3.1.11 Pregnancy
Although not an AE per se, pregnancy in either a subject or the partner of a subject taking 
trial medication should be reported to facilitate outcome monitoring by the Sponsor. 
The reporting period for pregnancy in a subject or partner begins following the first dose of 
study drug and continues until 12 weeks after the final dose of study drug. Pregnancy events 
must be reported within 24 hours of the site becoming aware of the pregnancy by faxing the 
Pregnancy Form in the study reference materials to BioMarin Pharmacovigilance (BPV). 
In addition, pregnancy in a subject is also reported on the End of Study eCRF. 
The investigator must make every effort to follow the subject through resolution of the 
pregnancy (delivery or termination) and to report the resolution on the Pregnancy Follow-up
in the eCRF. In the event of pregnancy in the partner of a study subject, the investigator 
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should make every reasonable attempt to obtain the woman’s consent for release of protected 
health information.
Abortion, whether therapeutic or spontaneous, should always be classified as an SAE (as the 
Sponsor considers these to be medically significant), recorded on the eCRF, and 
expeditiously reported to the Sponsor as an SAE.
10.4
Reporting Requirements
The Sponsor is responsible for identifying, preparing, and reporting all suspected unexpected
serious adverse reactions (SUSARs) to the relevant competent authorities, ethics committees, 
and investigators in accordance with requirements identified in the Clinical Trials 
Regulations.
10.4.1 Expedited Reporting Requirements
All SAEs that occur during the course of the AE Reporting Period (refer to Section 10.2.1), 
whether or not considered related to study drug, must be reported by faxing the 
study-specific SAE Report Form to BPV within 24 hours of the site becoming aware of the
event. Each SAE must also be reported on the appropriate eCRF. Investigators should not 
wait to collect information that fully documents the event before notifying BPV of an SAE. 
BioMarin may be required to report certain SAEs to regulatory authorities within 7 calendar 
days of being notified about the event; therefore, it is important that investigators submit any 
information requested by BioMarin as soon as it becomes available.
The study SAE reporting period is as follows: after informed consent but prior to initiation of 
study treatment, only SAEs associated with any protocol-imposed interventions will be 
reported. After informed consent is obtained and the first administration of study drug, all 
SAEs must be reported through 4 weeks following either the last administration of study drug 
or the Early Termination visit, whichever is longer. 
10.4.2 IRB/EC Reporting Requirements
Reporting of SAEs to the IRB/IEC/REB will be done in compliance with the standard 
operating procedures and policies of the IRB/IEC/REB and with applicable regulatory 
requirements. Adequate documentation must be obtained by BioMarin showing that the 
IRB/IEC/REB was properly and promptly notified as required.
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10.5
Follow-up of Subjects after Adverse Events
The investigator should follow all unresolved AEs SAEs until the events are resolved or have 
stabilized, the subject is lost to follow-up, or it has been determined that the study treatment 
or participation is not the cause of the AE/SAE. Outcome of AEs and resolution of SAEs 
(with dates) should be documented on the AE eCRF and in the subject’s medical record to 
facilitate source data verification.
For some SAEs, the Sponsor may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details (eg, hospital discharge summary, consultant 
report, autopsy report) deemed necessary to appropriately evaluate the SAE report.
10.6
Post-Study Adverse Events
At the last scheduled visit, the investigator should instruct each subject to report, to the 
investigator and/or to BPV directly, any subsequent SAEs that the subject’s personal 
physician(s) believes might be related to prior study treatment.
The investigator should notify the study Sponsor of any death or SAE occurring at any time 
after a subject has discontinued or terminated study participation, if the investigator believes 
that the death or SAE may have been related to prior study treatment. The Sponsor should 
also be notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that participated in 
this study. 
10.7
Urgent Safety Measures
The regulations governing clinical trials state that the sponsor and investigator are required to 
take appropriate urgent safety measures to protect subjects against any immediate hazards 
that may affect the safety of subject s, and that the appropriate regulatory bodies should be 
notified according to their respective regulations. According to the European Union Clinical 
Trial Directive 2001/20/EC, “…in the light of the circumstances, notably the occurrence of 
any new event relating to the conduct of the trial or the development of the investigational 
medicinal product where that new event is likely to affect the safety of the subjects, the 
sponsor and the investigator shall take appropriate urgent safety measures to protect the 
subjects against any immediate hazard. The sponsor shall forthwith inform the competent 
authorities of those new events and the measures taken and shall ensure that the 
IRB/IEC/REB is notified at the same time.” 
The Sponsor is responsible for identifying, preparing and reporting all suspected unexpected 
serious adverse reactions (SUSARs) to the relevant competent authorities, ethics committees 
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and investigators in accordance with the requirements identified in the Clinical Trials 
Regulations.
The reporting period for these events, which may require the implementation of urgent safety 
measures, is the period from the time of signing of the ICF through the completion of the last 
study visit or at the Early Termination visit. Investigators are required to report any events 
which may require the implementation of urgent safety measures to BioMarin within 
24 hours. 
Examples of situations that may require urgent safety measures include discovery of the 
following:
x
Immediate need to revise the IP administration (eg, modified dose amount, frequency 
not defined in protocol).
x
Lack of study scientific value, or detrimental study conduct or management.
x
Discovery that the quality or safety of the IP does not meet established safety 
requirements.
10.8
BioMarin Pharmacovigilance Contact Information
Contact information for BioMarin Pharmacovigilance is as follows:
BioMarin Pharmaceutical Inc.
Address:
105 Digital Drive
Novato, CA 94949 USA
Phone:
(415) 506-6179
Fax:
(415) 532-3144
E-mail:
drugsafety@bmrn.com
The investigator is encouraged to discuss with the medical monitor any AEs for which the 
issue of seriousness is unclear or questioned. Contact information for the medical monitor is 
as follows:
Name:
, MD
Address:
10 Bloomsbury Way 
London WC1A 2SL 
Phone:
Fax:
E-mail:
 
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11
APPROPRIATENESS OF MEASUREMENTS
The parameters to be evaluated in this study reflect the combined experience in the clinical 
study 111-202 and reflect the need to further define the efficacy and safety profile of 
BMN 111 in the context of ACH, a complex skeletal dysplasia disorder with multiple clinical 
manifestations.
The efficacy parameters to be evaluated in this study reflect the sponsor’s experience in the 
clinical study 111-202 and of previous studies of approved growth products (Kemp, 2009; 
Bright,2009). Evaluation of the parameters proposed in this study will document the effect of 
BMN 111 treatment on AGV in children with ACH and are relevant to assessing the medical 
complications of ACH in this patient population.  
The PK assessments in this study are generally recognized as reliable, accurate, and relevant.
Bone-related biomarkers and other biochemical markers of the pharmacological activity of 
BMN 111 in the blood or urine, as well as genomic biomarkers, are exploratory assessments.
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12
STUDY PROCEDURES 
An ICF must be signed and dated by the subject (or the subject’s legally authorized 
representative if the subject is less than age of majority), the investigator or designee and 
witness (if required) before any study-related procedures are performed.
12.1
Screening Visit (Day -30 to Day -1)
Screening Visit procedures and assessments that should be performed are noted below.
x
Optional parental height assessment (NOTE: can be done at any point in the study).
x
Demographics, medical history, including ACH-related history.
x
Diagnostic genetic testing (if needed).
x
Physical examination.
x
Tanner Stage of Pubertal Development. 
x
Menstrual history in female subjects (if applicable).
x
Pregnancy test (urine or serum) for female subjects who have begun menses or 
DUH 10 years old.
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
Anthropometric measurements. 
x
Weight.
x
HRQoL questionnaires (PedsQL and QoLISSY).
x
Functional Independence Assessment (WeeFIM).
x
Child Behavior Checklist (CBCL).
x
Hip clinical assessment. 
x
Hip imaging via pelvis X-ray (anterior-posterior [AP] view).
x
Sleep study (optional).
x
ECG.
x
Echocardiogram.
x
Clinical labs (hematology, chemistry, and urinalysis).
x
Thyroid function tests. 
x
25-hydroxy Vitamin D.
x
Salivary cortisol.
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x
Serum prolactin.
x
FSH/LH.
x
DXA (BMD and BMC of whole body less head, spine). 
x
Hand and wrist X-ray (PA view, left side).
x
Bilateral lower extremity X-rays (AP and lateral views).
x
Lumbar spine X-rays (AP and lateral views).
x
Concomitant medications.
x
Adverse events.
12.2
Treatment Visits
12.2.1 Day 1 (no visit window)
x
Physical examination.
x
Menstrual history in female subjects (if applicable)
x
Pregnancy test (urine or serum) for female subjects who have begun menses or 
DUH 10 years old.
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
Anthropometric measurements.
x
Weight.
x
ECG (pre-dose and post-dose).
x
Clinical labs (hematology, chemistry, and urinalysis).
x
Anti- BMN 111 immunogenicity. 
x
Bone metabolism blood biomarkers. 
x
Bone metabolism urine biomarkers.
x
BMN 111 activity urine biomarkers (cyclic guanosine monophosphate [cGMP]).
x
Urine chemistry.
x
PK (full).
x
Injection site photos (optional). 
x
Concomitant medications.
x
BMN 111 or placebo administration.
x
BMN 111 or placebo accountability.
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x
Adverse events.
x
Procedures/interventions/surgeries.
12.2.2 Day 2 (no visit window)
x
Menstrual history in female subjects.
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
BMN 111 activity urine biomarkers (cGMP).
x
Urine chemistry. 
x
Concomitant medications.
x
BMN 111 or placebo administration.
x
BMN 111 or placebo accountability.
x
Adverse events.
x
Procedures/interventions/surgeries.
12.2.3 Day 3 (no visit window)
x
Menstrual history in female subjects (if applicable).
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
Weight.
x
BMN 111 activity urine biomarkers (cGMP).
x
Urine chemistry. 
x
Concomitant medications.
x
BMN 111 or placebo administration.
x
BMN 111 or placebo accountability.
x
Adverse events.
x
Procedures/interventions/surgeries.
12.2.4 Day 10 (±1 day)
x
Physical examination.
x
Menstrual history in female subjects (if applicable).
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
Weight.
x
ECG (post-dose).
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x
Clinical labs (hematology, chemistry, and urinalysis).
x
Concomitant medications.
x
BMN 111 or placebo administration.
x
BMN 111 or placebo accountability.
x
Adverse events.
x
Procedures/interventions/surgeries.
12.2.5 Week 6 (±7 days)
x
Physical examination.
x
Menstrual history in female subjects (if applicable).
x
Pregnancy test (urine or serum) for female subjects who have begun menses or 
DUH 10 years old.
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
Weight.
x
Clinical labs (hematology, chemistry, and urinalysis).
x
BMN 111 activity urine biomarkers (cGMP).
x
Urine chemistry.
x
Genomic biomarkers (optional). 
x
Concomitant medications.
x
BMN 111 or placebo administration.
x
BMN 111 or placebo accountability.
x
Adverse events.
x
Procedures/interventions/surgeries.
12.2.6 Week 13 (± 7 days)
x
Physical examination.
x
Menstrual history in female subjects (if applicable).
x
Pregnancy test (urine or serum) for female subjects who have begun menses or 
are  10 years old.
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
Anthropometric measurements.
x
Weight.
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x
ECG (post-dose).
x
Clinical labs (hematology, chemistry, and urinalysis). 
x
Bone metabolism blood biomarkers. 
x
Bone metabolism urine biomarkers.
x
Anti-BMN 111 immunogenicity assessments. 
x
PK (partial).
x
Concomitant medications.
x
BMN 111 or placebo administration.
x
BMN 111 or placebo accountability.
x
Adverse events.
x
Procedures/interventions/surgeries.
12.2.7 Week 26 (±7 days)
x
Physical examination.
x
Tanner Stage of Pubertal Development. 
x
Menstrual history in female subjects (if applicable).
x
Pregnancy test (urine or serum) for female subjects who have begun menses or 
are  10 years old.
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
Anthropometric measurements.
x
Weight.
x
HRQoL questionnaires (PedsQL and QoLISSY).
x
Functional Independence Assessment (WeeFIM).
x
Child Behavior Checklist (CBCL).
x
Hip clinical assessment.
x
ECG (post-dose).
x
Clinical labs (hematology, chemistry, and urinalysis). 
x
25-hydroxy Vitamin D. 
x
Salivary cortisol.
x
Serum prolactin.
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x
FSH/LH.
x
Anti-BMN 111 immunogenicity assessments.
x
Bone metabolism blood biomarkers. 
x
Bone metabolism urine biomarkers.
x
BMN 111 activity urine biomarkers (cGMP).
x
Urine chemistry. 
x
PK (full).
x
DXA (BMD and BMC of whole body less head, spine). 
x
Hand and wrist X-ray (PA view, left side). 
x
Bilateral lower extremity X-rays (AP and lateral views). 
x
Injection site photos (optional). 
x
Concomitant medications.
x
BMN 111 or placebo administration.
x
BMN 111 or placebo accountability.
x
Adverse events.
x
Procedures/interventions/surgeries.
12.2.8 Week 39 (±7 days)
x
Physical examination.
x
Menstrual history in female subjects (if applicable).
x
Pregnancy test (urine or serum) for female subjects who have begun menses or 
DUH 10 years old.
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
Anthropometric measurements.
x
Weight.
x
ECG (post-dose).
x
Clinical labs (hematology, chemistry, and urinalysis). 
x
Anti-BMN 111 immunogenicity assessments. 
x
Bone metabolism blood biomarkers.
x
Bone metabolism urine biomarkers.. 
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x
PK (partial).
x
Concomitant medications.
x
BMN 111 or placebo administration.
x
BMN 111 or placebo accountability.
x
Adverse events.
x
Procedures/interventions/surgeries.
12.2.9 Week 52 (±7 days)
x
Physical examination. 
x
Tanner Stage of Pubertal Development. 
x
Menstrual history in female subjects (if applicable).
x
Pregnancy test (urine or serum) for female subjects who have begun menses or 
DUH 10 years old.
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
Anthropometric measurements.
x
Weight.
x
HRQoL questionnaires (PedsQL and QoLISSY).
x
Functional Independence Assessment(WeeFIM).
x
Child Behavior Checklist (CBCL).
x
Hip clinical assessment.
x
Sleep study (optional).
x
ECG (post-dose).
x
Clinical labs (hematology, chemistry, and urinalysis). 
x
Thyroid function tests. 
x
25-hydroxy Vitamin D.
x
Salivary cortisol.
x
Serum prolactin.
x
FSH/LH.
x
Anti-BMN 111 immunogenicity assessments.
x
Bone metabolism blood biomarkers. 
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x
Bone metabolism urine biomarkers.
x
Genomic biomarkers (optional). 
x
BMN 111 activity urine biomarkers (cGMP).
x
Urine chemistry.
x
PK (full).
x
DXA (BMD and BMC of whole body less head, spine). 
x
Hand and wrist X-ray (PA view, left side).
x
Bilateral whole leg, AP only.
x
Lumbar spine X-rays (AP and lateral views).
x
Injection site photos (optional). 
x
Concomitant medications.
x
BMN 111 or placebo administration.
x
BMN 111 or placebo accountability.
x
Adverse events.
x
Procedures/interventions/surgeries.
12.3
Week 56 (±7 Days) Safety Follow-Up Visit
x
Physical examination.
x
Menstrual history in female subjects (if applicable).
x
Pregnancy test (urine or serum) for female subjects who have begun menses or 
DUH 10 years old.
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
ECG. 
x
Clinical labs (hematology, chemistry, and urinalysis). 
x
Anti-BMN 111 immunogenicity assessments.
x
Bone metabolism blood biomarkers. 
x
Bone metabolism urine biomarkers. 
x
Concomitant medications.
x
Adverse events.
x
Procedures/interventions/surgeries.
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12.4
Early Termination
x
Physical examination.
x
Tanner Stage of Pubertal Development.
x
Menstrual history in female subjects (if applicable).
x
Pregnancy test (urine or serum) for female subjects who have begun menses or 
DUH 10 years old.
x
Vital signs (body temperature, heart rate, BP, respiratory rate).
x
Anthropometric measurements (only if the subject discontinues after Week 6). 
x
Weight.
x
Hip clinical assessment.
x
Sleep study (only if Early Termination visit occurs after Week 26 and subject has had 
a previous sleep study during the trial, ie, has entered the sleep sub-study).
x
ECG. 
x
Clinical labs (hematology, chemistry, and urinalysis).
x
Thyroid function tests. 
x
25-hydroxy Vitamin D.
x
Salivary cortisol.
x
Serum prolactin.
x
FSH/LH.
x
Anti-BMN 111 immunogenicity assessments.
x
Bone metabolism blood biomarkers. 
x
Bone metabolism urine biomarkers. 
x
DXA (BMD and BMC of whole body less head, spine (only if subject discontinues 
after 9 months).
x
Hand and wrist X-ray (PA view, left side) (obtained only if the subject discontinues 
after 9 months).
x
Bilateral X-rays of lower extremity including AP and lateral views (only if subject 
discontinues after 9 months). 
x
Lumbar spine X-rays (AP and lateral views) (only if subject discontinues after 
9 months). 
x
Injection site photos (only if an injection is given at this visit).
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x
Concomitant medications.
x
BMN 111 or placebo accountability. 
x
Adverse events.
x
Procedures/interventions/surgeries.
12.5
Contact for Study Follow-up
Contact by a study staff member to the caregiver will be required after the Week 6 visit every 
4 weeks (±10 days) when there are no study visits or contact in the preceding 4 weeks. 
During these contacts, study staff will ask about dose administration and seek information on 
AEs and SAEs by specific questioning. Information on all AEs and SAEs should be recorded 
in the subject’s medical record and on the AE eCRF.
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13
DATA QUALITY ASSURANCE
BioMarin personnel or designees will visit the study site prior to initiation of the study to 
review with the site personnel information about the IP, protocol and other regulatory
document requirements, any applicable randomization procedures, source document 
requirements, eCRFs, monitoring requirements, and procedures for reporting AEs, including 
SAEs. 
At visits during and after the study, a CRA will monitor the site for compliance with 
regulatory documentation, with a focus on accurate and complete recording of data on CRFs 
from source documents, adherence to protocol, randomization (if applicable), SAE reporting 
and drug accountability records. 
Sites will enter study data into eCRFs into the study electronic data capture (EDC) system. 
Data Quality Control will be performed by BioMarin Clinical Data Management or designee 
through implementation of quality control checks specified in the study data management 
plan and edit check specifications. Additional subject-reported study data may be entered 
into the study EDC system via electronic diary. 
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14
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
14.1
Statistical and Analytical Plans
The statistical analysis plan (SAP) will provide additional details on the planned statistical 
analysis and the final version must be finalized prior to database lock. The SAP will overrule 
any differences with the analytical plan described in the protocol . Unless otherwise stated, 
all analyses will be performed using SAS v. 9.4.
14.1.1 Interim Analyses
No formal futility/efficacy interim analyses are planned for this study.
14.1.2 Procedures for Accounting for Missing, Unused and Spurious Data
Because the completeness of the data affects the integrity and accuracy of the final study 
analysis, every effort will be made to ensure complete, accurate and timely data collection 
and, therefore, avoid missing data. In addition, a subject who prematurely discontinues study 
drug should be asked if they are willing to continue to participate in the study assessments for 
remaining duration of the study, as long as in the judgment of the investigator such continued 
participation would not detrimentally affect the health, safety, or welfare of the subject.
No missing data will be imputed for any analysis, except for unless otherwise specified for 
the efficacy analyses or for the missing dates for AEs and concomitant medications. Missing 
dates or partially missing dates will be imputed conservatively to ensure that an AE is 
considered treatment emergent and has the longest possible duration, if the partial 
information available indicates that the AE is likely treatment emergent. 
Additional details regarding the handling of missing data will be provided in the SAP. 
14.2
Efficacy Analysis
All efficacy analysis will be done on the efficacy population defined in Section 14.7.1
14.2.1 Primary Efficacy Analysis
The primary efficacy endpoint is the change from baseline in AGV at the 12–month time 
point. For a given interval [Date1, Date2], the AGV is defined as follows:
where the interval length in days is calculated as Date2 – Date1. AGV will be calculated for 
the following visits/intervals:
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x
Baseline: [Date of last height measurement in study 901 at least 6 months prior to
Date of Day 1 visit in study 301, Date of Day 1]
x
Week 13: [Date of Day 1, Date of Week 13]
x
Week 26: [Date of Day 1, Date of Week 26]
x
Week 39: [Date of Day 1, Date of Week 39]
x
Week 52 (12-month): [Date of Day 1, Date of Week 52]
The baseline of the AGV is established in the natural history study of Study111-901, based 
on the standing height measurements in the last 6 months prior to enrollment to Study 
111-301.  
The primary estimand is the difference in mean change from baseline in AGV at 12-month 
time point between the BMN 111 group and the placebo group. The estimand is defined on 
all randomized subjects who received at least one dose of double-blinded BMN 111 or 
placebo. The least-squares (LS) means of the change from baseline in AGV at 12-month will 
be used to estimate the primary estimand for the BMN 111 group and the placebo group 
based on an analysis of covariance (ANCOVA) model, with fixed-effect terms including 
treatment group, sex, and Tanner stage, and age and the baseline AGV as covariates. The 
following primary hypothesis will be tested (two-tailed):
H0: Difference in mean AGV change from baseline at 12 months between 
BMN 111 group and the placebo group = 0 
Ha: Difference in mean AGV change from baseline at 12 months between 
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Subjects who discontinue from the study drug will be encouraged to remain in the study and
their non-missing height measurements will continue to be used in calculating the AGV and
to be included in the analysis per intend to treat principle. In the event that missing data does
occur despite all efforts, missing standing height will be imputed based on multiple
imputation (MI) with pattern-mixture models (Little 1993; Molenberghs 2007) implemented 
in Proc MI of SAS where the missing, unobserved observations of the standing height are
assumed to follow missing not at random (MNAR) mechanism. Each imputation will require
sufficient standing height data collected from the subjects in the same randomization group 
who also discontinue treatment prematurely (but remain in the study), referred to as off-
treatment data, as these subjects will be used as the reference data for MI. Ten (10) sets of
imputations of the missing standing heights will be constructed from MI and the AGV at the
missing time points will be calculated based on these 10 sets of data. For 
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each subject whose value is imputed, the 10 imputed values will be provided in a data listing 
that will be included in the appendix of the CSR. The above-mentioned Mixed model will be 
applied to the 10 imputed data sets from MI. The analysis results based on the 10 imputed 
datasets will be summarized using Proc MIANALIZE in SAS. 
In the event there is insufficient data to perform the imputations for subjects who discontinue 
the treatment early, then the mixed model will be applied without multiple imputations. The 
study is considered positive if the primary test is significant in favor of BMN 111.  
The AGV and its change from baseline at each scheduled post-treatment visit will be 
summarized at Week 26 and Week 52 using descriptive statistics (mean, SD, median, Q1,Q3, 
minimum, and maximum) per group.  
14.2.2 Secondary Efficacy Analyses 
The key secondary efficacy endpoints are the change from baseline in height Z-score and the 
change from baseline in upper:lower body segment ratio. The estimand of the secondary 
efficacy endpoints is the difference in mean change from baseline in the corresponding 
endpoint at 12-month time point between the BMN 111 group and the placebo group 
(all randomized subjects).
The measurement of standing height at each scheduled visit will be converted to age-and sex-
appropriate standard score, also referred to as Z-score, by comparison with normal reference 
standards (not ACH). The height Z-score and its change from baseline will be summarized 
using descriptive statistics. The null hypothesis of no difference between the BMN 111 group 
and the placebo group in the mean change from baseline in the height Z-score at 12-month 
time point will also be tested based on 10 imputed data sets using an ANCOVA model, with 
fixed-effect terms including treatment group, sex, and Tanner stage, and age and the baseline 
Z-score as covariates. The analysis results based on the 10 imputed datasets will be 
summarized using Proc MIANALIZE in SAS. The upper:lower body segment ratio and its 
change from baseline will be similarly summarized and tested.    
Additional secondary efficacy endpoints include change from baseline in body proportions of 
the extremities, HRQoL (QoLISSY, PedsQL) scores, and functional independence 
(WeeFIM) scores. 
Details regarding the analysis methods for the additional secondary endpoints will be 
provided in the SAP. 
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14.2.3 Controlling for Multiplicity
The overall type I family-wise error rate for testing the primary and secondary efficacy 
endpoints will be controlled at the 0.05 significance level using the following 3-step serial 
gatekeeping multiple comparisons procedure (MCP). Following this MCP, advancement to 
the next step will only occur if the null hypotheses within a step and the previous step(s) are 
all rejected at the significance level of 0.05 in favor of BMN 111. If any null hypothesis 
within a step is not rejected or is rejected but not in favor of BMN 111, the hypothesis tests 
corresponding to all subsequent steps will not be considered statistically significant. 
All hypothesis tests will be two-sided.
1. The first step will be the test comparing the BMN 111 group to the placebo group for 
the primary efficacy endpoint, the change from baseline in AGV at 12-month time 
point. If the null hypothesis is not rejected (ie, p-value > 0.05) or is rejected but not in 
favor of BMN 111, all subsequent statistical tests will not be considered statistically 
significant. The study is considered positive if the primary test is significant in favor 
of BMN 111. 
2. The second step will be the test comparing the BMN 111 group to the placebo group 
for the secondary efficacy endpoint, the change from baseline in height Z-score at 
12-month time point. If the null hypothesis is not rejected (ie, p-value > 0.05) or is 
rejected but not in favor of BMN 111, the subsequent statistical test will not be
considered statistically significant. 
3. The third step will be the tests comparing the BMN 111 group to the placebo group 
for the secondary efficacy endpoint, the change from baseline in upper:lower body 
segment ratio at 12-month time point at a significance level of 0.05. 
By-subject listings will also be provided for efficacy endpoints.  
14.2.4 Sensitivity Analyses
To assess the robustness of the primary analysis result, sensitivity analyses such as the 
following will be performed: 
Mixed Model with Repeated Measures (MMRM)
The primary null hypothesis of no difference between the BMN 111 group and the placebo 
group in the mean change from baseline in AGV at the 12-month time point will be tested 
using a mixed model with repeated measures (MMRM), with fixed-effect terms including 
treatment group, visit, sex, Tanner stage, and interaction of treatment group and visit, and age 
and the baseline AGV as covariates, repeated over visits. All available AGV assessments 
from all scheduled visits up to 12-month will be used in the MMRM analysis.  
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MI Based on Missing At Random (MAR) Assumption
The sensitivity analyses will be based on the MI technique as proposed by Little and Rubin 
(1987) implemented in PROC MI of SAS where the missing, unobserved observations of the 
response variable are assumed to follow missing at random (MAR) mechanism. The MI 
procedure will be directly applied to standing height and AGV will be calculated based on 
imputed height. The ANCOVA model described in the primary analysis will be performed 
separately for each imputation dataset and a summary overall imputed samples will be 
provided for each analysis. 
Random Coefficients Model
The mean change from baseline (Day 1) in height at 12-month time point will be estimated 
for both the treatment group and the placebo group based on a MMRM, with fixed-effect
terms including treatment group, visit, sex, Tanner stage, and age and the baseline height as 
covariates, and random-effect terms of the intercept and the subject*visit interaction. For 
each randomized group, an AGV at 12-month time point will be defined as the mean change 
from baseline in height at 12-month from the MMRM model above.  
ANCOVA on Completers
In this sensitivity analysis, the estimand will be the difference of the means of the change 
from baseline in AGV at 12-month observed from subjects who have non-missing 
observation at 12-month between the two randomized groups. No missing data will be 
imputed. The LS means of the change from baseline in AGV at 12-month will be estimated 
for both the randomized groups by applying the mixed model described in the primary 
analysis. In this analysis, only subjects with observed AGV change from baseline at 12-
month will be included. No extrapolation or imputation will be performed for missing 12-
month standing height measurements.  
14.2.5 Exploratory Analyses
Exploratory endpoints include sleep apnea assessment, BMN 111 activity biomarkers and 
genomic biomarkers. 
Details regarding the analysis methods for the exploratory endpoints will be provided in the 
SAP.
14.3
Pharmacokinetic Analyses 
Blood samples from subjects randomized to receive BMN 111 will undergo pharmacokinetic 
testing.
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For subjects randomized to BMN 111, PK parameters generated over the course of the study 
will be evaluated and summarized with descriptive statistical measures (mean, standard 
deviation, percentage of coefficient of variation [CV%], minimum, median and maximum). 
Correlative analyses of some of the PK parameters with efficacy, safety and immunogenicity 
measures may be conducted.
14.4
Safety Analysis
All randomized subjects who receive at least one dose of double-blinded BMN 111 or 
placebo in this study will be included in the safety analysis. The safety analysis will be 
performed on safety population as defined in Section 14.7.2 and will be considered 
descriptive.
All AEs will be coded using the most current version of MedDRA will be used by the 
Sponsor to assign system organ class and preferred term classification to events and diseases, 
based on the original terms entered on the CRF.
All AEs will be coded using MedDRA. The incidence of AEs will be summarized by system 
organ class, preferred term, relationship to study treatment (as assessed by investigator), and 
severity. All AEs, including SAEs and AEs that lead to permanent discontinuation from the 
study and from the study treatment, will be listed. Hypersensitivity reactions and 
symptomatic hypotension are of interest, and the percentage of subjects who report these AEs 
will be presented. Hypersensitivity reactions will be defined in the SAP.
Clinical laboratory data will be summarized by the type of laboratory test. For each clinical 
laboratory test, descriptive statistics will be provided on baseline as well as all subsequent 
visits.  
Descriptive statistics for other safety endpoints such as vital signs, ECG results, X-ray and 
DXA assessments of bone morphology and quality, clinical hip assessment, CBCL, anti-
BMN 111 immunogenicity assessments, and bone metabolism biomarkers, will also be 
provided. Detailed statistical methods will be provided in the SAP. All other safety measures 
including laboratory tests, vital signs, ECG, X-ray and DXA assessments, clinical hip 
assessment, and anti-BMN 111 immunogenicity (discussed in the next section) will be 
summarized descriptively by group, listings will be provided for these safety endpoints. 
14.5
Immunogenicity Analysis
Immunogenicity will be summarized as change from baseline as well as by study time point 
in subjects randomized to receive BMN 111 or placebo. Results will be summarized as 
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incidence and titer for all cohorts. Additionally, immunogenicity may be assessed for 
correlations with measures of safety, PK, and efficacy.
14.6
Determination of Sample Size
With 55 subjects planned in each of the two randomized groups (one BMN 111 dose group 
and one placebo group), the power to detect a difference of 1.75 cm/year between the 
BMN 111 group and the placebo group in change from baseline in AGV at 12 months is 
approximately 90%, assuming that the pooled standard deviation of the change from baseline 
in AGV is 2.80, using a two-sided two-sample t-test at a 0.05 significance level. The power 
calculation is based on data from Study 111-202 (a phase 2, open-label, sequential cohort 
dose-escalation study) and Study 111-901 (a natural history study for pediatric subjects with 
achondroplasia). 
14.7
Analysis Populations
14.7.1 Efficacy Population
All randomized subjects who receive at least one dose of double-blinded BMN 111 or 
placebo in this study.
14.7.2 Safety Population 
All randomized subjects who receive at least one dose of double-blinded BMN 111 or 
placebo in this study. 
14.7.3 PK Population 
All randomized subjects who receive at least one dose of double-blinded BMN 111 in this 
study and have at least one evaluable PK concentration.  
14.8
Changes in the Conduct of the Study or Planned Analyses
Only BioMarin may modify the protocol. Any change in study conduct considered necessary 
by the investigator will be made only after consultation with BioMarin, who will then issue a 
formal protocol amendment to implement the change. The only exception is when an 
investigator considers that a subject’s safety is compromised without immediate action. In 
these circumstances, immediate approval of the chairman of the IRB/IEC/REB must be 
sought, and the investigator should inform BioMarin and the full IRB/IEC/REB within 
2 working days after the emergency occurs. 
With the exception of minor administrative or typographical changes, the IRB/IEC/REB 
must review and approve all protocol amendments. Protocol amendments that have an impact 
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on subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/IEC/REB prior to their implementation.
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by BioMarin and the 
IRB/IEC/REB, and all active subjects must again provide informed consent. 
Note: If discrepancies exist between the text of the statistical analysis as planned in the 
protocol, and the final SAP, a protocol amendment will not be issued and the SAP will
prevail.
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15
DATA MONITORING COMMITTEE
In addition to safety monitoring by BioMarin personnel, an independent DMC will act as an 
advisory body to BioMarin and will monitor the safety data and PK of subjects in the study. 
The DMC will include independent experts.
DMC data review will occur at regular time periods during the course of the study per the 
DMC charter (or ad hoc, if indicated).
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16
COMPENSATION AND INSURANCE
There will be no charge to study subjects to be in this study. BioMarin will pay all costs of 
tests, procedures, and treatments that are part of this study. In addition, after IRB/EC/REB 
approval, BioMarin may reimburse the cost of travel for study-related visits. BioMarin will 
not pay for any hospitalizations, tests, or treatments for medical problems of any sort, 
whether or not related to the study subject’s disease that are not part of this study. Costs 
associated with hospitalizations, tests, and treatments should be billed and collected in the 
way that such costs are usually billed and collected.
The investigator should contact BioMarin immediately upon notification that a study subject 
has been injured by the IP or by procedures performed as part of the study. Any subject who 
experiences a study-related injury should be instructed by the investigator to seek medical 
treatment at a pre-specified medical institution if possible, or at the closest medical treatment 
facility if necessary. The subject should be given the name of a person to contact to seek 
further information about, and assistance with, treatment for study-related injuries. 
The treating physician should bill the subject’s health insurance company or other third party 
payer for the cost of this medical treatment. If the subject has followed the investigator’s 
instructions, BioMarin will pay for reasonable and necessary medical services to treat the 
injuries caused by the IP or study procedures, if these costs are not covered by health 
insurance or another third party that usually pays these costs. In some jurisdictions, BioMarin 
is obligated by law to pay for study-related injuries without prior recourse to third party 
payer billing. If this is the case, BioMarin will comply with the law.
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17
CASE REPORT FORMS AND SOURCE DOCUMENTS
Electronic case report forms will be provided for each subject. The investigator must review 
and electronically sign the completed eCRF casebook to verify its accuracy.
eCRFs must be completed using a validated web-based application. Study site personnel will 
be trained on the application and will enter the clinical data from source documentation, 
except in the instances when electronic subject reported data is transmitted directly to EDC, 
as referenced in the study specific vendor management plan. 
Unless explicitly allowed in the CRF instructions, blank data fields are not acceptable. 
In the event of an entry error, or if new information becomes available, the value will be 
corrected by deselecting the erroneous response and then selecting or entering the factual 
response. In compliance with 21 CFR Part 11, the system will require the personnel making 
the correction to enter a reason for changing the value. The documented audit trail will 
include the reason for the change, the original value, the new value, the time of the correction 
and the identity of the operator.
BioMarin’s policy is that study data on the eCRFs must be verifiable to the source data, 
which necessitates access to all original recordings, laboratory reports, and subject records. 
In addition, all source data should be attributable (signed and dated). The investigator must 
therefore agree to allow direct access to all source data. Subjects (or their legally authorized 
representative) must also allow access to their medical records, and subjects will be informed 
of this and will confirm their agreement when giving informed consent. If an investigator or 
institution refuses to allow access to subject records because of confidentiality, arrangements 
must be made to allow an “interview” style of data verification.
A CRA designated by BioMarin will compare the eCRFs with the original source documents 
at the study site and evaluate them for completeness and accuracy before designating them as 
“Source Data Verified” (SDV). Electronic subject-reported data transmitted directly into 
EDC will not be SDV’d or queried.
If an error is discovered at any time or a clarification is needed, the CRA, or designee, will 
create an electronic query on the associated field. Site personnel will then answer the query 
by either correcting the data or responding to the query. The CRA will then review the 
response and determine either to close the query or re–query the site if the response does not 
fully address the question. This process is repeated until all open queries have been answered 
and closed. 
Before a subject’s eCRF casebook can be locked, data fields must be source data verified and 
all queries closed. Refer to the Clinical Monitoring Plan for details on which fields must be 
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source data verified. The Data Manager, or designee, will then set the status of the forms, 
visits, and the entire casebook to Locked. The investigator will then electronically sign the 
casebook, specifying that the information on the eCRFs is accurate and complete. As part of 
site close-out activities, an electronic copy of each site’s casebooks will be copied to a 
compact disc or digital versatile disc and sent to each study site for retention with other study 
documents. 
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18
STUDY MONITORING AND AUDITING
Qualified individuals designated by BioMarin will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations. The investigator agrees to allow these monitors direct access to the clinical 
supplies, dispensing, and storage areas and to the clinical files, including original medical 
records, of the study subjects, and, if requested, agrees to assist the monitors. The 
investigator and staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by BioMarin or its designees.
Members of BioMarin’s GCP Compliance Department or designees may conduct an audit of 
a clinical site at any time before, during, or after completion of the study. The investigator 
will be informed if an audit is to take place and advised as to the scope of the audit. 
Representatives of the FDA or other Regulatory Agencies may also conduct an inspection of 
the study. If informed of such an inspection, the investigator should notify BioMarin 
immediately. The investigator will ensure that the auditors have access to the clinical 
supplies, study site facilities, original source documentation, and all study files.
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19
RETENTION OF RECORDS
The investigator must retain all study records required by BioMarin and by the applicable 
regulations in a secure and safe facility. The investigator must consult a BioMarin 
representative before disposal of any study records, and must notify BioMarin of any change 
in the location, disposition or custody of the study files. The investigator /institution must 
take measures to prevent accidental or premature destruction of essential documents, that is, 
documents that individually and collectively permit evaluation of the conduct of a study and 
the quality of the data produced, including paper copies of study records (eg, subject charts)
as well as any original source documents that are electronic as required by applicable 
regulatory requirements. 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP. The investigator /institution 
should retain subject identifiers for at least 15 years after the completion or discontinuation 
of the study. Subject files and other source data must be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by a BioMarin agreement. BioMarin must be notified 
and will assist with retention should investigator /institution be unable to continue 
maintenance of subject files for the full 15 years. It is the responsibility of BioMarin to 
inform the investigator /institution as to when these documents no longer need to be retained.
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20
USE OF INFORMATION AND PUBLICATION
BioMarin recognizes the importance of communicating medical study data and therefore 
encourages the publication of these data in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study will be described in the Clinical Trial 
Agreement between BioMarin and the investigator/Institution. Consideration for authorship 
of all publications will be based on compliance with the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals (“Uniform Requirements”) of the 
International Committee of Medical Journal Editors 
(http://www.icmje.org/about-icmje/faqs/icmje-recommendations/) and good publication practices. 
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21
REFERENCES
Bartels, CF, Bukulmez, H, Padayatti, P, Rhee, DK et. al. Mutations in the transmembrane 
natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic 
dysplasia, type Maroteaux. Am J Hum Genet 75[1], 27-34. 2004. 
Bocciardi, R, Giorda, R, Buttgereit, J, Gimelli, S et. al. Overexpression of the C-type 
natriuretic peptide (CNP) is associated with overgrowth and bone anomalies in an individual 
with balanced t(2;7) translocation. Hum Mutat 28[7], 724-731. 2007.
Bright, GM, Mendoza, JR, Rosenfeld, RG. Recombinant human insulin-like growth factor-1
treatment: ready for primetime. Endocrinol Metab Clin North Am. 38[3]:625-638. 2009. 
Chusho, H, Tamura, N, Ogawa, Y, Yasoda, A et. al. Dwarfism and early death in mice 
lacking C-type natriuretic peptide. Proc Natl Acad Sci U S A 98[7], 4016-4021. 2001. 
Foldynova-Trantirkova, S, Wilcox, WR, Krejci, P. Sixteen years and counting: the current 
understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal 
dysplasias. Hum Mutat 33[1], 29-41. 2012.
Greulich W, Pyle S. Radiographic Atlas of Skeletal Development of the Hand and Wrist. 2nd 
ed. Stanford: Stanford University Press, 1971. [This publication is a book and therefore is not 
included in the submission.].
Hoover-Fong, JE, Schulze, KJ, McGready, J, Barnes, H et. al. Age-appropriate body mass 
index in children with achondroplasia: interpretation in relation to indexes of height. Am J 
Clin Nutr 88[2], 364-371. 2008. 
Horton, WA, Hall, JG, Hecht, JT. Achondroplasia. Lancet 370[9582], 162-172. 2007. 
Ireland PJ, McGill J, Zankl A, Ware RS, Pacey V, Ault J, Savarirayan R, Sillence D, 
Thompson EM, Townshend S, Johnston LM. Functional performance in young Australian 
children with achondroplasia. Dev Med Child Neurol. Oct;53(10):944-950. 2011.
Ireland P, Johnston LM. Measures of self-care independence for children with 
osteochondrodysplasia: a clinimetric review. Phys Occup Ther Pediatr. 32(1):80-96. 2012. 
Kemp, SF. Insulin-like growth factor-I deficiency in children with growth hormone 
insensitivity: current and future treatment options. BioDrugs 23[3]:155-163. 2009. 
Krejci, P, Masri, B, Fontaine, V, Mekikian, PB et. al. Interaction of fibroblast growth factor 
and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and 
extracellular matrix homeostasis. J Cell Sci 118[Pt 21], 5089-5100. 2005.
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Laederich MB, Horton WA. Achondroplasia: pathogenesis and implications for future 
treatment. Curr Opin Pediatr. Aug;22(4):516-523. 2010.
Little, R. J. A., and Rubin, D. B. Statistical Analysis with Missing Data, New York: 
John Wiley; 1987. p 200-220.
Little, R. J. A. (1993), “Pattern-Mixture Models for Multivariate Incomplete Data,” Journal 
of the American Statistical Association, 88, 125–134. 
Long, S, Wendt, D, Bell, S. A novel method for the large-scale production of PG-CNP37, a 
C-type natriuretic peptide analogue. J Biotechnol 162[2], 196-201. 2012.
Lorget, F, Kaci, N, Peng, J, oist-Lasselin, C et. al. Evaluation of the therapeutic potential of a 
CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 91[6], 
1108-1114. 2012. 
Marcus, CL, Brooks, LJ, Draper, KA, Gozal, D et. al. Diagnosis and management of 
childhood obstructive sleep apnea syndrome. Pediatrics 130[3], e714-e755. 2012. 
Molenberghs, G. and Kenward, M. G. (2007), Missing Data in Clinical Studies, New York: 
John Wiley & Sons.
Pejchalova, K, Krejci, P, Wilcox, WR. C-natriuretic peptide: an important regulator of 
cartilage. Mol Genet Metab 92[3], 210-215. 2007.
Shirley, ED, Ain, MC. Achondroplasia: manifestations and treatment. J Am Acad Orthop 
Surg 17[4], 231-241. 2009. 
Stamoyannou, L, Karachaliou, F, Neou, P, Papataxiarchou, K et. al. Growth and growth 
hormone therapy in children with achondroplasia: a two-year experience. Am J Med Genet 
72[1], 71-76. 1997.
Tanaka, H, Kubo, T, Yamate, T, Ono, T et. al. Effect of growth hormone therapy in children 
with achondroplasia: growth pattern, hypothalamic-pituitary function, and genotype. Eur J 
Endocrinol 138[3], 275-280. 1998. 
Tanner J, Whitehouse R. Assessment of skeletal maturity and prediction of adult height 
(TW2 method). 2nd ed. London: Academic Press, 1975. [This publication is a book and 
therefore is not included in the submission.].
Waters, KA, Everett, F, Sillence, D, Fagan, E et. al. Breathing abnormalities in sleep in 
achondroplasia. Arch Dis Child 69[2], 191-196. 1993. 
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Wendt, DJ, Dvorak-Ewell, M, Bullens, S, Lorget, F et. al. Neutral endopeptidase-resistant C-
type natriuretic peptide variant represents a new therapeutic approach for treatment of 
fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp Ther 353[1], 132-149.
2015.
Wynn, J, King, TM, Gambello, MJ, Waller, DK et. al. Mortality in achondroplasia study: a 
42-year follow-up. Am J Med Genet A 143A[21], 2502-2511. 2007. 
Yasoda, A, Kitamura, H, Fujii, T, Kondo, E et. al. Systemic administration of C-type 
natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology . 
2009.
Yasoda, A, Komatsu, Y, Chusho, H, Miyazawa, T et. al. Overexpression of CNP in 
chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10[1], 
80-86. 2004. 
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22
INVESTIGATOR RESPONSIBILITIES
22.1
Conduct of Study and Protection of Human Subjects 
In accordance with FDA Form 1572, the investigator will ensure that:
x
He or she will conduct the study in accordance with the relevant, current protocol and 
will only make changes in a protocol after notifying the sponsor, except when 
necessary to protect the safety, rights, or welfare of subjects.
x
He or she will personally conduct or supervise the study.
x
He or she will inform any potential subjects, or any persons used as controls, that the 
drugs are being used for investigational purposes and he or she will ensure that the 
requirements relating to obtaining informed consent in 21 CFR Part 50 and IRB 
review and approval in 21 CFR Part 56 are met. 
x
He or she will report to the sponsor adverse experiences that occur in the course of 
the investigation in accordance with 21 CFR 312.64. 
x
He or she has read and understands the information in the Investigator’s Brochure, 
including potential risks and side effects of the drug.
x
His or her staff and all persons who assist in the conduct of the study are informed 
about their obligations in meeting the above commitments
x
He or she will ensure that adequate and accurate records in accordance with 21 CFR 
312.62 and to make those records available for inspection in accordance with 21 CFR 
312.68.
x
He or she will ensure that the IRB/EC/REB complies with the requirements of 21 
CFR Part 56, and other applicable regulations, and conducts initial and ongoing 
reviews and approvals of the study. He or she will also ensure that any change in 
research activity and all problems involving risks to human subjects or others are 
reported to the IRB/EC/REB. Additionally, he or she will not make any changes in 
the research without IRB/EC/REB approval, except where necessary to eliminate 
apparent immediate hazards to human subjects. 
x
He or she agrees to comply with all other requirements regarding the obligations of 
clinical investigators and all other pertinent requirements in 21 CFR Part 312. 
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PI
PI

SAP_001.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to 
Evaluate the Efficacy and Safety of BMN 111 in Children with Achondroplasia 
 
NCT Number: NCT03197766 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 05 November 2019  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.1.9 Documentation of Statistical Methods
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Pg. 1 of 80 
 
 
105 Digital Drive 
Novato, CA 94949 
 
Statistical Analysis Plan 
 
Study 111-301 
 
A Phase 3, Randomized, Double-Blind, Placebo-
Controlled, Multicenter Study to Evaluate the 
Efficacy and Safety of BMN 111 in Children with 
Achondroplasia 
 
Version: Final 
Date: 05 November 2019 
 
 
The information in this document is considered privileged and confidential by BioMarin 
Pharmaceutical Inc., and may not be disclosed to others except to the extent necessary to 
obtain Institutional Review Board approval and informed consent, or as required by Federal 
and State Laws.  Persons to whom this information is disclosed must be informed that this 
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Study 111-301 Statistical Analysis Plan 
 
Proprietary and Confidential                       CFT-114417-ITEM Rev. 01 
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1 
SAP SYNOPSIS 
TITLE OF STUDY:  A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter 
Study to Evaluate the Efficacy and Safety of BMN 111 in Children with Achondroplasia  
PROTOCOL NUMBER:  111-301 
STUDY SITES:  Approximately 33 clinical centers worldwide 
PHASE OF DEVELOPMENT:  Phase 3 
OBJECTIVES:  
The primary objective of the study is to: 
x 
Evaluate change from baseline in annualized growth velocity at 52 weeks in subjects 
treated with BMN 111 compared with control subjects in the placebo group 
The secondary objectives of the study are to: 
x 
Evaluate change from baseline in height Z-score in subjects treated with BMN 111 
compared with control subjects in the placebo group at 52 weeks 
x 
Evaluate change from baseline in upper:lower body segment ratio in subjects treated with 
BMN 111 compared with control subjects in the placebo group at 52 weeks 
x 
Evaluate change from baseline in body proportion ratios of the extremities   
x 
Evaluate effect of BMN 111 on bone morphology/quality by X-ray and dual X-ray 
absorptiometry (DXA) 
x 
Evaluate potential changes in health-related quality of life (HRQoL) as measured by the 
Quality of Life in Short Stature Youth (QoLISSY) and the Pediatric Quality of Life 
Inventory (PedsQL) questionnaires 
x 
Evaluate potential changes in functional independence as measured by the Functional 
Independence Measure (Wee-FIM) clinician-reported outcome  
x 
Evaluate safety and tolerability of BMN 111 in children with ACH 
x 
Evaluate the pharmacokinetics of BMN 111 
x 
Evaluate immunogenicity of BMN 111 and assess impact on safety, PK, and efficacy 
measures 
x 
Evaluate change from baseline in bone metabolism biomarkers 
The exploratory objectives of the study are to: 
x 
Evaluate sleep study scores by polysomnography in a subset of subjects 
x 
Evaluate biomarkers of BMN 111 activity 
x 
Evaluate genomic biomarkers 
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STUDY DESIGN AND PLAN: This is a phase 3 randomized, double-blind, placebo-controlled, 
multicenter study to evaluate the effect of BMN 111 on growth velocity in children with ACH. 
Subjects who are 5 to < 18 years old, with documented ACH confirmed by genetic testing who 
have been enrolled in Study 111-901 for at least a 6-month period immediately before study entry, 
and meet all study eligibility criteria, will participate. Approximately 33 clinical centers worldwide 
will participate in the study. 
At least 110 eligible subjects will be stratified based on sex and Tanner stage (Stage I, and > Stage 
I, with no more than 20% of subjects > Tanner Stage I) at Screening, and randomly assigned in a 
1:1 ratio to one of two treatment groups (placebo or BMN 111 at 15μg/kg). 
After subjects have completed the treatment period of the study, those in both treatment and 
control groups may be eligible to receive BMN 111 in the extension study 111-302 after the 
Week 52/Study Completion Visit.  
ANALYSIS POPULATIONS:  
The Full Analysis Set (FAS) includes all randomized subjects with a signed informed consent.  The 
FAS will be used for all efficacy analyses. When applicable, additional sensitivity analyses will be 
carried out for the Per-Protocol (PP) population, defined as a subset of the FAS who are compliant 
with the protocol and do not have major protocol violations that affect the interpretability of 
efficacy data. 
The Safety Population is a subset of the FAS, and defined as all randomized consented subjects 
who receive at least one dose of double-blinded BMN 111 or placebo in this study. 
The PK Population is defined as all subjects in the FAS randomized to the BMN 111 treatment 
group, who receive at least one dose of BMN 111 in this study and have at least one evaluable PK 
concentration. 
The Immunogenicity Population is defined as all subjects in the Safety Population who have at 
least one evaluable immunogenicity sample.   
STUDY ENDPOINTS AND ANALYSES:  
Primary efficacy endpoint:  
The primary efficacy endpoint is the change from baseline in annualized growth velocity (AGV, 
cm/yr) at week 52. 
The primary analysis of the change from baseline in AGV at week 52 will be performed using an 
ANCOVA model. Missing values will be imputed, either using multiple imputation (MI) 
techniques or (if there is insufficient data to perform MI) alternative approaches to address missing 
data. Details of missing data imputation can be found in Section 14.3.2. 
The following sensitivity analysis and supplementary analyses will be performed to assess the 
robustness of the results of the primary analysis. 
x 
Primary analysis using the washout model (sensitivity).  
x 
Primary analysis on completers (supplementary).  
x 
Primary analysis excluding assessments that occur post limb lengthening or receipt of 
growth hormone/gonadotropin-releasing hormone (supplementary).  
Key secondary efficacy endpoints:  
These key secondary efficacy endpoints will be tested using hierarchical testing which controls the 
type I error rate (otherwise referred to as confirmatory testing): 
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Study 111-301 Statistical Analysis Plan 
 
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x 
Change from baseline in height Z-score at week 52 
x 
Change from baseline in upper to lower body segment ratio at week 52 
Other secondary efficacy endpoints:  
Non-confirmatory statistical testing will be performed for the secondary endpoints identified below 
(*).  Other endpoints will be summarized using descriptive statistics only.   
x 
Change from baseline in upper arm length to lower arm ratio* 
x 
Change from baseline in upper leg length to knee to heel ratio* 
x 
Change from baseline in upper leg length to tibial length ratio* 
x 
Change from baseline in arm span to standing height ratio* 
x 
Change from baseline in growth measures* (see Section 14.5.2 for list of measures) 
x 
Change from baseline in body mass index 
x 
Change from baseline in body mass index Z-score 
x 
Change from baseline in weight Z-scores 
x 
Change from baseline in pediatric quality of life inventory (PedsQL) 
x 
Change from baseline in quality of life short statured youth (QoLISSY) 
x 
Change from baseline in functional independence measure (Wee-FIM). 
Safety endpoints and analyses: 
Adverse events (AEs) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) Version 22 and presented by System Organ Class (SOC) and Preferred Term (PT).  
Summaries of AE’s will include all AE’s, serious adverse events (SAEs) and events of interest 
(EOI).  Exposure-adjusted summaries will also be provided. 
Clinical laboratory tests will be summarized descriptively.  Shift tables tabulating Common 
Terminology Criteria for Adverse Events (CTCAE) severity grade at baseline versus worst 
post-baseline grade will be provided. 
Vital signs will be summarized descriptively.  Shift tables tabulating shifts from pre-dose (diastolic 
%3PP+JGLDVWROLF%3PP+Jto lowest post-injection value (diastolic BP <40mmHg, 
GLDVWROLF%3PP+Jwill be provided.  Additional shift tables will describe similar pre/post-
injection shifts in vital signs. 
X-rays and DXA will be performed on the extremities and spine to evaluate changes in bone 
morphology and quality. Growth and bone age will be assessed by the means of X-rays of the 
wrist/hand. 
Anti-BMN 111 immunogenicity assessments will be summarized descriptively 
Behavioral assessments with the Childhood Behavioral Checklist (CBCL) will be summarized 
descriptively. 
 
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Study 111-301 Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
1 SAP SYNOPSIS ..................................................................................................................2 
2 APPROVAL (SIGNATURE AND DATE) .........................................................................9 
3 LIST OF ABBREVIATIONS ............................................................................................10 
4 INTRODUCTION .............................................................................................................12 
4.1 Objectives of Study ...................................................................................................12 
4.2 Study Design .............................................................................................................13 
4.3 Study Population .......................................................................................................14 
4.4 Study Dosage and Administration ............................................................................14 
4.5 Sample Size Determination .......................................................................................14 
4.6 Blinding and Randomization Methods .....................................................................15 
4.6.1 
Blinding Method ..........................................................................................15 
4.6.2 
Randomization Method ...............................................................................15 
4.6.3 
Interim Analysis ..........................................................................................16 
5 GENERAL ANALYSIS CONSIDERATIONS ................................................................17 
5.1 Analysis Populations .................................................................................................18 
5.1.1 
Full Analysis Set .........................................................................................18 
5.1.2 
Per-Protocol .................................................................................................18 
5.1.3 
Safety ...........................................................................................................19 
5.1.4 
PK ................................................................................................................19 
5.1.5 
Immunogenicity ...........................................................................................19 
5.2 Pooling of Data from Sites with Small Enrollment ..................................................19 
5.3 Study Day Derivation ................................................................................................20 
5.4 Visit Windows for Analysis ......................................................................................20 
5.5 Handling of Dropouts and Missing Data ..................................................................21 
5.5.1 
Partial Dates ................................................................................................21 
6 SUBJECT DISPOSITION .................................................................................................23 
7 DISCONTINUATION AND COMPLETION ..................................................................24 
8 PROTOCOL EXEMPTIONS AND DEVIATIONS .........................................................25 
9 DEMOGRAPHICS AND BASELINE CHARACTERISTICS.........................................26 
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10 MEDICAL HISTORY .......................................................................................................28 
11 PRIOR AND CONCOMITANT MEDICATIONS ...........................................................29 
12 COMPLIANCE..................................................................................................................30 
13 EXTENT OF EXPOSURE TO STUDY DRUG ...............................................................31 
14 EFFICACY EVALUATIONS ...........................................................................................32 
14.1 General Approaches for Analyzing Growth Parameters ...........................................32 
14.2 Statistical Testing ......................................................................................................33 
14.3 Primary Efficacy Endpoint ........................................................................................34 
14.3.1 Annualized Growth Velocity .......................................................................34 
14.3.2 Primary Analysis Method ............................................................................35 
14.3.3 Sensitivity and Supplementary Analyses Defined for AGV .......................38 
14.4 Key Secondary Efficacy Endpoint(s) ........................................................................39 
14.4.1 Height Z-Score ............................................................................................39 
14.4.2 Upper to Lower Body Segment Ratio .........................................................40 
14.5 Other Secondary Efficacy Endpoint(s) .....................................................................42 
14.5.1 Body Proportion Ratios ...............................................................................42 
14.5.2 Growth Measures ........................................................................................43 
14.5.3 Body Mass Index .........................................................................................45 
14.5.4 Weight Z-Scores ..........................................................................................45 
14.5.5 Health-Related Quality of Life and Functional Independence ....................46 
14.6 Exploratory Endpoints ..............................................................................................50 
14.6.1 Sleep Study Scores ......................................................................................50 
14.7 Examination of Efficacy by Subgroups ....................................................................51 
15 SAFETY EVALUATIONS ...............................................................................................52 
15.1 Adverse Events .........................................................................................................52 
15.1.1 Treatment-Emergent Adverse Events .........................................................52 
15.1.2 Events of Interest .........................................................................................53 
15.1.3 Injection Site Reaction Symptoms ..............................................................55 
15.2 Clinical Laboratory Tests ..........................................................................................56 
15.3 Vital Signs .................................................................................................................57 
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15.4 Electrocardiogram .....................................................................................................59 
15.5 Child Behavior Checklist ..........................................................................................60 
15.6 Echocardiogram ........................................................................................................61 
15.7 On-Study Procedures, Interventions and Surgeries ..................................................61 
15.8 Hip Monitoring and Rotation ....................................................................................61 
15.9 Pregnancy Testing .....................................................................................................62 
16 IMAGING SECONDARY ENDPOINT(S) ......................................................................63 
16.1 Bone Age ...................................................................................................................63 
16.2 Lower Limb X-Rays .................................................................................................63 
16.3 Lumbar Spine X-Rays ...............................................................................................64 
16.3.1 Vertebral Height ..........................................................................................64 
16.3.2 Transverse Diameter (Interpedicle Distance) ..............................................64 
16.3.3 Sagittal Width ..............................................................................................65 
16.3.4 Lumbar Spine Angles ..................................................................................65 
16.4 Dual Energy X-ray Absorptiometry ..........................................................................66 
16.4.1 Whole Body Less Head and Lumbar Spine ................................................66 
16.4.2 Regions of Interest in Distal Forearm .........................................................67 
17 BONE METABOLISM BIOMARKERS ..........................................................................68 
18 BMN 111 ACTIVITY URINE BIOMARKERS AND URINE CHEMISTRY ................69 
19 IMMUNOGENICITY ASSESSMENT .............................................................................70 
20 PHARMACOKINETICS AND PHARMACODYNAMICS ............................................74 
21 REFERENCES ..................................................................................................................75 
22 SUMMARY OF CHANGES TO STUDY SAP ................................................................76 
23 APPENDICES ...................................................................................................................78 
23.1 Child Behavior Checklist Domains ...........................................................................78 
 
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LIST OF TABLES 
Table 5.4.1:  Visit Windows for Observed Assessments in BMN 111-901 ............................20 
Table 5.4.2:  Visit Windows for Observed Assessments in 111-301 ......................................21 
 
LIST OF FIGURES 
Figure 4.2.1:  Study Design .....................................................................................................14 
 
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APPROVAL (SIGNATURE AND DATE) 
Biostatistician 
 
 
 
 
DD MON YYYY 
Statistical Programmer 
 
 
 
 
DD MON YYYY 
Clinical Science Lead 
 
 
 
 
DD MON YYYY 
Pharmacovigilan
 
 
 
 
DD MON YYYY 
Head of Biostati
 
 
 
 
DD MON YYYY 
Head of Clinical 
 
 
 
DD MON YYYY 
DocuSign Envelope ID: EDD6CAD1-7F9E-47AA-8325-D840B644FE2D
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Study 111-301 Statistical Analysis Plan 
 
Proprietary and Confidential                       CFT-114417-ITEM Rev. 01 
Pg. 10 of 80 
3 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
μg/kg 
microgram/kilogram 
ACH 
achondroplasia 
ADA 
anti-drug antibody 
ADaM 
Analysis Data Model 
AE 
adverse event 
AGV 
annualized growth velocity 
ANCOVA 
analysis of covariance 
ANP 
atrial natriuretic peptide 
ATC 
Anatomical Therapeutic Chemical 
BMC 
bone mineral content 
BMD 
bone mineral density 
BMI 
body mass index 
BMN 
BioMarin 
BNP 
brain natriuretic peptide 
BPV 
BioMarin Pharmacovigilance 
BSAP 
bone-specific alkaline phosphatase 
CBCL 
Child Behavior Checklist 
CRF 
case report form 
cGMP 
cyclic guanosine monophosphate 
CNP 
c-type natriuretic peptide 
CNP22 
c-type natriuretic peptide (22 amino acids in length) 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events (v4.0) 
DMC 
data monitoring committee 
DXA 
dual x-ray absorptiometry 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
ISR 
injection site reaction 
IXRS 
interactive web or voice response system 
LOCF 
last observation carried forward 
LS 
least squares 
MAR 
missing at random 
MCAR 
missing completely at random 
MCP 
multiple comparisons procedure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed model for repeated measures 
NAb 
neutralizing antibody 
NCI 
National Cancer Institute 
NMAR 
not missing at random 
PD 
pharmacodynamic 
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PedsQL 
Pediatric Quality of Life Inventory 
PK 
pharmacokinetic 
PP 
per-protocol 
PT 
preferred term 
QoLISSY 
Quality of Life in Short Statured Youth 
QTc-B 
Bazett’s corrected QT interval 
QTc-F 
Fridericia’s corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
standard error 
SMQ 
Standardized MedDRA query 
SOC 
system organ class 
TAb 
total antibody 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TLGs 
tables, listings, and graphs 
WeeFIM 
Functional independence measure for children 
WHO 
World Health Organization 
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4 
INTRODUCTION 
Study 111-301 (original protocol effective date: 01-September-2016, Japanese-specific 
protocol effective date: 18-April-2018) is a Phase 3 randomized, double-blind, 
placebo-controlled, multicenter study to evaluate the effect of BMN 111 on growth velocity 
in children with achondroplasia (ACH).  
This Final SAP is an amendment to the Final Draft SAP (dated: 15-May-2019).  The SAP 
has been amended to include modifications to address the FDA written response letter dated 
25-July-2019.  The key updates are summarized in Section 22. 
This SAP is based on Amendment 4 of the protocol (date: 01-February-2019), and describes 
the analyses and evaluations that will be provided for study 111-301, including the data from 
study 111-901 data for subjects who subsequently enrolled in study 111-301.  Where there 
are major differences between the protocol-defined analyses, and the SAP-defined analyses, 
these will be identified in the SAP.  The SAP-defined analyses prevail. 
4.1 
Objectives of Study 
The primary objective of the study is to: 
x Evaluate change from baseline in annualized growth velocity at 52 weeks in subjects 
treated with BMN 111 compared with control subjects in the placebo group 
The secondary objectives of the study are to: 
x Evaluate change from baseline in height Z-score in subjects treated with BMN 111 
compared with control subjects in the placebo group at 52 weeks. 
x Evaluate change from baseline in upper:lower segment body ratio in subjects treated 
with BMN 111 compared with control subjects in the placebo group at 52 weeks 
x Evaluate change from baseline in body proportion ratios of the extremities 
x Evaluate effect of BMN 111 on bone morphology/quality by X-ray and DXA 
x Evaluate potential changes in health-related quality of life (HRQoL) as measured by 
QoLISSY and PedsQL questionnaires. 
x Evaluate potential changes in functional independence as measured by the WeeFIM 
clinical-reported outcome. 
x Evaluate safety and tolerability of BMN 111 in children with ACH 
x Evaluate the pharmacokinetics of BMN 111 
x Evaluate immunogenicity of BMN 111 and assess impact on safety, PK and efficacy 
measures 
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x Evaluate change from baseline in bone metabolism biomarkers 
The exploratory objectives of the study are to: 
x Evaluate sleep study scores by polysomnography in a subset of subjects 
x Evaluate biomarkers of BMN 111 activity 
x Evaluate genomic biomarkers 
4.2 
Study Design 
Study 111-301 is a Phase 3 randomized, placebo-controlled, double-blind multicenter study 
to evaluate the effect of BMN 111 on growth in children with ACH. Subjects who are 5 to 
< 18 years old with documented ACH confirmed by genetic testing will have been enrolled in 
Study 111-901 (observational run-in study in pediatric patients with ACH) for at least a 
6-month period immediately before study entry, and meet all study eligibility criteria. 
Subjects who discontinue from the study drug will be encouraged to remain in the study and 
continue to undergo as many of the protocol-specified procedures and assessments as 
possible for the remainder of the study, as long as such continued participation does not 
detrimentally affect the health, safety, or welfare of the subject. 
This 60-week study (up to 4 weeks of screening, 52 weeks of treatment with an additional 
4 weeks of safety follow up) allows for assessment of the effect of daily BMN 111 
administration on change from baseline in AGV, height, and body proportions in subjects 
treated with BMN 111 compared with control subjects in the placebo group.  In addition, this 
study will help to further characterize safety and tolerability of BMN 111 in children with 
ACH. 
At least 110 eligible subjects will be stratified based on sex and Tanner stage (Stage I, and 
> Stage I, with no more than 20% of subjects > Tanner Stage I) at Screening, and randomly 
assigned in a 1:1 ratio to one of two treatment groups: placebo or BMN 111 at 15 μg/kg.  
Approximately 33 clinical centers worldwide will participate in the study. 
The 111-301 study design is presented below. 
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Figure 4.2.1:   Study Design 
Subjects who complete the 52 week treatment period in 111-301 study on randomized 
treatment, will be eligible to receive open label BMN 111 15 μg/kg daily in 111-302, to 
assess safety and efficacy of BMN 111 over the longer term. Subjects will have the option to 
enroll in 111-302 after the Week 52/Study Completion Visit. Week 52 assessments will serve 
as Baseline assessments for entry to study 111-302 if the visit occurs on the same day or 
within 2 weeks. Subjects who enroll into 111-302 more than 2 weeks after the 111-301 
Week 52 visit will have a separate Baseline visit; the same assessments as those performed at 
Week 52 will be repeated at that time. 
4.3 
Study Population 
Subjects who are 5 to < 18 years old with documented ACH confirmed by genetic testing, 
and have been enrolled in Study 111-901 for at least a 6-month period immediately before 
study entry, and meet all study eligibility criteria will participate in the study. 
4.4
Study Dosage and Administration 
BMN 111 will be administered as a single subcutaneous dose of 15 μg/kg given daily for 
52 weeks. The control group will receive subcutaneous injections with placebo daily for 
52 weeks.
4.5
Sample Size Determination 
With 55 subjects planned in each of the two randomized groups (one BMN 111 dose group 
and one placebo group), the power to detect a difference of 1.75 cm/year between the 
BMN 111 group and the placebo group in change from baseline in AGV at 12 months is 
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111-901 Baseline 
Growth Natural 
History Study ;, 6 
Months 
, 
Participation 
BMN 111 will be administered a<S a ~ingle subcutaneous injection of 15 µg/kg given daily 
for 52 \Veeks. The oontrol group will receive a .s[ngle subcutaneous injection of placebo 
given dai1¥for 52 weeks. 
N = At Leacst 110 
Subjects Enrolled in BMN 111-301 & Randomized to Treatment with BMN 11115µg/kg or placebo rontrol (1:1 ratiol 
♦ Fir-st 3 Doses of BMN 111 or placebo wrU be administered at the d inic 


 
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approximately 90%, assuming that the pooled standard deviation of the change from baseline 
in AGV is 2.80, using a two-sided two-sample t-test at a 0.05 significance level. The power 
calculation is based on data from Study 111-202 (a phase 2, open-label, sequential cohort 
dose-escalation study) and Study 111-901. 
4.6 
Blinding and Randomization Methods 
4.6.1 Blinding Method 
This is a placebo-controlled, double-blind study.  Blinding is strictly maintained during the 
study and a study specific masking plan describes how potentially unblinding data (i.e. PK 
and Biomarker data) are handled during the lifetime of the study. The study will remain 
blinded until after all data has been entered, and the final database has been locked. 
4.6.2 Randomization Method 
The centralized randomization with stratification is managed by an external vendor, using 
IXRS technology.  Eligible subjects will be randomized whilst at the site, and receive their 
first dose of study drug on the same day.  
In the original protocol, subjects were stratified based on sex and age (<= 11, > 11 years).  At 
the time of protocol amendment 2, the strata were changed and subjects randomized after this 
time were stratified by sex and Tanner Stage.  The original strata will be reported for all 
subjects; however all statistical analyses will reported as sex and Tanner Stage.  
At least 110 eligible subjects will be stratified based on sex and Tanner Stage (Stage I, and 
> Stage I) (with no greater than 20% of subjects > Tanner Stage I), and randomly assigned in 
a 1:1 ratio to one of two treatment groups: placebo or BMN 111 at 15 μg/kg. 
A separate stratified randomization scheme is in place for 
 subjects. This 
randomization scheme is set up to assure an overall approximate balance of 
 subjects 
randomized to both treatment arms. The subjects are stratified based on sex and Tanner Stage 
(Stage I, and > Stage I), and in addition the blocks across the strata are sequenced to assure 
an overall balance across the treatment arms.  
To achieve sex balance, approximately 50% of each sex will be enrolled, with neither to 
exceed 55%.  For placebo and BMN 111, the route of administration is subcutaneous 
injection and the frequency is daily. Approximately 33 clinical centers worldwide were 
expected to participate in the study, with a cap of 11 subjects at each site.  
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4.6.3 Interim Analysis 
No formal interim futility/efficacy analyses are planned for this study. 
An independent DMC is acting as an advisory body to BioMarin and provides input on the 
safety data collected in the study.  The safety outputs are generated by an external party with 
an external independent statistician.  DMC data review occurs approximately every 
 
during the study (or ad hoc, if necessary). 
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5 
GENERAL ANALYSIS CONSIDERATIONS 
The analyses described in this SAP are based on Amendment 4 of the protocol 
(dated 01-February-2019).   
Individual subject data that is reflected in data summaries will be provided in 
  Unless 
otherwise specified, all 
 will be by treatment group and ordered by subject number, 
where subject number includes the site number. 
Summary tables and figures are provided by treatment group with no overall population 
column.  There are certain exceptions (e.g. subject disposition, demographics, baseline 
characteristics and safety data) which are indicated in the relevant sections. 
Baseline annualized growth velocity (AGV) is defined in Section 14.3.1.  Baseline growth 
measures (other than AGV) and baseline weight are those assessed on Day 1 of dosing, 
regardless of timing relative to dosing. (Note: If no assessments are available, then the 
baseline assessment will be the last non-missing assessment prior to Day 1).  All other 
baseline assessments are the last non-missing on-study 301 assessments prior to 
administration of study drug.  Change from baseline is calculated as: [post-baseline value – 
baseline value]; Percent change from baseline is calculated as: ([post-baseline value – 
baseline value]/baseline value) x 100. 
The Screening visit will not be presented in descriptive summaries over time.  When the 
analysis windows have been applied (see Section 5.4), data collected at the screening visit 
may be included in the Baseline assessment.  All assessments will be listed, but only those 
assessments assigned to visits according to the windows applied (see Section 5.4) will be 
summarized in tables or graphically.  Exceptions to this are summaries of the worst 
post-baseline laboratory data in shift tables where all assessments are considered, and also 
the standing height assessments displayed in the spaghetti plots. 
Unless otherwise specified, the number of subjects, mean, 25th percentile, median, 
75th percentile and estimates of precision (e.g. SD, confidence interval) will be displayed to 
one more decimal place than the collected data.  Minimum and maximum values will be 
presented to the same decimal places as the collected data.  For summaries by visit, the 
number of subjects with non-missing observations (n) according to the analysis windows 
(see Section 5.4 for further details) at the derived visit will be presented. 
When summarizing categorical data, for mutually exclusive categories, the sum of the 
individual categories, including a separate “Missing” category, should equal 100%.  Unless 
otherwise specified, if categories have no data, then they will not be displayed. 
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All statistical analyses will be performed using SAS® version 9.4 or a later release (SAS 
Institute, North Carolina, USA) and results be presented in the form of tables, 
 and 
graphs (TLGs). All statistical analyses, including dataset creation and output generation, will 
be performed by Biostatistics and Statistical Programming personnel of BioMarin’s 
Biometrics department. 
5.1 
Analysis Populations 
A total of 5 analysis populations will be used for all summaries and analyses.  Subjects who 
have satisfied the population criteria will be classified in the designated population and 
analyzed accordingly.  
The analysis populations are described below.  For each population, the number and percent 
of subjects included, excluded, and the reason for exclusion (where applicable) will be 
summarized by treatment group and overall.  
 will be provided to identify any 
subjects not included in the population, and the reason for exclusion. 
The number of subjects in the Full Analysis Set (FAS) will also be summarized by 
randomization strata (i.e., Male Tanner Stage I, Female Tanner Stage I, Male Tanner Stage 
>I, Female Tanner Stage >I). 
5.1.1 Full Analysis Set 
The Full Analysis Set (FAS) is defined according to the intention-to-treat principle and 
includes all randomized subjects with a signed informed consent. The FAS will be used to 
present the baseline characteristics, and efficacy data by randomized treatment group.  All 
listings, excluding screen failures, will be produced on the FAS. 
5.1.2 Per-Protocol 
The Per-Protocol (PP) population will be determined consistent with the International 
Conference on Harmonisation (ICH) E9 Guideline 
(http://ww.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC
500002928.pdf) and is defined as a subset of the FAS population who are compliant with the 
protocol. 
The PP population will comprise of all subjects in the FAS who satisfy the following criteria: 
1) Subjects who met all inclusion/exclusion criteria. 
2) Subjects who had no major protocol deviations that could affect the results of the 
primary or key secondary endpoints (AGV, height Z-score, and upper to lower body 
segment ratio).** 
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3) Subjects who were assigned into the correct strata. 
4) Subjects who completed the treatment originally allocated (i.e., always received the 
assigned treatment (BMN 111 or placebo), had a Week 52 visit within the defined 
visit window (see Section 5.4), and were at least 90% compliant with study drug). 
Subjects who always received the assigned treatment (4) can only be determined once the 
study has been unblinded. 
**The major protocol deviations that would exclude a subject from the PP population are: 
x Evidence of taking growth hormone (coded as “somatropin and somatropin agonists”) 
or gonadotropin-releasing hormone (coded as “gonadotropin releasing hormone 
analogues”) 
x Evidence of having a limb lengthening procedure (i.e., a MedDRA preferred term of 
‘limb operation’). 
The PP population will be used for the analysis of the primary and two key secondary 
endpoints. 
5.1.3 Safety 
The Safety Population is defined as all subjects in the FAS who receive at least one dose of 
double-blind BMN 111 or placebo in this study. 
The Safety Population will be used to present the safety summaries by actual treatment 
received.  Subjects randomized to one treatment group, who only receive the study drug for 
the other treatment group, will be analyzed in the arm of the study drug they received. 
5.1.4 PK 
The PK Population is defined as all subjects in the FAS randomized to the BMN 111 
treatment group, who receive at least one dose of BMN 111 in this study and have at least 
one evaluable PK concentration. 
5.1.5 Immunogenicity 
The Immunogenicity Population is defined as all subjects in the Safety Population who have 
at least one evaluable immunogenicity sample.  Subjects randomized to one treatment group, 
who only receive the study drug for the other treatment group, will be analyzed in the arm of 
the study drug they received. 
5.2 
Pooling of Data from Sites with Small Enrollment 
Not applicable, as there are no analyses by site.  
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5.3 
Study Day Derivation 
Study day in 111-301 will be determined by subtracting the initial study drug start date from 
a visit date plus 1 if the visit date occurs on or after the initial study drug start date.  
Otherwise, the study day will be the visit date minus the initial study drug start date.  
Therefore, Study Day 1 will occur on the initial study drug start date.  i.e.  
x Study Day 1 = Day of first dose of study drug. 
x If Visit Date < Study Drug Start Date, then Study Day = (Visit Date - Study Drug 
Start Date) 
x If Visit Date > Study Drug Start Date, then Study Day = (Visit Date - Study Drug 
Start Date) +1 
5.4 
Visit Windows for Analysis 
An assessment for a subject will be classified according to the study day of the assessment 
where it falls within a window.   
Data in Study 111-901 for subjects who enrolled in Study 111-301 and are included in the 
corresponding analysis population will be used in efficacy summary tables and figures.  The 
analysis visits and windows for assessments in Study 111-901 are defined in Table 5.4.1. 
Unless otherwise specified, only the derived visits listed in the table will be included in 
summary tables and figures. 
Table 5.4.1:  Visit Windows for Observed Assessments in BMN 111-901 
Derived Visit 
Target Daya 
Analysis Windowa 
 6 Months Prior 
-182 
> -364 to  -182  
 12 Months Prior 
-364 
> -546 to  -364  
a Target days and analysis windows are relative to the 111-301 Day 1 date defined in Section 5.3 above. 
 
For each subject and growth measure in Study 111-901, the record closest to the target day 
within the analysis window will be retained for inclusion in summary tables. 
Spaghetti plots of standing height and standing height Z-scores will include all measures 
recorded in Study 111-901 up to and including WKH³0RQWKV3ULRU´assessment without 
applying windows.  This will allow for all subjecWVZLWKKHLJKWDVVHVVPHQWV months 
prior to Day 1 to have at least one assessment included.  
The analysis windows for assessments in Study 111-301 are defined in Table 5.4.2.  The 
analysis windows are designated for each scheduled visit and centered on a target day. If 
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there are two or more assessments within a designated window, the assessment that is closest 
to the target day will be used for analyses.  If the two closest assessments to the target day are 
equidistant from the target day, the assessments taken on a scheduled visit per CRF page will 
be used.  Unless otherwise specified, all analyses are based on derived visits. 
Table 5.4.2:  Visit Windows for Observed Assessments in 111-301 
Derived Visit 
Target Daya 
Analysis Windowa 
Baseline 
 
The last assessment prior to the first dose of study drug unless 
otherwise specified. 
Day 1 
Day 1 
Day 1 
Day 2 
Day 2 
Day 2 
Day 3 
Day 3 
Day 3 
Day 10 
Day 10 
Day 4 – 16 (-/+6) 
Week 6 
Day 43 
Day 22 - 64 (-/+21) 
Week 13 
Day 92 
Day 71 – 113 (-/+21) 
Week 26 
Day 183 
Day 162 - 204 (-/+21) 
Week 39 
Day 274 
Day 253 – 295 (-/+21) 
Week 52 
Day 365 
Day 344 – 386 (-/+21) 
a Target days and analysis windows are relative to the 111-301 Day 1 date defined in Section 5.3.  
 
5.5 
Handling of Dropouts and Missing Data 
.  Please refer to Section 14.3 for 
the proposed methodology for dealing with missing data in the efficacy analyses of the 
primary and two key secondary endpoints.  
 
. 
5.5.1 Partial Dates 
Where start and stop dates for medications or adverse events are incomplete, imputation rules 
will be applied.  
In the event that the start date of a medication/AE is partial, the following imputation rules 
will be applied: 
x If only day is missing, then the start date will be imputed as the first day of the month. 
If month and year are the same as the month and year of first dose of study drug then 
the start date will be imputed as the first dose date.  
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x If only year is non-missing, then the start date will be imputed as the first day of the 
year. If year is the same as the year of first dose of study drug then the start date will 
be imputed as the first dose date. 
In the event that the stop date of a medication/AE is partial, the following imputation rules 
will be applied: 
x If only day is missing, then the end date will be imputed as the last day of the month.  
x If only year is non-missing, then the end date will be imputed as the last day of the 
year. If the imputed date is beyond the study completed or discontinued date, the 
imputed date will be replaced with the study completed or discontinued date. 
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6 
SUBJECT DISPOSITION 
At least 110 subjects (55 per treatment group) are planned to be enrolled by approximately 
33 sites. 
Disposition will be presented based on the FAS.  The number of subjects in the FAS, the 
number of subjects who received study drug, the number of subjects who completed 
treatment on study drug, and the number of subjects who completed the study will be 
reported by treatment group. 
The total number of subjects who were in the FAS, received study drug, and completed the 
study (i.e., completed the Week 52 visit) or withdrew prematurely will be summarized by 
treatment group and depicted by a flowchart in the clinical study report (CSR). 
Disposition data will be listed by treatment group, and will indicate the investigator site.  In 
addition, for those subjects who were screen failures, the reason for screen failure will be 
listed. 
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DISCONTINUATION AND COMPLETION 
For subjects who prematurely discontinued from the study, the primary reason for 
discontinuation will be summarized. A similar summary will be provided for subjects who 
discontinued study drug. 
The number of subjects who completed study drug, and the number of subjects who 
completed the study will be summarized by treatment group. 
All summaries will be based on the FAS, and presented by treatment group and overall. 
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PROTOCOL EXEMPTIONS AND DEVIATIONS 
The number and percentage of subjects with any protocol deviation, any major protocol 
deviation, and any minor protocol deviation will be presented, according to the categories 
described in the study specific protocol deviation plan.  Reasons for major/minor deviations 
will be summarized. 
All summaries will be based on the FAS, and presented by treatment group and overall. 
All protocol deviations will be listed by treatment group, and ordered by subject. A separate 
listing of all major deviations which have been classified as a “Dosing Irregularity” will be 
provided. 
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DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics will be summarized for the FAS, and presented by 
treatment group and overall. 
Demographics will be summarized as: 
x Age at Day 1 (years) 
x Age at Day 1 ( WR 8 to < 11 11 to < 15 15 to < 18 years) 
x Sex (Male, Female) 
x Race (American Indian or Alaska Native, Asian [Japanese/Other], Black or African 
American, Native Hawaiian or Pacific Islander, White, Multiple, Not Provided Due to 
Patient Privacy Rules) 
x Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
Baseline characteristics will be summarized as: 
x Tanner Stage (I, > I; Derived as either genitalia (male) or breast (female) Tanner 
stage) 
x Weight (kg) 
x Weight Z-Score 
x Body Mass Index (kg/m2) 
x Body Mass Index Z-Score 
Baseline anthropometric growth measures will be summarized as: 
x Annualized Growth Velocity (AGV) (cm/yr) 
x Height Z-Score 
x Standing Height (cm) 
x Sitting Height (cm) 
x Head Circumference (cm) 
x Arm Span (cm) 
x Arm Span to Standing Height Ratio 
x Upper Arm Length (cm) 
x Lower Arm (Forearm) Length (cm) 
x Upper Arm Length to Lower Arm (Forearm) Length Ratio 
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x Lower Body Length (cm) = Standing Height – Sitting Height 
x Upper Leg Length (Thigh) (cm) 
x Knee to Heel Length (cm) 
x Tibial Length (cm)  
x Upper to Lower Body Segment Ratio 
x Upper Leg Length (Thigh) to Knee to Heel Length Ratio 
x Upper Leg Length (Thigh) to Tibial Length Ratio 
In addition to the demographics at baseline, subject’s Tanner Stage status will be summarized 
[n(%)] by visit and presented by treatment group and overall: 
x Tanner Stage (I, > I; Derived as either genitalia (male) or breast (female) Tanner 
stage) 
x Pubic hair Tanner Stage (I, II, III, IV, V, Not Done) 
x Breast Tanner Stage (Female only) (I, II, III, IV, V, Not Done) 
x Genitalia Tanner Stage (Male only) (I, II, III, IV, V, Not Done) 
 
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MEDICAL HISTORY 
Medical history will be solicited from each subject, including all major illnesses, diagnoses, 
and surgeries that the subject has ever had; any prior or existing medical conditions that 
might interfere with study participation or safety; and evaluation for knee, thigh, hip or groin 
pain, or change in gait/activity.  All medical history terms will be coded in accordance with 
MedDRA Version 22 so that each term is assigned a system organ class (SOC) and preferred 
term (PT).   
A predefined list of the achondroplasia-related PTs is provided in a separate project-level 
document.  Prior to the database lock and unblinding of this study, any PTs which have not 
previously been reported as achondroplasia-related will be identified via medical review, and 
will be added to this list.  The complete list of final terms will be retained in the study file, 
and documented in the CSR.  
All recorded medical history will be summarized on the FAS by system organ class (SOC) 
and by preferred term (PT), ordered by descending order of frequency of SOC in the overall 
population.  In addition, achondroplasia-related medical history will be summarized 
separately by SOC and PT in a similar manner. 
The number of subjects with abnormal physical exam results at screening will be 
summarized and listed. 
 
. 
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PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will be summarized for the FAS.  For analysis purposes, 
the following definitions will be used to determine prior and concomitant medications for the 
entire study period: 
x Prior medications: Any medications taken and ended prior to the initial study drug 
administration date will be considered prior medications. 
x Concomitant medications: Any medications taken on or after the initial study drug 
administration date up to 30 days after discontinuation of study treatment will be 
considered concomitant medications and included in summary tables. This also 
includes medications initially taken prior to the initial study drug administration date 
but continued or ended on or after the initial study drug administration date. 
All medications will be included in 
 
Concomitant medications will be summarized for the overall study period, and a separate 
summary will be provided which includes only those concomitant medications that were 
initiated on study.  
All medications will be coded using the latest version available within BioMarin of the 
World Health Organization Drug (WHO Drug) dictionary (Version March 2019).  Prior and 
concomitant medication use will be separately summarized by Anatomical Therapeutic 
Chemical (ATC) medication class (Level 2) and preferred name (i.e., generic medication 
name). If a medication doesn’t have ATC level 2, they are grouped as “ATC Level 2 
classification unavailable”.  A subject reporting the same medication more than once will be 
counted once when calculating the number and percentage of subjects who received that 
medication.  
. 
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COMPLIANCE 
Treatment compliance will be calculated based on the study drug preparation and study drug 
administration records captured in the eCRF, and summarized by treatment group for the 
safety population. 
For each daily injection, the amount of study drug taken will be calculated as the number of 
units in the syringe pre-injection, minus the number of units remaining in the syringe 
post-injection.  If the number of units in the syringe pre-injection is not captured in the eCRF, 
then it will be assumed to be the same as the planned dose. 
The total amount of study drug taken will be calculated as the amount of study drug taken 
(units) in the corresponding treatment duration. 
The total amount of study drug planned is determined based on the duration of treatment, and 
the planned units per day. 
Percentage compliance for each subject will be derived from the total amount of study drug 
intake divided by the planned study drug intake, and multiplied by 100: 
Treatment Compliance (%) = 
்௢௧௔௟ ஺௠௢௨௡௧ ௢௙ ௌ௧௨ௗ௬ ஽௥௨௚ ்௔௞௘௡ (௨௡௜௧௦)
்௢௧௔௟ ஺௠௢௨௡௧ ௢௙ ௌ௧௨ௗ௬ ஽௥௨௚ ௉௟௔௡௡௘ௗ (௨௡௜௧ௌ) x 100 
 
Treatment compliance will be calculated and summarized by treatment group.  
x Compliance with protocol-specified treatment regimen (%) 
x Compliance with protocol-VSHFLILHGWUHDWPHQWUHJLPHQ
 
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EXTENT OF EXPOSURE TO STUDY DRUG 
Dosing information is recorded by subjects (in the paper diary) and also by the site on visit 
days.  In the case of duplicate records with the same date, if the investigator confirms the 
date, then investigator reported dosing data will be used.  All summaries will be based on the 
safety population, and presented by treatment group. 
The day of the first dose of study drug is referred to as Day 1.  A missed dose is defined as a 
calendar day without a dose between the date of Day 1 and date of last dose. 
Descriptive statistics will be provided for the following variables:  
x Duration of treatment (days) 
= Date of last dose – Date of first dose + 1 
x Total number of doses administered 
= Number of doses administered between date of Day 1 and date of last dose 
x Total number of doses missed 
= Number of doses missed between date of Day 1 and date of last dose 
x Total amount of weight adjusted dose administered (ug/kg) 
x Average weight-adjusted daily dose administered (ug/kg/day) 
The frequency and percent of subjects will be provided for the following variables, where 
missed doses are counted between the date of first dose (Day 1) and date of last dose: 
x Number of subjects who missed at least one dose 
x Number of subjects who missed more than one dose 
x Number of subjects who missed more than 5 consecutive doses 
x Number of subjects who missed more than 10 consecutive doses 
The frequency and percent of all missed doses will be provided for the following variable: 
x Reason for missed dose (Site Error, Parent/Caregiver Error, Home Health Error, 
Adverse Event, Other, Missing). 
. 
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14 
EFFICACY EVALUATIONS 
14.1 
General Approaches for Analyzing Growth Parameters 
All growth parameters assessed by anthropometric measurements are measured at Day 1, 
Week 13, Week 26, Week 39 and Week 52. 
Growth parameters are measured 3 times for each assessment. It is the mean of these 3 
assessments that are considered for the summaries and analyses. In the event that all 3 are not 
available, the mean of the 2, or the individual assessment is taken.  
All efficacy endpoints will be assessed using the FAS. In addition, the primary and key 
secondary endpoints (AGV, height Z-score, and upper to lower body segment ratio) will also 
be assessed using the PP population.   
Estimand formulations are provided for the primary and key secondary endpoints. 
Visit windows are applied for all assessments (see Section 5.4) and are used to summarize 
the growth measures by visit. 
Confirmatory statistical testing controlling for the Type I error rate is only performed on the 
primary analyses for the primary and two key secondary endpoints.  Beyond these analyses, 
there is no control for multiplicity, and p-values from additional analyses on these endpoints 
or testing of other endpoints are non-confirmatory. 
Unless otherwise specified, all growth parameter assessments are considered for inclusion in 
analyses, including those collected after treatment discontinuation.  Therefore, with respect to 
the intercurrent event of “rescue therapy received”, the assessments will be included for 
subjects who have received growth hormone or gonadotropin-releasing hormone or had limb 
lengthening; however the impact of these intercurrent events will be explored in 
supplementary analyses censoring the data prior to the interventions. 
With the exception of AGV (see Section 14.3.1), summary tables for all growth measures 
including height Z-score, upper to lower body ratio, body proportion ratios, growth measures 
(see Section 14.5.2), body mass index (BMI), BMI Z-scores and weight Z-scores will include 
assessments from both the 111-901 study and 111-301 studies at the following time points: 
x - 12 Months (111-901)  
x - 6 Months (111-901)  
x Baseline (111-301) 
x Week 26 (111-301) 
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x Week 52 (111-301). 
Each table will include summaries of the absolute measures at each of these time points, and 
change from baseline at Week 26 and Week 52 (applying visit windows).  The tables will 
summarize data by treatment group. These summaries are on continuous data and will 
include the number of subjects with assessments, mean, SD, median, 25th and 75th percentile, 
minimum and maximum. 
Results of the statistical analyses will be provided in separate tables, including the least-
squares (LS) mean change from baseline at Week 52 for each treatment group, the treatment 
difference in LS means (calculated as BMN 111 – Placebo), the 95% confidence interval (CI) 
for the treatment difference, and corresponding 2-sided p-value. 
ANCOVA models will be used to determine the treatment difference at 52 weeks.  Unless 
otherwise specified, all models include the following baseline covariates: 
x Treatment group 
x Stratum: (Male Tanner Stage I, Female Tanner Stage I, Male Tanner Stage >I, 
Female Tanner Stage >I) 
x Age at baseline 
x AGV at baseline 
x Height Z-score at baseline 
Note: If a subject is incorrectly assigned to a stratum at the time of randomization, they will 
be analyzed according to their actual sex and Tanner stage.   
Subgroup analyses will only be performed for the primary analyses of the primary and key 
secondary endpoints (see Section 14.7). 
 will include the mean values used in analyses and summaries, and will be ordered by 
treatment group, subject and visit date.  An additional 
 of standing height will include 
all assessments (i.e., individual measures and means of the measures). 
14.2 
Statistical Testing 
The overall type I family-wise error rate for testing the primary and key secondary efficacy 
endpoints will be controlled at the 0.05 significance level using the following 3-step serial 
gatekeeping multiple comparisons procedure (MCP).  Following this MCP, advancement to 
the next step will only occur if the null hypotheses within a step and the previous step(s) are 
all rejected at the significance level of 0.05 in favor of BMN 111. If any null hypothesis 
within a step is not rejected or is rejected but not in favor of BMN 111, the hypothesis tests 
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corresponding to all subsequent steps will not be considered confirmatory. All hypothesis 
tests will be two-sided. 
1. The first step will be the test comparing the BMN 111 group to the placebo group for 
the primary efficacy endpoint, the change from baseline in AGV at Week 52 time 
point. If the null hypothesis is not rejected (i.e., p-value > 0.05) or is rejected but not 
in favor of BMN 111, all subsequent statistical tests will not be considered 
confirmatory. The study is considered positive if the primary test is significant in 
favor of BMN 111.  
2. The second step will be the test comparing the BMN 111 group to the placebo group 
for the secondary efficacy endpoint, the change from baseline in height Z-score at 
Week 52 time point. If the null hypothesis is not rejected (i.e., p-value > 0.05) or is 
rejected but not in favor of BMN 111, the subsequent statistical test will not be 
considered confirmatory.  
3. The third step will be the tests comparing the BMN 111 group to the placebo group 
for the secondary efficacy endpoint, the change from baseline in upper:lower body 
segment ratio at Week 52 time point at a significance level of 0.05.  
14.3 
Primary Efficacy Endpoint 
The primary efficacy objective is to evaluate the change from baseline in annualized growth 
velocity (AGV) at 52 weeks in subjects treated with BMN 111 compared with control 
subjects in the placebo group.  
14.3.1 Annualized Growth Velocity 
The primary efficacy endpoint is the change from baseline in AGV at the Week 52 
(12-month) time point.  For a given interval [Date1, Date2], the AGV is defined as follows: 
AGV (cm/yr) = 
ௌ௧௔௡ௗ௜௡௚ ு௘௜௚௛௧ ௔௧ ஽௔௧௘ ଶିௌ௧௔௡ௗ௜௡௚ ு௘௜௚௛௧ ௔௧ ஽௔௧௘ ଵ
ூ௡௧௘௥௩௔௟ ௅௘௡௚௧௛ (஽௔௬௦)
 x 365.25 
where the interval length in days is calculated as Date2 - Date1. 
AGV (cm/yr) will be calculated for the following visits: 
x Baseline: [Date of last height measurement in study 901 at least 6 months prior to 
Date of Day 1 visit in study 111-301, Date of Day 1] 
x Week 13: [Date of Day 1, Date of Week 13] 
x Week 26: [Date of Day 1, Date of Week 26] 
x Week 39: [Date of Day 1, Date of Week 39] 
x Week 52 (12-month): [Date of Day 1, Date of Week 52] 
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The baseline AGV is established in the observational run-in Study 111-901, based on the 
standing height measurements at least 6 months prior to enrollment to Study 111-301.  
The absolute values for AGV at Baseline, Week 26 and Week 52, and change from baseline 
at Week 26 and Week 52 will be summarized (n, mean, SD, median, 25th and 75th percentile, 
minimum, maximum) and presented by treatment group. 
A box and whisker plot will be provided for AGV (cm/yr) over time (Baseline, Week 26, and 
Week 52) for each treatment group. 
In addition, for the visits at Baseline, Week 26, and Week 52, scatter plots will be provided 
by sex and treatment group for (1) AGV by age at visit and (2) AGV by Tanner stage (I, II, 
III, IV, V) (using breast Tanner Stage for females, and genitalia Tanner Stage for males) at 
visit. 
AGV listings will include AGV for all height assessments at all scheduled visits. 
14.3.2 Primary Analysis Method 
Some aspects of the primary and other analyses for AGV have been revised relative to the 
protocol, based on interactions with health authorities and blinded data review. 
The primary analysis method described below is based on the protocol, but adds criteria 
necessary for the multiple imputation to be applicable. In case it cannot be applied, an 
alternative approach for imputing missing assessments is described.  Revisions have also 
been made to the sensitivity analyses defined in the protocol (see Section 14.3.3). 
The following primary hypothesis will be tested (two-tailed): 
H0: Difference in mean AGV change from baseline at week 52 between BMN 111 
group and the placebo group = 0 
Ha: Difference in mean AGV change from baseline at week 52 between BMN 111 
JURXSDQGWKHSODFHERJURXS 
The estimand formulation is as follows: 
x Population: FAS  
x Variable: Change from baseline in AGV at 52 weeks  
x Intercurrent event: Regardless of whether or not switching to rescue medication had 
occurred or subjects had discontinued from the study. 
x Population-level summary: Difference in estimated means between the treatment 
groups 
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The estimators for each of the analyses are defined in the relevant sections. 
Subjects who discontinue from study drug will be encouraged to remain in the study and 
their non-missing height measurements will continue to be used in calculating the AGV.  In 
the event that missing data does occur despite all efforts, missing standing height will be 
imputed based on multiple imputation (MI) with pattern-mixture models (Little 1993; 
Molenberghs and Kenward 2007, pp. 30, 34-37) implemented in PROC MI of SAS where the 
missing, unobserved observations of the standing height are assumed to follow a missing not 
at random (MNAR) mechanism.  Each imputation will require at least 5 subjects in the same 
treatment group who also discontinue treatment prematurely at a similar time point (i.e. no 
more than a 90 day difference between the last dose dates) and have standing height 
assessments post treatment discontinuation.  This is referred to as off-treatment data, and the 
data for these subjects with standing height assessments post treatment discontinuation will 
be used as the reference data in the MNAR statement within PROC MI. 
PROC MI will be used to impute missing standing height assessments at Week 52.  A 
regression method will be applied with the fully conditional specification (FCS) which can 
handle both monotone and non-monotone missing standing height data patterns.  The 
baseline covariates for age, strata, height Z-score and AGV and standing height will be 
included in the VAR statement along with the post-baseline standing height assessments 
(including off-treatment assessments) at Week 13, 26, 39 and 52.  Missing Week 52 standing 
height assessments will then be imputed from the subjects with reference data (as defined 
above) using the missing not at random (MNAR) option. 
A fixed seed of 5122019 will be specified to ensure reproducibility of the results and the 
number of imputations set to 10.   
In each of the imputed datasets, missing AGV at Week 52 and the corresponding missing 
change from baseline in AGV will be calculated using the imputed standing height.  Note, 
missing height Z-scores at Week 52 and the corresponding change from baseline will also be 
calculated.  For each subject whose missing Week 52 value is imputed, the 10 imputed 
values will be provided in a data listing that will be included in the appendix of the CSR.    
Each of the 10 imputed datasets will be analyzed using an ANCOVA model that includes the 
following fixed-effect terms: 
x Treatment group 
x Stratum (Male Tanner Stage I, Female Tanner Stage I, Male Tanner Stage >I, Female 
Tanner Stage >I) 
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x Baseline age 
x Baseline AGV  
x Baseline height Z-score  
SAS PROC MIXED will be used to perform the analysis. 
PROC MIXED; 
CLASS Stratum Treatment; 
MODEL Change from baseline in AGV at Week 52 = Baseline_Age Baseline_AGV 
Baseline_Height_Z-Score Treatment Stratum; 
LSMEANS Treatment / DIFF = control (“Placebo”) CL; 
RUN; 
For each imputed dataset, PROC MIXED will generate the least-squares (LS) mean change 
from baseline in AGV at Week 52 for each treatment group, along with the difference in LS 
means (calculated as BMN 111 – Placebo).  PROC MIANALYZE will then be used to 
combine all of the estimates across the 10 imputed datasets in order to generate an overall 
estimate for each treatment group, and for the difference between treatment groups, with a 
95% confidence interval for the difference and 2-sided p-value.  The study will be considered 
positive if the 2-sided p-value in favor of BMN 111 is <0.05. 
If there are less than 5 subjects with reference data as defined above then missing standing 
height at Week 52 (i.e. Day 365) will be imputed by applying the baseline AGV (cm/yr) to 
the last available height assessment as follows:  
Standing Height at Day 365 =  
Last Assessed Height + 
஺ீ௏ ௔௧ ஻௔௦௘௟௜௡௘
ଷ଺ହ.ଶହ
 x (365 - Study Day of Last Height Assessment) 
Based on this imputed standing height, the height z-score and AGV at Week 52 will be 
calculated.  The ANCOVA model will then be applied to AGV at Week 52.  
In the event that there are no subjects who discontinue treatment early with a missing 
assessment at Week 52 the ANCOVA model will be applied without any imputation. 
This ANCOVA model analysis without imputation will be repeated on the PP population. 
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14.3.3 Sensitivity and Supplementary Analyses Defined for AGV 
The following sensitivity and supplementary analyses are proposed for assessing the 
robustness of the results of the primary analysis.  All visits referred to in the analyses, are 
based on the analysis windows described in Section 5.4.  Summary tables for the models and 
descriptive summary statistics tables will be provided for each sensitivity analysis. 
Sensitivity Analysis: Washout model where missing data for an endpoint for both 
treatment groups will be imputed using data from the placebo arm.  
This approach addresses the same estimand as the primary analysis but with an alternative 
estimator. Employing this model, any potential BMN 111 treatment effect in those patients in 
the BMN 111 active group who are off-treatment will be washed out.  Specifically, for the 
washout imputation, the missing data in an endpoint for both treatment groups will be 
imputed using observed endpoint data from the placebo arm.  
PROC MI will be used to impute the missing standing height assessments at Week 52, as 
described for the primary analysis.  However, for this analysis, according to the washout 
specifications, only placebo data (including off treatment assessments) will be used in the 
missing not at random (MNAR) option to implement the control-based pattern imputation.  
Therefore, for the subjects in the BMN 111 active treatment group, no observed post baseline 
assessments will be considered in the imputation process. 
Supplementary Analysis 1: ANCOVA model on completers.  
This approach addresses the same estimand as the primary analysis, except that the 
intercurrent event is defined as subject discontinuation from the study. In this analysis, the 
estimator will be the difference between the two randomized groups in the mean change from 
baseline in AGV at Week 52, observed from subjects who have non-missing AGV 
observation at 52 weeks.  The LS means of the change from baseline in AGV at 52 weeks 
will be estimated for both the randomized groups by applying the ANCOVA model without 
multiple imputation described in the primary analysis.  In this analysis, only subjects with 
observed AGV change from baseline at 52 weeks will be included.  No imputation will be 
performed for missing 52-week standing height measurements.  
Supplementary Analysis 2: ANCOVA model excluding assessments that occur post 
either limb lengthening or growth hormone/gonadotropin-releasing hormone.  
This approach addresses the same estimand as the primary analysis except that the 
intercurrent event, defined as rescue treatment for achondroplasia, is handled differently. In 
the event that a subject has been receiving rescue medication from the start of the study, they 
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will be excluded from this supplementary analysis.  The analysis will be conducted on 
imputed data, as described for the primary analysis; however, any assessments that are 
measured following either limb lengthening or growth hormone/ gonadotropin-releasing 
hormone will be excluded from this analysis. The ANCOVA model described in the primary 
analysis will be applied, and the estimator will be the difference between the two randomized 
groups in the mean change from baseline in AGV at Week 52.   
14.4 
Key Secondary Efficacy Endpoint(s) 
The two secondary efficacy endpoints with confirmatory testing (referred to in this document 
as “key secondary endpoints”) are the change from baseline at Week 52 in height Z-score 
and the change from baseline at Week 52 in upper to lower body segment ratio.  
14.4.1 Height Z-Score 
Standing height is measured at Screening, Day 1, Week 13, Week 26, Week 39, and 
Week 52.  Each measurement of standing height will be converted to an age-and 
sex-appropriate standard deviation score (SDS), also referred to as a Z-score, by comparison 
with reference data available for average stature children from the Centers for Disease 
Control and Prevention (CDC).   
The following key secondary hypothesis will be tested (two-tailed): 
H0: Difference in mean height Z-score change from baseline at week 52 between 
BMN 111 group and the placebo group = 0 
Ha: Difference in mean height Z-score change from baseline at week 52 between 
%01JURXSDQGWKHSODFHERJURXS 
Height Z-score will be analyzed using the same methods and estimand formulation as the 
primary analysis.  If multiple imputation is applied for testing the primary endpoint then the 
null hypothesis of no difference between the BMN 111 group and the placebo group in the 
mean change from baseline in the height Z-score at the Week 52 time point will also be 
tested based on 10 imputed data sets.  Missing height Z-score at Week 52 will be calculated 
from the imputed standing height at this visit, as described for the primary endpoint.  If 
multiple imputation is not applied for the primary endpoint, then the Week 52 height Z-score 
will be imputed as described above in Section 14.3.2.   
SAS PROC MIXED will be used to test the null hypothesis using an ANCOVA model 
described below. 
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PROC MIXED; 
CLASS Stratum Treatment; 
MODEL Change from baseline in Height Z-score at Week 52 = Baseline_Age 
Baseline_AGV Baseline_Height_Z-score Treatment Stratum; 
LSMEANS Treatment / DIFF= control (“Placebo”) CL; 
RUN; 
The least-squares (LS) mean change from baseline in height Z-score at Week 52 will be 
presented for each treatment group, along with the difference in LS means (calculated as 
BMN 111 – Placebo), the 95% confidence interval for the difference, and 2-sided p-value.  In 
the event that the primary endpoint test is positive, the testing on the key secondary is 
considered to be confirmatory. The endpoint is considered positive if the 2-sided p-value in 
favor of BMN 111 is < 0.05. 
This analysis will be repeated on the PP population, using the same approach as described for 
the primary endpoint.  In addition, the sensitivity and supplementary analyses of height 
Z-score [described in section 14.3.3] will be performed using the FAS population.  
Summary tables are provided as described in Section 14.1.  In addition, a line plot of the 
mean (+/-SD) height Z-score will be presented foUYLVLWV0RQWKV3ULRU Months 
Prior, Baseline, Week 26 and Week 52 by treatment group.  
Height Z-scores derived for all visits will be included in data listings. 
14.4.2 Upper to Lower Body Segment Ratio 
Standing height and sitting height are measured at Screening, Day 1, Week 13, Week 26, 
Week 39, and Week 52. 
The upper to lower body segment ratio will be calculated at each visit as follows: 
Upper to Lower Body Segment Ratio = 
ௌ௜௧௧௜௡௚ ௛௘௜௚௛௧(௖௠)
ௌ௧௔௡ௗ௜௡௚ ௛௘௜௚௛௧(௖௠)ିௌ௜௧௧௜௡௚ ௛௘௜௚௛௧(௖௠) 
The upper to lower body segment ratio at Baseline, Week 26 and Week 52, and it’s change 
from baseline at Week 26 and Week 52 will be summarized (n, mean, SD, median, 25th and 
75th percentile, minimum, maximum) and presented by treatment group.  Figures will be 
provided as described in Section 14.1. 
The following key secondary hypothesis will be tested (two-tailed): 
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H0: Difference in mean upper:lower body segment ratio change from baseline 
at week 52 between BMN 111 group and the placebo group = 0 
Ha: Difference in mean upper:lower body segment ratio change from baseline 
at week 52 EHWZHHQ%01JURXSDQGWKHSODFHERJURXS 
The upper to lower body segment ratio will be analyzed using the same methods and 
estimand formulation as the primary analysis.  The primary analysis of the upper to lower 
body segment ratio will be assessed on the FAS.  If MI methods are used to impute Week 52 
results for the primary endpoint (AGV), then the same MI approach will be used to impute 
missing Week 52 upper to lower body segment ratios.  Missing sitting height at Week 52 will 
be imputed in the same manner as missing standing height, using PROC MI.  Missing upper 
to lower body segment ratios Week 52 will be calculated from the imputed values for sitting 
and standing height.  The difference between the BMN 111 group and the placebo group in 
the mean change from baseline in the upper:lower body segment ratio at Week 52 will be 
tested based on 10 imputed data sets.  
If multiple imputation is not applied for the primary endpoint, then missing sitting height and 
standing height at Week 52 will be imputed by applying the baseline AGV for sitting height 
and standing height to the last available sitting/standing height assessment (as described in 
Section 14.3.2).  Based on this imputed sitting height and standing height at Week 52, the 
upper:lower body segment ratio will be calculated, and the model described above will then 
be applied at Week 52.  
SAS PROC MIXED will be used to test the null hypothesis using an ANCOVA model 
described below. 
PROC MIXED; 
CLASS Stratum Treatment; 
MODEL Change from baseline in upper:lower body segment ratio at Week 52 = 
Baseline_Upper:Lower Body_Segment_Ratio Baseline_Age Baseline_AGV 
Baseline_Height_Z-score Treatment Stratum; 
LSMEANS Treatment /DIFF = control (“Placebo”) CL; 
RUN; 
The least-squares (LS) mean change from baseline in upper to lower body segment ratio at 
Week 52 will be presented for each treatment group, along with the difference in LS means 
(calculated as BMN 111 – Placebo), the 95% confidence interval for the difference, and 
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2-sided p-value.  In the event that the height Z-score endpoint test is positive, the testing on 
this key secondary endpoint is considered to be confirmatory. The endpoint is considered 
positive if the 2-sided p-value in favor of BMN 111 is < 0.05. 
This analysis will be repeated on the Per Protocol population.  In addition, the sensitivity and 
supplementary analyses of upper to lower body segment ratio [described in Section 14.3.3] 
will be performed using the FAS population.  
A line plot of the mean (+/-SD) upper to lower body segment ratio will presented at 
 12 0RQWKV3ULRU0RQWKV3ULRU%DVHOLQH:HHNDQG:HHNWLPHSRLQWVE\
treatment group.  
All upper to lower body segment ratios will be listed alongside the standing and sitting 
height. 
14.5 
Other Secondary Efficacy Endpoint(s) 
Any p-values resulting from analyses of these secondary efficacy endpoints are 
non-confirmatory. 
14.5.1 Body Proportion Ratios 
Body measurements are taken at Screening, Day 1, Week 13, Week 26, Week 39, and 
Week 52.  Each of the body proportion ratios below will be calculated to 2 decimal places. 
x Upper Arm Length to Lower Arm (Forearm) Length Ratio 
x Upper Leg Length (Thigh) to Knee to Heel Length Ratio 
x Upper Leg Length (Thigh) to Tibial Length Ratio 
x Arm Span to Standing Height Ratio 
The absolute values at  0RQWKV3ULRU0RQWKV3ULRUBaseline, Week 26 and 
Week 52, and change from baseline at Week 26 and Week 52 will be summarized (n, mean, 
SD, median, 25th and 75th percentile, minimum, maximum) and presented by treatment 
group. 
A line plot of the mean (+/-SD) each body proportion ratio will be SUHVHQWHGDW0RQWKV
3ULRU0RQWKV3ULRU%DVHOLQH:HHNDQG:HHNWLPHSRLQWVE\WUHDWPHQWJURXS 
Box plots of each ratio at Week 52 will be provided by treatment group. 
All assessments will be listed by treatment group, subject and visit. 
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Analysis: 
No imputation will be applied for missing Week 52 assessments.  Analyses will be based on 
observed data only, and SAS PROC MIXED will be used to test the null hypothesis of no 
treatment difference using an ANCOVA model described below, for each of the above body 
proportion ratios. 
PROC MIXED; 
CLASS Stratum Treatment; 
MODEL Change from baseline in body proportion ratio at Week 52 = 
Baseline_body proportion ratio Baseline_Age Baseline_AGV Baseline_Height_Z-
score Treatment Stratum; 
LSMEANS Treatment /DIFF = control (“Placebo”) CL; 
RUN; 
For each body proportion ratio, the least-squares (LS) mean change from baseline at 
Week 52 will be presented for each treatment group, along with the difference in LS means 
(calculated as BMN 111 – Placebo), the 95% confidence interval for the difference, and 
2-sided p-value. 
14.5.2 Growth Measures 
Each of the following anthropometric growth measures are recorded at Screening, Day 1, 
Week 13, Week 26, Week 39, and Week 52: 
x Standing Height (cm) 
x Sitting Height (cm) 
x Upper Leg Length (Thigh) (cm) 
x Knee to Heel Length (cm) 
x Tibial Length (cm) 
x Head Circumference (cm) 
x Upper Arm Length (cm) 
x Lower Arm (Forearm) Length (cm) 
x Arm Span (cm) 
In addition, a measure of lower body length will be calculated as follows: 
x Lower Body Length (cm) = Standing height – Sitting height 
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Baseline growth measures are those assessed on Day 1, regardless of timing relative to 
dosing.  All summaries and analyses will be based on the FAS. 
For each of the above growth measures (including lower body length), the absolute values at 
0RQWKV3ULRU0RQWKV3ULRUbaseline, Week 26 and Week 52, and change from 
baseline at Week 26 and Week 52, will be summarized (n, mean, SD, median, 25th and 
75th percentile, minimum, maximum) and presented by treatment group for each baseline age 
FDWHJRU\WRWRWRWR\HDUV 
Analysis: 
Subjects with missing standing height at Week 52 will have standing height imputed, as 
described in Section 14.3.2.  The same approach will be applied for missing sitting height 
assessments at Week 52. 
With the exception of sitting height and standing height, no imputation will be applied for 
missing Week 52 assessments.  Analyses will be based on observed data only.  
For each growth measure, the null hypothesis of no difference between the BMN 111 group 
and the placebo group in the mean change from baseline at the Week 52 visit will be tested. 
SAS PROC MIXED will be used to test the null hypothesis of no treatment difference using 
an ANCOVA model described below, for each of the above growth measures. 
PROC MIXED; 
CLASS Stratum Treatment; 
MODEL Change from baseline in growth measure at Week 52 = 
Baseline_growth_measure Baseline_AGV Baseline_Height_Z-score Treatment 
Stratum; 
LSMEANS Treatment /DIFF CL; 
RUN; 
For each growth measure, the least-squares (LS) mean change from baseline at Week 52 will 
be presented for each treatment group, along with the difference in LS means (calculated as 
BMN 111 – Placebo), the 95% confidence interval for the difference, and 2-sided p-value. 
Spaghetti plots of standing height will be provided by treatment group and sex. These 8 plots 
will include age-sex specific reference ranges for average stature children (from the Centers 
for Disease Control and Prevention (CDC)) and age-sex specific reference ranges for short 
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stature children (Hoover-Fong et al).  All assessments will be included, including all height 
assessments collected in the 901 study XSWRWKHPRQWKVSULRUDQDO\VLVYLVLW. 
All assessments will be listed by treatment group, subject and visit. 
14.5.3 Body Mass Index 
Weight (kg) and standing height are collected at Screening, Day 1, Week 13, Week 26, 
Week 39, and Week 52. 
Body Mass Index (BMI) will be calculated at each visit as: 
Body Mass Index (kg/m2) = 
ௐ௘௜௚௛௧ (௞௚)
ு௘௜௚௛௧ (௠)ଶ 
Each measurement of BMI will be converted to an age-and sex-appropriate standard 
deviation score (SDS), also referred to as a Z-score, by comparison with reference data 
available for average stature children from the Centers for Disease Control and Prevention 
(CDC). 
The absolute values at Baseline, Week 26 and Week 52, and change from baseline at 
Week 26 and Week 52 will be summarized (n, mean, SD, median, 25th and 75th percentile, 
minimum, maximum) and presented by treatment group for both BMI and BMI Z-Score. 
All assessments will be listed by treatment group, subject and visit. 
14.5.4 Weight Z-Scores 
Weight (kg) is measured at Screening, Day 1, Week 13, Week 26, Week 39, and Week 52.  
Each measurement of weight will be converted to an age-and sex-appropriate standard 
deviation score (SDS), also referred to as Z-score, by comparison with reference data 
available for average stature children from the Centers for Disease Control and Prevention 
(CDC). 
The weight of the subject on Day 1 will be used as the baseline measure, regardless of 
whether this is recorded pre or post-dose. 
The absolute values at Baseline, Week 26 and Week 52, and change from baseline at 
Week 26 and Week 52 will be summarized (n, mean, SD, median, 25th and 75th percentile, 
minimum, maximum) and presented by treatment group.  
All assessments will be listed by treatment group, subject and visit. 
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14.5.5 Health-Related Quality of Life and Functional Independence 
The Health-Related Quality of Life (HRQoL) questionnaires and functional independence 
questionnaires are captured at Screening, Week 26 and Week 52.  All summaries will be 
generated on the FAS. 
Each table will include summaries of the absolute measures at each of these time points, and 
change from baseline at Week 26 and Week 52. The tables will be summarized by treatment 
group.  
The statistical summaries will include the number of subjects with assessable data, mean, SD, 
median, 25th and 75th percentile, minimum and maximum. Subjects will not be included in a 
summary table if there is no baseline assessment available.  
Separate summary tables will be provided for the total summary scores and the individual 
domains (scales). Individual questions (items) are not included in the summary tables. 
Specific domains that are not considered clinically meaningful for the ACH indication are 
indicated. 
Age defined versions within the same questionnaire will be summarized together. If a subject 
progresses during the course of the study from one age defined questionnaire to the next age 
defined questionnaire the results will be summarized together and the baseline assessment 
from the child’s first questionnaire is referred to when summarizing change from baseline. 
Self-reports and parent-reports will be summarized separately. 
All subject data listings will include total scores, and domain (scale) scores. 
14.5.5.1 
Pediatric Quality of Life Inventory (PedsQL) 
The PedsQL scales were designed to measure the core dimensions of health, as delineated by 
the WHO, as well as role (school) functioning.  The following versions of the PedsQL are 
utilized in this protocol: 
Parent/Caregiver Reported 
x Parent Proxy-Report Children Ages 5-7 
x Parent Proxy-Report Children Ages 8-12 
x Parent Proxy-Report Adolescents Age 13-18  
Self-Reported 
x Child Self-Report Ages 8-12 
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x Adolescent Self-Report Ages 13-18 
The PedsQL consists of 4 scales of functioning (Physical, Emotional, Social, and School), 
which make up 3 summary scores. 
Each of the items within a scale is scored as 0 (never a problem), 1 (almost never a problem), 
2 (sometimes a problem), 3 (often a problem), to 4 (almost always a problem).  Items are 
then reverse scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 
3=25, and 4=0. 
Scales/Domains: 
x Physical Functioning (8 items, min score=0, max score=800) 
x Emotional Functioning (5 items, min score=0, max score=500) 
x Social Functioning (5 items, min score=0, max score=500) 
x School Functioning (5 items, min score=0, max score=500) 
If at least 50% of items are completed within a scale, then the mean score is calculated for 
each scale using the transformed values: 
Scale/Domain Score =  
ௌ௨௠ ௢௙ ௜௧௘௠ ௦௖௢௥௘௦
ே௨௠௕௘௥ ௢௙ ௜௧௘௠௦ ௔௡௦௪௘௥௘ௗ 
If more than 50% of the items are missing within a scale, then scale scores should not be 
calculated and be set to missing. (Varni, 1999) 
For each of the scales, the mean scores (based on transformed values), and change from 
baseline at each scheduled visit, will be summarized (n, mean, SD, median, 25th and 
75th percentile, minimum, maximum) by treatment group. 
Summary scores: 
In addition to the mean scale scores, the following summary scores will be calculated.  All 
calculations use the transformed data. 
x Psychosocial Health Summary Score (Sum of item scores/Number of items answered 
on Emotional, Social and School scales) 
x Physical Health Summary Score (Sum of item scores/Number of items answered on 
Physical scale) 
x Total Score (Mean Score, i.e., Sum of all items/Number of items answered on all 
scales) 
For each of the above summary scores, the absolute values, and change from baseline at each 
scheduled visit, will be summarized (n, mean, SD, median, 25th and 75th percentile, 
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minimum, maximum) and presented by treatment group. These scores are based on the 
transformed values. 
Domain (scale) scores and summary scores will be listed by treatment group, subject and 
visit date. 
14.5.5.2 
Quality of Life in Short Statured Youth (QoLISSY)  
The QoLISSY for parents, and the version for children and adolescents, consists of 
22 likert-scaled items assigned to the core QoL dimensions: Physical, Social and Emotional, 
and 14 additional items in the dimensions Coping and Beliefs.  In addition, the 
parent-reported version captures data on Future and Effects on parents. 
The two versions of the questionnaire being used in this study are: 
Parent/Caregiver Reported 
x QoLISSY parent version for short stature (4-18) 
Self-Reported 
x QoLISSY child version (patient reported >= 8 years) 
In both versions of the questionnaire, scoring is assigned to each individual item/question, 
according to whether the question is positively or negatively worded.  Positively worded 
items are scored 1, 2, 3, 4, 5 (1: not at all/never, 2: very/very often, 3: moderately/quite often, 
4: slightly/seldom, 5: extremely/always).  Negatively worded items are reverse scored 5, 4, 3, 
2, 1 (5: not at all/never to 1: extremely/always) so that a higher subscale score reflects higher 
quality of life. 
Each of the questions are assigned to domains. 
Domains 
The following domains are common to both the parent and child versions of the QoLISSY: 
x Physical (6 items) 
x Social (8 items) 
x Emotional (8 items) 
x Coping (10 items) 
x Belief (4 items) 
The parent-report version contains additional items from two parent-only domains. 
x Future (5 items) 
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x Effects on parent (10 items, excluding growth hormone question.) 
For each QoLISSY domain, the individual raw scores are summed to determine the raw 
domain total score.  In order to calculate a domain score, 80% of the items must be 
completed (Bullinger 2015). 
The QoLISSY raw domain total scores are then transformed to standard scores on a scale of 
0-100 to allow for easier comparison from one measure to another.  A score closer to 0 is 
indicative of poor quality of life and higher scores closer to 100 are indicative of a higher 
quality of life. 
For each domain, the raw mean is transformed to a standard score as follows: 
ܦ݋݉ܽ݅݊ ݐݎܽ݊ݏ݂݋ݎ݉݁݀ ݏܿ݋ݎ݁=   (ܴܽݓ ܯ݁ܽ݊െ1)
4
ݔ 100  
For each domain, the absolute values of the transformed scores, and change from baseline at 
each scheduled visit, will be summarized (n, mean, SD, median, 25th and 75th percentile, 
minimum, maximum) and presented by treatment group. 
Summary Scores 
The QoLISSY Total Score is calculated by summing the means in the physical, social, and 
emotional subscales and dividing by 3. The absolute value of the Total Score, and change 
from baseline at each scheduled visit, will be summarized (n, mean, SD, median, 25th and 
75th percentile, minimum, maximum) and presented by treatment group. 
Domain (scale) scores and summary scores will be listed by treatment group, subject and 
visit date. 
14.5.5.3 
Functional Independence Measure (WeeFIM) 
The WeeFIM (Functional Independence Measure for children) instrument is a functional 
independence assessment tool that measures functional performance across three domains 
(self-care, mobility and cognition) from the caregiver’s perspective. 
Performance of a child on each of the individual items within the WeeFIM is assigned to one 
of seven levels on an ordinal scale that represent the function from complete and modified 
independence (levels 7 and 6) without a helping person to modified and complete 
dependence (levels 5 to 1) with a helping person. 
If individual items (questions) within a domain are missing, the item result is imputed to 1, 
per guidance in The WeeFIM Clinical Guide v 6.49. 
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If all items for a domain score are missing the domain score will be considered missing, and 
the Total score will not be calculated. 
For each of the following domains and the total score, the absolute values at each scheduled 
visit, and change from baseline at each scheduled visit, will be summarized (n, mean, SD, 
median, 25th and 75th percentile, minimum, maximum) by treatment group: 
x Self-care Score (min score=8, max score=56) 
x Mobility Score (min score=5, max score =35) 
x Cognition Score (min score=5, max score=35) 
x Total WeeFIM rating (min=18, max=126) 
Domain and total scores will be listed by treatment group and subject number. 
Note: Although each domain will be summarized so that all aspects of this validated scale are 
reported, the cognition aspect of the WeeFIM (cognition subtotal score) is considered not to 
be of concern for subjects with achondroplasia. 
14.6 
Exploratory Endpoints 
14.6.1 Sleep Study Scores 
An optional sleep sub-study will be performed in a limited number of qualified sleep centers 
for a subset of subjects.  A sleep-testing device will be used to assess the presence and 
severity of sleep-disordered breathing by measurement of blood oxygen saturation, pulse 
rate, and airflow during overnight monitoring.  Sleep study data is collected at Screening, and 
Week 52. 
Due to a small number of subjects enrolled in the optional sleep study (n=8) only listings of 
episodes of sleep apnea will be provided.  These listings will include: 
x Number of episodes of apnea per hour (Apnea Index).   
x Number of episodes of hypopnea per hour (Hypopnea Index).  
x Number of episodes /Duration of obstructive apneas 
x Number of episodes /Duration of central apneas 
x Number of episodes /Duration of mixed apneas 
x Number of episodes /Duration of obstructive hypopneas 
x Number of desaturations 
All parameters collected in the sleep study will be listed. 
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14.7 
Examination of Efficacy by Subgroups 
Subgroup analyses will be conducted on the primary and two key secondary efficacy 
endpoints, and will be based on the imputed data described for the primary analysis.  Only 
subgroup categories with sufficient data will be analyzed.  The ANCOVA model described in 
Section 14.3.2 will be applied separately for each category within a subgroup. 
A Forest plot will provide an overall summary, and for each subgroup category, the 
difference between treatment group LS means (estimated as BMN 111-placebo), and the 
95% confidence interval for the difference, at Week 52. 
Subgroup categories of interest include: 
x Sex (Male, Female) 
x Age at Baseline WRWRWRWR\HDUV 
x Tanner stage at Baseline (I, >I) 
x Stratum (Male Tanner Stage I, Female Tanner Stage I, Male Tanner Stage >I, Female 
Tanner Stage >I). 
x Baseline Height Z-Score (- 6, > -WR-5, > -WR-4, > -4) 
x %DVHOLQH$*9!WR! cm/yr) 
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15 
SAFETY EVALUATIONS 
The safety population will be used for all summaries where assessments/events are reported 
by treatment group. 
Summary tables will include all safety events up to 30 days following treatment 
discontinuation.  
 
Safety will be assessed by examining the incidence, severity (determined using the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4), and relationship to study drug 
of all treatment-emergent adverse events (TEAEs) reported during the study period.  In 
addition, changes from baseline in clinical laboratory results and vital signs will be assessed. 
15.1 
Adverse Events 
Adverse events (AEs) will be coded in accordance with Medical Dictionary for Regulatory 
Activities (MedDRA) Version 22.  MedDRA coding will be performed prior to database 
lock.  Coding of the severity of adverse events is performed by the investigators using NCI 
CTCAE version 4, where events are coded from CTCAE Grade 1 to Grade 5.  
Only treatment-emergent adverse events (TEAEs) defined as any adverse event that newly 
appeared, increased in frequency, or worsened in severity following initiation of study drug 
administration are reported by the investigators and consequently are included in the 
summary tables. 
In the event that the start date of an AE is incomplete or missing, conservative imputation 
rules are applied so that where there is uncertainty, the event is considered treatment 
emergent. Similarly the AE end dates are imputed in a conservative manner to a maximum 
length (Section 5.5.1). 
15.1.1 Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) will be summarized by treatment group.  In 
summaries by system organ class (SOC) and/or preferred term (PT), subjects with more than 
one AE of the same SOC or PT will be counted once within that SOC/PT.  The tables are 
ordered by the frequency of the highest reporting level (SOC or PT) in the table within the 
active treatment group.   
The following summary tables will be provided: 
x Overview of the incidence of adverse events 
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x Incidence and exposure-adjusted event rates of TEAEs by system organ class (SOC), 
preferred term (PT) and CTCAE grade 
x Incidence of TEAEs by system organ class (SOC), preferred term (PT) and highest 
CTCAE grade 
x Incidence and exposure-adjusted event rates of TEAEs by PT 
x Incidence and exposure-adjusted event rates of TEAEs by SOC 
x Incidence and exposure-adjusted event rates of drug-related TEAEs by SOC, PT and 
CTCAE grade 
x Incidence of serious adverse events (SAEs) by SOC and PT 
x Incidence of TEAEs leading to study or study drug discontinuation by PT 
x Incidence of TEAEs leading to study drug interruption by PT 
x Incidence of TEAEs leading to study drug dose reduction by PT 
x Incidence and exposure-adjusted event rates of achondroplasia-related TEAEs by 
SOC and PT* 
* Achondroplasia-related TEAE’s will be identified using the PT’s identified for 
achondroplasia-related medical history (see Section 10).  In addition, all AEs will be 
reviewed prior to database lock and the list updated as required. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15.1.2 Events of Interest 
Events of interest (EOI) will be summarized by PT and treatment group.   
The following are identified as events of interest: 
Injection site reactions (ISR) 
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x TEAEs with a MedDRA High Level Term (HLT) of “Injection site reaction”. 
Hypotension 
x TEAEs with PT: Blood pressure ambulatory decreased, Blood pressure decreased, 
Blood pressure diastolic decreased, Blood pressure orthostatic decreased, Blood 
pressure systolic decreased, Blood pressure systolic inspiratory decreased, Diastolic 
hypotension, Hypotension, Orthostatic hypotension. 
Heart rate change 
x TEAEs with a PT: Atrial tachycardia, Postural orthostatic tachycardia syndrome, 
Rebound tachycardia, Sinus tachycardia, Supraventricular tachycardia, Tachycardia, 
Tachycardia paroxysmal, Ventricular tachycardia, Bradycardia. 
Hypersensitivity SMQ 
x TEAEs with a PT included in the MedDRA hypersensitivity SMQ 
Algorithmic Anaphylaxis SMQ (with sponsor-defined time restrictions) 
x TEAEs with a PT included in the MedDRA anaphylactic reaction SMQ, with an 
additional time restriction: a narrow scope PT at any time, or two broad scope PTs 
from different classes where both PTs are within 24 hours of the same dose. 
Fractures 
x TEAEs with a MedDRA HLT: Fractures NEC, Limb fractures, Pelvic fractures, Skull 
and face fractures, Spinal column fractures, thoracic cage fractures non-spinal 
Slipped Capital Femoral Epiphysis (SCFE) 
x TEAEs with a PT: Epiphyseal disorder, Epiphyseal injury 
Avascular necrosis and osteonecrosis 
x TEAEs with a PT: Osteonecrosis, Osteonecrosis of jaw, Osteonecrosis of external 
auditory canal, Necrosis ischaemic 
Events of interest will be summarized as follows: 
x Incidence and exposure-adjusted event rates of injection site reaction events by PT 
x Incidence and exposure-adjusted event rates of injection site reaction events by PT 
DQGGXUDWLRQRI,65 PLQ!PLQDQGPLQ!PLQDQGPLQ!PLQ
DQGKRXUV, >24hours)  
x Incidence and exposure-adjusted event rates of hypotension by PT 
x Incidence and exposure-adjusted event rates of heart rate change events by PT 
x Incidence and exposure-adjusted event rates of hypersensitivity (SMQ) 
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x Profile of injection site reaction events 
x Profile of hypotension 
x Profile of heart rate change events 
Profile summaries include: highest CTCAE grade, number of events per subject, time from 
first dose to first event onset, duration of events (days), action taken with study drug, 
outcome of events. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15.1.3 Injection Site Reaction Symptoms 
Injection site reactions (ISRs) associated with single symptoms are recorded on the AE page 
(as a single symptom).  ISR’s with multiple symptoms are recorded as an AE of “Injection 
Site Reaction” on the AE page and the associated individual symptoms are recorded on the 
ISR symptom page. 
In order to describe all ISR symptoms recorded, summaries will be based on the data 
collected on the ISR Symptoms page and also those single symptoms recorded as an adverse 
event. 
Incidence and exposure-adjusted event rates of ISR Symptoms will be summarized by PT 
and treatment group.   
ISR Symptoms will be listed. 
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15.2 
Clinical Laboratory Tests 
Clinical laboratory tests (hematology, chemistry and urinalysis), are performed at Screening, 
and pre-dose at Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52 and the 
Safety Follow-up visit. This study uses a centralized laboratory.  All laboratory results are 
presented using SI units.  When results are reported beyond analytical ranges, the reported 
numeric value will be used and included in summaries. 
All summary tables will include laboratory assessments from baseline up to 30 days post 
treatment discontinuation.  
 
’. 
Laboratory tests will be graded as low/normal/high based on laboratory normal ranges.  In 
addition, for laboratory tests with CTC grading available, all non-missing numeric results 
will be used to determine CTC grade programmatically, based on CTCAE v4.0.  
 For the following parameters, the distinction is made between significantly low/high results: 
x Glucose (Hypoglycemia/Hyperglycemia) 
x Hemaglobin (Anemia/Hemaglobin increased) 
x Lymphocytes (Lymphocyte count decreased/Lymphocyte count increased) 
x Potassium (Hypokalemia/Hyperkalemia) 
x Sodium (Hyponatremia/Hypernatremia) 
x Calcium (Hypocalcemia/Hypercalcemia) 
The absolute values for pre-dose laboratory results at each scheduled visit, change from 
baseline in pre-dose laboratory results, and percent change from baseline in pre-dose 
laboratory results at each scheduled visit will be summarized (n, mean, SD, median, 25th and 
75th percentile, minimum, maximum) and presented by treatment group.   
Shift tables from baseline to worst post-baseline value (including scheduled and unscheduled 
visits) based on the CTC grading (Normal – Grade 5) will be generated for each Lab 
parameter where CTCAE grading is available, excluding parameters where CTCAE Grade 
does not rely on quantitative results alone (e.g. potassium and uric acid).  Percentages are 
based on the number of subjects with each Baseline CTCAE grade (Normal, Grade 1, 
Grade 2, Grade 3, Grade 4, Grade 5, Missing, Overall). 
For laboratory tests where grades are not defined by CTCAE, or where CTCAE grading does 
not rely on quantitative results alone (e.g. potassium and uric acid), shift tables will be 
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generated using the low/normal/high classification to compare to baseline to the worst 
post-baseline value.   
Line plots of the mean result (+/- SD) for the pre-dose absolute values by scheduled visit for 
each treatment group will be provided for the following parameters: 
x Hematology: erythocytes, hematocrit, hemoglobin, leukocytes, neutrophils, platelets. 
x Chemistry: alanine aminotransferase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bicarbonate, bilirubin, blood urea nitrogen, calcium, chloride, 
creatinine, direct bilirubin, glucose, lactate dehydrogenase, phosphate, potassium, 
protein, sodium, thyrotropin, vitamin D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
15.3 
Vital Signs 
Vital Signs (heart rate, systolic/diastolic blood pressure, respiratory rate and body 
temperature,) are assessed at Screening, Day 1, Day 2, Day 3, Day 10, Week 6, Week 13, 
Week 26, Week 39, Week 52 and the Safety Follow-up visit. 
All summary tables will include vital signs recorded from baseline up to 30 days post 
treatment discontinuation. 
The vital signs that are collected pre-dose and post-dose are: 
x Pre-dose: body temperature, heart rate, systolic/diastolic blood pressure and 
respiratory rate. 
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x Post-dose: heart rate and systolic/diastolic blood pressure only. 
o Day 1: 0-1 hr. (Q15min); 1-2hr (Q30min) 
o Day 2-3: 0-2 hr. (Q30min) 
o All other dosing visits: 0-1 hr. (Q30min) 
The absolute values for pre-dose vital signs at each scheduled visit, and change from baseline 
in pre-dose vital signs at each scheduled visit will be summarized (n, mean, SD, median, 25th 
and 75th percentile, minimum, maximum) and presented by treatment group.  Line plots will 
be generated which present the mean pre-dose absolute values (+/- SD) by scheduled visit for 
each treatment group. 
In addition, for heart rate and systolic/diastolic blood pressure, pre-dose assessments, and 
change from pre-dose to multiple post-dose time points at each scheduled visit will be 
similarly summarized and presented by treatment group.  Line plots will be generated which 
present the mean pre-dose and post-dose absolute values (+/- SD) by treatment group for 
each visit separately. 
The percentage of subjects experiencing at least one instance of a decrease of 20% in 
diastolic blood pressure from pre-dose to post dose will be summarized [n(%)] by treatment 
group at Baseline, Day 2, Day 3, Day 10, Week 6, Week 13, Week 26, Week 39, and 
Week 52. 
6KLIWWDEOHV'LDVWROLF%3PP+J'LDVWROLF%3PP+g) from pre-dose to lowest 
post-GRVHYDOXHFDWHJRU\'LDVWROLF%3PP+J'LDVWROLF%30mmHg) will be 
generated by visit and at any time. 
6KLIWWDEOHV'LDVWROLF%3PP+J'LDVWROLF%3PP+g) from pre-dose to lowest 
post-GRVHYDOXHFDWHJRU\'LDVWROLF%3PP+J'LDVWROLF%3PP+JZLOOEH
generated by visit and at any time. 
Shift tabOHV6\VWROLF%3PP+JSOXV[$JH6\VWROLF%3PP+JSOXV[$JH
from pre-dose to lowest post-dose value category ((Systolic BP < (70mmHg plus 2 x Age), 
6\VWROLF%3PP+JSOXV[$JHZLOOEHJHQHUDWHGE\YLVLWDQGoverall (overall will be 
the lowest overall post-dose value category at any time on study).  Subject’s age used in this 
calculation is the integer value. 
 
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15.4 
Electrocardiogram 
Electrocardiogram (ECG) data are recorded at Screening, Day 1, Day 10, Week 13, Week 26, 
Week 39, Week 52, and at the Safety Follow-up visit. 
ECG assessments are performed in triplicate on Day 1 (pre-dose and post-dose) and on study 
day visits (post-dose only).  On days when PK samples are being drawn, post-dose ECGs 
should be performed within a 5-minute window prior to the 30-minute PK assessment 
(i.e. around the time of CMax). 
Summaries will be provided over all assessments, and repeated with the requirement that all 
post-dose ECG assessments should occur around the expected time of CMax.  The mean 
results of the ECG assessments meeting these criteria will be used for summaries and 
analyses.   
All measures and means of the measures will be included in the listings. 
The following ECG results will be summarized (n, mean, SD, median, 25th and 
75th percentile, minimum, maximum) and presented by treatment group at Baseline 
(pre-dose and post-dose), and post-dose at Day 10, Week 13, Week 26, Week 39, Week 52: 
x ECG Mean Heart Rate (beats/min) 
x QT interval (msec) 
x QTcB interval (msec) 
x QTcF interval (msec) 
x PR interval (msec) 
x RR interval (msec) 
x QRS Duration (msec) 
The following endpoints will be summarized [n (%)] at Baseline, Day 10, Week 13, 
Week 26, and Week 52, and across all time points (using the highest mean QTc value), and 
presented by treatment group. 
x 3HUFHQWDJHRIVXEMHFWVZLWK47F%!WRPV!WRPV!PVec 
x Percentage of subjects with QTcF >450 WRPV!480 WRPV, >500 msec 
The following endpoints will be summarized [n (%)] at Baseline, Day 10, Week 13, 
Week 26, and Week 52, and across all time points, and presented by treatment group. 
x Percentage of subjects experiencing at least one instance of a (decrease in mean heart 
rate from pre-dose baseline >25% and a mean heart rate <50 beats/min) post-dose. 
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x Percentage of subjects experiencing at least one instance of an (increase in mean heart 
rate from pre-dose baseline >25% and a mean heart rate >100 beats/min) post-dose. 
The following endpoints will be summarized [n (%)] across all time points and presented by 
treatment group. 
x Percentage of subjects with a QTcF increase of 60ms from pre-dose baseline at any 
time 
x Percentage of subjects with QTcF changes from pre-GRVHEDVHOLQHRI!DQG
msec, or >60 msec at any time 
x Percentage of subjects with both an increase in PR interval from pre-dose baseline 
>25% and a PR>200 msec at any time. 
x Percentage of subjects with both an increase in QRS from pre-dose baseline >25% 
and QRS >120 msec at any time 
Listings will be provided, and ordered by treatment group, subject and visit: 
x All ECG results. 
x All ECG results for subjects with a QTc increase of 60msec from pre-dose Baseline. 
15.5 
Child Behavior Checklist 
The Child Behavior Checklist (CBCL) questionnaire is captured at Screening, Week 26 and 
Week 52.  All summaries will be generated on the Safety Population and include all 
assessments recorded up to 30 days following treatment discontinuation.  Listings will 
include all reported data. 
The CBCL 1.5-5 years old and the CBCL 6-18 years old comprise questions addressing 
symptoms related to mood, behavior issues, and sleep disturbance.  It is completed by the 
parent or primary caregiver.  
The CBCL 1.5-5 years old is used in this study for children aged 5 to < 6 years old. It 
consists of 100 questions, scored on a three-point Likert scale (0=Not True (as far as you 
know), 1= Somewhat or Sometimes True, 2=Very True or Often True). The time frame for 
item responses is the past 2 months. 
The CBCL 6-18 years old is used in children aged 6 up to 18 years old.  It consists of 
113 questions, scored on a three-point Likert scale (0=Not True (as far as you know), 
1= Somewhat or Sometimes True, 2=Very True or Often True). The time frame for item 
responses is the past six months. 
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Note: No data is collected from the language scale, as it is supplemental and not required to 
calculate any of the behavior measures. 
The checklist yields scores in the following areas: 
CBCL 1.5-5 
CBCL 6-18 
x 
Emotionally reactive 
x 
Anxious/Depressed 
x 
Withdrawn 
x 
Somatic Complaints 
x 
Attention Problems 
x 
Aggressive Behavior 
x 
Anxious/Depressed 
x 
Withdrawn/Depressed 
x 
Somatic Complaints 
x 
Social problems 
x 
Thought Problems 
x 
Attention Problems 
x 
Rule Breaking Behavior 
 
The table in Appendix 23.1 shows how the domains are constructed with regards to the 
individual questions.  The scores for each individual question within a domain are summed to 
give a domain score. 
Each domain score above and total score will be summarized (n, mean, SD, median, 25th and 
75th percentile, minimum, maximum) by treatment group at Baseline, Week 26 and 
Week 52, as will change from baseline at Week 26 and Week 52 (where baseline measures 
exist). 
Where possible, the CBCL 1.5-5 and CBCL 6-18 will be summarized together. If a subject 
progresses during the course of the study from one version to the next the results will be 
summarized together and the baseline assessment from the child’s first questionnaire (1.5-5) 
will be referred to when summarizing change from baseline. 
Domain scores and total score will be listed by treatment group and subject number. 
15.6 
Echocardiogram 
Echocardiogram results are only collected at the Screening visit, and will be listed by 
treatment group and subject. 
15.7 
On-Study Procedures, Interventions and Surgeries 
Any procedures, interventions of surgeries that occur on study (post first dose of study drug) 
will be captured, along with start and stop date.  These will be coded using the latest 
available MedDRA version and details provided in a listing. 
15.8 
Hip Monitoring and Rotation 
All hip monitoring clinical assessments, including hip rotation, will be listed by treatment 
group, subject and assessment date. 
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15.9 
Pregnancy Testing 
A pregnancy test will be performed at the following visits for female subjects who have 
EHJXQPHQVHVRUDUH\HDUVRIDJH6FUHHQLQJ'D\:HHN:HHN:HHN6, 
Week 39, Week 52, Early Termination and at the Safety Follow-up visit. 
. 
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16 
IMAGING SECONDARY ENDPOINT(S) 
All summaries of imaging data will be based on the Safety Population.  All visits referred to 
in the analyses, are based on the analysis windows described in Section 5.4.  Therefore, 
where summaries are based on data collected at the Screening visit, they will be referred to as 
Baseline assessments once the analysis window is applied. 
16.1 
Bone Age 
An X-ray of the left hand and wrist will be performed at Screening, Week 26 and Week 52, 
and bone age determined using the Greulich and Pyle Atlas. 
Bone age at Baseline, Week 26 and Week 52, and change from baseline at Week 26 and 
Week 52 will be summarized (n, mean, SD, median, 25th and 75th percentile, minimum, 
maximum) by treatment group and presented by sex and overall.  
Each measurement of bone age will be converted to an age-and sex-appropriate standard 
deviation score (SDS), also referred to as a Z-score, by comparison with reference data 
available for average stature children (Greulich and Pyle, 1959). Bone age Z-scores at 
Baseline, Week 26 and Week 52, and change from baseline at Week 26 and Week 52 will be 
summarized (n, mean, SD, median, 25th and 75th percentile, minimum, maximum) and 
presented by treatment group. 
In addition, for the visits at Baseline and Week 52, scatter plots will be provided which 
display bone age z-score on the y-axis, and age in years at that visit on the x-axis, identifying 
the two treatment groups.  A separate plot will be generated for each sex and overall. 
16.2 
Lower Limb X-Rays 
For each of the following parameters, excluding femur length, the absolute values for both 
the left and right leg at Baseline, Week 26 and Week 52, and change from baseline at 
Week 26 and Week 52 will be summarized (n, mean, SD, median, 25th and 75th percentile, 
PLQLPXPPD[LPXPDQGSUHVHQWHGE\WUHDWPHQWJURXSIRUHDFKEDVHOLQHDJHFDWHJRU\
WRWRWRWR\HDUV  As the assessment of femur length was 
introduced mid-study, subjects will not have a measurement of femur length at baseline, and 
data will be listed only.  
x Left/Right Femur length (cm) 
x Left/Right Tibia length (cm)  
x Left/Right Fibula length (cm) 
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x Left/Right Tibia bowing angle (degrees) 
x Left/Right Distance between ankle joint and distal growth plate of fibula (cm) 
In addition, change from baseline in tibial length (y-axis) at Week 52 will be presented on a 
boxplot, with a separate box for each leg and WUHDWPHQWJURXSZLWKEDVHOLQHDJHFDWHJRU\
WRWRWRWR\HDUVRQWKH[-axis.  A similar plot will also be 
generated for change from baseline in fibula length at Week 52. 
All assessments will be listed by treatment group, subject and visit. 
16.3 
Lumbar Spine X-Rays 
Lumbar spine x-rays (AP and lateral views) are performed at Screening and Week 52.  
Assessments will be listed by treatment group, subject and visit. 
16.3.1 Vertebral Height 
Vertebral heights (anterior, medial, and posterior) will be measured for each individual 
vertebra (L1, L2, L3, L4, and L5).   
The following ratios will be calculated for each individual vertebra (L1, L2, L3, L4, and L5) 
and reported to 1 decimal place: 
x Anterior height (cm) to medial height (cm) 
x Anterior height (cm) to posterior height (cm) 
x Medial height (cm) to posterior height (cm) 
For each of the above ratios, the absolute values at Baseline and Week 52, and change from 
baseline at Week 52 will be summarized (n, mean, SD, median, 25th and 75th percentile, 
minimum, maximum) and presented by treatment group. 
16.3.2 Transverse Diameter (Interpedicle Distance) 
The transverse diameter (interpedicle distance) will be measured for each individual vertebra 
(L1, L2, L3, L4, and L5) at Baseline and Week 52. 
For each vertebra, the absolute values at Baseline and Week 52, and the change from 
baseline at Week 52 will be summarized (n, mean, SD, median, 25th and 75th percentile, 
minimum, maximum) and presented by treatment group foUHDFKEDVHOLQHDJHFDWHJRU\ 5 
WRWRWRWR\HDUV 
In addition, change from baseline in transverse diameter (y-axis) for each individual vertebra 
(x-axis) will be presented on a boxplot at Week 52 for each treatment group.  Separate plots 
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will be generated for each EDVHOLQHDJHFDWHJRU\WRWRWRWR
< 18 years). 
16.3.3 Sagittal Width 
The spinal canal width (sagittal width) will be measured for each individual vertebra (L1, L2, 
L3, L4, and L5) at Baseline and at Week 52. 
For each individual vertebra, the absolute values at Baseline and Week 52, and the change 
from baseline at Week 52 will be summarized (n, mean, SD, median, 25th and 75th percentile, 
PLQLPXPPD[LPXPDQGSUHVHQWHGE\WUHDWPHQWJURXSIRUHDFKEDVHOLQHDJHFDWHJRU\ 5 
WRWRWRWR\HDUV 
In addition, change from baseline in sagittal width (y-axis) for each individual vertebra 
(x-axis) will be presented on a boxplot at Week 52 for each treatment group. Separate plots 
will be generated for each EDVHOLQHDJHFDWHJRU\WRWRWRWR
< 18 years). 
16.3.4 Lumbar Spine Angles 
The following angles will be measures on the lumbar spine x-rays: 
x Sacral tilt (degrees) 
x Lordosis (inward curve of the spine) (degrees) 
x Kyphosis (convex curvature of the spine) (degrees) 
Each angle will be measured on the spine x-rays and compared to Baseline at Week 52 to 
determine any worsening of sacral tilt, lordosis (inward curve of the spine) or kyphosis 
(convex curvature of the spine). 
The absolute values of the sacral tilt, lordosis and kyphosis angles at Baseline and Week 52, 
and change from baseline at Week 52 will be summarized (n, mean, SD, median, 25th and 
75th percentile, minimum, maximum) and presented by treatment group for each baseline age 
FDWHJRU\WRWRWR WR\HDUV. 
The following summaries will similarly be presented for each EDVHOLQHDJHFDWHJRU\WR
< WRWRWR\HDUV 
A worsening in sacral tilt angle will be summarized [n(%)] by treatment group as follows: 
x Percentage of subjects with an increase in sacral tilt DQJOHRIWRGHJUHHVDW
week 52 
x Percentage of subjects with an increase in sacral tilt DQJOHRIGHJUHHVDWZHHN 
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A worsening in lumbar lordosis will be summarized [n(%)] by treatment group as follows: 
x 3HUFHQWDJHRIVXEMHFWVZLWKDQLQFUHDVHLQORUGRVLVDQJOHRIWRGHJUHHVDW
week 52 
x 3HUFHQWDJHRIVXEMHFWVZLWKDQLQFUHDVHLQORUGRVLVDQJOHRIGHJUHHVDWZHHN 
A worsening in kyphosis angle will be summarized [n(%)] by treatment group as follows: 
x 3HUFHQWDJHRIVXEMHFWVZLWKDQLQFUHDVHLQN\SKRVLVDQJOHRIWRGHJUHHVDW
week 52 
x 3HUFHQWDJHRIVXEMHFWVZLWKDQLQFUHDVHLQN\SKRVLVDQJOHRIGHJUHHVDWZHHN 
16.4 
Dual Energy X-ray Absorptiometry 
A dual energy x-ray absorptiometry (DXA) scan is performed at Screening, Week 26 and 
Week 52, in order to collect relevant BMC/BMD data (including Z-scores) for whole body 
less head, and the lumbar spine.  The scans of the distal forearm were removed from the 
original protocol at a later date, and hence data is limited.  
All DXA data will be summarized separately for each scanner manufacturer (GE - Lunar 
Prodigy or Hologic – Discovery Horizon).  Subjects who have results from more than one 
scanner type will be excluded from summaries, and their data will be listed only. 
16.4.1 Whole Body Less Head and Lumbar Spine 
The absolute values at Baseline, Week 26 and Week 52, and change from baseline at Week 
26 and Week 52 will be summarized (n, mean, SD, median, 25th and 75th percentile, 
minimum, maximum) and presented by treatment group for the following measures of bone 
mineral content (BMC) and bone mineral density (BMD): 
x Whole Body Less Head BMC (g) 
x Whole Body Less Head BMD (g/cm2) 
x Whole Body BMC (g) 
x Whole Body BMD (g/cm2) 
x Lumbar Spine BMC (g) 
x Lumbar Spine BMD (g/cm2) 
BMD Z-scores will be provided in the DXA reports, and the absolute values at Baseline, 
Week 26 and Week 52, and change from baseline at Week 26 and Week 52 will be 
summarized (n, mean, SD, median, 25th and 75th percentile, minimum, maximum) and 
presented by treatment group and scanner for each of the following: 
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x Whole Body Less Head BMD Z-Score 
x Whole Body BMD Z-Score 
x Lumbar Spine BMD Z-Score 
The absolute values of total body percent fat, android percent fat, and gyenoid percent fat at 
Baseline, Week 26 and Week 52 will be listed. 
Box plots of whole body less head BMD Z-scores will be provided by treatment group, and 
scanner. 
16.4.2 Regions of Interest in Distal Forearm 
Due to sparsity of data, available data will be listed by treatment group, subject and visit.  No 
summaries will be presented. 
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17 
BONE METABOLISM BIOMARKERS 
Bone metabolism biomarkers will be collected to assess changes in bone metabolism.  The 
safety population will be used for all summaries. 
Samples for bone metabolism blood biomarkers (collagen X and bone-specific alkaline 
phosphatase [BSAP]) are collected pre-dose at Day 1, Week 13, Week 26, Week 39, 
Week 52 and at the Safety Follow-up visit. 
For each biomarker, the absolute values, and change from baseline at Week 13, Week 26, 
Week 39, and Week 52 will be summarized (n, mean, SD, median, 25th and 75th percentile, 
minimum, maximum) and presented by treatment group. 
For each biomarker, the change from baseline will also be summarized by visit in a box plot 
and presented by treatment group. 
Bone metabolism biomarkers will be listed by treatment group and subject. 
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18 
BMN 111 ACTIVITY URINE BIOMARKERS AND URINE CHEMISTRY 
Samples for BMN 111 activity urine biomarker, cyclic guanosine monophosphate [cGMP], 
and urine chemistry are collected pre-dose and 1, 2 and 4hr post-dose at Day 1, Day 2, Day 3, 
Week 6, Week 26, and Week 52.  Each collection will be tested for biomarker concentration 
and urine creatinine concentration for normalization. The safety population will be used for 
all summaries. 
The absolute values for pre-dose urine cGMP normalized by creatinine and urine chemistry 
(creatinine, potassium, sodium) results at each scheduled visit, and change from pre-dose to 
multiple post-dose time points at each scheduled visit will be summarized (n, mean, SD, 
median, 25th and 75th percentile, minimum, maximum) and presented by treatment group. 
The absolute values for pre-dose urine cGMP normalized by creatinine and urine chemistry 
(creatinine, potassium, sodium) results at each scheduled visit, and the maximum change 
from pre-dose to post-dose will be summarized (n, mean, SD, median, 25th and 
75th percentile, minimum, maximum) and presented by treatment group at each scheduled 
visit and overall. 
The maximum change from pre-dose cGMP normalized by creatinine will also be 
summarized in a box plot by visit and presented by treatment group. 
BMN 111 activity urine biomarkers will be listed by treatment group and subject. 
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19 
IMMUNOGENICITY ASSESSMENT 
Serum samples for anti-drug antibody (ADA) tests will be drawn pre-dose on Day 1, 
Week 13, Week 26, Week 39, Week 52 and the Safety Follow-up or Early Termination visit.  
Blood (serum) samples for testing drug-specific IgE will be drawn on Day 1 and in the event 
of a Grade 3 or significant hypersensitivity adverse event, or at the investigator’s discretion.  
ADA tests will include anti-BMN 111 total antibody (TAb); TAb cross-reactive with 
endogenous CNP, BNP or ANP; and anti-BMN 111 neutralizing antibody (NAb). 
NAb testing and TAb testing for cross-reactivity with endogenous CNP, ANP or BNP will be 
performed only on baseline and TAb positive samples. NAb testing will not be performed if 
the TAb is negative. A listing for each ADA test will be provided. 
Summary tables will include all safety events up to 30 days following treatment 
discontinuation.  
. 
The immunogenicity population will be used for all summaries.  The data conversion rules 
for immunogenicity analysis are listed below: 
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Operational Data Conversion Table for Immunogenicity Analysis 
 
 
Assay 
Result 
Type 
Result = “Concentration 
(Titer Units)” 
Pos/Neg for 
Incidence Table 
Numerical Value 
for Display 
Numerical Value 
for Calculation 
Anti-
BMN111 
TAb 
Numeric 
Titer 
Negative Screen 
Negative 
1 
0 
Negative Immunodepletion 
Negative 
1 
0 
Negative Titer (<10) 
Negative 
1 
0 
* Value * (e.g. 20, 30, …) 
Positive 
e.g. 20, 30, … 
e.g. 20, 30, … 
Imputed values - none 
MRD of assay: 10 
Anti-
BMN111 
NAb 
Numeric 
Titer 
Negative Screen 
Negative 
1 
0 
Negative Immunodepletion 
Negative 
1 
0 
Negative Titer (<5) 
Negative 
1 
0 
* Value * (e.g. 10, 20, …) 
Positive 
e.g. 10, 20, … 
e.g. 10, 20, … 
Imputed values – if TAb negative then impute result as ‘Negative’ for same study visit 
MRD of Assay: 5 
ANP 
Reactivity 
Binary 
Negative Screen 
Negative 
 
 
Negative Immunodepletion 
Negative 
Positive Immunodepletion 
Positive 
 
 
Imputed values – if TAb negative then impute result as ‘Negative’ for same study visit 
BNP 
Reactivity 
Binary 
Negative Screen 
Negative 
 
 
Negative Immunodepletion 
Negative 
 
 
Positive Immunodepletion 
Positive 
 
 
Imputed values – if TAb negative then impute result as ‘Negative’ for same study visit 
CNP-22 
Reactivity 
Binary 
Negative Screen 
Negative 
 
 
Negative Immunodepletion 
Negative 
 
 
Positive Immunodepletion 
Positive 
 
 
Imputed values – if TAb negative then impute result as ‘Negative’ for same study visit 
 
  
 
The incidence [n(%)] of TAb titer positive results will be summarized for each scheduled 
visit, and overall (described as ‘Ever Positive’) as follows: 
ܰݑܾ݉݁ݎ ݋݂ ݏݑܾ݆݁ܿݐݏ ݓ݅ݐ݄ ܽ ݌݋ݏ݅ݐ݅ݒ݁ ݐ݁ݏݐ ݎ݁ݏݑ݈ݐ
ܰݑܾ݉݁ݎ ݋݂ ݏݑܾ݆݁ܿݐݏ ݓ݅ݐ݄ ݊݋݊െ݉݅ݏݏ݅݊݃ ܶܣܾ ݎ݁ݏݑ݈ݐכ 100 
The incidence [n(%)] of NAb positive test results, and positive cross-reactivity results for 
ANP, BNP and CNP, will also be calculated based on the number of subjects with a 
non-missing TAb result, and summarized at each scheduled visit and overall. 
The absolute values (numerical values) of TAb titers and NAb titers will be summarized (n, 
mean, SD, median, 25th and 75th percentile, minimum, maximum) at Day 1, Week 13, 
Week 26, Week 39 and Week 52, and presented by treatment group. 
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The mean (SD) TAb titer, number of hypersensitivity adverse events (HAEs) excluding 
injection site reactions, and number of subjects experiencing HAE’s will be summarized by 
the highest HAE CTCAE Grade, and presented by TAb status (negative or positive) and 
treatment group. 
A line graph of the mean TAb titer (+/- SD) will be presented over time for each visit by 
treatment group.  A similar figure will be generated for NAb titers. 
The change from baseline in AGV at Week 52 will be plotted against the mean TAb titer for 
each subject, where the mean is calculated across all post-baseline TAb titers for each 
subject.  The Pearson correlation coefficient will be included in the figure to describe the 
association. 
The change from baseline in AGV at Week 52 will be plotted against the mean NAb titer for 
each subject, where the mean is calculated across all post-baseline NAb titers for each 
subject.  The Pearson correlation coefficient will be included in the figure to describe the 
association. 
The relationship between immunogenicity (ADA status: negative or positive) and measures 
of safety and efficacy will further be presented graphically by treatment group: 
x Box plot of change from baseline in AGV at week 52 by TAb status 
x Box plot of change from baseline in AGV at week 52 by NAb status 
x Box plot of number of hypersensitivity adverse events by TAb status 
x Box plot of number of hypersensitivity adverse events (excluding ISRs) by TAb 
status 
x Box plot of maximum severity hypersensitivity adverse event by TAb status 
x Box plot of number of injection site reaction adverse events by TAb status 
x Box plot of maximum duration of injection site reaction adverse event by TAb status 
In addition, the following listings will be provided:  
x Total antibody titers and neutralizing antibody titers 
x Hypersensitivity adverse events with antibody results 
x Drug-specific IgE, total IgE, C4 and serum tryptase for hypersensitivity reaction 
visits 
x TAb cross reactivity to endogenous natriuretic peptides 
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x TAb cross reactivity by subject and cardiac disorder or HLGT ‘fluid and electrolyte 
imbalance’ related adverse event. 
x Mean antibody titers and AGV 
All immunogenicity listings will be ordered by treatment group, 4-digit subject number (i.e., 
the subject ID, excluding the site number) and visit. 
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20 
PHARMACOKINETICS AND PHARMACODYNAMICS 
BMN 111 concentrations and pharmacokinetic (PK) parameters will be summarized 
descriptively by visit for all subjects in the PK population.  If supported by the data, the 
exposure-response relationship between BMN 111 exposure and immunogenicity, efficacy, 
biomarker, and safety pharmacodynamic (PD) endpoints of interest will be explored. Details 
of the PK/PD analyses are separately documented in the Clinical Pharmacology Analysis 
Plan. 
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21 
REFERENCES 
Bullinger M, Sommer R, Pleil A, et al. Evaluation of the American-English Quality of Life in 
Short Stature Youth (QoLISSY) questionnaire in the United States, Health Qual Life 
Outcomes, 2015: 13:43. 
Greulich, W and Pyle, S. Radiographic Atlas of Skeletal Development of the Hand and 
Wrist, 1959: Stanford University Press. 
Hoover-Fong, JE, Schulze, KJ, McGready, J, Barnes, H et. al. Age-appropriate body mass 
index in children with achondroplasia: interpretation in relation to indexes of height. Am J 
ClinNutr 88[2], 364-371. 2008. 
Little, R. J. A., “Pattern-Mixture Models for Multivariate Incomplete Data,” Journal of the 
American Statistical Association, 1993; 88, 125–134. 
Molenberghs, G. and Kenward, M. G. (2007), Missing Data in Clinical Studies, New York: 
John Wiley & Sons. 
Varni JW, et al. The PedsQL™: Measurement Model for the Pediatric Quality of Life 
Inventory. Medical Care, 1999; 37(2):126-139  
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22 
SUMMARY OF CHANGES TO STUDY SAP 
Version 
Affected Section 
(Number of Section 
in Previous SAP) 
Summary of Revisions 
Number 
Date 
Final SAP 
05-Nov-19 
1.0 (NA) 
Signature page added. 
Final SAP 
05-Nov-19 
4.6.2 (2.6.2) 
The Japanese randomization has been described in more detail. 
Final SAP 
05-Nov-19 
5.1.2 (3.1.2) 
Gonadotropin-releasing hormones have been added as an 
exclusion from the Pre Protocol analysis population. 
Final SAP 
05-Nov-19 
5.4 (3.4) 
111-901 analysis visit windows have been updated. 
Final SAP 
05-Nov-19 
5.4 (3.4) 
A spaghetti plot of standing height Z-scores has been added. 
Final SAP 
05-Nov-19 
8.0 (6.0) 
A listing of major deviations classified as “dosing irregularity” 
has been added. 
Final SAP 
05-Nov-19 
9.0 (7.0) 
Baseline characteristics growth measures are re-ordered.  
Tanner Stages, other than (I,>I) are not included in baseline 
summary. 
Final SAP 
05-Nov-19 
10.0 (8.0 and 
Appendix) 
Details of Achondroplasia-related terms are removed from the 
SAP appendix, and located in a study file. 
Final SAP 
05-Nov-19 
10.0 (8.0) 
Physical exam results listing added. 
Final SAP 
05-Nov-19 
11.0 (9.0) 
The concomitant medications are to be summarized by ATC 
level 2, not 4. 
Final SAP 
05-Nov-19 
13.0 (11.0) 
Definition for missed dose has been added.  Dose interruptions 
have been replaced with a summary of “Reasons for missed 
dose”. 
Final SAP 
05-Nov-19 
14.0 (12.0) 
Estimands have been clarified for the primary and key 
secondary endpoints. 
Details have been added to describe imputation methods for 
missing Week 52 assessments for standing height, AGV, height 
Z-Score, sitting height and upper-to-lower body segment ratio. 
Final SAP 
05-Nov-19 
14.2 (12.2) 
Terminology for the testing strategy has been changed from 
“statistically significant “ to “confirmatory”. 
Final SAP 
05-Nov-19 
14.3.3 (12.3.3) 
There is now one sensitivity analysis and 2 supplementary 
analyses: 
A washout model has been introduced as the sensitivity analysis 
The completers analysis is now a supplementary analysis (not 
sensitivity). 
The analysis excluding data post limb lengthening/growth 
hormone is now a supplementary analysis (not sensitivity). 
The random coefficient model sensitivity analysis has been 
removed. 
Final SAP 
05-Nov-19 
14.7 (12.7) 
More detail has been added for subgroup analyses, and 
subgroups of height Z-score thresholds and AGV thresholds 
have been added 
Final SAP 
05-Nov-19 
15.1.1 (13.1.1) 
A table of the incidence of TEAE’s by SOC, PT and highest 
CTCAE grade has been added. 
Final SAP 
05-Nov-19 
15.1.1 (13.1.1) 
The Achondroplasia-related AE table is now exposure-adjusted 
Final SAP 
05-Nov-19 
15.1.2 (13.1.2) 
Events of Special Interest are now Events of Interest. 
Final SAP 
05-Nov-19 
15.1.2 (13.1.2) 
Events suggestive of hypotension are removed. Profile of events 
suggestive of hypotension, and profile of hypersensitivity 
(SMQ) tables have been removed. 
Final SAP 
05-Nov-19 
15.1.2 (13.1.2) 
Incidence and exposure-adjusted ISR tables by duration of ISR 
have been added. 
Final SAP 
05-Nov-19 
16.1 (14.1) 
Bone Age presented by sex and overall.  Plots of Z-scores. 
Final SAP 
05-Nov-19 
16.2 (14.2) 
Lower limb x-rays: Left and Right leg assessments included.  
Percent change from baseline removed. 
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Final SAP 
05-Nov-19 
16.2 (14.2) 
Lumbar spine x-rays: Percent change from baseline removed. 
Final SAP 
05-Nov-19 
16.4 (14.4) 
DXA data will be presented separately for each scanner (GE or 
Hologic).  Summaries of fat removed. 
Final SAP 
05-Nov-19 
17.0 (15.0) 
Biomarker plots added. 
Final SAP 
05-Nov-19 
18.0 (16.0) 
Urine chemistry parameters added. 
 
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23 
APPENDICES 
23.1 
Child Behavior Checklist Domains 
Domain/Subscale 
CBCL 1.5-5 
CBCL 6-18 
EMOTIONALLY REACTIVE 
21. Disturbed by change 
46. Twitches 
51. Panics 
79. Shifts between sad-excite 
82. Sudden mood change 
83. Sulks a lot 
92. Upset by new 
97. Whining 
99. Worries 
 
ANXIOUS/DEPRESSED 
10. Too dependent 
33. Feelings easily hurt 
37. Upset when separated 
43. Looks unhappy 
47. Nervous 
68. Self-conscious 
87. Fearful 
90. Unhappy, sad, depressed 
14. Cries a lot 
29. Fears 
30. Fears school 
31. Fears doing bad 
32. Must be perfect 
33. Feels unloved 
35. Feels worthless 
45. Nervous, tense 
50. Fearful, anxious 
52. Feels too guilty 
71. Self-conscious 
91. Talks or thinks of suicide 
112. Worries 
WITHDRAWN/DEPRESSED 
 
5. Enjoys a little 
42. Rather be alone 
65. Won’t talk 
69. Secretive 
75. Shy, timid 
102. Lacks energy 
103. Sad 
111. Withdrawn 
WITHDRAWN 
2. Acts too young 
4. Avoids eye contact 
23. Doesn’t answer 
62. Refuses active games 
67. Unresponsive to affection 
70. Little affection 
71. Little interest 
98. Withdrawn 
 
SOMATIC COMPLAINTS 
1. Aches, pains 
7. Can’t stand things out of place 
12. Constipated 
19. Diarrhea 
24. Doesn’t eat well 
39. Headaches 
45. Nausea 
52. Painful bowel movements 
47. Nightmares 
49. Constipated 
51. Feels dizzy 
54. Overtired 
56a. Aches, pains 
56b. Headaches 
56c. Nausea 
56d. Eye problems 
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78. Stomachaches 
86. Too concerned with neatness 
93. Vomits 
56e. Skin problems 
56f. Stomachaches 
56g. Vomiting 
SOCIAL PROBLEMS 
 
11. Too dependent 
12. Lonely 
25. Doesn’t get along 
27. Jealous 
34. Others out to get him/her 
36. Accident prone 
38. Gets teased 
48. not liked 
62. Clumsy 
64. Prefers younger kids 
79. Speech problems 
THOUGHT PROBLEMS 
 
9. Can’t get mind off thoughts 
18. Harms self 
40. Hears things 
46. Twitching 
58. Picks skin 
59. Sex parts in public 
60. Sex parts too much 
66. Repeats acts 
70. Sees things 
76. Sleeps less 
83. Stores things 
84. Strange behavior 
85. Strange ideas 
92. Sleep talks/walks 
100. Trouble sleeping 
ATTENTION PROBLEMS 
5. Can’t concentrate 
6. Can’t sit still 
56. Clumsy 
59. Quickly shifts 
95. Wanders away 
 
1. Acts young 
2. Fails to finish 
8. Can’t concentrate 
10. Can’t sit still 
13. Confused 
17. Daydreams 
41. Impulsive 
61. Poor schoolwork 
78. Inattentive 
80. Stares blankly 
RULE BREAKING BEHAVIOR 
 
2. Drinks alcohol 
26. Lacks guilt 
28. Breaks rules 
39. Bad friends 
43. Lies, cheats 
63. Prefers older kids 
67. Runs away 
72. Sets fires 
73. Sex problems 
81. Steals at home 
82. Steals outside home 
90. Swearing 
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96. Thinks of sex too much 
98. Tardy 
99. Uses tobacco 
101. Truant 
105. Uses drugs 
106. Vandalism 
AGGRESSIVE BEHAVIOR 
8. Can’t stand waiting 
15. Defiant 
16. Demands must be met 
18. Destroys others things 
20. Disobedient 
27. Lacks guilt 
29. Easily frustrated 
35. Gets in fights 
40. Hits others 
42. Hurts unintentionally 
44. Angry moods 
53. Attacks people 
58. Punishment doesn’t change 
behavior 
66. Screams 
69. Selfish 
81. Stubborn 
85. Temper 
88. Uncooperative 
96. Wants attention 
3. Argues a lot 
16. Mean to others 
19. Demands attention 
20. Destroys own things 
21. Destroys others’ things 
22. Disobedient at home 
23. Disobedient at school 
37. Gets in fights 
57. Attacks people 
68. Screams a lot 
86. Stubborn, sullen 
87. Mood changes 
88. Sulks 
89. Suspicious 
94. Teases a lot 
95. Temper 
97. Threatens others 
104. Loud 
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