Clinical trial NCT04085523
Conditions: Achondroplasia
Keywords: Achondroplasia Dwarfism
Sponsor: Ascendis Pharma A/S
Start date: 2020-06-24; Completion date: 2024-10-01
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The trial is a multicenter, double-blind, randomized, placebo-controlled, dose escalation trial of weekly TransCon CNP administered subcutaneously in prepubertal children 2 to 10 years old, inclusive, with Achondroplasia.

Detailed description:

Arms: arm 1: TransCon CNP 6 mcg CNP/kg delivered once weekly by subcutaneous injection. arm 2: TransCon CNP 20 mcg CNP/kg delivered once weekly by subcutaneous injection. arm 3: TransCon CNP 50 mcg CNP/kg delivered once weekly by subcutaneous injection. arm 4: TransCon CNP 100 mcg CNP/kg delivered once weekly by subcutaneous injection. arm 5: Placebo mimicking 6, 20, 50, or 100 mcg CNP/kg delivered once weekly by subcutaneous injection. arm 6: Participants who completed the 52-week blinded treatment period continued into the 104-week open-label extension period and received treatment with TransCon CNP (navepegritide) doses escalated up to a maximum of 100 mcg/kg delivered once weekly by subcutaneous injection.
Interventions: intervention 1: TransCon CNP intervention 2: Placebo for TransCon CNP
Intervention descriptions: intervention 1: TransCon CNP drug product is a lyophilized powder in a single-use vial containing either TransCon CNP 3.9 mg CNP-38/vial or TransCon CNP 0.80 mg CNP-38/vial. Prior to use, the lyophilized powder is reconstituted with sterile water for injection and administered by subcutaneous injection via syringe and needle. intervention 2: Weekly subcutaneously injection of placebo.

Protocol documents:
Prot_000.pdf: 
Official Title: 
ACcomplisH: A Phase 2, multicenter, double-blind, 
randomized, placebo-controlled, dose escalation trial 
evaluating safety, efficacy, and pharmacokinetics of 
subcutaneous doses of TransCon CNP administered once 
weekly for 52 weeks in prepubertal children with 
achondroplasia followed by an Open-Label Extension Period 
NCT Number: 
NCT04085523 
Document Date:  Protocol Version 5: 28 December 2022 


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CLINICAL TRIAL PROTOCOL 
PRODUCT NAME: TransCon CNP 
PROTOCOL NUMBER: TCC-201 
IND NUMBER: 142685 
EUDRACT NUMBER: 2019-002754-22 
PHASE: 2 
PROTOCOL TITLE: ACcomplisH: A Phase 2, multicenter, double-blind, randomized, 
placebo-controlled, dose escalation trial evaluating safety, efficacy, and 
pharmacokinetics of subcutaneous doses of TransCon CNP administered 
once weekly for 52 weeks in prepubertal children with achondroplasia 
followed by an Open-Label Extension Period 
PROTOCOL DATE: Version 1, 5 July 2019 
Version 2, 1 September 2020 
Version 3, 8 January 2021 
Version 4, 12 August 2021 
Version 5, 28 December 2022 
PROTOCOL VERSION: 5 
SPONSORED BY: Ascendis Pharma Growth Disorders A/S 
Tuborg Boulevard 12, DK-2900, Hellerup, Denmark 
GLOBAL MEDICAL 
MONITOR: 
, MD 
Ascendis Pharma, Inc. 
1000 Page Mill Rd, Palo Alto, California 94304, USA 
BACK-UP MEDICAL 
MONITOR, EUROPE: 
, MD PhD 
Ascendis Pharma A/S 
Tuborg Boulevard 12, DK-2900, Hellerup, Denmark 
BACK-UP MEDICAL 
MONITOR: 
, MD 
Ascendis Pharma, Inc. 
1000 Page Mill Rd, Palo Alto, California 94304, USA 
CONFIDENTIAL 
This document contains proprietary and confidential information of Ascendis Pharma Growth Disorders A/S 
or its affiliates.  Acceptance of this document constitutes agreement by the recipient that no previously 
unpublished information contained herein will be published or disclosed without the prior written approval 
of Ascendis Pharma Growth Disorders A/S or its affiliates with the exception that this document may be 
disclosed to study personnel under your supervision who need to know the contents for conducting the study 
and appropriate Institutional Review Boards (IRBs)/Ethics Committees (EC) under the condition that the 
personnel have agreed to keep this information confidential.  The foregoing shall not apply to disclosure 
required by governmental regulations or laws, however, Ascendis Pharma Growth Disorders A/S or its 
affiliates shall be promptly notified of any such disclosure. 
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STATEMENT OF COMPLIANCE  
This trial will be conducted in accordance with the following:  
• Protocol-related and trial-related documents 
• Declaration of Helsinki 
• Good Clinical Practice (GCP) as outlined by the International Conference on Harmonization 
(ICH) E6 (R2) and regional regulations 
• Regional participant data protection laws and regulations 
• Other applicable regional and local regulations 
• US Federal Regulations, as applicable 


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1. 
APPROVAL SIGNATURES  
1.1. 
SPONSOR  
I agree to conduct this trial in accordance with the requirements of this Clinical Trial Protocol 
and also in accordance with the following: 
x Protocol-related and trial-related documents 
x Declaration of Helsinki 
x Good Clinical Practice (GCP) as outlined by the International Conference on Harmonization 
(ICH) E6 (R2) and regional regulations 
x Regional participant data protection laws and regulations 
x Other applicable regional and local regulations 
x Clinical trial contractual obligations 
x US Federal Regulations, as applicable 
 
CLINICAL TRIAL TITLE: 
ACcomplisH: A Phase 2, multicenter, double-blind, randomized, placebo-controlled, dose 
escalation trial evaluating safety, efficacy, and pharmacokinetics of subcutaneous doses of 
TransCon CNP administered once weekly for 52 weeks in prepubertal children with 
achondroplasia followed by an Open-Label Extension Period. 
See Appended Electronic Signature 
 
, MD 
 
Ascendis Pharma, Inc 
 
Date 
PPD
PPD


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SUMMARY OF CHANGES – VERSION 5, 28 December 2022  
Rationale 
The following substantial changes are made from protocol v 4.0 to protocol v 5.0: 
Section (s) 
Change 
Rationale 
Front page 
Updated contact information for medical 
monitors  
Change in Sponsor staff 
10.1.3.20; Synopsis 
Adding information of a new separate 
long-term open-label extension study for 
participants completing treatment in the 
TCC-201 protocol. 
Introducing the potential option to 
continue treatment in a separate long-
term open-label extension study 
(ASND0039) for the participants who 
are eligible and if no safety concerns for 
continued treatment with TransCon CNP 
have been identified. 
10.1.3.21; Synopsis; 
Appendix 1 
(Schedule of Events 
– OLE) 
Follow-Up Visit not required for 
participants who will continue in the 
separate long-term open-label study 
(ASND0039). 
The assessments scheduled to be 
performed at the Follow-Up Visit will be 
performed in the long-term open-label 
extension study for the participants who 
continue in that study. 
11.8.1  
Change of “Bone Age X-ray” to “Hand 
and Wrist X-ray”. 
Clarification of the scope of assessments 
made from the x-ray of the hand and 
wrist, as the images will not only be 
assessed for bone age but also for bone 
growth.  
11.8.2  
Adding “bone growth” to the assessments 
made from the anterior-posterior standing 
lower extremity x-rays. 
Clarification of the scope of assessments 
made from the x-ray of the lower 
extremity, as the images will also be 
assessed for bone growth. 
12.4.2  
Updated SAE reporting  
Reporting of Serious Adverse Events 
and pregnancies may contain personal 
identifiable information covered by data 
privacy regulation. As emails/fax are not 
considered to be adequately secure for 
sharing this type of information the 
current reporting method may therefore 
impose a risk of data breach.  
In order to mitigate this risk, Ascendis 
Pharma is changing the reporting 
method to secure online reporting 
through the Ascendis Safety Reporting 
Portal (safety.ascendispharma.com). 
This change has previously been 
implemented in a non-substantial 
protocol addendum version 1.0 and is 
now incorporated in the full protocol. 
 


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2. 
SYNOPSIS  
PRODUCT 
NUMBER/NAME 
TransCon CNP 
PROTOCOL NUMBER 
TCC-201 
IND NUMBER 
142685 
EUDRACT NUMBER 
2019-002754-22 
DEVELOPMENT 
PHASE 
2 
PROTOCOL TITLE 
ACcomplisH: A Phase 2, multicenter, double-blind, randomized, 
placebo-controlled, dose escalation trial evaluating safety, efficacy, 
and pharmacokinetics of subcutaneous doses of TransCon CNP 
administered once weekly for 52 weeks in prepubertal children with 
achondroplasia followed by an Open-Label Extension Period 
INDICATION 
Achondroplasia 
OBJECTIVES 
Primary: 
In prepubertal children with achondroplasia (ACH) at 52 weeks 
x To determine the safety of once weekly subcutaneous (SC) doses 
of TransCon CNP  
x To evaluate the effect of once weekly SC doses of TransCon CNP 
on annualized height velocity (AHV) 
Secondary: 
x To evaluate the effect of once weekly SC doses of TransCon CNP 
on body proportionality (upper to lower body segment ratio) in 
prepubertal children with ACH at 52 weeks  
x To evaluate the pharmacokinetic (PK) properties of once weekly 
SC doses of TransCon CNP 
x To assess the potential immunogenic response to once weekly SC 
doses of TransCon CNP 
Exploratory: 
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PLANNED TRIAL 
SITES 
Approximately 35 
PLANNED NUMBER 
OF PARTICIPANTS 
Minimum of 60  
TRIAL POPULATION 
Minimum of 60 male and female prepubertal children with ACH aged 
2 to 10 years old 
ELIGIBILITY 
CRITERIA 
Inclusion Criteria 
1. Clinical diagnosis of ACH with genetic confirmation (See 
Section 11.11) 
2. Age between 2 to 10 years old (inclusive) at Screening Visit 
3. Prepubertal (Stage 1 breasts for girls or testicular volume < 4ml 
for boys) at Screening Visit (See Section 11.3) 
4. Able to stand without assistance 
5. Caregiver willing and able to administer subcutaneous injections 
of study drug  
6. Written, signed informed consent of the parent(s) or legal 
guardian(s) of the participant and written assent of the participant 
as required by the institutional review board/human research 
ethics committee/independent ethics committee (IRB/HREC/IEC) 
Exclusion Criteria 
1. Clinically significant findings at Screening that: 
x are expected to require surgical intervention during 
participation in the trial or  
x are musculoskeletal in nature, such as Salter-Harris fractures 
and severe hip pain or 
x otherwise are considered by investigator or Medical Monitor 
to make a participant unfit to receive study drug or undergo 
trial related procedures 
2. Have received treatment (>3 months) of human growth hormone 
(hGH) or other medications known to affect stature or body 
proportionality at any time 
3. Have received any dose of medications intended to affect stature 
or body proportionality within the previous 6 months of Screening 
Visit 
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4. Have received any study drug or device intended to affect stature 
or body proportionality at any time  
5. History or presence of injury or disease of the growth plate(s), 
other than ACH, that affects growth potential of long bones  
6. History of any bone-related surgery that affects growth potential 
of long bones, such as orthopedic reconstructive surgery and 
osteotomy (Limb-lengthening with full recovery is allowed with a 
minimum of 12 months of bone healing. Foramen magnum 
decompression and laminectomy with full recovery are allowed 
with minimum of 6 months of bone healing. History of 8 plate 
epiphysiodesis is allowed, but the plates must have been removed 
prior to Screening with minimum 4 weeks of healing.)  
7. Have a form of skeletal dysplasia other than ACH or known 
medical conditions that result in short stature or abnormal growth 
[such as severe achondroplasia with developmental delay and 
acanthosis nigricans (SADDAN), hypochondroplasia, growth 
hormone deficiency, Turner syndrome, pseudoachondroplasia, 
inflammatory bowel disease,  chronic renal insufficiency, active 
celiac disease1, Vitamin D deficiency2, untreated hypothyroidism3, 
poorly controlled diabetes mellitus (HbA1c ≥8.0%) or diabetic 
complications4] 
1Celiac disease responsive to a gluten-free diet is allowed 
2Vitamin D deficiency or insufficiency treated with 
supplementation is allowed. Vitamin D deficiency is defined as 
25(OH)D level <20ng/mL (<49.9 nmol/L), insufficiency is 
defined as 25(OH)D level 20-30ng/mL (49.92 - 74.86 nmol/L).  
Participants with Vitamin D deficiency or insufficiency must be 
on Vitamin D regimen before randomization.  
3Participants with hypothyroidism must be clinically euthyroid 
for 3 months prior to Screening Visit and, in the opinion of the 
investigator, have achieved any catch-up growth expected from 
thyroxine replacement 
4Participants with diabetes mellitus must have been on stable 
medication regimen for 3 months prior to randomization (dose 
adjustments are allowed but addition or discontinuation of 
medications in this time period is disallowed) 
8. History or presence of malignant disease, other than basal cell 
epithelioma/carcinoma or completely resected squamous skin 
cancer with no recurrence for 12 months per medical records 
9. History or presence of the following: 
• Chronic anemia (resolved iron deficiency anemia is allowed) 
• Significant cardiovascular disease per the judgement of the 
investigator, such as congenital heart disease (uncomplicated 
patent ductus arteriosus and atrial or ventricular septal defect 


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with repair are allowed), aortic insufficiency, clinically 
significant arrhythmias, congestive heart failure with NYHA 
class II and above, or other conditions that impair regulation of 
blood pressure or heart rate 
• Condition that impacts hemodynamic stability (such as 
autonomic dysfunction, orthostatic intolerance) 
• History of chronic renal insufficiency  
• Chronic or recurrent illness that can affect hydration or volume 
status. This may include conditions associated with decreased 
nutritional intake or increased volume loss 
• Bone fracture within 6 months prior to Screening Visit (within 
2 months for fracture of digits) 
• Any disease or condition that, in the opinion of the 
investigator, may make the participant unlikely to fully 
complete the trial, may confound interpretation of trial results, 
or presents undue risk from receiving study drug 
10. Child has significant electrocardiogram abnormalities, including 
evidence of a previous myocardial infarction, left ventricular 
hypertrophy, flat T waves (particularly in the inferior leads) or 
more than minor non-specific ST-T wave changes or:  
• QRS >90 milliseconds (msec) 
• QT interval corrected using Fridericia’s formula (QTcF) 
>440 msec 
• PR interval >170 msec 
• Complete right or left bundle branch block 
11. Requires, or anticipated to require, chronic (> 4 weeks) or 
repeated (more than twice per year) treatment with oral 
corticosteroids during participation in the trial (low and mid-dose 
inhaled corticosteroids are allowed. High-dose inhaled 
corticosteroids are not allowed.). See Appendix 5 for definition of 
high doses of inhaled corticosteroids. 
12. Use of medication known to prolong the QT/QTc interval within 
7 days or 5 half-lives (whichever is longer) prior to the Screening 
Visit (see https://crediblemeds.org/ for the list of medications that 
are known to prolong the QT/QTc interval. Note: Only 
medications on the Known Risk list are excluded, not those on the 
Possible or Conditional Risk lists) 
13. Ongoing treatment with any medication that affects blood pressure 
or heart rate 
14. Known hypersensitivity to the components of the study drug 
[trehalose, tris(hydroxymethyl)aminomethane, succinate and 
PEG] 


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15. Any other reason that in the opinion of the investigator would 
prevent the child from complying with the trial requirements or 
completing the trial 
ROLLOVER 
CRITERIA 
Participants are eligible for the Open-Label Extension Period if they 
fulfill the following rollover criteria: 
1. Have completed the 52 weeks randomized treatment period 
2. Written, signed informed consent of the parent(s) or legal 
guardian(s) of the participant and written assent of the participant 
as required by the institutional review board/human research 
ethics committee/independent ethics committee (IRB/HREC/IEC) 
to continue into the Open-Label Extension (OLE) Period   
3. Do not fulfill any of the Holding/stopping study drug conditions 
or symptoms (see Section 9.6)  
TRIAL DESIGN 
This trial is a multicenter trial consisting of two treatment periods. A 
52 week double-blind, randomized, placebo controlled, dose 
escalation trial evaluating up to 5 different dose levels of weekly 
TransCon CNP administered subcutaneously in prepubertal children 
2 to 10 years old, inclusive, with ACH. After completing 52 weeks of 
their assigned cohort dose, participants who fulfill the rollover criteria 
can continue into the 104 weeks Open-Label Extension Period. In this 
extension period, participants may receive the highest dose level of 
TransCon CNP that has been reviewed and recommended by the Data 
Monitoring Committee (DMC) for safety. 
 
Trial Design Scheme: 
 
Trial design scheme in the Randomized and Open-Label Extension 
period. In the Randomized Treatment Period, participants in each 
cohort will receive their randomized treatment for 52 weeks, after 
which they are rolled over into the Open-Label Extension. The 
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initiation of a new, subsequent cohort in the Randomized Period is 
gated by a DMC that reviews 3 months of safety data of the current 
cohort to determine if the dose is safe, after which the DMC can 
recommend to proceed with the next cohort. In the Open-Label 
Extension Period, participants may receive the highest dose level of 
TransCon CNP that has been reviewed and recommended by the Data 
Monitoring Committee (DMC) for safety and has passed DMC safety 
review.   
Cohort 
Planned Dose Level 
Approximate Number 
Of Participants** 
1 
6 µg CNP/kg/week 
9 on TransCon CNP, 3 on placebo 
2 
20 µg CNP/kg/week 
≥9 on TransCon CNP, ≥3 on 
placebo 
3 
50 µg CNP/kg/week 
≥9 on TransCon CNP, ≥3 on 
placebo 
4 
100 µg CNP/kg/week 
≥9 on TransCon CNP, ≥3 on 
placebo 
5 
> 100 µg CNP/kg/week* ≥9 on TransCon CNP, ≥3 on 
placebo 
*At a dose to be determined, if needed, based on emerging data 
**Minimum of 12 participants per cohort will be enrolled. Plan to 
enroll approximately 14 participants per cohort to account for 
potential dropouts due to COVID-19. 
Visit Schedule Diagram in the Randomized and Open-Label 
Extension Periods 
 
Screening Visit (up to approximately 1 to 4 weeks prior to 
randomization): 
Following informed consent, participants will complete the Screening 
Visit to determine eligibility. 
Screening evaluations will include: 
1. PRO/ObsRO validation battery 
2. Verification of eligibility 


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3. Demographics (date of birth, age at screening, biological sex, 
ethnicity, race) 
4. Medical history including family history of ACH, age of 
diagnosis, date of diagnosis (if available), type of mutation, and 
historical anthropometric measurements, as available 
5. Prior and concomitant medications 
6. Vital sign measurements (Temperature, HR, BP) 
7. Full physical examination (general appearance, HEENT, Neck 
(including thyroid), Lung/pulmonary, Chest, CV, Abdomen, Back, 
GU, Neurological, Extremities, and Skin), including assessment of 
pubertal status and thorough skeletal exam 
8. Baseline qualitative assessment of sleep and snoring pattern 
(clinical assessment for monitoring) 
9. Weight 
10. Standing height 
11. Sitting height 
12. 12-lead ECG 
13. Genetic confirmation of ACH (if not done previously). See 
Section 11.11 
14. Blood collection for the following laboratory assessments: 
a. 
Chemistry 
b. TSH 
c. 
Hemoglobin A1c 
d. Hematology 
e. 
Lipid panel 
f. 
25(OH) Vitamin D 
g. Anti-drug antibodies 
h. Biomarkers 
15. Urine collection 
16. 
 
Screening Visit may be conducted remotely (e.g. at the participant’s 
home), at the discretion of the investigator, to minimize the risk of 
exposure to an infection during a pandemic or due to other restrictions 
that prevent the participant from being able to travel to the site. In 
such an event, consent may be obtained remotely as allowed by the 
applicable IRB/EC requirements, and the Investigator will conduct the 
scheduled assessments remotely with assistance from the home health 
nurse (HHN) who will be with the participant. If the PRO/ObsRO 
validation battery cannot be completed during the Screening Visit due 
to the visit being conducted remotely, the battery should be completed 
separately at approximately 14 days prior to Visit 1, up to 7 days prior 
to Visit 1.  
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All anthropometric measurements per medical records for up to one 
year prior to Screening Visit should be collected. If measurement(s) 
are not available within one year, the last available measurement(s) 
prior to Screening Visit should be collected. 
Thorough skeletal physical exam will be performed by palpating the 
bone structure and joints for tenderness and mobility and other 
abnormal changes not normally found in children with ACH. Special 
attention will be paid to the hip exam, which will include a supine 
assessment of abduction and adduction of hips to assess for pain and 
any limitation of range of motion. If changes are noted further 
evaluation will be required as clinically indicated, including imaging 
and/or orthopedic consultation. DMC will be apprised of any safety 
findings. 
Qualitative assessment of sleep and snoring pattern should include 
questions about neck hyperextension during sleep, loud and irregular 
snoring, glottal stops, observed sleep apnea, deep compensatory sighs, 
self-arousals, secondary enuresis, night-time emesis, morning 
headaches, daytime somnolence, or changes in school performance or 
behavior (Pauli 2019). 
For the assessment of pubertal status, boys will be assessed for testis 
volumes, and girls for breast development according to Tanner stages 
(Tanner 1976).  Pubic hair rating will also be recorded according to 
Tanner stages but will not be used to assess eligibility.  All 
participants must be Tanner Stage 1 for breast development 
(girls) - no glandular development/breast buds, and Tanner Stage 1 for 
gonadal development (boys) - testicular volume < 4 mL 
(Emmanuel 2019). Tanner stage progression during the course of the 
trial will not impact study treatment. See Appendix 3 for details. 
In case the Screening Visit is conducted remotely, full physical exam 
including pubertal assessment and thorough skeletal exam, may be 
conducted at Visit 1 before administration of study drug, with the 
understanding that an exam consistent with Tanner stage ≥ 2 is 
exclusionary. If the full physical exam and thorough skeletal exam are 
done pre-dose at Visit 1, an additional thorough skeletal exam and 
limited symptom directed physical exam at Visit 1 are not required. 
Visit 1 (Randomization/Week 0): 
Participants meeting all entry criteria will return to the clinic for 
Visit 1.   
The following will be performed prior to randomization and study 
drug administration: 
1. Subset of PRO/ObsRO validation battery 
2. Review of changes in medical history 
3. Review of concomitant medications 


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4. Review adverse events (including review of ACH comorbidities 
based on age, including risk of sleep apnea and cervical medullary 
compression (CMC)) 
5. Vital sign measurements (Temperature, HR, BP), including 
orthostatic HR and BP 
6. Limited symptom-directed physical examination (at investigator’s 
discretion), injection site inspection, and thorough skeletal 
physical exam 
7. Qualitative assessment of changes of sleep and snoring pattern 
8. Weight 
9. All anthropometric measurements 
10. Radiographic assessment of bone 
a. Left hand and wrist bone age X-ray  
b. Dual-energy X-ray absorptiometry (DXA)  
c. Anterior-posterior (AP) standing lower extremity X-ray 
d. AP and lateral spine X-ray 
11. Blood collection for the following laboratory assessments: 
a. Chemistry 
b. Hematology 
c. Pharmacokinetics 
d. Biomarkers 
e. Anti-drug antibodies 
12. 
 
13. After completion of these assessment, participants can proceed to 
randomization and study drug administration: 
14. Randomization 
15. Study drug administration at site and diary dispensing 
If for any reason the PRO/ObsRO validation battery for the Screening 
Visit was not completed prior to Visit 1, the same battery should be 
completed during Visit 1 prior to study drug administration in lieu of 
the subset scheduled for Visit 1. 
Orthostatic vital signs (HR, BP) will be taken at rest (preferably 
supine) and upon standing. Orthostatic hypotension is defined as 
decrease in SBP of ≥ 20 mmHg (Stewart 2018). Accompanying 
tachycardia is defined as change of heart rate increment of ≥40 bpm 
and absolute orthostatic HR ≥130 bpm (for ages 13 years and 
younger) (Singer 2012). 
Thorough skeletal physical exam will be performed and additional 
imaging assessments may be conducted as clinically indicated based 
on the physical exam findings.   
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Limited symptom-directed physical examination of other systems 
should be performed at the discretion of the investigator to verify no 
clinically relevant changes have occurred since the Screening Visit. 
Injection site must be visually inspected prior to dosing.  
If the Screening Visit was conducted remotely, full physical 
examination must be performed at Visit 1 before administration of 
study drug. Additional thorough skeletal exam and limited symptom 
directed physical exam are not required. 
Anthropometric measurements should be taken following the 
Anthropometric Parameter Manual. For any anthropometric 
parameters that could not be measured during the visit, the reason 
must be documented.  
Radiographic assessments may not be required at Visit 1, with 
Medical Monitor approval, if the same assessments were conducted 
within approximately 3 months prior to Visit 1. If radiographic 
assessments cannot be completed prior to study drug administration 
due to scheduling conflicts, the assessments may be completed at up 
to 24 hours after study drug administration. 
Bone age using X-ray imaging will be assessed in the left hand and 
wrist for all participants unless a medical reason prohibits.  
DXA will be performed only for participants aged 5 years and older. 
The first dose of study drug will be administered on-site to provide 
training to the caregiver on study drug administration. Participant will 
be monitored for at least 2 hours in the clinic after injection for any 
acute reactions. Visual inspection of the injection site and vital signs 
measurements (Temperature, HR, and BP) will be performed at 1 
hour and 2 hours after injection. Participants should be monitored 
longer as clinically indicated based on any clinically significant 
changes that emerge during the 2 hours. 
For participants who weigh ≥11 kg, the following will also be 
performed after injection of study drug: 
• Blood collection for pharmacokinetic analyses at approximately 8, 
24, and 48 hours after injection 
• Orthostatic vital signs (HR, BP) at rest (preferably supine) and 
upon standing prior to blood collection at approximately 8, 24, 
and 48 hours after injection 
• Inspection of injection site at approximately 8, 24, and 48 hours 
after injection 
• ECG collection at approximately 48 hours after injection prior to 
PK blood collection 
Allowances will be made for accommodation. Exceptions to the 
extended PK blood collection will be considered on an individual 
basis (e.g. if travel creates an undue hardship for a family). 
Assessments at 24 hours and 48 hours after injection, including 


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orthostatic vital signs, ECG collection, blood collection, and injection 
site assessment may be conducted remotely by HHN.  
Phone Visit (Week 2 ±3 days): 
All participants will be contacted by phone during Week 2 (±3 days) 
for follow up. During the call, the study staff will ask the caregiver 
about the general well-being of the child, inquire regarding correct 
administration of study drug, record any AEs, record any concomitant 
medication changes and answer any questions. 
Visit 2 (Week 4 ±3 days), Visit 3, 4, 5, 6, (Week 8, 12, 26, 
39 ±7 days) Visit: 
The following will be performed: 
1. Subset of PRO/ObsRO validation battery (Visit 3, 4, 5, 6 only) 
2. Review changes in concomitant medications 
3. Review of adverse events (including review of ACH comorbidities 
based on age, including risk of sleep apnea and CMC) 
4. Vital sign measurements (Temperature, BP, HR) 
5. Limited, symptom-directed physical examination, injection site 
inspection, and thorough skeletal physical exam (Visit 2, 3, 4, 
6 only) 
6. Full physical examination, including assessment of pubertal status, 
injection site inspection, and thorough skeletal physical exam 
(Visit 5 only) 
7. Qualitative assessment of changes of sleep and snoring pattern 
8. Weight  
9. Standing height and sitting height only (Visit 2, 3, 4, 6 only) 
10. All anthropometric measurements (Visit 5 only) 
11. Radiographic assessment of bone 
a. AP standing lower extremity X-ray (Visit 4 only) 
b. AP and lateral spine X-ray (Visit 4 only) 
12. 12-lead ECG (Visit 2, 3, and 5 only) 
13. Study drug and diary dispensing  
14. Blood collection for the following laboratory assessments: 
a. Chemistry 
b. Hematology 
c. Lipid panel (Visit 3 and 6 only) 
d. 25(OH) Vitamin D (Visit 5 only) 
e. Pharmacokinetics 
f. Biomarkers (except Visit 3) 
g. Anti-drug antibodies (except Visit 3) 
15. Urine collection (Visit 4, 5, and 6 only) 
16. 
 (Visits 3, 4, 5, and 
6 only) 
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Visit windows for all visits after Visit 1 may be increased due to 
extenuating circumstances such as Covid-19 travel restrictions, with 
the approval of the Medical Monitor.  
At Visit 2 (Week 4) and Visit 5 (Week 26), blood collection for 
pharmacokinetics must be at trough level. Therefore, study drug 
cannot be administered within 6 days prior to these visits.  
Visit 2, 3, 4, and 6 may be conducted remotely with assistance from 
the home health nurse (HHN), at the discretion of the Investigator. A 
portable stadiometer will be used to measure standing and sitting 
height and a portable scale to measure weight. Radiographic 
assessments at Visit 4 may be conducted remotely (e.g. at a 
community imaging center). 
Visit 5 may only be conducted remotely when regional/institutional 
restrictions prohibit site visits (e.g. facility closed due to pandemic). If 
Visit 5 must be conducted remotely, a portable stadiometer will be 
used to measure standing and sitting height and a portable scale to 
measure weight. A physical assessment will be performed by the 
HHN under the remote supervision of the Investigator.  
Visit 7 (Week 52 ±7 days) or ET Visit: 
This visit will serve as the last visit in the Randomized Period and the 
first visit in the Open-Label Extension Period.  
At Visit 7, blood collection for pharmacokinetics must be at trough 
level. Therefore, study drug cannot be administered within 6 days 
prior to the visit. For participants who do not roll over to the Open-
Label Extension, no further dose of study drug will be administered. 
Visit 7 may only be conducted remotely when regional/institutional 
restrictions prohibit site visits (e.g. facility closed due to pandemic). If 
Visit 7 is conducted remotely, a portable stadiometer will be used to 
measure standing and sitting height and a portable scale to measure 
weight. A physical assessment will be performed by the HHN under 
the remote supervision of the Investigator.   
The following will be performed: 
1. PRO/ObsRO validation battery 
2. Review changes in concomitant medications 
3. Review adverse events (including review of ACH comorbidities 
based on age, including risk of sleep apnea and CMC) 
4. Vital signs measurement (Temperature, HR, BP) 
5. Full physical examination including assessment of pubertal status, 
injection site inspection, and thorough skeletal physical exam 
6. Qualitative assessment of changes of sleep and snoring pattern 
7. Weight 
8. All anthropometric measurements 


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9. Radiographic assessment of bone 
a. Left hand and wrist Bone age X-ray 
b. DXA 
c. AP Standing lower extremity X-ray 
d. AP and lateral spine X-ray 
10. 12-lead ECG  
11. Blood collection for the following laboratory assessments: 
a. Chemistry  
b. Hematology  
c. 25(OH) Vitamin D  
d. Lipid panel 
e. Pharmacokinetics  
f. Biomarkers  
g. Anti-drug antibodies 
12. Urine collection 
13. 
 
Radiographic assessments at Visit 7 may be conducted remotely (e.g. 
at a community imaging center). Alternatively, radiologic assessments 
may be deferred until the participant is able to travel to the site.  
Radiographic assessments may not be required at Visit 7, with 
Medical Monitor approval, if the same assessments were conducted 
within approximately 3 months prior to Visit 7. 
Immediately following completion of 52 weeks in the Randomized 
Period, all participants, including those randomized to placebo, may 
continue into the Open-Label Extension Period to receive TransCon 
CNP if they fulfill the rollover criteria (see Section 8.1.3 ). If the 
Investigator or Medical Monitor has concerns about continuing the 
participant in the Open-Label Extension Period (e.g. potential safety 
concerns or emergent fulfillment of holding/stopping criteria) 
participant may end treatment at the end of the Randomized Period.  
For those participants not rolling over to the Open-Label Extension 
Period, a follow-up visit should be scheduled after 5 weeks (please 
see section below on follow-up visit). 
Follow-Up Visit (Week 57 ±7 days): 
Participants who are not continuing in the Open-Label Extension 
Period will attend a follow-up visit 5 weeks after Visit 7 to review any 
adverse events, to collect blood samples for assessment of anti-drug 
antibodies and answer any questions. The Follow-up visit may be 
conducted remotely (e.g. at the participant’s home) by the HHN at the 
discretion of the investigator to minimize the risk of exposure to an 
infection during a pandemic, or due to other restrictions that prevent 
the participant from being able to travel to the site for the blood 
collection. 
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OPEN-LABEL EXTENSION PERIOD VISITS: 
Visit 7 (Week 52 ±7 days) 
For participants continuing in the Open-Label Extension Period, all 
Visit 7 assessments for the Open-Label Extension Period must be 
done immediately following completion of the Visit 7 assessments for 
the Randomized Period. 
Prior to any protocol related activities for the Open-Label Extension 
Period, signed informed consent will be obtained for each potential 
participant in accordance with GCP and regional regulatory 
requirements. The format and content of the ICF must be approved by 
the appropriate institutional review board/ethics committee (IRB/EC) 
prior to implementation.   
During the Open-Label Extension Period, the Investigator should 
ascertain an individual’s risk for becoming pregnant or fathering a 
child, and take appropriate steps for participants that attain 
reproductive potential during participation in the trial (see 
Appendix 6). 
After completion of all scheduled assessments for the Randomized 
Period, the following will be performed: 
1. Informed consent 
2. Assessment of childbearing potential according to Appendix 6  
3. Urinary hCG test for females of childbearing potential (according 
to Appendix 6) 
4. Study drug and diary dispensing 
For participants who received placebo during the Randomized Period, 
this will be the first dose of TransCon CNP, and in order to maintain 
the blind, all participants must undergo the same safety monitoring. 
Study drug must be administered on-site and participants will be 
monitored for at least 2 hours in the clinic after injection for any acute 
reactions. Visual inspection of the injection site and vital signs 
measurements (Temperature, HR, and BP) will be performed at 1 
hour and 2 hours after injection. Participants should be monitored 
longer as clinically indicated based on any clinically significant 
changes that emerge during the 2 hours.  
For participants who weigh ≥11 kg, the following will also be 
performed after injection of study drug: 
• Blood collection for pharmacokinetic analyses at approximately 8, 
24, and 48 hours after injection 
• Orthostatic vital signs (HR and BP) at rest (preferably supine) and 
upon standing prior to blood collection at approximately 8, 24, 
and 48 hours after injection 
• Inspection of injection site at approximately 8, 24, and 48 hours 
after injection 


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• ECG collection at approximately 48 hours after injection prior to 
PK blood collection 
Allowances will be made for accommodation.  Exceptions to the 
extended PK blood collection will be considered on an individual 
basis (e.g. if travel creates an undue hardship for a family).  
Assessments at 24 hours and 48 hours after injection, including 
orthostatic vital signs, ECG collection, blood collection, and injection 
site assessment may be conducted remotely by HHN. 
Phone Visit (Week 54 ±3 days): 
All participants will be contacted by phone during Week 54 (±3 days) 
for follow up. During the call, the study staff will ask the caregiver 
about the general well-being of the child, inquire regarding correct 
administration of study drug procedures, record any AEs, record any 
concomitant medication changes, and answer any questions. 
Visit 8 (± 3 days), 9, 10, 11, 12, 13, 14, 15, 16/ET (Week 56, 65, 78, 
91, 104, 117, 130, 143, 156  (±7 days): 
The following will be performed: 
1. PRO/ObsRO validation battery (Visit 12, 16/ET) 
2. Subset of PRO/ObsRO validation battery (Visit 10 and 14) 
3. Review changes in concomitant medications 
4. Review adverse events (including review of ACH comorbidities 
based on age, including risk of sleep apnea and CMC) 
5. Vital sign measurements (Temperature, HR, BP) 
6. Weight  
7. Standing height and sitting height (Visit 8, 9, 11, 13, and 15) 
8. All anthropometric measurements (Visit 10, 12, 14, and 16/ET) 
9. Full physical examination, injection site inspection, and thorough 
skeletal exam (Visit 10, 12, 14, and 16/ET) 
10. Limited physical examination, injection site inspection, and 
thorough skeletal exam (Visit 8, 9, 11, 13, and 15) 
11. Assessment of pubertal status and childbearing potential according 
to Appendix 6 
12. Qualitative assessment of changes of sleep and snoring pattern 
13. Radiographic assessments  
a. X-ray of left hand and wrist for bone age (Visit 12 and 16/ET) 
b. Anterior-posterior (AP) standing lower extremity X-ray (Visit 
9, 12, 13, and 16/ET) 
c. Dual-energy X-ray absorptiometry (DXA) for bone mineral 
density (participants 5 years and older only) (Visit 12 and 
16/ET) 
d. Anterior-posterior and lateral spine X-ray (Visit 9, 12, 13, and 
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14. 12-lead ECG (Visit 8, 10, 12, 14 and 16/ET and Visit 9 and 11 if 
dose is escalated at the visit) 
15. Blood collection for the following laboratory assessments 
a. Chemistry 
b. Hematology 
c. 25(OH) Vitamin D (Visit, 10, 12, 14, and 16/ET) 
d. Lipid panel (Visit 10, 12, 14, and 16/ET) 
e. Pharmacokinetics (Visit 8, 10, 12, 14, and 16/ET and Visit 9 
and 11 if dose is escalated at the visit) 
f. Anti-drug antibodies 
g. Biomarkers 
16. Urine collection  
17. Urine collection for Human Chorionic Gonadotropin (hCG) for 
females of childbearing potential only (see Appendix 6) 
18. Study drug and diary dispensing (Visit 8, 9, 10, 11, 12, 13, 14, and 
15) 
19. 
 (Visit 9, 10, 11, 12, 13, 14, 15, and 16/ET) 
Visit 8, 9, 11, 13 and 15 may be conducted remotely with assistance 
from the home health nurse (HHN), at the discretion of the 
Investigator. Pubertal assessments will be deferred until the next on-
site visit. A portable stadiometer will be used to measure standing and 
sitting height and a portable scale to measure weight. Scheduled 
radiographic assessments at Visit 9 and 13 may be performed within 1 
week prior to or after the visit if all scheduled assessments cannot be 
completed within the same day. Radiographic assessments may also 
be conducted remotely (e.g. at a community imaging center).  
Visit 10, 12, 14 and 16/ET may only be conducted remotely when 
regional/institutional restrictions prohibit site visits (e.g. facility 
closed due to pandemic). A portable stadiometer will be used to 
measure standing and sitting height and a portable scale to measure 
weight. A physical assessment will be performed by the HHN under 
the remote supervision of the Investigator, but the pubertal assessment 
will be deferred until the next on-site visit. Radiographic assessments 
at Visit 9, 12, 13 and 16/ET may be conducted remotely (e.g. at a 
community imaging center). Alternatively, radiologic assessments 
may be deferred until the participant is able to travel to the site. 
Radiographic assessments may not be required at Visit 16/ET, with 
Medical Monitor approval, if the same assessments were conducted 
within approximately 3 months prior to Visit 16/ET.  
During the Open-Label Extension Period, the Investigator should 
ascertain an individual’s risk for becoming pregnant or fathering a 
child and take appropriate steps for participants that attain 
reproductive potential during participation in the trial. This should be 
captured in the eCRF. Pregnancy prevention counseling and 
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pregnancy testing should be provided as appropriate and can be 
tailored per the Investigator’s judgement based on maturity and 
cultural norms. (see Appendix 6).  
Evaluation of childbearing potential and inclusion of related safety 
measures like pregnancy testing will be included throughout the 
Open-Label Extension Period (see Appendix 6). It is not deemed 
necessary to include these measures in the Randomized Period 
because if a child progressed from Tanner 1 at baseline to 
reproductive potential in less than one year it would be considered 
pathologic pubertal tempo and would lead to study drug 
discontinuation under Stopping Rules (see Section 9.6).  
Immediately following the completion of treatment in the Open-Label 
Extension period (Visit 16), participants may be offered participation 
in a separate Long-Term Open-Label Extension Study (ASND0039). 
Follow-Up Visit Open-Label Extension (Week 161 ±7 days): 
Participants will attend a follow-up visit 5 weeks after Visit 16 to 
review any adverse events, to collect blood samples for assessment of 
anti-drug antibodies and answer any questions. The Follow-up visit 
may be conducted remotely (e.g. at the participant’s home) by the 
HHN at the discretion of the investigator to minimize the risk of 
exposure to an infection during a pandemic, or due to other 
restrictions that prevent the participant from being able to travel to the 
site for the blood collection. The follow-up visit is not applicable for 
participants who will continue in the separate Long-Term Open-Label 
Extension Study (ASND0039). 
Study Drug Dosing: 
TransCon CNP (or placebo) will be dosed at 6 to 100 μg 
CNP/kg/week, and if adequate safety is demonstrated at 100 μg 
CNP/kg/week, dosing may advance to a higher dose cohort based on 
emerging data. 
  The initial volume of study drug (TransCon CNP or placebo) 
administered will be calculated using the weight measurement 
obtained at Visit 1.  The dose volume will be adjusted at each visit 
based on the participant’s weight at the corresponding visits.  Study 
drug will be dispensed for weekly administration by the caregiver, 
except for the first dose administered at the trial site.   
Data Monitoring Committee Meetings for Cohort Initiation and 
Dose Escalation in the Open-Label Extension Period 
Data monitoring committee meetings will be held by the Sponsor 
upon review of the following data to assess whether the next cohort 
should be initiated as planned: 
1. Initiation of Cohort 2: Cohort 1 data with a minimum of 12 weeks 
of follow up for all participants 
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2. Initiation of Cohort 3: Cohort 2 data with a minimum of 12 weeks 
of follow up for all participants and available data from all other 
cohorts 
3. Initiation of Cohort 4: Cohort 3 data with a minimum of 12 weeks 
of follow up for all participants and available data from all other 
cohorts 
An independent Data Monitoring Committee (DMC) will attend each 
DMC meeting to provide recommendations on the action to be taken 
(i.e. proceed to the next dose cohort as planned, modify the dose of 
the next cohort, or stop dose escalation).  
The DMC will be provided with the following unblinded data at each 
DMC meeting: 
1. Summary of safety data including but not limited to AEs, vital 
signs, and laboratory findings 
2. Details of SAEs and AEs leading to discontinuation of study drug 
3. Summary of anthropometric measurements of cohorts that 
completed at least 26 weeks 
4. Other relevant available data at the request of the DMC, including 
available PK data  
Following the Data Monitoring Committee meeting, the Sponsor will 
take into consideration the recommendation of the DMC to decide to 
either proceed to the next dose level as planned, modify the dose of 
the next cohort, or stop dose escalation for the Randomized Period.  If 
available data are inadequate to decide on the action to be taken, the 
decision may be deferred until after data through Visit 5 (Week 26) of 
the highest dosed cohort are available, at which time the Data 
Monitoring Committee meeting will be reconvened.  
Another DMC meeting will be held upon completion of 26 weeks of 
treatment (Visit 5) for the all participants in Cohort 4 to assess 
whether additional higher dose levels (up to 200 µg CNP/kg/week) 
should be investigated based on emerging data. After review of the 
data and consultation with the DMC, the Sponsor will decide whether 
a higher dose level should be investigated.  
The DMC will also make a recommendation regarding dose 
escalation for the Open-Label Extension Period, which could be up to 
the highest dose level of TransCon CNP that has been reviewed by the 
DMC for safety and has passed DMC safety review. Dose escalation 
for the individual participant should be implemented at the next 
scheduled visit (except Visit 8) in the Open-Label Extension Period. 
After discussion with the Medical Monitor, an Investigator may 
choose to not increase the dose for an individual participant or may 
decrease to a prior dose. 
If one serious adverse drug reaction or two severe adverse drug 
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will be halted. Additionally, an urgent DMC meeting will be called to 
determine whether dosing should be halted in that cohort or across the 
entire trial. If deemed appropriate after review of all available safety 
data, the DMC may recommend that dose escalation be re-started. If 
the DMC does not feel that enough data is available to make a 
recommendation, they may defer a decision and recommend a time at 
which the data should be re-evaluated. 
Additionally, the DMC will be notified, and a meeting may be called 
for each incident of study drug discontinuation for reasons related to 
safety. 
If dose escalation is discontinued prior to initiating the Cohort 4, 
participants to be enrolled in the cohorts not yet filled may receive the 
highest tolerated dose level investigated (or placebo), instead of the 
planned higher doses. The decision to complete all four planned 
cohorts will be made by the Sponsor after review of available data and 
consultation with the DMC.    
In addition, ad hoc DMC meetings may be called by the Sponsor at 
any time for review of newly identified safety concerns. 
INVESTIGATIONAL 
PRODUCT 
TransCon CNP Drug Product 
TransCon CNP is a long-acting essentially inactive prodrug 
 
  TransCon CNP releases active CNP via auto-cleavage of the 
TransCon Linker in a controlled manner based on physiologic pH and 
temperature.  As such, the TransCon technology is designed to 
provide sustained exposure of active CNP over 7 days, allowing an 
optimal pharmacokinetic profile for use in ACH.  
The drug product formulation containing TransCon CNP is a 
lyophilized powder in a single-use vial, i.e. TransCon CNP 3.9 mg 
  Prior to use, the lyophilized powder must be 
reconstituted with sterile water for injection from a prefilled syringe.  
  This 
solution will be administered by SC injection via syringe and needle. 
REFERENCE 
PRODUCT(S) 
Reference product will be supplied as one of two placebos: 
x Placebo for TransCon CNP drug product 
x sWfI (sterile water for injection) Placebo for TransCon CNP drug 
product 
Placebo for TransCon CNP drug product contains the same excipients 
as TransCon CNP drug product but does not contain TransCon CNP.  
Prior to use, the lyophilized powder must be reconstituted with sterile 
water for injection from a prefilled syringe.  This solution will be 
administered by SC injection via syringe and needle. 
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sWfI Placebo for TransCon CNP drug product consists of sWfI. The 
sWfI is supplied in the same prefilled syringe as the one used for 
reconstitution of the lyophilized powder of the Placebo for TransCon 
CNP drug product. The procedure for preparation and administration 
of sWfI Placebo for TransCon CNP drug product is the same as for 
Placebo for TransCon CNP drug product, only the vial with excipients 
will be replaced with an empty sterile vial. The diluent (sWfI) is 
injected into the empty vial and the dosing volume of sWfI will be 
drawn from the vial into the injection syringe and administered SC.  
If Placebo for TransCon CNP drug product is not available, sWfI 
Placebo for TransCon CNP drug product will be used until Placebo 
for TransCon CNP drug product becomes available.  
Placebo for TransCon CNP drug product will be available prior to the 
start of Cohort 2, so this procedure will only be utilized in Cohort 1.  
When Placebo for TransCon CNP drug product is available for Cohort 
1, study drug will be prepared and administered by a caregiver (after 
proper training). Total dose volume for participants in Cohort 1 is 
expected to be ≤ 0.05ml (based on 95th percentile weight of 32.5 kg 
for children with ACH at 10.5 years of age). At such low volumes, 
risk of possible discomfort associated with hypotonicity is minimal 
and does not pose a significant safety concern. 
The dose of Cohort 1 is 6 µg CNP/kg/week (0.006 mg/kg/week) and 
the concentration of reconstituted study drug is 3.6 mg CNP/mL. 
Therefore, study drug will be administered at 
0.006/3.6 = 0.0017mL/kg.  
TREATMENT 
REGIMEN 
Until Placebo containing the excipients become available, every dose 
of TransCon CNP or placebo will be prepared and administered by an 
unblinded site staff or home healthcare service. In order to maintain 
the blind, study drug will be prepared out of sight of the investigator, 
caregiver, and the participant. Once Placebo for TransCon CNP 
becomes available, study drug should be administered by the 
caregiver. The injections will be given SC once weekly 
(approximately every 7 days).  The dose (volume) of study drug will 
be adjusted according to the participant’s weight at each visit. 
For the first four weeks of study drug administration by the caregiver, 
once weekly home healthcare service will be offered to accommodate 
home administration of study drug. Extended support might be 
offered until participants/parents/caregivers are comfortable to take 
over administration of the study drug. 
Each participant will receive their assigned cohort dose for 52 weeks 
in the Randomized Period, after which they may roll over to the 
Open-Label Extension Period where all participants will receive 
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BLINDING 
This trial consists of a 52-week randomized, double-blind, 
randomized, placebo-controlled treatment period. Participants will be 
randomized to either TransCon CNP or placebo in 3:1 ratio within 
each cohort.  Once all participants enrolled in a dose cohort have 
completed (or withdrawn from) their Randomized Period and the 
database has been locked, the treatment allocation for that dose cohort 
will be unblinded. 
The Randomized Period will be followed by a 104-week Open-Label 
Extension treatment period where all participants will receive 
TransCon CNP.  
TRIAL AND 
TREATMENT 
DURATION 
The total duration of the trial for an individual participant is up to 
approximately 165 weeks. Duration includes up to approximately 
4 weeks of screening, plus 156 weeks of treatment (52 weeks of 
treatment in the Randomized Period and additional 104 weeks of 
treatment in the Open-Label Extension Period) and a 5-week 
follow-up period.   
STOPPING RULES 
The investigator or Medical Monitor (and, if needed, with DMC 
review) may temporarily hold or stop the dosing of study drug to a 
participant at any time during the trial. For participants that 
discontinue study drug for reasons related to safety, unblinding of the 
treatment assignment for the participant may occur if deemed 
necessary by the Sponsor to assess a potential safety signal or by the 
investigator to provide adequate medical care to the participant. In 
case of medical emergency, the investigator will have direct access to 
unblinding of the treatment through the Interactive web response 
system. Examples of conditions or symptoms that may warrant 
holding or stopping study drug at the investigator’s or Medical 
Monitor’s discretion include: 
1. Severe fracture of long bones or growth plates regardless of 
causality 
2. Evidence of symptomatic persistent orthostatic intolerance, lasting 
over 24 hours not explained by other probable causes. Orthostatic 
hypotension is defined as decrease in SBP of ≥20 mmHg 
(Stewart 2018). Accompanying tachycardia is defined as change 
of heart rate increment of ≥40 bpm and absolute orthostatic HR 
≥130 bpm (for ages 13 years and younger) (Singer 2012) 
3. Skeletal abnormalities typically not associated with ACH, growth 
or other concurrent medical conditions, such as 
a. Scoliosis 
b. Severe hip pain 
c. Findings from thorough skeletal exam requiring imaging or 
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d. Clinically relevant findings on radiologic assessments (new 
onset or worsening of tibial bowing, joint abnormalities at the 
elbows, evidence of slipped capital femoral epiphysis) 
4. A severe or serious adverse reaction 
5. QTc value > 500 msec, or an extension > 60 msec from baseline 
in absence of possible causes other than the study drug 
6. Diagnosis of heart disease requiring pharmaceutical or surgical 
intervention to maintain heart function 
7. Any other sign that warrants holding or discontinuing study drug 
at the discretion of the investigator or Medical Monitor  
The investigator, with Sponsor Medical Monitor notification, must 
stop study drug for an individual participant in the presence of the 
following symptoms at any time during the trial: 
1. Closed epiphysis (bone age >14.0 years for females or >16.0 years 
for males) 
2. Slipped capital femoral epiphysis 
3. Pregnancy, intention of becoming pregnant, and females who 
become of childbearing potential and who do not use highly 
effective contraceptive measures. Highly effective contraceptive 
measures are methods that can achieve a failure rate of less than 
1% per year when used consistently and correctly (see 
Appendix 6).  
If study drug is held or discontinued due to safety concerns, 
approval by the Medical Monitor is required prior to resumption 
of study drug. Consideration of dose changes due to safety 
concerns may occur on an individual basis. 
Any participant who discontinues study drug should be encouraged to 
remain in the trial and attend all subsequent trial visits and complete 
all assessments.  If, however, trial participation is fully discontinued 
for withdrawal of consent, an ET Visit should be performed.  
CRITERIA FOR 
EVALUATION 
Safety Endpoints 
The following safety endpoints will be assessed for both blinded 
Randomized Period and Open-Label Extension Period: 
• Incidence of AEs 
• All blood chemistry, hematology, lipid panel, and urinalysis 
parameters 
• Vital sign measurements and physical examination assessments 
• 12-lead ECG 
• Radiographic findings from: 
− 
Bone age X-ray 
− 
DXA 
− 
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 
AP and lateral spine X-ray 
x Incidence of anti-drug antibodies 
Efficacy Endpoints 
Primary endpoint 
x AHV as measured at 52 weeks of weekly TransCon CNP 
treatment or placebo 
Secondary endpoints 
Change in upper to lower body segment ratio as measured at 
52 weeks of weekly TransCon CNP treatment or placebo 
Exploratory Endpoints 
Pharmacokinetic Endpoints 
x Plasma concentration of Total CNP 
x Plasma concentration of Free CNP  
x Plasma concentration of mPEG and mPEG-linker 
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STATISTICAL 
METHODS 
Details of applicable statistical methods will be provided in a 
Statistical Analysis Plan.  
The Full Analysis Set will include all randomized participants who 
have received at least one dose of investigational product and have a 
non-missing baseline height as well as at least one post-baseline 
height measurement. Participants will be analyzed according to study 
treatment as randomized. The Safety Analysis Set will include all 
randomized participants who have received at least one dose of 
investigational product. Participants will be analyzed according to 
study treatment as treated. The efficacy analyses will be based on the 
Full Analysis Set and safety analyses will be based on the Safety 
Analysis Set. 
In general, analysis will be done by dose levels, and placebo 
participants will be pooled. Data from clinical assessments will be 
summarized using descriptive statistics. Categorical data will be 
presented using counts and percentages of participants. Continuous 
variables will be presented using number of participants, mean, 
standard deviation (SD), standard error (SE), median, minimum and 
maximum. Statistical significance is defined as P <0.05 (2-sided). 
For the primary efficacy endpoint, AHV at Week 52, the primary 
analysis is ANCOVA model with the AHV at Week 52 as the 
response variable, treatment (dose groups and placebo) as factors, 
baseline age, sex, and baseline height SDS as covariates. The similar 
ANCOVA model, with the baseline of the corresponding parameter as 
a covariate, will be applied to secondary and exploratory efficacy 
endpoints. As a sensitivity analysis for the primary efficacy endpoint, 
AHV at Week 52, the change from baseline to Week 52 in AHV will 
be analyzed using ANCOVA model with treatment and sex as factors, 
baseline age, baseline height SDS, and baseline AHV as covariates. 
Once the highest tolerated dose is established, the following 
sequential testing procedure will be used for the comparison between 
the highest tolerated dose group and pooled placebo group. 
The primary analysis for AHV at Week 52 will be performed first. If 
the p-value for comparing the highest tolerated dose group and pooled 
placebo is <0.05, then the formal hypothesis test for upper to lower 
body segment ratio will be performed. 
Descriptive analysis for safety will mainly include the incidence and 
type of TEAEs, safety laboratory values, vital signs, radiographic 
findings, ECG parameters and antibody parameters.   
SAMPLE SIZE 
DETERMINATION 
A sample size of 9 in active groups (per cohort) and 12 in the placebo 
group (combined across cohorts) will provide 97% power to detect a 
treatment difference of 2 cm/year in 12 month AHV at a 2-sided 
significance level of 5%, assuming the SD is 1.1 cm/yr. 


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3. 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................................2 
1. 
APPROVAL SIGNATURES .......................................................................................3 
1.1. 
Sponsor .........................................................................................................................3 
SUMMARY OF CHANGES – VERSION 5, 28 DECEMBER 2022 .............................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS ...........................................................................................29 
4. 
LIST OF ABBREVIATIONS.....................................................................................35 
5. 
INTRODUCTION ......................................................................................................38 
5.1. 
Background and Rationale ..........................................................................................38 
5.1.1. 
Achondroplasia ...........................................................................................................38 
5.1.2. 
Current Standard Therapy for ACH ...........................................................................38 
5.1.3. 
Fibroblast Growth Factor Receptor Type 3 ................................................................38 
5.1.4. 
C-type Natriuretic Peptide ..........................................................................................39 
5.1.5. 
Impact of ACH on Well-Being and Functioning in Children with the 
Condition and Their Caregivers ..................................................................................40 
5.2. 
Relevant Findings from Nonclinical Studies ..............................................................40 
5.3. 
Clinical Experience .....................................................................................................41 
5.4. 
Trial Rationale ............................................................................................................42 
5.5. 
Summary of Important Risks and Potential Benefits .................................................42 
5.5.1. 
Important Risks ...........................................................................................................42 
5.5.2. 
Potential Risks ............................................................................................................43 
5.5.2.1. 
Cardiovascular Changes .............................................................................................43 
5.5.2.2. 
Adverse Bone Overgrowth .........................................................................................43 
5.5.3. 
Potential Benefits ........................................................................................................43 
6. 
OBJECTIVES .............................................................................................................44 
6.1. 
Primary Objectives .....................................................................................................44 
6.2. 
Secondary Objectives .................................................................................................44 
6.3. 
Exploratory Objectives ...............................................................................................44 
7. 
TRIAL DESIGN .........................................................................................................45 
7.1. 
Overall Trial Design and Plan ....................................................................................45 
7.1.1. 
Measures Taken to Maximize Study Integrity and Minimize Bias ............................47 
7.2. 
Trial Sites ....................................................................................................................48 


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8. 
PARTICIPANT POPULATION ................................................................................48 
8.1. 
Eligibility Criteria .......................................................................................................48 
8.1.1. 
Inclusion Criteria ........................................................................................................48 
8.1.2. 
Exclusion Criteria .......................................................................................................48 
8.1.3. 
Rollover Criteria for Open-Label Extension Period ...................................................50 
8.2. 
Premature Participant Withdrawal ..............................................................................51 
8.2.1. 
Study Drug Discontinuation and Participant Withdrawal ..........................................51 
8.2.1.1. 
Study Drug Discontinuation .......................................................................................51 
8.3. 
Participant Replacement Criteria ................................................................................51 
9. 
TREATMENTS ..........................................................................................................51 
9.1. 
Investigational Product ...............................................................................................51 
9.1.1. 
Labeling ......................................................................................................................52 
9.1.2. 
Accountability, Storage, and Dispensing ....................................................................52 
9.2. 
Reference Product .......................................................................................................53 
9.3. 
Treatment Administered .............................................................................................53 
9.4. 
Selection of Trial Doses ..............................................................................................54 
9.5. 
Treatment Assignment ................................................................................................55 
9.5.1. 
Treatment Assignment During Randomized Period ...................................................55 
9.5.2. 
Dose Escalation ..........................................................................................................56 
9.6. 
Holding/Stopping Study Drug ....................................................................................57 
9.7. 
Prior and Concomitant Medications ...........................................................................58 
9.7.1. 
Prohibited Therapies ...................................................................................................59 
10. 
TRIAL PROCEDURES..............................................................................................59 
10.1. 
Trial Duration .............................................................................................................59 
10.1.1. 
Trial Periods and Visits ..............................................................................................59 
10.1.2. 
Screening Visit (approximately Week -4 to -1) ..........................................................60 
10.1.3. 
Randomized Treatment Period (Week 0 to Week 52) and Open-Label 
Extension Period (Week 52 – Week 156)...................................................................63 
10.1.3.1. 
Visit 1 (Randomization/Week 0) ................................................................................64 
10.1.3.2. 
Phone Visit (Week 2 ±3 days) ....................................................................................66 
10.1.3.3. 
Visit 2 (Week 4 ±3 days) ............................................................................................66 
10.1.3.4. 
Visit 3 (Week 8 ±7 days) ............................................................................................66 
10.1.3.5. 
Visit 4 (Week 12 ±7 days): .........................................................................................67 


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10.1.3.6. 
Visit 5 (Week 26 ±7 days): .........................................................................................68 
10.1.3.7. 
Visit 6 (Week 39 ±7 days): .........................................................................................69 
10.1.3.8. 
Visit 7 (Week 52 ±7 days) or ET Visit: ......................................................................70 
10.1.3.9. 
Follow-up Visit (Week 57 ±7 days):  For Participants Not Continuing in the 
Open-Label Extension ................................................................................................71 
10.1.3.10. Visit 7 (Week 52 ±7 days): .........................................................................................71 
10.1.3.11. Phone Visit (Week 54 ±3 days): .................................................................................72 
10.1.3.12. Visit 8 (Week 56 ±3 days): .........................................................................................72 
10.1.3.13. Visit 9 (Week 65) ±7 Days .........................................................................................73 
10.1.3.14. Visit 10 (Week 78) ±7 Days .......................................................................................74 
10.1.3.15. Visit 11 (Week 91) ±7 Days .......................................................................................75 
10.1.3.16. Visit 12 (Week 104) ±7 Days .....................................................................................76 
10.1.3.17. Visit 13 (Week 117) ±7 Days .....................................................................................77 
10.1.3.18. Visit 14 (Week 130) ±7 Days .....................................................................................78 
10.1.3.19. Visit 15 (Week 143) ±7 Days .....................................................................................78 
10.1.3.20. Visit 16 (Week 156) ±7 Days/Early Termination Visit ..............................................79 
10.1.3.21. Follow-Up Visit (Week 161 ±7 days): .......................................................................80 
10.1.4. 
Unscheduled Visits (UV) ............................................................................................81 
10.1.5. 
Early Termination (ET) Visits ....................................................................................81 
11. 
ASSESSMENTS.........................................................................................................81 
11.1. 
Vital Sign Measurements ............................................................................................81 
11.2. 
Electrocardiogram (ECG) ...........................................................................................82 
11.3. 
Physical Examinations ................................................................................................82 
11.4. 
Qualitative Assessment of Sleep and Snoring Pattern ................................................83 
11.5. 
Anthropometric Measurements ..................................................................................83 
11.6. 
PRO/ObsRO Validation Battery .................................................................................83 
11.7. 
 ........................................................84 
11.8. 
Radiographic Assessment of Bone .............................................................................85 
11.8.1. 
Hand and Wrist X-ray .................................................................................................85 
11.8.2. 
Anterior-posterior (AP) Standing Lower Extremity X-ray ........................................86 
11.8.3. 
Dual-energy X-ray Absorptiometry (DXA) ...............................................................86 
11.8.4. 
Anterior-posterior and Lateral Spine X-ray ................................................................86 
11.9. 
Weekly Diary ..............................................................................................................86 
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11.10. 
Adverse Event Review ...............................................................................................86 
11.11. 
Laboratory Assessments .............................................................................................87 
11.12. 
Treatment Period Administration ...............................................................................89 
12. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND REPORTING .........89 
12.1. 
Adverse Events ...........................................................................................................89 
12.1.1. 
Definition ....................................................................................................................89 
12.2. 
Methods and Timing for Assessing and Recording Safety Variables ........................90 
12.2.1. 
Adverse Event Reporting Period ................................................................................91 
12.2.2. 
Severity, Causality, and Outcome Assessment ...........................................................91 
12.2.2.1. 
Severity Rating ...........................................................................................................91 
12.2.2.2. 
Causality Rating ..........................................................................................................91 
12.2.2.3. 
Outcome Assessment ..................................................................................................92 
12.3. 
Procedures for Eliciting, Recording and Reporting Adverse Events .........................92 
12.3.1. 
Eliciting Adverse Events ............................................................................................92 
12.3.2. 
Recording Procedures for All Adverse Events ...........................................................93 
12.3.3. 
Specific Instructions for Recording Adverse Events ..................................................94 
12.4. 
Serious adverse events (SAE) and suspected unexpected serious adverse 
reactions (SUSAR) .....................................................................................................96 
12.4.1. 
Non-Serious Adverse Events Leading to Discontinuation .........................................96 
12.4.2. 
Reporting ....................................................................................................................96 
13. 
SAFETY MONITORING ..........................................................................................97 
14. 
STATISTICS ..............................................................................................................98 
14.1. 
General ........................................................................................................................98 
14.2. 
Endpoints ....................................................................................................................98 
14.2.1. 
Safety Endpoints .........................................................................................................98 
14.2.2. 
Efficacy Endpoints ......................................................................................................98 
14.2.3. 
Pharmacokinetic Endpoints ........................................................................................99 
14.3. 
Statistical Analysis ......................................................................................................99 
14.4. 
Planned Analysis ......................................................................................................100 
14.5. 
Sample Size Calculation ...........................................................................................101 
14.6. 
Significance ..............................................................................................................101 
15. 
TRIAL CONDUCT ..................................................................................................101 
15.1. 
Site Initiation ............................................................................................................101 


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15.2. 
Data Handling and Record Keeping .........................................................................101 
15.2.1. 
Collection of Data .....................................................................................................101 
15.2.2. 
Coding Dictionaries ..................................................................................................102 
15.2.3. 
Data Handling ...........................................................................................................102 
15.2.4. 
Direct Access to Source Data/Documents ................................................................102 
15.2.5. 
Record Keeping ........................................................................................................102 
15.3. 
Data Quality Control .................................................................................................103 
15.3.1. 
Monitoring Procedures .............................................................................................103 
15.3.2. 
Data Management .....................................................................................................103 
15.4. 
Auditing Procedures .................................................................................................104 
15.5. 
Laboratory Quality Standards ...................................................................................104 
15.6. 
Trial Termination or Completion..............................................................................104 
15.7. 
Changes to the Protocol ............................................................................................105 
15.8. 
Other Changes in Trial Conduct ...............................................................................105 
15.9. 
Use of Information and Publication ..........................................................................105 
16. 
ETHICAL AND LEGAL CONSIDERATIONS ......................................................105 
16.1. 
Data Monitoring Committee .....................................................................................105 
16.2. 
Informed Consent .....................................................................................................106 
16.2.1. 
Subject Identification Card .......................................................................................106 
16.3. 
IRB/EC Approvals ....................................................................................................106 
17. 
REFERENCES .........................................................................................................108 
SIGNATURE OF AGREEMENT ...............................................................................................113 
18. 
APPENDICES ..........................................................................................................114 
APPENDIX 1. SCHEDULE OF EVENTS IN THE RANDOMIZED PERIOD .....................115 
APPENDIX 2. SCHEDULE OF EVENTS IN THE OPEN-LABEL PERIOD ........................118 
APPENDIX 3. TANNER STAGING CRITERIA ....................................................................121 
APPENDIX 4. BLOOD VOLUME DRAWN AT EACH VISIT .............................................122 
APPENDIX 5. DEFINITION OF HIGH DOSES OF INHALED 
CORTICOSTEROIDS ..............................................................................................123 
APPENDIX 6. DEFINITION OF CHILDBEARING POTENTIAL AND 
CONTRACEPTIVE REQUIREMENTS ..................................................................124 
 
LIST OF TABLES  


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Table 1: 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
WHO Toxicity Grading Scale ....................................................................................91 
 
LIST OF FIGURES  
Figure 1: 
Schematic Overview of the Interactions Between the Intracellular Pathways 
of the Fibroblast-Growth-Factor-Receptor 3 (FGFR3) and the C-Type 
Natriuretic Peptide (CNP) Receptors [Natriuretic peptide receptor-B 
(NPR-B) and -C (NPR-C)] in Bone Growth ...............................................................39 
Figure 2: 
Trial Design Scheme ...................................................................................................46 
 
 


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4. 
LIST OF ABBREVIATIONS  
μg 
Microgram 
 
 
ACH 
achondroplasia 
AE 
adverse event 
AEM 
Achondroplasia Experience Measure 
AHV 
Annualized height velocity 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AP 
Anterior-posterior 
 
 
AST 
Aspartate aminotransferase 
BMD 
bone mineral density 
BMI 
body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Cº 
Celsius 
CFR 
Code of Federal Regulations 
 
 
cGMP 
Cyclic guanosine monophosphate 
cm 
Centimeter 
Cmax 
Maximum plasma drug concentration 
CMC 
Cervical medullary compression 
CNP 
C-type natriuretic peptide 
COVID 
Corona Virus Disease  
CRF 
Case report form 
CRO 
contract research organization 
CTX-I 
C‑terminal cross-linked telopeptide of type I collagen 
CV 
cardiovascular 
DMC 
Data Monitoring Committee 
DXA 
dual-energy X-ray absorptiometry 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
Electronic case report form 
EDC 
electronic data capture 
ER 
Emergency room 
CCI
CCI
CCI


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ET 
Early termination 
Fº 
Fahrenheit 
FDA 
United States Food and Drug Administration 
FGFR3 
fibroblast growth factor receptor type 3 
G380R 
glycine-to-arginine substitution at codon 380 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GMP 
Good Manufacturing Practice 
GU 
Genitourinary 
HbA1c 
Hemoglobin A1c 
hCG 
Human Chorionic Gonadotropin  
HDL 
High-density lipoprotein 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
hGH 
Human growth hormone 
HHN 
Home health nurse 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IFU 
Instructions for Use 
IM 
Investigator meeting 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
Kg 
Kilogram 
LDL 
Low-density lipoprotein 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHS 
Natural History Study 
NPR-B 
Natriuretic peptide receptor-B 
NPR-C 
Natriuretic peptide receptor-C 
mPEG 
methoxypolyethylene glycol 
NOAEL 
No observed adverse effect level 
NOEL 
No observed effect level 
NTproCNP 
amino-terminal propeptide of C-type natriuretic peptide 
NYHA 
New York Heart Association Functional Classification 
ObsRO 
observer-reported outcome 


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OLE 
Open-Label Extension 
PINP 
propeptide of type I procollagen, N‑terminal 
PEG 
polyethylene glycol 
PK 
pharmacokinetics 
PR 
PR interval of ECG 
PRO 
patient-reported outcome 
QoL 
quality of life 
QRS 
duration of ventricular muscle depolarization of ECG 
QT 
duration of ventricular depolarization and repolarization of ECG 
QTc 
corrected QT interval 
QTcF 
corrected QT interval by Fridericia’s formula 
RBC 
Red blood cell 
SAD 
single ascending dose  
SADDAN 
Severe achondroplasia with developmental delay and acanthosis nigricans 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SDS 
Standard Deviation Score 
SE 
standard error 
SF-36 
36-Item Short Form Survey 
SIV 
Site initiation visit 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
sWFI 
Sterile water for injection 
t1/2 
terminal elimination half-life 
TEAE 
Treatment-emergent adverse event 
TENS 
Toxic epidermal necrolysis 
Tmax 
time of maximum observed concentration 
URI 
upper respiratory infection 
UV 
Unscheduled visit 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 


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5. 
INTRODUCTION  
5.1. 
BACKGROUND AND RATIONALE  
5.1.1. 
Achondroplasia  
Achondroplasia (ACH) is the most common skeletal dysplasia and the most frequent form of 
short-limbed dwarfism (Horton 2007).  The condition occurs with a frequency of 1 in 10,000 to 
30,000 live births, affecting 250,000 men and women equally worldwide (Horton 2007, 
Laederich 2010).  Although a heritable condition, more than 80% of cases of ACH are due to a 
sporadic mutation (Horton 2007).   
ACH results in severe skeletal complications that lead to numerous comorbidities at various 
developmental stages.  Cervico-medullary compression resulting from foramen magnum stenosis 
is thought to be the major contributing factor to fatal cardiorespiratory arrest in infants with ACH 
(Horton 2007).  Additionally, a newborn with ACH may suffer from a small cranial-cervical 
junction leading to hydrocephalus requiring shunting (Horton 2007).  Mid-facial hypoplasia with 
relative hypertrophy of the adenoids and tonsils, short Eustachian tubes, and hypoglossal canal 
stenosis in infants and young children may lead to chronic otitis media and subsequent hearing 
loss, speech delays, and obstructive sleep apnea.  Older children and adults suffer from 
premature synchondroses closure of the vertebrae and ossification center fusion leading to spinal 
stenosis with subsequent neurogenic claudication (Horton 2007).  Due to short arms and limited 
range of motion of the joints, individuals with ACH have difficulty with personal care, such as 
dressing and personal hygiene, and require therapy to cope with the limitations (Unger 2017).  
Bowing of the legs can lead to difficulty walking and chronic knee pain.   
5.1.2. 
Current Standard Therapy for ACH  
No effective medicinal product is available for treatment of ACH.  All existing interventions are 
intended to alleviate specific comorbidities of the condition, and do not address the underlying 
pathophysiology (Trotter 2005, Horton 2007, Wright 2012, Ireland 2014).  Cervico-medullary 
decompression is performed in infants and young children to treat central sleep apnea and 
alleviate neurological complications from spinal cord compression (Ho 2004).  Newborns with 
ACH may also suffer from hydrocephalus requiring ventricular shunting.  Adolescents and adults 
with lumbar stenosis may undergo laminectomy (Carlisle 2011).  Challenges associated with 
height and reach may be alleviated by limb lengthening surgery, but the procedure comes with 
significant pain and morbidity over many months (Ornitz 2017, Unger 2017). 
As none of the available therapies address the underlying pathophysiology of ACH, individuals 
with the condition undergo multiple surgeries and other interventions throughout their lives.  A 
clear unmet medical need exists for an effective therapy to treat ACH. 
5.1.3. 
Fibroblast Growth Factor Receptor Type 3  
ACH is caused by a gain-of-function autosomal dominant mutation in the fibroblast growth 
factor receptor type 3 (FGFR3) gene with 100% penetrance.  In cartilage, FGFR3 activation 
negatively regulates growth by inhibiting proliferation and terminal differentiation of growth 
plate chondrocytes, thereby reducing the rate of cartilage formation and turnover necessary for 
bone elongation.  


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Figure 1: 
Schematic Overview of the Interactions Between the Intracellular Pathways 
of the Fibroblast-Growth-Factor-Receptor 3 (FGFR3) and the C-Type 
Natriuretic Peptide (CNP) Receptors [Natriuretic peptide receptor-B 
(NPR-B) and -C (NPR-C)] in Bone Growth  
 
Adapted from (Peake 2014, Ornitz 2015); FGF; Fibroblast Growth Factor 
FGFR3 is a tyrosine-kinase receptor activating signal transducer and activator of transcription 
1 (STAT1) and the mitogen-activated protein kinase (MAPK)-pathway [RAS-RAF-MEK-ERK], 
which both have inhibiting effects on endochondral ossification (chondrocyte proliferation and 
differentiation, respectively) (Figure 1).  
5.1.4. 
C-type Natriuretic Peptide  
CNP influences growth by some of the same intracellular signaling pathways as FGFR3, 
mediated through its receptors NPR-B and NPR-C (Figure 1).  NPR-B mediates an increase in 
cyclic guanosine monophosphate (cGMP), substantiated to evoke an inhibition of RAF, thus 
blocking the MAPK-activity (Miyazawa 2002, Krejci 2005) resulting in increased growth, 
evident in animal models and humans overexpressing CNP (Yasoda 2004, Bocciardi 2007, 
Hannema 2013).  On the other hand, absence of CNP or a non-functional NPR-B receptor result 
in dwarfism (Chusho 2001, Nakao 2015).  The diminished growth in CNP-deficient rats can be 
rescued by continuous SC CNP administration (Hirota 2018), providing evidence that exogenous 
CNP can reach chondrocyte NPR-B receptors. 


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The NPR-C receptor is an important receptor for CNP with a lower affinity for CNP relative to 
NPR-B (Koller 1991, Potter 2006).  NPR-C deficiency leads to increased growth (Colvin 1996, 
Matsukawa 1999).  On the other hand, NPR-C mediates an intracellular signal that counteracts 
the NPR-B mediated signal (Figure 1). This is especially believed to be the case at 
supra-physiological CNP plasma concentration (Peake 2014). 
Thus, the mechanism of action of CNP is believed to be via inhibition of the downstream 
signaling pathway of the FGFR3, thereby counteracting the overactivation of the 
FGFR3 pathway, characteristic for ACH, and thus restoring normal chondrogenesis 
(Laederich 2010). 
In clinical trials in ACH children employing daily administration of vosoritide (a synthetic 
analogue of CNP), the impact on bone growth, measured as annualized height velocity (AHV), 
amounts to an additional 1-2 cm per year (BioMarin 2018) , from a baseline average growth 
velocity of approximately 5 cm/year (Hoover-Fong 2008, BioMarin 2018). 
5.1.5. 
Impact of ACH on Well-Being and Functioning in Children with the Condition 
and Their Caregivers  
Little is known about the impact of ACH on the functioning and well-being of children or the 
impact of caring for these children on their caregivers because much of the research conducted 
has focused on adults.  There is evidence that children with ACH have lower functioning and 
impaired quality of life (QoL), possibly associated with lower self-esteem and social 
stigmatization; and 36-Item Short Form Survey (SF-36) scores, for both the Physical and Mental 
components, have been shown to be below national means (Ireland 2011, Dogba 2014, 
Wigg 2016, Dhiman 2017, Matsushita 2019).  Further, this impairment in QoL is greater 
compared to children with short stature due to growth hormone deficiency or idiopathic short 
stature (Sommer 2017).  Unfortunately, to date there are no measures that specifically assess 
these impacts on the daily functioning and well-being of the child with ACH. 
Evidence for the impact on functioning and well-being for caregivers’ of children with ACH is 
even more scarce, with a literature search on the topic identifying only 1 publication suggesting 
that caregivers’ future outlook for their children with ACH focused on over-coming 
economic-occupational fears, and doubts concerning their ability to settle down and rear a family 
(Cacciaguerra 1981).  Additionally, anecdotal evidence, including caregiver testimonials at the 
2018 FDA public advisory committee meeting on ACH, suggests a substantial impact on 
caregivers and highlights the need to further understand the experience of these caregivers 
(FDA 2018). 
Additionally, there is no current information about the participant/caregiver treatment experience 
of participation in an ACH clinical trial.  As new treatments for this condition are developed it 
will be critical to better understand this experience. 
5.2. 
RELEVANT FINDINGS FROM NONCLINICAL STUDIES  
Please refer to the current version of the TransCon CNP Investigator’s Brochure for a full 
discussion of nonclinical data.  
In animal studies, TransCon CNP has shown the expected pharmacological effects on cartilage 
homeostasis and bone growth. 


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Cardiovascular (CV) changes (decreased blood pressure, increased heart rate (HR) and the heart 
rate corrected QT [QTc] interval) were observed in cynomolgus monkeys at doses of ≥300 µg 
CNP/kg but did not result in any clinical signs; the QTc increases were not biologically 
significant.  The CV no observed adverse effect level in cynomolgus monkeys was 100 µg 
CNP/kg.  In the pivotal repeat-dose toxicity studies in juvenile animals with a normal 
FGFR3 pathway, the no observed adverse effect level (NOAEL) for off-target effects after 
weekly SC administrations was the highest dose tested (up to 4000 µg CNP/kg/wk in rats).  The 
repeat-dose toxicity studies were conducted in juvenile animals with an intact FGFR3-pathway 
and a normal balance between FGFR3 activation and CNP mediated suppression of the 
FGFR3-pathway.  When administering CNP to intact animals, this balance is disturbed and 
skeletal overgrowth, eventually leading to adverse exaggerated pharmacology can be observed.  
The only adverse findings observed were related to CNP’s pharmacological effect on the physeal 
chondrocytes. 
5.3. 
CLINICAL EXPERIENCE  
In the Phase 1, randomized, first-in-human, double-blind, placebo-controlled SAD trial, 
TransCon CNP was given by SC injection to healthy adult male participants.  The primary 
objective was to determine the safety and tolerability of single-ascending SC doses of TransCon 
CNP. Other objectives were to evaluate the PK properties and exploratory biomarkers after 
administration of TransCon CNP. The trial was conducted under GCP, EC, and Declaration of 
Helsinki guidelines. 
TransCon CNP was generally well tolerated as single ascending doses in healthy male adults.  
No serious AEs were reported, and no participant was withdrawn due to an AE.  Dose levels up 
to 150 μg CNP/kg were investigated with no dose limiting toxicities. 
No clinically significant trends were observed in clinical laboratory assessments, vital sign 
measurements, ECG parameters, or physical examination findings.  Continuous ECG monitoring 
via Holter monitor revealed no clinically relevant effects on any of the studied ECG parameters, 
including heart rate or PR, QRS, and QT intervals at all investigated dose levels. 
Potential adverse immune response upon exposure to TransCon CNP was evaluated.  By using 
population derived assay cut points, all samples were confirmed negative for anti-CNP 
antibodies.  In addition, individual changes in anti-PEG antibody levels were <3 fold compared 
to individual predose levels and were not considered clinically relevant. 
Pharmacokinetic parameters were generally consistent with the target profile.  Exposure, as 
assessed by Cmax and AUC, of Total CNP, Free CNP-38, mPEG. and mPEG-linker increased 
proportionally with dose administered.  A slow rise to peak concentrations were observed for all 
analytes (median Tmax ranging from 45 to 66 hours post dose for Free CNP), with long and dose-
independent elimination half-lives (t½ was 112 − 128 hours for Free CNP and 137 − 163 hours 
for Total CNP).   
The effect of TransCon CNP on cGMP levels was dose dependent, and the data supports 
administration of TransCon CNP as a way to deliver active CNP in a sustained manner. 
Endogenous CNP biosynthesis did not appear to be affected by single administration of 
TransCon CNP, as evidenced by no changes in plasma NTproCNP levels irrespective of CNP 
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5.4. 
TRIAL RATIONALE  
Because of the short half-life of native CNP (2-3 minutes), continuous IV administration is 
required to restore bone growth in ACH mice (Yasoda 2009).  Proof-of-principle for a mutated 
CNP analogue (vosoritide) with increased resistance to degradation by neutral endopeptidase has 
been obtained in the nonclinical setting.  Daily administration of CNP to mice, with phenotypical 
traits similar to those observed in individuals with ACH, suggests that the daily administration of 
the CNP analogue vosoritide is capable of improving the major phenotypical dwarfism traits 
(Lorget 2012, Wendt 2015).  In clinical trials in ACH children employing daily administration of 
vosoritide, the impact on bone growth, measured as AHV, amounts to an additional 1-2 cm per 
year (BioMarin 2018), from a baseline average growth velocity of approximately 5 cm/year 
(Hoover-Fong 2008, BioMarin 2018). 
TransCon technology is designed to provide sustained exposure of active CNP.  Applying the 
TransCon technology to CNP results in a mean apparent half-life of Free CNP of approximately 
120 h in human adult volunteers.  This is in contrast to the short systemic half-life of endogenous 
CNP in humans of only 2 to 3 minutes (Hunt 1994), and the half-life of vosoritide of 
20-23 minutes (BioMarin 2018).  The aim of TransCon CNP therapy is to treat the underlying 
pathophysiology of ACH by inhibiting the effects of constitutive FGFR3 overactivation 24 hours 
a day, aiming to ameliorate and prevent the comorbidities of ACH.   
A study in a mouse model of ACH (FGFR3 gain of function mutation) demonstrated that 
TransCon CNP exposure was able to modify synchondrosis closure and long-bone growth-plate 
cartilage homeostasis.  In a 6-month pharmacology study in healthy juvenile monkeys an 
increase in long bone growth was observed. 
The data from the non-IND Phase 1 clinical trial (TransCon CNP TCC-101) demonstrated the 
ability of TransCon CNP to sustain elevated plasma levels of CNP with a weekly SC injection. 
TransCon CNP is intended to promote growth of bones by acting on the chondrocytes within the 
growth plates. Therefore, clinical trials to assess the efficacy of TransCon CNP are conducted in 
children with open growth plates. 
5.5. 
SUMMARY OF IMPORTANT RISKS AND POTENTIAL BENEFITS  
5.5.1. 
Important Risks  
TransCon CNP has not been investigated in individuals with ACH, and therefore the risks are 
unknown.  In the Phase 1 clinical trial investigating single doses of TransCon CNP up to 
150 μg CNP/kg in healthy adult male participants, TransCon CNP was generally well tolerated.  
In the general toxicity studies with healthy juvenile animals, no off-target (non-bone related) 
adverse findings were observed.  The only significant adverse findings were related to the 
expected pharmacology of CNP on bone growth and are regarded to be a consequence of the 
exaggerated pharmacology when dosing animals without the activating FGFR3 mutation to 
counterbalance the effect of exogenous CNP administration.   


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5.5.2. 
Potential Risks  
The following effects are considered potential risks with the use of TransCon CNP in children 
with ACH: 
5.5.2.1. 
Cardiovascular Changes  
Decreased blood pressure, increased heart rate (HR), and increased heart rate corrected QT 
(QTc) interval were observed in cynomolgus monkeys at doses of ≥300 µg CNP/kg.  The 
changes did not result in any clinical signs, and the QTc interval increases were not biologically 
significant (Ando 2005).  Throughout the non-clinical studies, a no observed effect limit (NOEL) 
for cardiovascular (CV) findings of 100 µg CNP/kg/wk was established.  The predicted steady 
state Total CNP Cmax at 6 µg CNP/kg/wk in the pediatric population is 22 to 23-fold lower than 
the observed Cmax at the NOEL dose (100 µg CNP/kg/wk) in cynomolgus monkeys.  
Hypotensive effects were reported to correlate with high peak plasma CNP concentrations in 
adults administered exogenous CNP (Igaki 1998).  However, this correlation was not observed in 
the phase 1 clinical trial, TCC-101 (tested up to 150 µg CNP/kg), likely due to the much lower 
Cmax and peak-to-trough ratio with TransCon CNP, and no clinically relevant effects on the 
studied ECG parameters were found.   
5.5.2.2. 
Adverse Bone Overgrowth  
TransCon CNP has not been tested in children with ACH and, therefore, whether adverse bone 
overgrowth could occur is unknown.  Mutations leading to an overproduction of CNP in people 
without activating mutations in FGFR3 result in skeletal overgrowth, including long hands and 
feet, scoliosis and ankle valgus deformity (Bocciardi 2007, Moncla 2007, Tassano 2013, 
Ko 2015).   
In the repeat-dose toxicity studies of TransCon CNP in healthy juvenile animals without an 
activating mutation in FGFR3, an exaggerated effect related to CNP’s biology on the growth 
plate was observed.  Skeletal overgrowth and sequelae thereof such as physeal clefting, physeal 
fractures (Salter-Harris Type 1) and bone deformities were found. When administering CNP to 
animals without the ACH mutation, the balance between the activity of FGFR3 and CNP is 
disturbed.  In the context of ACH, in which FGFR3 is overactivated, sustained increase in CNP 
exposure is expected to modulate/decrease FGFR3 signaling and promote a more physiologic 
balance between the two pathways.  The aim of treatment with TransCon CNP is to normalize 
the effect of constitutively overactivated FGFR3. 
5.5.3. 
Potential Benefits  
Clinical trials of TransCon CNP in children with ACH have not been conducted.  Based on the 
published studies of CNP administration in mouse models of ACH (Lorget 2012, Wendt 2015) 
and nonclinical studies using TransCon CNP, treatment with TransCon CNP may promote 
proportional growth of the long bones and alleviate the comorbidities associated with premature 
closure of the synchondroses in children with ACH.  Body disproportionality is a hallmark of 
ACH that leads to common comorbidities that may limit functioning and well-being, as well as 
caregiver burden, such as short limbs, joint and back pain, and limited range of motion 
(Horton 2007, Ireland 2014, Unger 2017).  Premature closure of the synchondroses contribute to 
hydrocephalus, spinal stenosis, ear infections, hearing problems, and respiratory problems. 


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The PK profile observed for TransCon CNP in healthy adult male participants (Trial TCC-101) 
showed dose-proportional increases in Cmax, with apparent t1/2 of Free CNP ranging from 112 to 
128 h.  TransCon CNP has the potential to provide full 7-day (168-h) CNP coverage at expected 
therapeutic ranges.  Delivery of CNP via the TransCon technology is expected to provide the 
following benefits: 
x Maximize growth-promoting effects of CNP by maintaining CNP levels in circulation at 
therapeutic levels for the entire duration between doses. 
x Minimize potential non-skeletal effects of CNP, such as hypotensive and natriuretic effects, 
by reducing the fluctuations between peak and trough levels.  Hypotensive effects have been 
reported to correlate with high peak plasma CNP concentrations in adults administered 
exogenous CNP (Igaki 1998), but this correlation was not observed in the Phase 1 clinical 
trial (Trial TCC-101) at doses up to 150 μg CNP/kg.  Results of nonclinical studies have not 
indicated a natriuretic potential at the studied dose levels. 
6. 
OBJECTIVES  
6.1. 
PRIMARY OBJECTIVES  
In prepubertal children with achondroplasia (ACH) at 52 weeks 
x To determine the safety of once weekly subcutaneous (SC) doses of TransCon CNP  
x To evaluate the effect of once weekly SC doses of TransCon CNP on AHV 
6.2. 
SECONDARY OBJECTIVES  
x To evaluate the effect of once weekly SC doses of TransCon CNP on body proportionality 
(upper to lower body segment ratio) in prepubertal children with ACH at 52 weeks 
x To evaluate the pharmacokinetic (PK) properties of once weekly SC doses of TransCon CNP 
x To assess the potential immunogenic response to once weekly SC doses of TransCon CNP 
6.3. 
EXPLORATORY OBJECTIVES  
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7. 
TRIAL DESIGN  
7.1. 
OVERALL TRIAL DESIGN AND PLAN  
This trial is a multicenter trial consisting of two treatment periods: A 52 week double-blind, 
randomized, placebo controlled, dose escalation trial evaluating up to 5 different dose levels of 
weekly TransCon CNP administered subcutaneously in prepubertal children 2 to 10 years old, 
inclusive, with ACH. For this part of the trial participants are randomized into 2 treatment groups 
for each cohort in a 3:1 TransCon CNP: placebo ratio, with approximately ≥9 participants on 
TransCon CNP and ≥3 participants on placebo in each cohort.  Participants are to remain on the 
same dose of study drug throughout the entire 52-week Randomized Treatment Period. 
After completing 52 weeks of their assigned cohort dose (or placebo), participants who fulfill the 
rollover criteria can continue into the 104 weeks Open-Label Extension Period. In this extension 
period, participants may receive the highest dose level of TransCon CNP that has been reviewed 
and recommended by the Data Monitoring Committee (DMC) for safety and has passed DMC 
safety review.  
The total duration of the randomized trial period for an individual participant is:  
For participants who do not continue in the Open-Label Extension Period: Up to approximately 
61 weeks (including approximately 4 weeks of screening plus 52 weeks of treatment, and a 
5 weeks follow-up period).  
For participants who continue in the Open-Label Extension Periods: Up to approximately 
165 weeks (up to approximately 4 weeks of screening plus 156 weeks of treatment, including 
52 weeks of placebo-controlled treatment period followed by an additional 104 weeks of 
treatment in the Open-Label Extension Period and a 5 weeks follow-up period).  
This is summarized in the scheme below:  
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Trial Design Scheme 
 
Figure 2: 
Trial Design Scheme  
 
(Figure 2) Trial design scheme in the Randomized and Open-Label Extension period. In the 
Randomized Period, participants in each cohort will receive their allocated cohort dose for 
52 weeks, after which they are rolled over into the Open-Label Extension. The initiation of a 
new, subsequent cohort in the Randomized Period is gated by a DMC that reviews 3 months of 
safety data of the current cohort to determine if the dose is safe, after which the DMC can 
recommend to proceed with the next cohort (including dose escalation).  
In the Open-Label Extension Period, participants may receive the highest dose level of TransCon 
CNP that has been reviewed and recommended by the Data Monitoring Committee (DMC) 
for safety and has passed DMC safety review.   
x  Screening Period: Up to approximately 4 weeks  
x Randomized Treatment Period: 52 weeks  
x Open-Label Extension Period: 104 weeks 
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Cohort 
Planned Dose Level 
Approximate Number of Participants** 
1 
6 µg CNP/kg/week 
9 on TransCon CNP, 3 on placebo 
2 
20 µg CNP/kg/week 
≥9 on TransCon CNP, ≥3 on placebo 
3 
50 µg CNP/kg/week 
≥9 on TransCon CNP, ≥3 on placebo 
4 
100 µg CNP/kg/week 
≥9 on TransCon CNP, ≥3 on placebo 
5 
> 100 µg CNP/kg/week* 
≥9 on TransCon CNP, ≥3 on placebo 
* At a dose to be determined, if needed, based on emerging data 
**Minimum of 12 participants per cohort will be enrolled. Plan to enroll approximately 14 participants per cohort to 
account for potential dropouts due to COVID-19. 
Visit Schedule Diagram in the Randomized and Open-Label Extension Periods: 
 
7.1.1. 
Measures Taken to Maximize Study Integrity and Minimize Bias  
The randomized, double-blinded, placebo-controlled period of this trial is included to minimize 
bias in the assessment of the effect and safety of TransCon CNP. Participants will be randomized 
to either TransCon CNP or placebo in 3:1 ratio within each cohort.  
Once all participants enrolled in a dose cohort have completed (or withdrawn from) their 
Randomized Period and the database has been locked, the treatment allocation for that dose 
cohort will be unblinded. 
This Randomized Period will be followed by a 104-week Open-Label Extension treatment period 
where all participants will receive TransCon CNP.  
Participant visits should be performed at approximately the same time of day for all visits.  Also, 
assessments should be performed in a similar fashion at each visit.  Additionally, all efforts will 
be made to keep missing data to a minimum, including the following: 
• Investigators will be trained about the importance of participant retention 
• Investigators will be instructed to encourage participants to complete all scheduled visits, 
including any participants who discontinue the study drug early 


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• The Informed Consent Form (ICF) will include a statement educating participants about the 
scientific importance of their data even if the participant discontinues study drug early 
• Special efforts will be made to provide assistance to participants/families who might 
discontinue due to travel or cost barriers, such as offers of transportation to the clinic 
• All study visits have visit windows to allow flexibility for clinic attendance (See Appendix 1 
and Appendix 2: Schedule of Events in the Randomized and Open-Label Extension Period, 
respectively) 
• Every effort will be made to maintain contact with participants or other family members  
7.2. 
TRIAL SITES  
The trial will be conducted at approximately 35 sites worldwide. 
8. 
PARTICIPANT POPULATION  
Minimum of sixty (60) male and female prepubertal children with ACH, age 2 to 10 years, 
inclusive. 
8.1. 
ELIGIBILITY CRITERIA  
8.1.1. 
Inclusion Criteria  
1. Clinical diagnosis of ACH with genetic confirmation (See Section 11.11) 
2. Age between 2 to 10 years old (inclusive) at Screening Visit 
3. Prepubertal (Stage 1 breasts for girls or testicular volume < 4ml for boys) at Screening Visit 
(See Section 11.3) 
4. Able to stand without assistance 
5. Caregiver willing and able to administer subcutaneous injections of study drug  
6. Written, signed informed consent of the parent(s) or legal guardian(s) of the participant and 
written assent of the participant as required by the institutional review board/human research 
ethics committee/independent ethics committee (IRB/HREC/IEC)   
8.1.2. 
Exclusion Criteria  
1. Clinically significant findings at Screening that: 
• are expected to require surgical intervention during participation in the trial or  
• are musculoskeletal in nature, such as Salter-Harris fractures and severe hip pain or 
• otherwise are considered by investigator or Medical Monitor to make a participant unfit 
to receive study drug or undergo trial related procedures 
2. Have received treatment (>3 months) of human growth hormone (hGH) or other medications 
to affect stature or body proportionality at any time 
3. Have received any dose of medications intended to affect stature or body proportionality 
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4. Have received any study drug or device intended to affect stature or body proportionality at 
any time  
5. History or presence of injury or disease of the growth plate(s), other than ACH, that affects 
growth potential of long bones  
6. History of any bone-related surgery that affects growth potential of long bones, such as 
orthopedic reconstructive surgery and osteotomy (Limb-lengthening with full recovery is 
allowed with a minimum of 12 months of bone healing. Foramen magnum decompression 
and laminectomy with full recovery are allowed with minimum of 6 months of bone healing. 
History of 8 plate epiphysiodesis is allowed, but the plates must have been removed prior to 
Screening with minimum 4 weeks of healing.)  
7. Have a form of skeletal dysplasia other than ACH or known medical conditions that result in 
short stature or abnormal growth [such as severe achondroplasia with developmental delay 
and acanthosis nigricans (SADDAN), hypochondroplasia, growth hormone deficiency, 
Turner syndrome, pseudoachondroplasia, inflammatory bowel disease,  chronic renal 
insufficiency, active celiac disease1, Vitamin D deficiency2, untreated hypothyroidism3, 
poorly controlled diabetes mellitus (HbA1c ≥8.0%) or diabetic complications4] 
1Celiac disease responsive to a gluten-free diet is allowed.  
2Vitamin D deficiency or insufficiency treated with supplementation is allowed. Vitamin D 
deficiency is defined as 25(OH)D level <20ng/mL (<49.9 nmol/L). Vitamin D insufficiency 
is defined as 25(OH)D level 20-30ng/mL (49.92 -74.86 nmol/L). Participants with Vitamin D 
deficiency or insufficiency must be on Vitamin D regimen before randomization.  
3Participants with hypothyroidism must be clinically euthyroid for 3 months prior to 
Screening Visit and, in the opinion of the investigator, have achieved any catch-up growth 
expected from thyroxine replacement 
4Participants with diabetes mellitus must have been on stable medication regimen for 
3 months prior to randomization (dose adjustments are allowed but addition or 
discontinuation of medications in this time period is disallowed) 
8. History or presence of malignant disease, other than basal cell epithelioma/carcinoma or 
completely resected squamous skin cancer with no recurrence for 12 months per medical 
records 
9. History or presence of the following: 
• Chronic anemia (resolved iron deficiency anemia is allowed) 
• Significant cardiovascular disease per the judgement of the investigator, such as 
congenital heart disease (uncomplicated patent ductus arteriosus and atrial or ventricular 
septal defect with repair are allowed), aortic insufficiency, clinically significant 
arrhythmias, congestive heart failure with NYHA class II and above, or other conditions 
that impair regulation of blood pressure or heart rate 
• Condition that impacts hemodynamic stability (such as autonomic dysfunction, 
orthostatic intolerance) 
• History of chronic renal insufficiency  


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• Chronic or recurrent illness that can affect hydration or volume status.  This may include 
conditions associated with decreased nutritional intake or increased volume loss. 
• Bone fracture within 6 months prior to Screening Visit (within 2 months for fracture of 
digits) 
• Any disease or condition that, in the opinion of the investigator, may make the participant 
unlikely to fully complete the trial, may confound interpretation of trial results, or 
presents undue risk from the receiving study drug 
10. Child has significant electrocardiogram abnormalities, including evidence of a previous 
myocardial infarction, left ventricular hypertrophy, flat T waves (particularly in the inferior 
leads) or more than minor non-specific ST-T wave changes or:  
• QRS >90 milliseconds (msec) 
• QT interval corrected using Fridericia’s formula (QTcF) >440 msec 
• PR interval >170 msec 
• Complete right or left bundle branch block 
11. Requires, or anticipated to require, chronic (> 4 weeks) or repeated (more than twice per 
year) treatment with oral corticosteroids during participation in the trial (low and mid-dose 
inhaled corticosteroids are allowed. High-dose inhaled corticosteroids are not allowed.). See 
Appendix 5 for definition of high doses of inhaled corticosteroids. 
12. Use of medication known to prolong the QT/QTc interval within 7 days or 5 half-lives 
(whichever is longer) prior to the Screening Visit (see https://crediblemeds.org/ for the list of 
medications that are known to prolong the QT/QTc interval.  Note: Only medications on the 
Known Risk list are excluded, not those on the Possible or Conditional Risk lists) 
13. Ongoing treatment with any medication that affects blood pressure or heart rate 
14. Known hypersensitivity to the components of the study drug [trehalose, 
tris(hydroxymethyl)aminomethane, succinate and PEG] 
15. Any other reason that in the opinion of the investigator would prevent the child from 
complying with the trial requirements or completing the trial 
8.1.3. 
Rollover Criteria for Open-Label Extension Period  
Participants are eligible for the Open-Label Extension Period if they fulfill the following rollover 
criteria: 
1. Have completed the 52 weeks randomized treatment period 
2. Written, signed informed consent of the parent(s) or legal guardian(s) of the 
participant and written assent of the participant as required by the institutional review 
board/human research ethics committee/independent ethics committee 
(IRB/HREC/IEC) to continue into the Open-Label Extension (OLE) Period   
3. Do not fulfill any of the holding/stopping study drug conditions or symptoms (see 
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8.2. 
PREMATURE PARTICIPANT WITHDRAWAL  
Premature participant withdrawal occurs when an enrolled participant ceases participation in the 
trial, regardless of the circumstances, prior to the expected completion of the trial.   
In the case of premature participant withdrawal, the investigator should schedule an Early 
Termination (ET) Visit to collect data, particularly AE follow-up data (if applicable), and to 
collect blood for final laboratory evaluations.  This visit should contain all appropriate 
assessments and the reason(s) for trial discontinuation should be documented.   
The investigator/site staff should make every attempt to contact the participant to arrange the 
appropriate follow-up assessment(s) for such participants. 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
8.2.1. 
Study Drug Discontinuation and Participant Withdrawal  
8.2.1.1. 
Study Drug Discontinuation  
Unless informed consent is withdrawn*, participants who permanently discontinue study drug 
should:  
x Attend all subsequent visits up to Visit 7 if discontinued during the Randomized Period, and 
up to Visit 16 if discontinued during the Open-Label Extension Period. Additionally, ET 
Visit should be completed as soon as possible after discontinuation of study medication. 
* If the participant is not willing to attend all subsequent trial visits, an ET Visit should be 
scheduled and this should be considered a withdrawal of consent from further participation in 
the trial.  
See Section 10.1.5 for details on ET Visit.  
8.3. 
PARTICIPANT REPLACEMENT CRITERIA  
Participants who terminate early are not expected to be replaced.  
9. 
TREATMENTS  
9.1. 
INVESTIGATIONAL PRODUCT  
TransCon CNP is a long-acting essentially inactive prodrug 
 
  TransCon CNP releases 
active CNP via auto-cleavage of the TransCon Linker in a controlled manner based on 
physiologic pH and temperature.  As such, the TransCon technology is designed to provide 
sustained exposure of circulating CNP over 7 days, allowing an optimal pharmacokinetic profile 
for use in ACH.  
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The drug product formulation containing TransCon CNP is a lyophilized powder in a single-use 
vial, 
.  Prior to use, the lyophilized powder must be 
reconstituted with sterile water for injection from a prefilled syringe.  
 
  This solution will be administered by SC injection via 
syringe and needle. 
9.1.1. 
Labeling  
All study drug will be labeled according to Good Manufacturing Practice (GMP) and local 
regulatory requirements.  The labels are trial-specific and carry unique identification pack 
numbers. Participants will be provided with dosing and storage instructions.  
9.1.2. 
Accountability, Storage, and Dispensing  
Investigator will be responsible for study drug, ancillary supplies, and associated procedures, 
exercising accepted medical and pharmaceutical practices.  
Study drug must be kept in a locked, temperature-controlled, and temperature-monitored area 
with limited access and stored according to its labeling.  Investigator or dedicated trial staff must 
evaluate the storage temperature and inform Ascendis Pharma immediately if study drug has 
been stored outside the specified conditions on the label.  TransCon CNP must be stored at 2°C 
to 8°C and protected from light. The prefilled syringe with sterile Water for Injection (sWfI) 
(diluent) must be stored at 2°C to 30°C. 
The trial will use an internet-based interactive web response system (IWRS) to capture drug 
inventory and accountability data, including receipt of study drug and supplies by the site, 
treatment assignment for each participant, distribution to participants, return to the site from 
participants, and return to the Sponsor (or destruction with the Sponsor’s approval).  The IWRS 
system complies with all applicable regulatory requirements for record keeping and record 
retention in clinical trials [21 CFR Part 11 and ICH E6 (R2) GCP].   
Investigator will be responsible for ensuring accountability and reconciliation of study drug. 
Site staff will provide training on proper storage to each participant at Visit 1.  Once Placebo for 
TransCon CNP drug product becomes available, this training will also include a review of the 
Instructions for Use (IFU) and on-site administration of the first dose of study drug by the 
caregiver.  A copy of the IFU will be provided to the participants to take home. For participants 
that begin participation in the trial prior to the Placebo for TransCon CNP drug product 
becoming available, site staff will provide training on study drug administration at the next visit 
following availability of Placebo for TransCon CNP drug product.  
NOTE: Under no circumstances will the investigator allow study drugs to be used for other 
than as directed by this protocol. 
See Pharmacy Manual and IFU for further details. 
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9.2. 
REFERENCE PRODUCT  
Reference product will be supplied as one of two placebos: 
• Placebo for TransCon CNP drug product 
• sWfI Placebo for TransCon CNP drug product 
Placebo for TransCon CNP drug product contains the same excipients as TransCon CNP drug 
product but does not contain TransCon CNP.  Prior to use, the lyophilized powder must be 
reconstituted with sWfI from a prefilled syringe.  This solution will be administered by SC 
injection via syringe and needle. 
sWfI Placebo for TransCon CNP drug product consists of sWfI. The sWfI is supplied in the 
same prefilled syringe as the one used for reconstitution of the lyophilized powder of the Placebo 
for TransCon CNP drug product. The procedure for preparation and administration of sWfI 
Placebo for TransCon CNP drug product is the same as for Placebo for TransCon CNP drug 
product, only the vial with excipients will be replaced with an empty, sterile vial. The diluent 
(sWfI) is injected into the empty vial and the dosing volume of sWfI will be drawn from the vial 
into the injection syringe and administered SC. 
If Placebo for TransCon CNP drug product is not available, sWfI Placebo for TransCon CNP 
drug product will be used until Placebo for TransCon CNP drug product becomes available. 
Placebo for TransCon CNP drug product will be available prior to the start of Cohort 2, so this 
procedure will only be utilized in Cohort 1.  When Placebo for TransCon CNP drug product is 
available for Cohort 1, study drug will be prepared and administered by a caregiver (after proper 
training). Total dose volume for participants in Cohort 1 is expected to be ≤ 0.05ml (based on 
95th percentile weight of 32.5 kg for children with ACH at 10.5 years of age). At such low 
volumes, risk of possible discomfort associated with hypotonicity is minimal and does not pose a 
significant safety concern. 
The dose of Cohort 1 is 6 µg CNP/kg/week (0.006 mg/kg/week) and the concentration of 
reconstituted study drug is 3.6 mg CNP/mL. Therefore, study drug will be administered at 
0.006/3.6 = 0.0017mL/kg.  
The 5%ile for weight for a 2-year-old female with achondroplasia is approximately 9kg and the 
95%ile for a 10-year-old male with achondroplasia is approximately 30kg (Hoover-Fong 2007).  
Therefore, the anticipated dose range is approximately 0.0017×9 = 0.015mL to 
0.0017×30 = 0.05mL.  As study drug will be administered using insulin syringes, volumes will 
be rounded to the nearest unit (0.01mL). Further details regarding dose volume is provided in the 
Pharmacy Manual. 
9.3. 
TREATMENT ADMINISTERED  
Until Placebo for TransCon CNP becomes available, every dose of study drug will be prepared 
and administered by an unblinded site staff or home healthcare service. In order to maintain the 
blind, study drug will be prepared out of sight of the investigator, caregiver and the participant. 
When Placebo for TransCon CNP is available, study drug should be administered by the 
caregiver. The injections will be given SC once weekly (approximately every 7 days).  The 
initial volume of study drug (TransCon CNP or placebo) administered will be calculated using 
the weight measurement obtained at Visit 1. The dose (volume) of study drug will be adjusted 


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according to the participant’s weight at each visit. Study drug will be dispensed for weekly 
administration by the caregiver, except for the first dose administered at the trial site. The last 
dose of study drug in the Randomized Period will be administered at least 6 days prior to Visit 7. 
For the first four weeks of study drug administration by the caregiver, once weekly home 
healthcare service will be offered to accommodate home administration of study drug. Extended 
support might be offered until participants/caregivers are comfortable to take over administration 
of the study drug.  
Each participant will receive their assigned cohort dose for 52 weeks in the Randomized Period, 
after which they may roll over to the Open-Label Extension Period where all participants will 
receive TransCon CNP.   
In the Open-Label Extension Period, participants may receive the highest dose level of TransCon 
CNP that has been reviewed and recommended by the Data Monitoring Committee (DMC) 
for safety and has passed DMC safety review.   
Each injection will have a volume ≤750 µL and is to be administered by the caregiver (following 
training by study staff).  Participants may participate in the administration of study drug if 
deemed developmentally appropriate by the investigator and supervised by the caregiver. Study 
drug should always be drawn up by caregiver or healthcare professional. One dose may need to 
be administered as 2 or more injections depending on the dose volume.  There are a total of 
8 possible injection areas: right abdomen, left abdomen, right anterior thigh, left anterior thigh, 
right buttocks, left buttocks, right posterior upper arm, and left posterior upper arm, with 
multiple possible sites within each of these 8 injection areas.  Participants should be instructed to 
rotate injection sites. If multiple injections are required to give one dose, each injection should be 
administered at different injection area. 
All presentations of study drug are provided in a single-use vial.  
9.4. 
SELECTION OF TRIAL DOSES  
TransCon CNP is an inactive prodrug.  The Phase 1 clinical trial with TransCon CNP 
demonstrated that a dose range up to 150 µg CNP/kg was well-tolerated in healthy adult male 
volunteers.  Plasma concentration of Free CNP, the active form of drug, reached a Cmax of 
approximately 40 pmol/L after single injection of 150 µg CNP/kg in adult males, which is 
approximately 20-fold higher than endogenous levels seen in children with ACH.  With a 
half-life of ~120 h, free CNP levels in plasma were sustained above anticipated effective 
threshold for 7 days following administration without affecting production of endogenous CNP. 
Based on the available non-clinical safety data with a NOAEL of 30 µg CNP/kg/wk in the 
26-week cynomolgus monkey toxicity study and the only adverse effect seen in the chronic 
toxicity studies being related to exaggerated pharmacology in animals with a normal 
FGFR3 pathway, a safety factor of 5, based on dose-levels, was considered acceptable.  This 
results in a starting dose of 6 µg CNP/kg/wk.  
In individuals with ACH, CNP levels are normal or marginally elevated (Olney 2015).  
Additionally, it has been demonstrated that a high FGFR3 activity in chondrocytes can 
de-sensitize the NPR-B receptors towards CNP activation (Robinson 2017, Shuhaibar 2017).  As 
FGFR3 is constitutively active in ACH individuals, this could potentially induce tissue resistance 
to CNP activation of NPR-B receptors.  Higher exposure to CNP may thus be needed to 


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sufficiently suppress the FGFR3-pathway in children with ACH.  Because the NOAEL was 
established in animals without the activating FGFR3 mutation, CNP exposures above the 
non-clinical NOAELs of 30 µg CNP/kg/week may be needed and tolerated in children with 
ACH. 
The starting dose is substantially below the NOEL for cardiovascular changes in cynomolgus 
monkeys (100 µg CNP/kg) and the highest dose in the clinical Phase 1 trial (TCC-101) where 
extensive cardiovascular monitoring was included and none of the cardiovascular findings in the 
non-clinical studies were observed.   
Additionally, simulation estimations of steady state exposure in the anticipated weight range 
(~10 to 35 kg) of the ACH children in the proposed TransCon CNP TCC-201 trial have been 
performed based on Phase 1 data in adults and subsequent allometric scaling to the paediatric 
population.  The modelling showed that 6 µg CNP/kg/week dose is expected to result in a plasma 
Free CNP-38 Cmax at steady state of ~ 0.77 – 1.1 pM. This range overlaps with endogenous 
plasma CNP levels of 1-3 pM, and thus represents a conservative choice for starting dose in a 
dose escalation trial.   
Maximum dose level of 200 µg CNP/kg/week was set based on the same simulation estimation 
of steady state exposure, which predicted a comparable Free CNP-38 Cmax between a child 
weighing 35 kg (approximately 95th percentile for weight in a 11-year-old child with ACH) 
receiving weekly dose of 200 µg CNP/kg at steady state and the mean Free CNP-38 Cmax that 
was observed after single dose of 150 µg CNP/kg in healthy adults in TCC-101. Free CNP 
38 Cmax is predicted to be lower in smaller children (e.g. 2 year old child with ACH) when 
administered the same dose level. The dose levels to be investigated in TransCon CNP 
TCC-201 trial are designed to investigate exposure levels previously tested and shown to be safe 
and well-tolerated in healthy adult males.  As PK data become available from TCC-201, the data 
will be reviewed to ensure children are not overexposed to TransCon CNP.  Prior to determining 
if cohort 5 should be initiated at a dose > 100 μg CNP/kg/week, the safety data and height 
velocity at 6 months in cohort 4 for all participants will be assessed, in addition to all data from 
prior cohorts. The dose level of Cohort 5 will be determined taking into consideration the 
updated PK model that will incorporate the available PK data from TCC-201 to ensure exposure 
to Free CNP-38 does not exceed levels observed in TCC-101. 
9.5. 
TREATMENT ASSIGNMENT  
9.5.1. 
Treatment Assignment During Randomized Period  
At Visit 1, participants will be randomized to TransCon CNP or placebo in a 3:1 ratio in one of 
the following cohorts: 
Cohort 1: TransCon CNP 6 µg CNP/kg/week or placebo 
Cohort 2: TransCon CNP 20 µg CNP/kg/week or placebo 
Cohort 3: TransCon CNP 50 µg CNP/kg/week or placebo 
Cohort 4: TransCon CNP 100 µg CNP/kg/week or placebo 
Cohort 5: TransCon CNP > 100 µg CNP/kg/week* or placebo 
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Each participant will receive their assigned cohort dose for 52 weeks in the Randomized Period, 
after which they may roll over to the Open-Label Extension Period where all participants will 
receive TransCon CNP.   
9.5.2. 
Dose Escalation  
Data Monitoring Committee meetings will be held by the Sponsor upon review of the following 
data to assess whether the next cohort should be initiated as planned: 
• Initiation of Cohort 2: Cohort 1 data with a minimum of 12 weeks of follow up for all 
participants 
• Initiation of Cohort 3: Cohort 2 data with a minimum of 12 weeks of follow up for all 
participants and available data from all other cohorts 
• Initiation of Cohort 4: Cohort 3 data with a minimum of 12 weeks of follow up for all 
participants and available data from all other cohorts 
An independent Data Monitoring Committee (DMC) will attend each meeting to provide 
recommendations on the action to be taken (i.e. proceed to the next dose level as planned, 
modify the dose of the next cohort, or stop dose escalation).  
The DMC will be provided with the following unblinded data at each Data Monitoring 
Committee meeting: 
1. Summary of safety data including but not limited to AEs, vital signs, and laboratory findings 
2. Details of SAEs and AEs leading to discontinuation of study drug 
3. Summary of anthropometric measurements of cohorts that completed at least 26 weeks 
4. Other relevant available data at the request of the DMC, including available PK data 
Following the Data Monitoring Committee meeting, the Sponsor will take into consideration the 
recommendation of the DMC to decide to either proceed to the next dose cohort as planned, 
modify the dose of the next cohort, or stop dose escalation.  If available data are inadequate to 
decide on the action to be taken, the decision may be deferred until after data through 
Visit 5 (Week 26) of the highest dosed cohort are available, at which time the DMC meeting will 
be reconvened.  
A DMC meeting will also be held when all participants in Cohort 4 have a minimum of 12 weeks 
of follow up. If 100 µg CNP/kg/week is deemed safe at this meeting, then participants in the 
Open-Label Period may be dose increased to 100 µg CNP/kg/week.   
Upon completion of 26 weeks of treatment (Visit 5) for all participants in Cohort 4, a DMC 
meeting will be held to assess whether additional higher dose levels (up to 200 µg CNP/kg/week) 
should be investigated based on emerging data. After review of the data and consultation with 
the DMC, the Sponsor will decide whether a higher dose level should be investigated.  
The DMC will make the recommendation regarding dose escalation for cohorts in the Open-
Label Extension Period, which could be up to the highest dose level of TransCon CNP that has 
been reviewed by the DMC for safety and has passed DMC safety review. Dose escalation for 
the individual participant should be implemented at the next scheduled visit (except Visit 8) in 


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the Open-Label Extension Period. After discussion with the Medical Monitor, an Investigator 
may choose to not increase the dose for an individual participant or may decrease to a prior dose. 
If one serious adverse drug reaction or two severe adverse drug reactions occur in a particular 
cohort, dose escalation will be halted. Additionally, an urgent DMC meeting will be called to 
determine whether dosing should be halted in that cohort or across the entire trial. If deemed 
appropriate after review of all available safety data, the DMC may recommend that dose 
escalation be re-started. If the DMC does not feel that enough data is available to make a 
recommendation, they may defer a decision and recommend a time at which the data should be 
re-evaluated. 
Additionally, the DMC will be notified and a meeting may be called for each incident of study 
drug discontinuation for reasons related to safety. 
If dose escalation is discontinued prior to initiating the 4th cohort, participants to be enrolled in 
the cohorts not yet filled may receive the highest tolerated dose level investigated (or placebo), 
instead of the planned higher doses.  The decision to complete all four planned cohorts will be 
made by the Sponsor after review of available data and consultation with the DMC.    
In addition, ad hoc DMC meetings may be called by the Sponsor at any time for review of newly 
identified safety concerns.  
Refer to the DMC charter for further details. 
9.6. 
HOLDING/STOPPING STUDY DRUG  
The investigator or Medical Monitor (and, if needed, with DMC review) may temporarily hold or 
stop the dosing of study drug to a participant at any time during the trial. For participants that 
discontinue study drug for reasons related to safety, unblinding of the treatment assignment for 
the participant may occur if deemed necessary by the Sponsor to assess a potential safety signal 
or by the investigator to provide adequate medical care to the participant.  In case of medical 
emergency, the investigator will have direct access to unblinding of the treatment through the 
Interactive web response system. Examples of conditions or symptoms that may warrant holding 
or stopping study drug at the investigator’s or Medical Monitor’s discretion include: 
1. Severe fracture of long bones or growth plates regardless of causality 
2. Evidence of symptomatic persistent orthostatic intolerance, lasting over 24 hours not 
explained by other probable causes. Orthostatic hypotension is defined as decrease in SBP of 
≥20 mmHg (Stewart 2018). Accompanying tachycardia is defined as change of heart rate 
increment of ≥40 bpm and absolute orthostatic HR ≥130 bpm (for ages 13 years and 
younger) (Singer 2012) 
3. Skeletal abnormalities typically not associated with ACH, growth or other concurrent 
medical conditions, such as 
• Scoliosis 
• Severe hip pain 
• Findings from thorough skeletal exam requiring imaging or consultation with orthopedics 
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• Clinically relevant findings on radiologic assessments (new onset or worsening of tibial 
bowing, joint abnormalities at the elbows, evidence of slipped capital femoral epiphysis) 
4. A severe or serious adverse reaction 
5. QTc value > 500 msec, or an extension > 60 msec from baseline in absence of possible 
causes other than the study drug 
6. Diagnosis of heart disease requiring pharmaceutical or surgical intervention to maintain heart 
function 
7. Any other sign that warrants holding or discontinuing study drug at the discretion of the 
investigator or Medical Monitor 
The investigator, with Sponsor Medical Monitor notification, must stop study drug for an 
individual participant in the presence of the following symptoms at any time during the trial: 
1. Closed epiphysis (bone age >14.0 years for females or >16.0 years for males) 
2. Slipped capital femoral epiphysis 
3. Pregnancy, intention of becoming pregnant, and females who become of childbearing 
potential and who do not use highly effective contraceptive measures. Highly effective 
contraceptive measures are methods that can achieve a failure rate of less than 1% per year 
when used consistently and correctly (see Appendix 6).  
If study drug is held or discontinued due to safety concerns, approval by the Medical 
Monitor is required prior to resumption of study drug. Consideration of dose changes due 
to safety concerns may occur on an individual basis. 
Any participant who discontinues study drug should be encouraged to remain in the trial and 
attend all subsequent trial visits and complete all assessments. However, if trial participation is 
fully discontinued, an ET Visit should be performed. 
9.7. 
PRIOR AND CONCOMITANT MEDICATIONS  
Prior and concomitant medications include all prescription or over-the-counter medications, 
vitamins and herbal/nutritional supplements.   
Prior medication is considered any therapy/medication(s) that the participant has taken prior to 
the Screening Visit and will be recorded on the appropriate eCRF page. At minimum, all 
medications taken within 90 days prior to Screening Visit should be recorded. Additionally, 
medications taken at any time prior to signing the informed consent that affect stature must be 
reported, such as hGH and chronic oral corticosteroid use, regardless of when the medication 
was last taken.   
Concomitant medication is considered any medication other than the study drug that is 
administered after signing the informed consent up until the last completed trial visit.  Any 
change in documented, permitted concomitant medication being taken at the beginning of the 
clinical trial must be recorded in the eCRF. 
Medications that are considered necessary for the children’s welfare may be given at the 
discretion of the investigator.  The administration of medication must be recorded in the 


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appropriate source document and on the case report form (CRF) for the duration of participation 
in the trial. 
9.7.1. 
Prohibited Therapies  
The following medications are prohibited throughout the trial: 
• hGH or other medicinal products known to promote growth of long bones 
In case of any questions regarding current or prior medication, Sponsor Medical Monitor should 
be contacted. 
If use of a prohibited medication becomes necessary, administration of study drug may be 
discontinued at the discretion of the Investigator and Sponsor Medical Monitor.  The participant 
should be encouraged to complete all scheduled visits per protocol. 
10. TRIAL PROCEDURES  
10.1. TRIAL DURATION  
The total duration of the trial for an individual participant is approximately 165 weeks.  
• Screening Period: Up to approximately 4 weeks 
• Randomized Treatment Period: 52 weeks and for participants who do not continue in the 
Open-Label Extension Period a follow-up period of 5 weeks. 
• Open-Label Extension Period: 104 weeks and a follow-up period of 5 weeks. 
All visits for each participant should be scheduled at approximately the same time of day. 
10.1.1. Trial Periods and Visits  
See Appendix 1 and Appendix 2 for Schedules of Events.  
Following the Screening Visit, each participant attends: 
− 
Visit 1 (Randomization/Week 0).  The visit will be the date of randomization. 
− 
Phone Visit (Week 2) ±3 days. This visit will occur 11 to 17 days after Visit 1. 
− 
Visit 2 (Week 4) ±3 days (trough visit, pre-dose).  The visit will occur 25 to 31 days 
after Visit 1. 
− 
Visit 3 (Week 8) ±7 days (any time).  The visit will occur 49 to 63 days after Visit 1. 
− 
Visit 4 (Week 12) ±7 days (any time).  The visit will occur 77 to 91 days after Visit 1. 
− 
Visit 5 (Week 26) ±7 days (trough visit, pre-dose).  The visit will occur 175 to 189 days 
after Visit 1. 
− 
Visit 6 (Week 39) ±7 days (any time).  The visit will occur 266 to 280 days after Visit 1. 
− 
Visit 7 (Week 52) ±7 days (trough visit, pre-dose).  The visit will occur 357 to 371 days 
after Visit 1. 


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− 
Follow-up Visit (Week 57) ±7 days. The visit will occur 393 – 407 days after Visit 1. 
Only for participants not continuing in the Open-Label Extension Period. 
Open-Label Extension Period: 
− 
Visit 7 (Week 52) ±7 days. The visit will occur 357 to 371 days after Visit 1.  The visit 
must be conducted on the same day as Visit 7 in the Randomized Period. 
− 
Phone Visit (Week 54) ±3 days. This visit will occur 375 to 381 days after Visit 7. 
− 
Visit 8 (Week 56) ±3 days (any time).  The visit will occur 389 to 395 days after Visit 1. 
− 
Visit 9 (Week 65) ±7 days (any time).  The visit will occur 448 to 462 days after Visit 1. 
− 
Visit 10 (Week 78) ±7 days (any time).  The visit will occur 539 to 553 days after Visit 
1. 
− 
Visit 11 (Week 91) ±7 days (any time).  The visit will occur 630 to 644 days after Visit 
1. 
− 
Visit 12 (Week 104) ±7 days (any time).  The visit will occur 721 to 735 days after 
Visit 1. 
− 
Visit 13 (Week 117) ±7 days (any time).  The visit will occur 812 to 826 days after 
Visit 1. 
− 
Visit 14 (Week 130) ±7 days (any time).  The visit will occur 903 to 917 days after 
Visit 1. 
− 
Visit 15 (Week 143) ±7 days (any time).  The visit will occur 994 to 1008 days after 
Visit 1. 
− 
Visit 16 (Week 156) ±7 days (any time).  The visit will occur 1085 to 1099 days after 
Visit 1. 
− 
Follow-up Visit (Week 161) ±7 days. The visit will occur 1120 – 1134 days after Visit 
1. 
Visit windows for all visits after Visit 1 may be increased due to extenuating circumstances such 
as Covid-19 travel restrictions, with the approval of the Medical Monitor. 
10.1.2. Screening Visit (approximately Week -4 to -1)  
The Screening Visit may occur up to approximately 4 weeks prior to randomization, during 
which clinical data will be collected and screening procedures will be performed to determine 
eligibility.  The Screening Visit window may be extended at the discretion of the Medical 
Monitor. 
Prior to any protocol related activities, screening procedures, or assignment of a Participant 
Number, informed consent will be obtained from each potential participant in accordance with 
GCP and regional regulatory requirements.  The format and content of the ICF must be approved 
by the appropriate institutional review board/ethics committee (IRB/EC) prior to 
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The following must be performed during the Screening Period: 
1. PRO/ObsRO validation battery  
2. Verification of eligibility 
3. Demographics (date of birth, age at screening, biological sex, ethnicity, race) 
4. Medical history including family history of ACH, age of diagnosis, date of diagnosis (if 
available), type of mutation, and historical anthropometric measurements, as available 
5. Prior and concomitant medications 
6. Vital sign measurements (Temperature, HR, BP) 
7. Full physical examination, including assessment of pubertal status and thorough skeletal 
exam 
8. Baseline qualitative assessment of sleep and snoring pattern (clinical assessment for 
monitoring) 
9. Weight 
10. Standing height 
11. Sitting height 
12. 12-lead ECG 
13. Genetic confirmation of ACH (if not done previously).  See Section 11.11. 
14. Blood collection for the following laboratory assessments: 
a. Chemistry 
b. TSH 
c. Hemoglobin A1c 
d. Hematology 
e. Lipid panel 
f. 25(OH) Vitamin D 
g. Anti-drug antibodies 
h. Biomarkers 
15. Urine collection 
16. 
 
NOTE: PRO/ObsRO validation battery must be completed by the caregiver without 
assistance and should be completed prior to conducting any clinical assessments.  The same 
caregiver should complete all PRO/ObsRO validation batteries throughout participation in 
the trial.  The PRO/ObsROs should be completed at the visit if possible. If the same caregiver is 
unable to attend a particular visit, an alternate caregiver may complete the PRO/ObsROs at the 
visit. 
The 
 should be completed by the investigator after all clinical assessments are completed. 
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Screening Visit may be conducted remotely (e.g. at the participant’s home), at the discretion of 
the investigator, to minimize the risk of exposure to an infection during a pandemic or due to 
other restrictions that prevent the participant from being able to travel to the site. In such an 
event, consent may be obtained remotely as allowed by the applicable IRB/EC requirements, and 
the Investigator will conduct the scheduled assessments remotely with assistance from the home 
health nurse (HHN) who will be with the participant. 
If the PRO/ObsRO validation battery cannot be completed during the Screening Visit due to the 
visit being conducted remotely, the battery should be completed separately at approximately 
14 days prior to Visit 1, up to 7 days prior to Visit 1.  
All anthropometric measurements per medical records for up to one year prior to Screening Visit 
should be collected.  If measurement(s) are not available within one year, the last available 
measurement(s) prior to Screening Visit should be collected.  Method of measurement (standing 
vs recumbent, wall-mounted vs free-standing stadiometer in medical clinic vs other setting) 
should also be recorded. 
Thorough skeletal physical exam will be performed by palpating the bone structure and joints for 
tenderness and mobility and other abnormal changes not normally found in children with ACH. 
Special attention will be paid to the hip exam, which will include a supine assessment of 
abduction and adduction of hips to assess for pain and any limitation of range of motion. If 
changes are noted further evaluation will be required as clinically indicated, including imaging 
and/or orthopedic consultation. DMC will be apprised of any safety findings. 
Qualitative assessment of sleep and snoring pattern should include questions about neck 
hyperextension during sleep, loud and irregular snoring, glottal stops, observed sleep apnea, deep 
compensatory sighs, self-arousals, secondary enuresis, night-time emesis, morning headaches, 
daytime somnolence, or changes in school performance or behavior (Pauli 2019).  See 
Section 11.4 for details.  
For the assessment of pubertal status, boys will be assessed for testis volumes, and girls for 
breast development according to Tanner stages (Tanner 1976).  Pubic hair rating will also be 
recorded according to Tanner stages but will not be used to assess eligibility.  All participants 
must be Tanner Stage 1 for breast development (girls) - no glandular development/breast buds, 
and Tanner Stage 1 for gonadal development (boys) - testicular volume < 4 mL 
(Emmanuel 2019).  Tanner stage progression during the course of the trial will not impact study 
treatment.  See Appendix 3 for details. 
In case the Screening Visit is conducted remotely, full physical exam including pubertal 
assessment and thorough skeletal exam, may be conducted at Visit 1 before administration of 
study drug, with the understanding that an exam consistent with Tanner stage ≥ 2 is 
exclusionary. If the full physical exam and thorough skeletal exam are done pre-dose at Visit 1; 
an additional thorough skeletal exam and limited symptom directed physical exam at Visit 1 are 
not required 
The analysis of anti-drug antibodies may only be conducted after randomization and is not 
required for eligibility verification.   
Upon confirmation of eligibility, the participant will be randomized following Medical Monitor 
or designee confirmation.   


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If unavailable from medical records, genetic test for ACH will be performed. The test may be 
performed at any time after signing the consent and before Visit 1. Further testing may be 
pursued on an individual basis as indicated. Mutations other than those resulting in G380R 
substitution in FGFR3 may be used as genetic confirmation of ACH, pending review of Medical 
Monitor. 
Participants who sign the informed consent form but do not meet one or more eligibility criteria 
(including withdrawing of consent) prior to first study drug dosing will be considered screen 
failures.  A minimal set of screen failure information is required to ensure transparent reporting 
of screen failure participants.  Minimal information includes demography and screen failure 
details (eligibility criteria). 
The decision to rescreen will be made on a case by case basis after discussion with Medical 
Monitor, including which screening procedures may not need repeating.  Rescreened participants 
will receive a new Screening ID upon rescreening if they have not previously participated in 
ACHieve study (TCC-NHS-01).  Participants that participated in ACHieve will not be given a 
new Screening ID if they are Rescreened.  For all re-screened participants, the reason for the 
initial screen failure must be documented.   
See Section 11 for further details on procedures listed above.  
10.1.3. Randomized Treatment Period (Week 0 to Week 52) and Open-Label Extension 
Period (Week 52 – Week 156)  
During the Treatment Period, participants are randomized in a 3:1 ratio of TransCon CNP to 
placebo.  The dose is dependent on the cohort the participant is enrolled into:  
• Cohort 1: TransCon CNP 6 µg CNP/kg/week (Estimated 9 on TransCon CNP, 3 on placebo) 
• Cohort 2: TransCon CNP 20 µg CNP/kg/week (Estimated ≥9 on TransCon CNP, ≥3 on 
placebo) 
• Cohort 3: TransCon CNP 50 µg CNP/kg/week (Estimated ≥9 on TransCon CNP, ≥3 on 
placebo) 
• Cohort 4: TransCon CNP 100 µg CNP/kg/week (Estimated ≥9 on TransCon CNP, ≥3 on 
placebo) 
• Cohort 5*: TransCon CNP >100 µg CNP/kg/week (Estimated ≥9 on TransCon CNP, ≥3 on 
placebo) 
* Up to 200 µg CNP/kg/week, if needed, at a dose to be determined based on emerging data  
NOTE: Participants remain on the same dose of study drug throughout the 52 week 
Treatment Period 
During the Open-Label Extension Period, all participants receive TransCon CNP at the highest 
dose determined to be safe by DMC based on the data from the Randomized Period.  


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10.1.3.1. Visit 1 (Randomization/Week 0)  
Participants meeting all entry criteria will return to the clinic for Visit 1.   
The following will be performed prior to randomization and study drug administration: 
1. Subset of PRO/ObsRO validation battery 
2. Review changes in medical history 
3. Review of concomitant medications 
4. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
5. Vital sign measurements (Temperature, HR, BP), including orthostatic HR and BP 
6. Limited symptom-directed physical examination (at investigator’s discretion), injection site 
inspection, and thorough skeletal exam 
7. Qualitative assessment of changes of sleep and snoring pattern 
8. Weight 
9. All anthropometric measurements  
10. Radiographic assessment of bone 
a. Left hand and wrist bone age X-ray 
b. Dual-energy X-ray absorptiometry (DXA) 
c. Anterior-posterior (AP) Standing lower extremity X-ray 
d. AP and lateral spine X-ray 
11. Blood collection for the following laboratory assessments: 
a. Chemistry 
b. Hematology 
c. Pharmacokinetics 
d. Biomarkers 
e. Anti-drug antibodies 
12. 
 
13. After completion of these assessment, participants can proceed to randomization and study 
drug administration: 
a. Randomization 
b. Study drug administration at site and diary dispensing 
If for any reason the PRO/ObsRO validation battery for the Screening Visit was not completed 
prior to Visit 1, the same battery should be completed during Visit 1 prior to study drug 
administration in lieu of the subset scheduled for Visit 1. 
Orthostatic vital signs (HR and BP) will be taken at rest (preferably supine) and upon standing. 
Orthostatic hypotension is defined as decrease in SBP of ≥ 20 mmHg (Stewart 2018).  
Accompanying tachycardia is defined as change of heart rate increment of ≥40 bpm and absolute 
orthostatic HR ≥130 bpm (for ages 13 years and younger) (Singer 2012). 
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Limited symptom-directed physical examination of other systems should be performed at the 
discretion of the investigator to verify no clinically relevant changes have occurred since the 
Screening Visit. Injection site must be visually inspected prior to dosing.  
If the Screening Visit was conducted remotely, full physical examination, including pubertal 
status assessment, must be performed at Visit 1 before administration of study drug. Additional 
thorough physical exam and limited symptom directed physical exam are not required. 
Thorough skeletal physical exam will be performed and additional imaging assessments may be 
conducted as clinically indicated based on the physical exam findings.   
Anthropometric measurements should be taken following the Anthropometric Parameter Manual.  
For any anthropometric parameters that could not be measured during the visit, the reason must 
be documented.  
Radiographic assessments may not be required at Visit 1, with Medical Monitor approval, if the 
same assessments were conducted within approximately 3 months prior to Visit 1. If 
radiographic assessments cannot be completed prior to study drug administration due to 
scheduling conflicts, the assessments may be completed at up to 24 hours after study drug 
administration. 
Bone age using X-ray imaging will be assessed in the left hand and wrist for all participants 
unless a medical reason prohibits.  
DXA will be performed only for participants aged 5 years and older. 
The first dose of study drug will be administered on-site to provide training to the caregiver on 
study drug administration. Participant will be monitored for at least 2 hours in the clinic after 
injection for any acute reactions. Visual inspection of the injection site and vital signs 
measurements (Temperature, HR, and BP) will be performed at 1 hour and 2 hours after 
injection. Participants should be monitored longer as clinically indicated based on any clinically 
significant changes that emerge during the 2 hours.  
For participants who weigh ≥11 kg, the following will also be performed after injection of study 
drug: 
• Blood collection for pharmacokinetic analyses at approximately 8, 24, and 48 hours after 
injection 
• Orthostatic vital signs (HR and BP) at rest (preferably supine) and upon standing prior to 
blood collection at approximately 8, 24, and 48 hours after injection 
• Inspection of injection site at approximately 8, 24, and 48 hours after injection 
• ECG collection at approximately 48 hours after injection prior to PK blood collection 
Allowances will be made for accommodation.  Exceptions to the extended PK blood collection 
will be considered on an individual basis (e.g. if travel creates an undue hardship for a family).  
Assessments at 24 hours and 48 hours after injection, including orthostatic vital signs, ECG 
collection, blood collection, and injection site assessment may be conducted remotely by HHN. 


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10.1.3.2. Phone Visit (Week 2 ±3 days)  
All participants will be contacted by phone during Week 2 (±3 days) for follow up. During the 
call, the study staff will ask the caregiver about the general well-being of the child, inquire 
regarding correct administration of study drug procedures, record any AEs, record any 
concomitant medication changes, and answer any questions. 
10.1.3.3. Visit 2 (Week 4 ±3 days)  
At Visit 2, blood collection for pharmacokinetics must be at trough level. Therefore, study drug 
cannot be administered within 6 days prior to the visit. Study drug may be administered after all 
blood collection is completed. Visit 2 may be conducted remotely with assistance from the home 
health nurse (HHN). A portable stadiometer will be used to measure standing and sitting height 
and a portable scale to measure weight.  
The following will be performed: 
1. Review changes in concomitant medications  
2. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
3. Vital sign measurements (Temperature, HR, BP) 
4. Limited, symptom-directed physical examination at investigator’s discretion, injection site 
inspection, and thorough skeletal physical exam  
5. Qualitative assessment of changes of sleep and snoring pattern  
6. Weight 
7. Standing height and sitting height only 
8. 12-lead ECG 
9. Study drug and diary dispensing 
10. Blood collection for the following laboratory assessments: 
a. Chemistry 
b. Hematology 
c. Pharmacokinetics 
d. Biomarkers 
e. Anti-drug antibodies 
10.1.3.4. Visit 3 (Week 8 ±7 days)  
Visit 3 may be conducted remotely with assistance from the home health nurse (HHN). A 
portable stadiometer will be used to measure standing and sitting height and a portable scale to 
measure weight. 


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The following will be performed: 
1. Subset of PRO/ObsRO validation battery 
2. Review changes in concomitant medications 
3. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
4. Vital sign measurements (Temperature, BP, HR)  
5. Limited, symptom-directed physical examination at investigator’s discretion, injection site 
inspection, and thorough skeletal physical exam 
6. Qualitative assessment of changes of sleep and snoring pattern  
7. Weight 
8. Standing height and sitting height only 
9. 12-lead ECG 
10. Study drug and diary dispensing 
11. Blood collection for the following laboratory assessments: 
a. Chemistry 
b. Hematology  
c. Lipid panel 
d. Pharmacokinetics  
12. 
 
10.1.3.5. Visit 4 (Week 12 ±7 days):  
Visit 4 may be conducted remotely with assistance from the home health nurse (HHN). A 
portable stadiometer will be used to measure standing and sitting height and a portable scale to 
measure weight. 
The following will be performed: 
1. Subset of PRO/ObsRO validation battery 
2. Review changes in concomitant medications 
3. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
4. Vital sign measurements (Temperature, BP, HR) 
5. Limited, symptom-directed physical examination at investigator’s discretion, injection site 
inspection, and thorough skeletal physical exam 
6. Qualitative assessment of changes of sleep and snoring pattern  
7. Weight 
8. Standing height and sitting height only 
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9. Radiographic assessment of bone 
a. AP standing lower extremity X-ray 
b. AP and lateral spine X-ray 
10. Study drug and diary dispensing 
11. Blood collection for the following laboratory assessments: 
a. Chemistry 
b. Hematology  
c. Pharmacokinetics  
d. Biomarkers  
e. Anti-drug antibodies 
12. Urine collection  
13. 
 
Scheduled radiographic assessments may be performed within 1 week prior to or after the visit if 
all scheduled assessments cannot be completed within the same day. Radiographic assessments 
at Visit 4 may be conducted remotely (e.g. at a community imaging center). 
10.1.3.6. Visit 5 (Week 26 ±7 days):  
At Visit 5, blood collection for pharmacokinetics must be at trough level.  Therefore, study drug 
cannot be administered within 6 days prior to the visit. Study drug may be administered after all 
blood collection is completed. Visit 5 may only be conducted remotely when 
regional/institutional restrictions prohibit site visits (e.g. facility closed due to pandemic). If Visit 
5 is conducted remotely, a portable stadiometer will be used to measure standing and sitting 
height and a portable scale to measure weight, but full anthropometric measurements will be 
deferred until the participant is able to travel to the site. A physical assessment will be performed 
by the HHN under the remote supervision of the Investigator, but the pubertal assessment will be 
deferred until the next on-site visit. 
The following will be performed: 
1. Subset of PRO/ObsRO validation battery 
2. Review changes in concomitant medications 
3. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
4. Vital sign measurements (Temperature, HR, BP) 
5. Full physical examination, including assessment of pubertal status, injection site inspection, 
and thorough skeletal physical exam 
6. Qualitative assessment of changes of sleep and snoring pattern 
7. Weight  
8. All anthropometric measurements 
9. 12-lead ECG  
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10. Study drug and diary dispensing  
11. Blood collection for the following laboratory assessments: 
a. Chemistry  
b. Hematology  
c. 25(OH) Vitamin D 
d. Pharmacokinetics  
e. Biomarkers  
f. Anti-drug antibodies  
12. Urine collection 
13. 
 
10.1.3.7. Visit 6 (Week 39 ±7 days):  
Visit 6 may be conducted remotely with assistance from the home health nurse (HHN). A 
portable stadiometer will be used to measure standing and sitting height and a portable scale to 
measure weight. 
The following will be performed: 
1. Subset of PRO/ObsRO validation battery 
2. Review changes in concomitant medications 
3. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
4. Vital sign measurements (Temperature, HR, BP) 
5. Limited, symptom-directed physical examination at investigator’s discretion, injection site 
inspection, and thorough skeletal physical exam 
6. Qualitative assessment of changes of sleep and snoring pattern 
7. Weight 
8. Standing height and sitting height only 
9. Study drug and diary dispensing  
10. Blood collection for the following laboratory assessments: 
a. Chemistry  
b. Hematology  
c. Lipid panel 
d. Pharmacokinetics 
e. Biomarkers  
f. Anti-drug antibodies 
11. Urine collection 
12. 
 
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10.1.3.8. Visit 7 (Week 52 ±7 days) or ET Visit:  
This visit will serve as the last visit in the Randomized Period and the first visit in the Open-
Label Extension Period.  
At Visit 7, blood collection for pharmacokinetics must be at trough level.  Therefore, study drug 
cannot be administered within 6 days prior to the visit. For participants who do not roll over to 
the Open-Label Extension Period, no further dose of study drug will be administered. 
Visit 7 may only be conducted remotely when regional/institutional restrictions prohibit site 
visits (e.g. facility closed due to pandemic). If Visit 7 is conducted remotely, a portable 
stadiometer will be used to measure standing and sitting height and a portable scale to measure 
weight. A physical assessment will be performed by the HHN under the remote supervision of 
the Investigator. 
The following will be performed: 
1. PRO/ObsRO validation battery 
2. Review changes in concomitant medications 
3. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
4. Vital signs measurement (Temperature, HR, BP) 
5. Full physical examination including assessment of pubertal status, injection site inspection, 
and thorough skeletal physical exam 
6. Qualitative assessment of changes of sleep and snoring pattern 
7. Weight 
8. All anthropometric measurements 
9. Radiographic assessment of bone 
a. Left hand and wrist Bone age X-ray 
b. DXA 
c. AP Standing lower extremity X-ray 
d. AP and lateral spine X-ray 
10. 12-lead ECG  
11. Blood collection for the following laboratory assessments: 
a. Chemistry  
b. Hematology  
c. 25(OH) Vitamin D 
d. Lipid panel 
e. Pharmacokinetics  
f. Biomarkers  
g. Anti-drug antibodies 
12. Urine collection  
13. 
 
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Radiographic assessments at Visit 7 may be conducted remotely (e.g. at a community imaging 
center). Alternatively, radiologic assessments may be deferred until the participant is able to 
travel to the site.  Radiographic assessments may not be required at Visit 7, with Medical 
Monitor approval, if the same assessments were conducted within approximately 3 months prior 
to Visit 7. 
Immediately following completion of 52 weeks in the Randomized Period, all participants, 
including those randomized to placebo, may continue into the Open-Label Extension Period to 
receive TransCon CNP if they fulfill the rollover criteria (see Section 8.1.3 ). If the Investigator 
or Medical Monitor has concerns about continuing the participant in the Open-Label Extension 
Period (e.g. potential safety concerns or emergent fulfillment of holding/stopping criteria) 
participant may end treatment at the end of the Randomized Period.  
10.1.3.9. Follow-up Visit (Week 57 ±7 days):  For Participants Not Continuing in the 
Open-Label Extension  
Participants who are not continuing in the Open-Label Extension Period will attend a follow-up 
visit 5 weeks after Visit 7 to review any adverse events, to collect blood samples for assessment 
of anti-drug antibodies and answer any questions. The Follow-up visit may be conducted 
remotely (e.g. at the participant’s home) by the HHN at the discretion of the investigator to 
minimize the risk of exposure to an infection during a pandemic, or due to other restrictions that 
prevent the participant from being able to travel to the site for the blood collection. 
OPEN-LABEL EXTENSION PERIOD VISITS: 
10.1.3.10. Visit 7 (Week 52 ±7 days):  
For participants continuing in the Open-Label Extension Period, all Visit 7 assessments for the 
Open-Label Extension Period must be done immediately following the Visit 7 assessments for 
the Randomized Period. 
Prior to any protocol related activities for the Open-Label Extension Period, signed informed 
consent will be obtained for each potential participant in accordance with GCP and regional 
regulatory requirements. The format and content of the ICF must be approved by the appropriate 
institutional review board/ethics committee (IRB/EC) prior to implementation.   
During the Open-Label Extension Period, the Investigator should ascertain an individual’s risk 
for becoming pregnant or fathering a child and take appropriate steps for participants that attain 
reproductive potential during participation in the trial. This should be captured in the eCRF. 
Pregnancy prevention counseling and pregnancy testing should be provided as appropriate and 
can be tailored per the Investigator’s judgement based on maturity and cultural norms. (see 
Appendix 6). 
After completion of all scheduled assessments for the Randomized Period, the following will be 
performed: 
1. Informed consent 
2. Assessment of childbearing potential according to Appendix 6  
3. Urinary hCG test (for females of childbearing potential according to Appendix 6) 


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4. Study drug and diary dispensing 
For participants who received placebo during the Randomized Period, this will be the first dose 
of TransCon CNP, and in order to maintain the blind, all participants must undergo the same 
safety monitoring. Study drug must be administered on-site and participants will be monitored 
for at least 2 hours in the clinic after injection for any acute reactions. Visual inspection of the 
injection site and vital signs measurements (Temperature, HR, and BP) will be performed at 1 
hour and 2 hours after injection. Participants should be monitored longer as clinically indicated 
based on any clinically significant changes that emerge during the 2 hours.  
For participants who weigh ≥11 kg, the following will also be performed after injection of study 
drug: 
• Blood collection for pharmacokinetic analyses at approximately 8, 24, and 48 hours after 
injection 
• Orthostatic vital signs (HR and BP) at rest (preferably supine) and upon standing prior to 
blood collection at approximately 8, 24, and 48 hours after injection 
• Inspection of injection site at approximately 8, 24, and 48 hours after injection 
• ECG collection at approximately 48 hours after injection prior to PK blood collection 
Allowances will be made for accommodation.  Exceptions to the extended PK blood collection 
will be considered on an individual basis (e.g. if travel creates an undue hardship for a family).  
Assessments at 24 hours and 48 hours after injection, including orthostatic vital signs, ECG 
collection, blood collection, and injection site assessment may be conducted remotely by HHN. 
10.1.3.11. Phone Visit (Week 54 ±3 days):  
All participants will be contacted by phone during Week 54 (±3 days) for follow up. During the 
call, the study staff will ask the caregiver about the general well-being of the child, inquire 
regarding correct administration of study drug procedures, record any AEs, record any 
concomitant medication changes, and answer any questions. 
10.1.3.12. Visit 8 (Week 56 ±3 days):   
Visit 8 may be conducted remotely with assistance from the home health nurse (HHN). A 
portable stadiometer will be used to measure standing and sitting height and a portable scale to 
measure weight. Pubertal assessment will be deferred until the next on-site visit. 
The following will be performed: 
1. Review changes in concomitant medications 
2. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
3. Vital sign measurements (Temperature, HR, BP) 
4. Limited, symptom-directed physical examination at investigator’s discretion, injection site 
inspection, and thorough skeletal physical exam 
5. Qualitative assessment of sleep and snoring pattern 
6. Assessment of pubertal status and childbearing potential according to Appendix 6 


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7. Weight 
8. Standing height and sitting height  
9. 12-lead ECG 
10. Blood collection for the following laboratory assessments 
a. Chemistry 
b. Hematology 
c. Pharmacokinetics 
d. Biomarkers 
e. Anti-drug antibodies 
11. Urine collection (including hCG test for females of childbearing potential (according to 
Appendix 6) 
12. Study drug and diary dispensing 
10.1.3.13. Visit 9 (Week 65) ±7 Days  
Visit 9 may be conducted remotely with assistance from the home health nurse (HHN). A 
portable stadiometer will be used to measure standing and sitting height and a portable scale to 
measure weight. Pubertal assessment will be deferred until the next on-site visit. 
The following will be performed: 
1. Review changes in concomitant medications 
2. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
3. Vital sign measurements (Temperature, HR, BP) 
4. Limited, symptom-directed physical examination at investigator’s discretion, injection site 
inspection, and thorough skeletal physical exam 
5. Qualitative assessment of sleep and snoring pattern 
6. Assessment of pubertal status and childbearing potential according to Appendix 6 
7. Standing height and sitting height  
8. 12-lead ECG * 
9. Weight 
10. Radiographic assessments 
a. Anterior-posterior (AP) standing lower extremity X-ray 
b. Anterior-posterior and lateral spine X-ray  
11. Blood collection for the following laboratory assessments: 
a. Chemistry 
b. Hematology 
c. Pharmacokinetics * 
d. Biomarkers 


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e. Anti-drug antibodies 
12. Urine collection (including hCG test for females of childbearing potential according to 
Appendix 6) 
13. 
 
14. Study drug and diary dispensing 
15. Scheduled radiographic assessments may be performed within 1 week prior to or after the 
visit if all scheduled assessments cannot be completed within the same day. Radiographic 
assessments at Visit 9 may be conducted remotely (e.g. at a community imaging center). 
* 
ECG and blood collection for pharmacokinetics should be performed prior to study drug 
administration and only at visits where the dose is escalated. 
10.1.3.14. Visit 10 (Week 78) ±7 Days  
Visit 10 may only be conducted remotely when regional/institutional restrictions prohibit site 
visits (e.g. facility closed due to pandemic). If Visit 10 is conducted remotely, a portable 
stadiometer will be used to measure standing and sitting height and a portable scale to measure 
weight, but full anthropometric measurements will be deferred until the participant is able to 
travel to the site. A physical assessment will be performed by the HHN under the remote 
supervision of the Investigator, but the pubertal assessment will be deferred until the next on-site 
visit. 
The following will be performed: 
1. Subset of PRO/ObsRO validation battery 
2. Review changes in concomitant medications 
3. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
4. Vital sign measurements (Temperature, HR, BP) 
5. All anthropometric measurements 
6. 12-lead ECG 
7. Full physical examination, injection site inspection, and thorough skeletal physical exam 
8. Qualitative assessment of sleep and snoring pattern 
9. Assessment of pubertal status and childbearing potential according to Appendix 6 
10. Weight 
11. Blood collection for the following laboratory assessments: 
a. Chemistry 
b. Hematology 
c. 25(OH) Vitamin D 
d. Lipid panel 
e. Pharmacokinetics 
f. Biomarkers 
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g. Anti-drug antibodies 
12. Urine collection (including hCG test for females of childbearing potential according to 
Appendix 6) 
13. 
 
14. Study drug and diary dispensing  
10.1.3.15. Visit 11 (Week 91) ±7 Days  
Visit 11 may be conducted remotely with assistance from the home health nurse (HHN). A 
portable stadiometer will be used to measure standing and sitting height and a portable scale to 
measure weight. Pubertal assessment will be deferred until the next on-site visit. 
The following will be performed: 
1. Review changes in concomitant medications 
2. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
3. Vital sign measurements (Temperature, HR, BP) 
4. Limited, symptom-directed physical examination at investigator’s discretion, injection site 
inspection, and thorough skeletal physical exam 
5. Qualitative assessment of sleep and snoring pattern 
6. Assessment of pubertal status and childbearing potential according to Appendix 6 
7. Standing height and sitting height  
8. 12-lead ECG * 
9. Weight 
10. Blood collection for the following laboratory assessments: 
a. Chemistry 
b. Hematology 
c. Pharmacokinetics * 
d. Biomarkers 
e. Anti-drug antibodies 
11. Urine collection (including hCG test for females of childbearing potential according to 
Appendix 6) 
12. 
 
13. Study drug and diary dispensing 
* 
ECG and blood collection for pharmacokinetics should be performed prior to study drug 
administration and only at visits where the dose is escalated. 
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10.1.3.16. Visit 12 (Week 104) ±7 Days  
Visit 12 may only be conducted remotely when regional/institutional restrictions prohibit site 
visits (e.g. facility closed due to pandemic). If Visit 12 is conducted remotely, a portable 
stadiometer will be used to measure standing and sitting height and a portable scale to measure 
weight, but full anthropometric measurements will be deferred until the participant is able to 
travel to the site. A physical assessment will be performed by the HHN under the remote 
supervision of the Investigator, but the pubertal assessment will be deferred until the next on-site 
visit. 
The following will be performed: 
1. PRO/ObsRO validation battery 
2. Review changes in concomitant medications 
3. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
4. Vital sign measurements (Temperature, HR, BP) 
5. All anthropometric measurements 
6. Full physical examination, injection site inspection, and thorough skeletal physical exam 
7. Qualitative assessment of sleep and snoring pattern 
8. Assessment of pubertal status and childbearing potential according to Appendix 6 
9. Weight 
10. Radiographic assessments 
a. X-ray of left hand and wrist for bone age 
b. Dual-energy X-ray absorptiometry (DXA) for bone mineral density (participants 5 years 
and older only) 
c. Anterior-posterior and lateral spine X-ray  
d. Anterior-posterior (AP) standing lower extremity X-ray 
11. 12-lead ECG 
12. Blood collection for the following laboratory assessments 
a. Chemistry 
b. Hematology 
c. 25(OH) Vitamin D 
d. Lipid panel 
e. Pharmacokinetics 
f. Biomarkers 
g. Anti-drug antibodies 
13. Urine collection (including hCG test for females of childbearing potential according to 
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14. 
 
15. Study drug and diary dispensing 
Radiographic assessments at Visit 12 may be conducted remotely (e.g. at a community imaging 
center). Alternatively, radiologic assessments may be deferred until the participant is able to 
travel to the site.  
10.1.3.17. Visit 13 (Week 117) ±7 Days  
Visit 13 may be conducted remotely with assistance from the home health nurse (HHN). A 
portable stadiometer will be used to measure standing and sitting height and a portable scale to 
measure weight. Pubertal assessment will be deferred until the next on-site visit. 
The following will be performed: 
1. Review changes in concomitant medications 
2. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
3. Vital sign measurements (Temperature, HR, BP) 
4. Limited, symptom-directed physical examination at investigator’s discretion, injection site 
inspection, and thorough skeletal physical exam 
5. Qualitative assessment of sleep and snoring pattern 
6. Assessment of pubertal status and childbearing potential according to Appendix 6 
7. Standing height and sitting height  
8. Weight 
9. Radiographic assessments 
a. Anterior-posterior (AP) standing lower extremity X-ray 
b. Anterior-posterior and lateral spine X-ray  
10. Blood collection for the following laboratory assessments 
a. Chemistry 
b. Hematology 
c. Biomarkers 
d. Anti-drug antibodies 
11. Urine collection (including hCG test for females of childbearing potential according to 
Appendix 6) 
12. 
 
13. Study drug and diary dispensing 
14. Scheduled radiographic assessments may be performed within 1 week prior to or after the 
visit if all scheduled assessments cannot be completed within the same day. Radiographic 
assessments at Visit 13 may be conducted remotely (e.g. at a community imaging center). 
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10.1.3.18. Visit 14 (Week 130) ±7 Days  
Visit 14 may only be conducted remotely when regional/institutional restrictions prohibit site 
visits (e.g. facility closed due to pandemic). If Visit 14 is conducted remotely, a portable 
stadiometer will be used to measure standing and sitting height and a portable scale to measure 
weight, but full anthropometric measurements will be deferred until the participant is able to 
travel to the site. A physical assessment will be performed by the HHN under the remote 
supervision of the Investigator, but the pubertal assessment will be deferred until the next on-site 
visit. 
The following will be performed: 
1. Subset of PRO/ObsRO validation battery 
2. Review changes in concomitant medications 
3. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
4. Vital sign measurements (Temperature, HR, BP) 
5. All anthropometric measurements 
6. Full physical examination, injection site inspection, and thorough skeletal physical exam 
7. Qualitative assessment of sleep and snoring pattern 
8. Assessment of pubertal status and childbearing potential according to Appendix 6 
9. Weight 
10. 12-lead ECG 
11. Blood collection for the following laboratory assessments 
a. Chemistry 
b. Hematology 
c. 25(OH) Vitamin D 
d. Lipid panel 
e. Pharmacokinetics 
f. Biomarkers 
g. Anti-drug antibodies 
12. Urine collection (including hCG test for females of childbearing potential according to 
Appendix 6) 
13. 
 
14. Study drug and diary dispensing  
10.1.3.19. Visit 15 (Week 143) ±7 Days  
Visit 15 may be conducted remotely with assistance from the home health nurse (HHN). A 
portable stadiometer will be used to measure standing and sitting height and a portable scale to 
measure weight. Pubertal assessment will be deferred until the next on-site visit. 
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The following will be performed: 
1. Review changes in concomitant medications 
2. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
3. Vital sign measurements (Temperature, HR, BP) 
4. Limited, symptom-directed physical examination at investigator’s discretion, injection site 
inspection, and thorough skeletal physical exam 
5. Qualitative assessment of sleep and snoring pattern 
6. Assessment of pubertal status and childbearing potential according to Appendix 6 
7. Standing height and sitting height  
8. Weight 
9. Blood collection for the following laboratory assessments 
a. Chemistry 
b. Hematology 
c. Biomarkers 
d. Anti-drug antibodies 
10. Urine collection (including hCG test for females of childbearing potential according to 
Appendix 6) 
11. 
 
12. Study drug and diary dispensing 
10.1.3.20. Visit 16 (Week 156) ±7 Days/Early Termination Visit  
No further dose of study drug will be administered after Visit 16. Visits 16 may only be 
conducted remotely when regional/institutional restrictions prohibit site visits (e.g. facility closed 
due to pandemic). If Visit 16 is conducted remotely, a portable stadiometer will be used to 
measure standing and sitting height and a portable scale to measure weight. A physical 
assessment will be performed by the HHN under the remote supervision of the Investigator. 
The following will be performed: 
1. PRO/ObsRO validation battery 
2. Review changes in concomitant medications 
3. Review adverse events (including review of ACH comorbidities based on age, including risk 
of sleep apnea and CMC) 
4. Vital sign measurements (Temperature, HR, BP) 
5. All anthropometric measurements 
6. Full physical examination, injection site inspection, and thorough skeletal physical exam 
7. Qualitative assessment of sleep and snoring pattern 
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8. Assessment of pubertal status and childbearing potential according to Appendix 6 
9. Weight 
10. 12-lead ECG 
11. Radiographic assessments 
a. X-ray of left hand and wrist for bone age 
b. Dual-energy X-ray absorptiometry (DXA) for bone mineral density (participants 5 years 
and older only) 
c. Anterior-posterior and lateral spine X-ray  
d. Anterior-posterior (AP) standing lower extremity X-ray 
12. Blood collection for the following laboratory assessments 
a. Chemistry 
b. Hematology 
c. 25(OH) Vitamin D 
d. Lipid panel 
e. Pharmacokinetics 
f. Biomarkers 
g. Anti-drug antibodies 
13. Urine collection (including hCG test for females of childbearing potential according to 
Appendix 6) 
14. 
 
Radiographic assessments at Visit 16 may be conducted remotely (e.g. at a community imaging 
center). Alternatively, radiologic assessments may be deferred until the participant is able to 
travel to the site. Radiographic assessments may not be required at Visit 16, with Medical 
Monitor/Medical Expert approval, if the same assessments were conducted within approximately 
3 months prior to Visit 16. 
Immediately following completion of treatment in the study at Visit 16, all participants may be 
offered to continue in a separate long-Term Open-Label _Extension Study (ASND0039) if they 
fulfill the eligibility criteria for the study. In the separate study, participants will continue to 
receive TransCon CNP. If the Investigator or Medical Monitor has concerns about continuing the 
participant in the separate Long-Term Open-Label Extension Study (e.g. potential safety 
concerns or emergent fulfillment of holding/stopping criteria), the participant will end treatment 
with TransCon CNP.  
10.1.3.21. Follow-Up Visit (Week 161 ±7 days):  
Participants who will not continue in the separate Long-Term Open-Label Extension Study 
(ASND0039), will attend a follow-up visit 5 weeks after Visit 16 to review any adverse events, 
to collect blood samples for assessment of anti-drug antibodies and answer any questions. The 
Follow-up visit may be conducted remotely (e.g. at the participant’s home) by the HHN at the 
discretion of the investigator to minimize the risk of exposure to an infection during a pandemic, 
or due to other restrictions that prevent the participant from being able to travel to the site for the 
blood collection. 
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10.1.4. Unscheduled Visits (UV)  
Unscheduled Visits are those visits that occur between regularly scheduled visits at investigator 
discretion to manage an already documented AE, assess a potential AE, abnormal/alarming 
laboratory values, and/or clinical findings.  Unscheduled Visits may be conducted remotely with 
assistance from the home health nurse (HHN). Only focused assessments (guided by the reason 
for the visit) will occur at these visits.  In such cases, the participant’s caregiver will be contacted 
to arrange an UV. 
10.1.5. Early Termination (ET) Visits  
ET Visits are performed for any early termination/withdrawal of a participant from this clinical 
trial.  This does not apply to participants who have discontinued study drug but consented to 
continue trial visits.  The structure and assessments of the ET Visit should as much as possible be 
similar to Visit 7 if performed during the Randomized Period and Visit 16 if performed during 
the Open-Label Extension Period. Radiographic assessments may not be required, with Medical 
Monitor approval, if the same assessments were conducted within approximately 3 months prior 
to the ET Visit.  
11. 
ASSESSMENTS  
11.1. VITAL SIGN MEASUREMENTS  
Participants should rest for at least 5 minutes before vital sign measurement and vital signs 
should be taken prior to any blood draws.  The following vital signs should be measured: 
• Heart Rate (measured in beats per minute) 
• Blood Pressure (seated BP will be taken measured in mm Hg) 
• Temperature [measured in degrees Celsius (°C) or Fahrenheit (°F)] 
All vital signs above must be measured at all visits.  Orthostatic HR and systolic/diastolic BP 
will also be measured at Visit 1 prior to administration of study drug when the participant is at 
rest for 5 minutes (preferably supine) and again after standing at 3 minutes for assessment of 
orthostatic hypotension. Orthostatic hypotension is defined as decrease in SBP of ≥ 20 mmHg 
(Stewart 2018). Accompanying tachycardia is defined as change of heart rate increment of 
≥40 bpm and absolute orthostatic HR ≥130 bpm (for ages 13 years and younger) (Singer 2012).  
Additionally, at Visit 1 and Visit 7 (in the Open-Label Extension Period), all vital signs must be 
monitored at 1 hour and 2 hours post injection of the study drug.   
For participants that undergo blood collection for pharmacokinetic analyses at 8, 24, and 
48 hours following first dose (at Visit 1 in the Randomized Period and Visit 7 in the Open-Label 
Extension Period), orthostatic systolic/diastolic BP and HR will be measured prior to each PK 
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11.2. ELECTROCARDIOGRAM (ECG)  
An ECG must be collected at Screening and Visits 1, 2, 3, 5, and 7/ET in the Randomized 
Period, and at Visits 8, 10, 12, 14, and 16/ET in the Open-Label Extension. In addition, ECGs 
will be collected at Visits 9 and 11 if the dose is escalated at the visit. This schedule allows any 
child who switches from placebo to study drug to have ECGs performed in the same schedule as 
those who began study drug treatment in the Randomized Period. At Visit 1 on the Randomized 
Period and Visit 7 in the Open-Label Extension Period, ECG will be collected only at 
approximately 48 hours after the first dose for participants that undergo blood collection for PK 
analysis at that time. Standard 12-lead ECG will be recorded when the participant is in a resting 
state, prior to blood collection if scheduled at the same time.  ECGs will be read centrally.  If 
adequate tracing is unable to be collected at the site, external ECGs may be allowed for safety 
monitoring.   
11.3. PHYSICAL EXAMINATIONS  
Full physical examination must be performed at the Screening Visit, Visit 5 (Week 26), 
Visit 7 (Week 52)/ET, and in the Open-Label Extension Period Visit 10 (Week 78), 
Visit 12 (Week 104), Visit 14 (week 130), and Visit 16/ET (week 156) and includes assessment 
of all major body systems including general appearance, HEENT, Neck (including thyroid), 
Lung/pulmonary, Chest, CV, Abdomen, Back, GU, Neurological, Extremities, and Skin.  
At the Screening Visit, Visit 5, and at Visit 7/ET in the Randomized Period and at all visits in the 
Open-Label Extension Period, physical examination must also include an assessment of pubertal 
status.  Boys will be assessed for testis volumes, and girls for breast development according to 
Tanner stages (Tanner 1976).  Pubic hair rating will also be recorded according to Tanner stages 
but will not be used to assess eligibility.  At randomization, all participants must be Tanner Stage 
1 for breast development (girls) - no glandular development/breast buds, and Tanner Stage 1 for 
gonadal development (boys) - testicular volume < 4 mL (Emmanuel 2019).  Tanner stage 
progression during the course of the trial will not impact study treatment.  See Appendix 3 for 
details. In the Open-Label Extension Period, assessment for child-bearing potential will also be 
performed, if applicable (see Appendix 6).   
At all other on-site visits, limited physical examination should be performed. Limited, symptom-
directed physical examination should include assessment of all major body systems (as listed 
above) at the investigator’s discretion.  
Physical examination should include a visual inspection of the injection sites at every visit.  At 
Visit 1 in the Randomized Period and Visit 7 in the Open-Label Extension Period, visual 
inspection of the injection site must be performed prior to injection of study drug and at 1 hour 
and 2 hours after injection of study drug.  For participants that undergo blood collection for 
pharmacokinetic analyses at 8, 24, and 48 hours following first dose, injection site will be 
inspected at the time of each blood collection. Clinically significant findings should be assessed 
for whether they qualify as AEs as defined in Section 12 Adverse Event Assessment and 
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Additionally, thorough skeletal physical exam will be performed at all visits in both the 
Randomized Period and the Open-Label Extension Period by palpating the bone structure and 
joints for tenderness and mobility and other abnormal changes not normally found in children 
with ACH.  Special attention will be paid to the hip exam, which will include a supine 
assessment of abduction and adduction of hips to assess for pain and any limitation of range of 
motion. If changes are noted further evaluation will be required as clinically indicated, including 
imaging and/or orthopedic consultation. DMC will be apprised of any safety findings.  Such 
findings should be assessed for whether they qualify as AEs as defined in Section 12 Adverse 
Event Assessment and Reporting.  
11.4. QUALITATIVE ASSESSMENT OF SLEEP AND SNORING PATTERN  
Qualitative assessment of sleep and snoring pattern is required at all visits in both the 
Randomized Period and the Open-Label Extension Period, and a sleep study considered if any 
changes are noted.  Assessment should include questions about neck hyperextension during 
sleep, loud and irregular snoring, glottal stops, observed sleep apnea, deep compensatory sighs, 
self-arousals, secondary enuresis, night-time emesis, morning headaches, daytime somnolence, 
or changes in school performance or behavior (Pauli 2019).  Such findings should be assessed for 
whether they qualify as AEs as defined in Section 12 Adverse Event Assessment and Reporting. 
11.5. ANTHROPOMETRIC MEASUREMENTS  
Anthropometric measurements, including weight, should be taken following the procedures 
described in the Anthropometric Parameter Manual.  All individuals involved in anthropometry 
measurements must have a documented record of understanding of the manual prior to taking 
measurements for the trial. Refer to the anthropometric measurement manual for detailed 
instructions. 
11.6. PRO/OBSRO VALIDATION BATTERY  
Three child/parent experience measures are currently being developed and are collectively 
referred to as the Achondroplasia Experience Measures (AEMs).  They consist of:  
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The Validation Battery consists of the AEMs and other questionnaires needed for the 
psychometric testing.  The Validation Battery must be completed at the Screening Visit and Visit 
7/ET in the Randomized Period, and at Visits 12 and 16/ET in the Open-Label Extension Period.  
Completion of the Validation Battery is expected to take approximately 30-45 minutes.  If the 
PRO/ObsRO validation battery cannot be completed during the Screening Visit due to the visit 
being conducted remotely, the battery should be completed separately at approximately 14 days 
prior to Visit 1, up to 7 days prior to Visit 1. If for any reason the PRO/ObsRO validation battery 
for the Screening Visit was not completed prior to Visit 1, the same battery should be completed 
during Visit 1 prior to study drug administration in lieu of the subset scheduled for Visit 1. A 
subset of the Validation Battery must also be completed at Visits 1, 3, 4, 5, and 6 in the 
Randomized Period, and at Visits 10 and 14 in the Open-Label Extension Period.  
The measures in the validation battery are Generic Patient-Reported Outcomes Measurement 
Information System (PROMIS) Parent Proxy SF Upper Extremity, Global Health and SF 
Depressive Symptoms, Satisfaction with Life Scale – Child (SWLS-C), Pediatric Quality of Life 
Inventory (PedsQL), 
, Growth Hormone Deficiency-Child 
Impact Measure (GHD-CIM), DISABKIDS Chronic Generic Module (DCGM-37), Sheehan 
Disability Scale, 
, Parent Experience of 
Child Illness (PECI), Activity Impairment Assessment (AIA), Perceived Stress Scale (PSS), 
 and Endicott Work Productivity Scale (EWPS), Euroqol 
5-Dimensional Questionnaire Youth Proxy version 1 (EQ-5D-Y Proxy1), and a resource
utilization questionnaire.
NOTE: PRO/ObsRO validation batteries must be completed by the caregiver without 
assistance and should be completed prior to conducting any clinical assessments.  The same 
caregiver should complete all PRO/ObsRO validation batteries throughout participation in 
the trial.  The PRO/ObsRO validation batteries should be completed at the visit if possible. If 
the same caregiver is unable to attend a particular visit, an alternate caregiver may complete the 
PRO/ObsRO validation batteries at the visit. All PRO/ObsROs should be done when scheduled 
even if the same meaures where not completed at Screening Visit and/or Visit 1.   
Refer to the PRO/ObsRO Validation Battery and instructions for further details. 
In countries where these PRO/ObsRO batteries are available, all participants will be expected to 
complete the PRO/ObsRO validation batteries.  For Cohort 1, completion of the PRO/ObsRO 
validation batteries is expected for participants from sites in US. 
11.7. 
 
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11.8. RADIOGRAPHIC ASSESSMENT OF BONE  
The type and frequency of radiographic assessments has been carefully chosen to minimize 
exposure to radiation for the trial participants as shown below. Total exposure during the trial is 
expected to be approximately 7.4 mSv/participant.   
Randomized Period: 
• AP standing lower extremity X-ray 3 times over 12 months – 0.18 mSv 
• AP and lateral lumbar spine X-ray 3 times over 12 months – 3.0 mSv 
• Bone age of left hand and wrist 2 times over 12 months – 0.002 mSv 
• DXA 2 times over 12 months – 0.002 mSv 
Open-Label Extension Period: 
• AP standing lower extremity X-ray 4 times over 24 months – 0.24 mSv 
• AP and lateral lumbar spine X-ray 4 times over 24 months – 4.0 mSv 
• Bone age of left hand and wrist 2 times over 24 months – 0.002 mSv 
• DXA 2 times over 24 months – 0.002 mSv 
Radiographic assessments may not be required at Visit 1 with Medical Monitor approval, if the 
assessments were conducted within approximately 3 months prior to Visit 1. If radiographic 
assessments cannot be completed prior to study drug administration at Visit 1 due to scheduling 
conflicts, the assessments may be completed at up to 24 hours after study drug administration.  
On Visit 4 in the Randomized Period and Visits 9, 12 and 13 in the Open-Label Extension 
Period, scheduled radiographic assessments may be performed within 1 week prior to or after the 
visit if all scheduled assessments cannot be completed within the same day. They may also be 
conducted remotely (e.g. at a community imaging center). 
Radiographic assessments at Visit 7/ET and 16/ET may be conducted remotely (e.g. at a 
community imaging center). Alternatively, radiologic assessments may be deferred until the 
participant is able to travel to the site. Radiographic assessments may not be required at Visit 
7/ET and 16/ET, with Medical Monitor approval, if the same assessments were conducted within 
approximately 3 months prior to Visit 7 or Visit 16/ET, respectively. 
Refer to the radiographic assessment manual for details of the procedures for the radiographic 
assessment of bone. 
11.8.1. Hand and Wrist X-ray  
Hand and wrist X-ray imaging will be conducted at Visit 1, Visit 7/ET, and in Visits 12 and 
16/ET (in the Open-Label Extension Period). The assessment will be in the left hand and wrist 
for all participants unless a medical reason prohibits, in which case the right hand and wrist may 
be used. Images will be used to assess bone age and bone growth.  


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11.8.2. Anterior-posterior (AP) Standing Lower Extremity X-ray  
Standing X-ray films of lower extremity along the AP axis will be collected at Visit 1, 4 and 
7/ET in the Randomized Period, and Visit 9, 12, 13, 16/ET in the Open-Label Extension Period. 
Standing lower extremity X-ray will be used to monitor changes in varus deformities, bone 
growth and possible adverse changes in growth plates. 
11.8.3. Dual-energy X-ray Absorptiometry (DXA)  
DXA will be performed at Visit 1, and Visit 7/ET in the Randomized Period and Visits 12 and 
16/ET (in the Open-Label Extension Period).  The assessment will be done only for participants 
aged 5 years and older. DXA will be used to assess any changes in bone mineral density (BMD).  
11.8.4. Anterior-posterior and Lateral Spine X-ray  
X-ray of the spine, along the AP and lateral axes, will be taken at Visit 1, 4, and 7/ET in the 
Randomized Period and at Visits 9, 12, 13, 16/ET in the Open-Label Extension Period. Spine 
X-ray will be used to monitor any changes in kyphosis, lordosis, scoliosis, and morphology of 
vertebral bodies. 
11.9. WEEKLY DIARY  
Participants/caregivers are trained on the weekly diary during Visit 1 and instructed to return the 
diary at every visit for site staff review as part of concomitant medication review, adverse event 
review and study drug compliance.  Diary must be completed from Visit 1 until completion of 
Visit 7/ET Visit in the Randomized Period, and from Visit 7 in the Open-Label Extension Period 
until completion of Visit 16/ET. 
Participants/caregivers will be required to complete a weekly diary to capture the following:  
• Study drug, starting at Visit 1 (dose, administration date and time, and injection location) 
• Changes to concomitant medications  
• Changes to the participant’s health or well-being, including any procedures, ER visits, and 
hospitalizations. 
11.10. ADVERSE EVENT REVIEW  
At each visit, the participant and/or caregiver should be asked about the following to assess for 
any potential AEs: 
• General well-being  
• Any changes to health or medications since the previous visit; specifically, any ear infections 
or sleep apnea or neurological symptoms suggestive of cord compression 
• Symptoms of hypotension such as dizziness, headache, lightheadedness, blurry vision, and 
loss of consciousness since the previous visit 
• Emergency/urgent care visits or hospitalizations since the previous visit 
At each visit, site staff will review diary with the participant and the caregiver, and any data 
related to changes in health or medications should be further assessed for potential AEs.   


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Additionally, changes from baseline noted during a physical examination should be assessed for 
potential AEs. 
Additional assessments, including a physical examination or additional laboratory assessment, 
may be performed at the discretion of the investigator even if not required at the specific study 
visit or if an UV must be scheduled.   
See Section 12 for details on reporting AEs. 
11.11. LABORATORY ASSESSMENTS  
Safety labs and immunogenicity samples are important for safety assessment in this trial.  
Samples for immunogenicity (antibody measurements) are stored for up to 8 years after the end 
of the trial in order to make additional antibody tests and characterizations possible at the request 
of health authorities. All other samples will be destroyed no later than the end of the trial. 
The objective of the PK assessments is to understand the relation between exposure and biologic 
activity.  Pediatric blood volume limit guidelines were utilized to minimize blood collection 
volumes and assay technologies were chosen that are capable of sensitively detecting analytes 
using the lowest possible volume of blood for analysis. 
The TCC-201 trial has been designed to minimize deviations from the normally conducted 
procedures for the diagnosis and treatment of ACH.  To reduce stress and pain and at the same 
time ensure safety of the children that participate in TCC-201, sparse sampling of PK blood 
collection is employed and the volume of blood to be drawn at each trial visit will be restricted 
based on the weight of the child at each visit following the recommendations published by the 
European Commission titled “Ethical considerations for clinical trials on medicinal products 
conducted with minors”, dated 18 September 2017.  See Appendix 4 for details. 
The following laboratory assessments are performed.  See Appendix 1 and Appendix 2 for the 
Schedule of Events. 
1. Genetic confirmation of ACH 
If unavailable from medical records, a blood sample will be collected and used to identify the 
FGFR3 mutation for ACH.  The test may be performed at any time after signing the consent and 
before Visit 1. The central lab will test for the G380R substitution in FGFR3 (i.e. G to A 
transition or G to C transversion at nucleotide 1138 of FGFR3 gene), but further testing may be 
pursued on an individual basis as indicated. Other mutations may be used as genetic 
confirmation of ACH, pending review of Medical Monitor. 
2. Chemistry 
a. Sodium 
b. Potassium 
c. Chloride 
d. Bicarbonate 
e. Magnesium 
f. Phosphate 
g. Calcium 
h. Glucose 
i. Alkaline Phosphatase 


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j. Aspartate Aminotransferase (AST) 
k. Alanine Aminotransferase (ALT) 
l. Creatinine 
m. Creatine Phosphokinase 
a. Albumin 
b. Direct Bilirubin 
c. Total Bilirubin 
d. BUN 
e. Gamma Glutamyl Transferase 
f. Lactate Dehydrogenase 
g. Total Protein 
h. Uric Acid 
3. Thyroid stimulating hormone (TSH) 
4. Hemoglobin A1c (HbA1c) 
5. Hematology 
a. Hemoglobin 
b. Hematocrit 
c. RBC Count 
d. WBC Count 
e. Differential Cell Count 
f. Platelet Count 
6. Lipid panel 
a. Total cholesterol 
b. LDL 
c. HDL 
d. Triglycerides 
7. 25(OH) Vitamin D 
8. Urinalysis Panel 
9. Urine Chemistry 
a. Urine Calcium 
b. Urine Creatinine 
c. Urine Phosphate 
10. PK Assessments 
a. Free CNP 
b. Total CNP 
c. mPEG and mPEG-linker 
11. Biomarkers (blood) 
a. Exploratory biomarkers of pharmacodynamic response to treatment with TransCon CNP, 
 
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12. Immunogenicity Assessments 
a. Anti-drug antibodies 
11.12. TREATMENT PERIOD ADMINISTRATION  
The first dose of study drug will be administered by the caregiver in the clinic, and the 
participant will be observed for at least 2 hours for assessment of adverse reactions.  Caregiver 
will administer all subsequent weekly doses of study drug for 52 weeks during the Randomized 
Period plus 104 weeks during the Open-Label Extension Period. The last dose of randomized 
study drug will be administered at least 6 days prior to Visit 7 (Week 52).  At each visit, 
injection sites should be examined, and injection site rotation should be reinforced. 
12. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND REPORTING  
12.1. ADVERSE EVENTS  
12.1.1. Definition  
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product 
(IMP) or other protocol-imposed intervention, regardless of attribution. This includes the 
following: 
• AEs not previously observed in the participant that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with achondroplasia that were not 
present prior to the AE reporting period.  
• Complications that occur as a result of protocol-mandated interventions (e.g. invasive 
procedures such as cardiac catheterizations).  
• If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention.  
• Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
Serious Adverse Events Definition 
An AE should be classified as an SAE if any of the following criteria are met: 
• It results in death (i.e. the AE cause or leads to death).  
• It is life threatening (i.e. the AE, in the view of the investigator, places the participant at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe form 
or was allowed to continue, might have caused death).  
• It requires or prolongs inpatient hospitalization (see Section 12.3.3). 
• It results in persistent or significant disability/incapacity (i.e. the AE results in substantial 
disruption of the participant’s ability to conduct normal life functions).  


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• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the study drug.  
• It is considered a significant medical event by the investigator based on medical judgment 
(e.g. may jeopardize the participant or may require medical/surgical intervention to prevent 
one of the outcomes listed above). 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of an 
adverse event (e.g. rated as mild, moderate, or severe according to Table 1; see Section 12.2.2.1); 
the event itself may be of relatively minor medical significance (such as severe headache without 
any further findings). 
Severity and seriousness need to be independently assessed for each adverse event recorded on 
the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor immediately 
(i.e. no more than 24 hours after learning of the event; see Section 12.4.2 for reporting 
instructions). 
Special Situation Definition 
Special situations are non-standard medical conditions that provide valuable information (e.g. 
clinical, safety) about a medicinal product, even when they do not occur in association with an 
adverse event or medical condition. Examples of special situations include and should all be 
captured in the eCRF: 
• Pregnancy 
• Breastfeeding 
• Overdose 
• Drug abuse 
• Misuse 
• Off label use 
• Occupational exposure 
• Lack of therapeutic efficacy 
• Medication error 
The Medical Monitor will review all safety information on an ongoing basis. The key safety data 
will also be reviewed periodically by Data Monitoring Committee (DMC) in accordance with its 
governing charter).   
12.2. METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES  
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to Ascendis Pharma, in accordance with FDA CFR 
312.32 (IND Safety Reports) and ICH E6. 


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12.2.1. Adverse Event Reporting Period  
The Adverse Event Reporting Period is the period requiring reporting of AEs and SAEs for any 
patients exposed to the study drug and/or study related procedures. Reporting period begins from 
the time informed consent is obtained and ends at the last study visit. After this period, 
investigators should only report SAEs that are attributed to prior study treatment. 
12.2.2. Severity, Causality, and Outcome Assessment  
12.2.2.1. Severity Rating  
Assessment of Severity of Adverse Events 
The World Health Organization (WHO) toxicity grading scale will be used for assessing adverse 
event severity.  Table 1 will be used for assessing severity for adverse events that are not 
specifically listed in the WHO toxicity grading scale. 
Table 1: 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
WHO Toxicity Grading Scale  
Grade 
Severity 
1 
Mild; transient or mild discomfort ( 48 hours); no medical intervention or therapy required 
2 
Moderate; mild to moderate limitation in activity; some assistance may be needed; no or 
minimal medical intervention or therapy required 
3 
Severe; marked limitation in activity; some assistance usually required; medical intervention 
or therapy required; hospitalization possible 
4 
Life-threatening; extreme limitation in activity; significant assistance required; significant 
medical intervention or therapy required, hospitalization or hospice care probable 
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition of a 
serious adverse event (see Section 12.1.1). 
12.2.2.2. Causality Rating  
All AEs and SAEs whether volunteered by the participant, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means must be 
reported appropriately. 
Each reported AE or SAE must be described by its duration (i.e. start and end dates), regulatory 
seriousness criteria if applicable, suspected relationship to the study drug (see following 
guidance), and actions taken. To ensure consistency of AE and SAE causality assessments, 
investigators should apply the following general guideline: 
Related (Yes) – There is a plausible temporal relationship between the onset of the AE and 
administration of the study drug. The AE cannot be readily explained by the participant’s 
clinical state, intercurrent illness, or concomitant therapies. The AE follows a known pattern 
of response to the study drug or with similar treatments. And/or the AE abates or resolves 
upon discontinuation of the study drug or dose reduction and, if applicable, reappears upon 
re-challenge. 


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Not Related (No) – Evidence exists that the AE has an etiology other than the study drug 
(e.g. preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication). The AE has no plausible temporal relationship to study drug administration (e.g. 
cancer diagnosed 2 days after first dose of study drug). 
Expected adverse events are those adverse events that are listed or characterized in the current 
Investigator Brochure (IB). There are no events that are considered to be expected for assessment 
of Serious Adverse Reactions based on the reference safety information in the current version of 
the IB. Unexpected adverse events are those not listed in the current IB or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the description 
in the P.I. or IB (For example, under this definition, hepatic necrosis would be unexpected if the 
P.I. or IB only referred to elevated hepatic enzymes or hepatitis). In the case of TransCon CNP, 
all events are considered to be unexpected. 
12.2.2.3. Outcome Assessment  
Participants will be followed until AEs have either resolved, participants have returned to their 
baseline status, or participants are deemed stable or commensurate with ongoing disease 
processes. One of five outcomes listed below must be recorded:  
Recovered/Resolved – The event has stopped. The stop date of the event must be recorded. 
Recovering/Resolving – The participant is clearly recovering from an event. The event is not 
yet completely resolved. 
Not Recovered/Not Resolved – The event is still ongoing. (Could include stable and 
commensurate with ongoing disease processes). 
Recovered/Resolved with Sequelae – The event has reached a state where no further 
changes are expected, and the residual symptoms are assumed to persist. An example is 
hemiparesis after stroke.   
The stop date of the event must be recorded. In case of SAE, the sequelae should be 
specified. 
Fatal – The participant has died as a consequence of the event. Date of death is recorded as 
stop date for the AE. 
Unknown – Unknown to investigator, e.g. participant lost to follow up. 
12.3. PROCEDURES FOR ELICITING, RECORDING AND REPORTING ADVERSE 
EVENTS  
12.3.1. Eliciting Adverse Events  
A consistent methodology for eliciting AEs at all participant evaluation time points should be 
adopted. Examples of non-directive questions include: 
• “How have you felt since your last clinical visit?” 
• “Have you had any new or changed health problems since you were last here?” 


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12.3.2. Recording Procedures for All Adverse Events  
All AEs will be documented in response to question about the participant’s well-being and 
whether any possible changes in well-being have occurred since the previous visit. Additionally, 
at each visit, site staff will review participant diary data with the participant/caregiver, to 
determine if diary entries reflect any AEs. 
AEs, including SAEs, will be documented through to the end of the participation in the trial. All 
AEs must be recorded on the appropriate eCRF. AEs either observed by the investigator or 
reported by the participant must be recorded regardless of causality. For any participant who 
withdraws from treatment, correspondence with the participant’s caregiver (e.g. phone call, 
email) will be conducted at least 5 weeks after final dose to evaluate for AEs. The following 
attributes must be documented for each reported AE: 
• Subject ID  
• Description  
• Onset date (if AE was present on Day 1, include whether onset was prior to or after the first 
dose of the study drug) 
• Resolution date, if applicable 
• Severity 
• Causality (relationship to the study drug)  
• Outcome 
• Action taken 
• Determination of “seriousness criteria” (whether serious or not serious) 
Any pre-existing condition, medical history, signs, symptoms, and illnesses present at the 
Screening visit will be captured as baseline (preexisting) events, if appropriate, to assure that any 
change(s) in these experiences during the trial also are recorded as an AE and a complete safety 
profile is obtained. An event that occurs after signing of ICF but prior to the first study drug 
administration will be reported as a non–treatment-emergent AE. Any new or worsening pre-
existing medical conditions that occurs from the time of the first study drug administration until 
the last study visit will be recorded as an AE. 
Routine titration of chronic, concomitant medications will not be considered to meet the criteria 
for AEs. 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviation (e.g. hypertension for elevated BP that persists and 
requires chronic treatment and follow-up, or increased blood pressure for elevated blood pressure 
that occurs for a limited time and does not persist or require ongoing treatment). 
An accidental overdose is not an AE if there are no signs or symptoms. Any undesirable medical 
occurrence resulting from an accidental overdose is an AE and should be recorded and reported 
on the appropriate eCRF. Regardless of classification as an AE or not, all overdoses should be 
documented, and the participant(s) monitored. Since accidental overdoses with the study drug 


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could have serious clinical consequences and/or represent a compliance issue, they should be 
reported to the Medical Monitor immediately and evaluated by the Sponsor. 
12.3.3. Specific Instructions for Recording Adverse Events  
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g. dosage modification or titration, treatment 
interruption, or treatment discontinuation)  
• Results in a medical intervention (e.g. potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• Is clinically significant in the investigator’s judgment  
It is the investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g. 
significant increase of alkaline phosphatase and bilirubin associated with cholestasis), only the 
diagnosis (i.e. cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating whether the test result is above or below the normal range (e.g. “elevated potassium,” 
as opposed to “abnormal potassium”).  If the laboratory abnormality can be characterized by a 
precise clinical term per standard definitions, the clinical term should be recorded as the adverse 
event.  For example, an elevated serum potassium level of 7.0 mEq/L should be recorded as 
“hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF. 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must be 
reported as an adverse event if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g. dosage modification, treatment interruption, or 
treatment discontinuation) 
• Results in a medical intervention or a change in concomitant therapy 
• Is clinically significant in the investigator’s judgment 


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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g. high 
blood pressure), only the diagnosis (i.e. hypertension) should be recorded on the Adverse Event 
eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g. record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available as separate AEs. If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
Injection Related Reaction  
Each sign or symptoms will be recorded as a separate adverse event on the adverse event eCRF. 
Adverse events that occur during or within 24 hours after study drug administration, should be 
captured as individual signs and symptoms on the Adverse Event eCRF rather than an overall 
diagnosis (e.g. record hypertension and dyspnea as separate events rather than a diagnosis of 
infusion related reaction or anaphylactic reaction). 
Deaths  
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death”. 
Hospitalizations for Medical or Surgical Procedures  
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a participant is hospitalized to undergo a medical or surgical procedure as 
a result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a participant is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. Hospitalizations for 
the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
preexisting conditions  
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study or  
• Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the 
study  


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Preexisting Medical Conditions  
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be 
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g. “more frequent headaches”). 
Pregnancy  
If a female participant becomes pregnant while receiving the study drug or within 5 weeks after 
the last dose of study drug, or if the female partner of a male study participant becomes pregnant 
while the study participant is receiving the study drug or within 5 weeks, a Pregnancy report 
should be completed and expeditiously submitted to Ascendis Pharma within 24 hours. Follow-
up to obtain the outcome of the pregnancy should also occur and the outcome reported to 
Ascendis Pharma. Abortion, whether accidental, therapeutic, or spontaneous, should always be 
classified as serious, and expeditiously reported as an SAE. Similarly, any congenital 
anomaly/birth defect in a child born to a female participant exposed to the study drug should be 
expeditiously reported as an SAE. Additional information regarding pregnancy can be found in 
Appendix 6. 
Product Complaints  
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial. 
12.4. SERIOUS ADVERSE EVENTS (SAE) AND SUSPECTED UNEXPECTED 
SERIOUS ADVERSE REACTIONS (SUSAR)  
12.4.1. Non-Serious Adverse Events Leading to Discontinuation  
If situation permits, non-serious events (including laboratory abnormalities and pregnancies) that 
may require permanent discontinuation of study drug should be discussed with the Medical 
Monitor prior to making any final decision. 
12.4.2. Reporting  
All initial and follow-up information regarding SAEs and Special Situations reporting must 
be reported by the investigator to the Sponsor or its representatives within 24 hours of 
discovery, including those related to protocol-mandated procedures and regardless of suspected 
causality. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 12.1.1 for seriousness criteria), severity (see 
Section 12.2.2.1), and causality (see Section 12.2.2.2).   


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Reporting must not be delayed by waiting for additional information. The minimum information 
required for reporting an SAE and Special Situations are the AE term (diagnosis), patient, study 
drug, reporter, and the investigator’s initial causality assessment. Additional information must be 
reported to the Sponsor or its representatives as a follow-up report. All SAEs and Pregnancies 
(including follow-up information) must be submitted via: 
safety.ascendispharma.com 
SAEs and Special Situations information is collected and reported via SAE Forms provided by 
the Sponsor or its representative. Pregnancy information is collected and reported via Pregnancy 
Forms provided by the Sponsor or its representative. The Sponsor (or its representatives) is 
responsible for reporting within the time frame required by applicable regulations all SAEs 
qualifying as SUSARs to: 
• Investigators 
• Central IRBs/HRECs/IECs (if applicable) 
• National ethics committees (if applicable) 
• Appropriate regulatory authorities 
It is the investigators’ responsibility to comply with the requirements of their local 
IRB/HREC/IEC for reporting SUSARs, other SAEs, and any new and/or relevant safety 
information provided by the Sponsor or its representatives. At minimum, SUSARs must be 
brought to the attention of these review boards in accordance with regional regulations. 
13. SAFETY MONITORING  
The Sponsor will conduct an ongoing review of all trial data, with particular attention given to 
laboratory findings, AEs, and concomitant medications. Any important safety trends or other 
findings considered related to the study drug will be reported to the investigators and to 
regulatory authorities. In particular, the Sponsor will notify investigators and regulatory 
authorities of AEs that:  
• Fulfill the criteria for SUSARs.  
• Occur at a meaningfully greater frequency than described in the current Investigator’s 
Brochure or Reference Safety Information. 
Any AE that occurs during the clinical trial must be monitored and followed up until: 
• It has resolved or receded 
• Pathology laboratory findings have returned to normal 
• Steady-state has been achieved 
• It has been shown to be unrelated to the study drug and/or trial related procedure 
Details will be described in the Safety Management Plan. 


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14. 
STATISTICS  
14.1. GENERAL  
Details of applicable statistical methods will be provided in a statistical analysis plan (SAP) 
which will be finalized before database lock.  If discrepancies exist between the text of the 
statistical analysis as planned in the protocol and the final SAP, the final SAP will define the 
planned analysis of record.  
In general, analyses will be done by dose cohort, and placebo participants will be pooled as 
placebo group.  Data from clinical assessments will be summarized using descriptive statistics.  
Categorical data will be presented using counts and percentages of participants.  Continuous 
variables will be presented using number of participants, mean, standard deviation (SD), 
standard error (SE), median, minimum and maximum.  Statistical significance is defined as 
P <0.05 (2-sided). 
14.2. ENDPOINTS  
14.2.1. Safety Endpoints  
The following safety endpoints will be assessed for both blinded Randomized Period and 
Open-Label Extension Period: 
• Incidence of AEs 
• All blood chemistry, hematology, lipid panel, and urinalysis parameters 
• Vital sign measurements and physical examination assessments 
• 12-lead ECG 
• Radiographic findings from: 
− 
Bone age X-ray 
− 
DXA 
− 
AP standing lower extremity X-ray 
− 
AP and lateral spine X-ray 
• Incidence of antibodies against drug 
14.2.2. Efficacy Endpoints  
Primary Endpoint: 
• AHV as measured at 52 weeks of weekly TransCon CNP treatment or placebo 
Secondary Endpoints: 
• Change in upper to lower body segment ratio as measured at 52 weeks of weekly TransCon 
CNP treatment or placebo 


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Exploratory Endpoints: 
14.2.3. Pharmacokinetic Endpoints  
x Plasma concentration of Total CNP 
x Plasma concentration of Free CNP  
x Plasma concentration of mPEG and mPEG-linker 
14.3. STATISTICAL ANALYSIS  
The Full Analysis Set will include all randomized participants who have received at least one 
dose of investigational product and have a non-missing baseline height as well as at least one 
post-baseline height measurement. Participants will be analyzed according to study treatment as 
randomized. The Safety Analysis Set will include all randomized participants who have received 
at least one dose of investigational product. Participants will be analyzed according to study 
treatment as treated. The efficacy analyses will be based on the Full Analysis Set and safety 
analyses will be based on the Safety Analysis Set. 
CCI


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In general, analysis will be done by dose levels, and placebo participants will be pooled.  Data 
from clinical assessments will be summarized using descriptive statistics.  Categorical data will 
be presented using counts and percentages of participants. Continuous variables will be 
presented using number of participants, mean, standard deviation (SD), standard error (SE), 
median, minimum and maximum. 
For the primary efficacy endpoint, AHV at Week 52, the primary analysis is ANCOVA model 
with the AHV at Week 52 as the response variable, treatment (dose groups and placebo) as 
factors, baseline age, sex, and baseline height SDS as covariates. The similar ANCOVA model, 
with the baseline of the corresponding parameter as a covariate, will be applied to secondary and 
exploratory efficacy endpoints. As a sensitivity analysis for the primary efficacy endpoint, AHV 
at Week 52, the change from baseline to Week 52 in AHV will be analyzed using ANCOVA 
model with treatment and sex as factors, baseline age, baseline height SDS, and baseline AHV as 
covariates. 
Once the highest tolerated dose is established, the following sequential testing procedure will be 
used for the comparison between the highest tolerated dose group and pooled placebo group. 
The primary analysis for AHV at Week 52 will be performed first. If the p-value for comparing 
the highest tolerated dose group and pooled placebo is <0.05, then the formal hypothesis test for 
upper to lower body segment ratio will be performed.  
Reporting of the safety data is descriptive and will mainly include the incidence and type of 
adverse events, laboratory changes, vital signs, radiographic findings, 12-lead ECG parameters 
and incidence of anti-drug antibodies. Abnormal laboratory data and abnormal physical 
examinations will be listed as appropriate.   
Refer to SAP for details. 
All participants who will receive the study drug and for whom the primary PK data are 
considered sufficient and interpretable will be included in the PK analysis. The PK parameters 
and their statistical evaluation will be included in the Clinical Study Report or as an appendix.  
Potential impact of any anti-drug antibodies detected will be included in the evaluation.  
Refer to PK Analysis Plan for details. 
14.4. PLANNED ANALYSIS  
Planned Analysis will include the following: 
• DMC analysis: Summary analysis for DMC meetings are planned to monitor safety and 
determine dose escalation (the analysis scope and frequency will be specified in the DMC 
charter). 
• Interim by-cohort analysis: In each cohort, after all participants have completed or withdrawn 
from the Randomized Period and the database for the Randomized Period has been locked 
and unblinded for the same cohort, interim by-cohort analysis will be performed. 
• Primary analysis: The primary analysis will be performed after all participants have 
completed or withdrawn from the Randomized Period and the database for the Randomized 
Period has been locked and unblinded. 


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• Final analysis: The final analysis will be performed after all participants have completed or 
withdrawn from the study and the clinical trial database has been locked. 
14.5. SAMPLE SIZE CALCULATION  
A sample size of 9 in active groups (per cohort) and 12 in the placebo group (combined across 
cohorts) will provide 97% power to detect a treatment difference of 2 cm/year in 12-month AHV 
at a 2-sided significance level of 5%, assuming the SD is 1.1 cm/yr. 
14.6. SIGNIFICANCE  
Statistical significance is defined as P <0.05 (2-sided). 
15. TRIAL CONDUCT  
15.1. SITE INITIATION  
Prior to participation, investigational sites and investigators will be evaluated for appropriate 
qualifications and ability to execute the trial.  Each investigational site must undergo appropriate 
training on the trial protocol and ancillary trial procedures and documents through participation 
in a Site Initiation Visit (SIV) or Investigator Meeting (IM).  Protocol and GCP training must 
take place before any participants are enrolled at a site.  SIVs and IMs will include, but may not 
be limited to, study drug preparation and administration procedures, data collection 
requirements, and participant eligibility requirements. 
15.2. DATA HANDLING AND RECORD KEEPING  
15.2.1. Collection of Data  
Data will be collected in the eCRF.  The eCRF is an integral part of the trial and subsequent 
reports. It must be used to capture trial-specific data collected and must be kept current to reflect 
participant status during the course of the trial.  Only a Participant Identification Number will be 
used to identify the participant.  The investigator must keep a separate Participant Identification 
Code List with participant names and medical record numbers or other personal identifier(s). 
The trial will use an Internet-based remote data entry system to collect clinical trial data at the 
investigational sites.  The system complies with 21 CFR Part 11 and ICH E6 (R2) GCP.  The 
system will be used to enter, modify, maintain, archive, retrieve, and transmit data.  The system 
is configured based on the requirements from the Sponsor.  Source documents are to be retained 
to enable a reconstruction and evaluation of the trial.  Source documents include the site files and 
trial worksheets provided by the Sponsor.  Data will be recorded in the trial worksheets as 
appropriate to complete and/or clarify the source data. 
The design of the computerized system complies with all the applicable regulatory requirements 
for record keeping and record retention in clinical trials [21 CFR Part 11 and ICH E6 (R2) GCP].  
Clinical investigators must retain either the original or a certified copy of all source documents, 
including query resolution correspondence.  The system is designed so that changes to any 
record do not obscure the original information.  The audit record clearly indicates that a change 
was made and clearly provides a means to locate and read the prior information.  All changes to 


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the data have an electronic audit trail, in accordance with 21 CFR 11.10(e).  Electronic signatures 
will be used in conformance with 21 CFR Part 11. 
15.2.2. Coding Dictionaries  
Prior and concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system.  
Coexistent diseases and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). See Data Management Plan for details.  
15.2.3. Data Handling  
eCRFs should be completed in a timely manner to enable the Sponsor or designee to perform 
central monitoring of safety data.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system.  Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock, the investigator will use 
her/his log in credentials to confirm that the forms have been reviewed, and that the entries 
accurately reflect the information in the source documents.  The eCRF captures the data required 
per the protocol schedule of events and procedures.  System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or 
sponsor, who routinely review the data for completeness, correctness, and consistency.  The site 
is responsible for responding to the queries in a timely manner, within the system, either by 
confirming the data as correct or updating the original entry, and by providing the reason for the 
update (e.g. data entry error).  At the conclusion of the trial, Sponsor will provide the site with a 
certified copy of the electronic CRFs submitted by that site.  This archive must be stored in 
accordance with the records retention requirements outlined in Section 15.2.1. 
15.2.4. Direct Access to Source Data/Documents  
The investigator/trial site is to provide direct access to source data/documents for trial-related 
monitoring, audits, IRB/EC review, and regulatory inspection.  This includes access to Electronic 
Medical Record system and any other electronic systems containing source data or trial-related 
documents. 
15.2.5. Record Keeping  
The investigator is responsible for maintaining adequate records to fully document the conduct 
of the trial consistent with that noted in ICH E6 (R2), including but not limited to the following: 
1. All versions of the Investigator’s Brochure 
2. Signed Protocol and Amendments in effect during the conduct of the trial 
3. Signed ICFs 
4. Source documents, including adequate case histories, questionnaires, and participant diaries 
5. Signed, dated, and completed eCRFs and documentation of data corrections 
6. Notification of SAEs and related reports 
7. Dated and documented IRB/EC approvals and approval by regulatory authorities, as required 


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8. Normal laboratory reference ranges  
9. Laboratory certifications 
10. Curricula Vitae of all clinical investigators 
11. Completed Forms FDA 1572, as applicable 
12. SIV documentation 
13. Delegation of Authority Log 
14. Participant Screening & Enrollment Log(s) 
15. Participant Identification Code List 
16. Study drug accountability documentation 
17. Signed agreements between involved parties 
18. Relevant communication, including that related to monitor site visits (e.g. letters, meeting 
notes, notes from telephone calls) 
19. Interim, annual, or final reports to IRBs/ECs and regulatory authorities, as required 
20. Audit certificate(s), if applicable 
15.3. DATA QUALITY CONTROL  
15.3.1. Monitoring Procedures  
The Sponsor and/or its representative may make periodic visits to the investigational site to 
assess compliance with trial procedures and regulatory requirements; to ensure that the safety, 
welfare, and privacy of participants are being protected; and to verify the accuracy and integrity 
of the trial data.  In addition, independent Quality Assurance site audits may be conducted as 
verification of the quality and compliance of trial conduct. 
The Sponsor and/or its representative will periodically review the trial data to ensure that data 
are being appropriately collected and reported.  Queries and corrections will be made as needed. 
15.3.2. Data Management  
Sponsor or designee will be responsible for activities associated with the data management of 
this trial.  The standard procedures for handling and processing records will be followed per GCP 
and CRO’s standard operating procedures (SOPs).  A comprehensive data management plan will 
be developed including a data management overview, database development, validation and 
maintenance, data entry and processing, external data transfer, data validation and archive, and 
medical coding processes.  Trial site personnel will be responsible for providing resolutions to all 
data queries.  The investigator will be required to document electronic data review to ensure the 
accuracy of the corrected and/or clarified data.   


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15.4. AUDITING PROCEDURES  
In addition to the routine monitoring , a GCP Quality Assurance audit may be initiated by the 
Sponsor.  The investigator must ensure that participants/caregivers are aware of and consent to 
personal information being reviewed during the data verification process as a part of 
monitoring/auditing/inspection by the Sponsor, properly authorized agents of the Sponsor, or 
competent authorities.  In addition, participation and personal information is treated as strictly 
confidential to the extent that applicable law permits and to which it is not publicly available.  
The purpose of audits and inspections is to evaluate compliance with the principles of GCP, 
international and local regulatory requirements, and the trial protocol.  The audit or inspection 
may include, for example, a review of all source documents, drug records, original clinic medical 
notes, and some or all of the facilities used in the trial. 
The audits may be conducted by the Sponsor or Sponsor’s selected agent in accordance with 
Sponsor’s SOP or SOPs of the selected and properly authorized agent.  A competent authority 
may also wish to conduct an inspection during the trial or after its completion.  If an inspection is 
requested by a competent authority, the investigator must inform the Sponsor immediately that 
this request has been made.  The investigator and his/her institution will permit all monitoring, 
audits, and regulatory inspections, providing direct access to source data. 
15.5. LABORATORY QUALITY STANDARDS  
Laboratory tests or evaluations for safety described in this protocol will be conducted in 
accordance with quality laboratory standards as described in the SOPs of the central laboratories.  
Some blood samples may be used for laboratory test validation.  
The safety laboratories must provide a list of reference ranges for applicable analyses.  The 
methods employed for each assay should be available on request.  Any change in the laboratory 
procedures, reference values, etc., during the trial must promptly be communicated to the 
Sponsor.  The laboratories may also be audited by the Sponsor or by competent authorities. 
15.6. TRIAL TERMINATION OR COMPLETION  
The investigator should notify the IRB/EC in writing of the completion or early termination of 
the trial.  Completion of the trial is defined as the completion of the last participant’s last visit.  
Upon trial completion or termination, applicable regulatory reporting requirements will be 
followed.  The Sponsor reserves the right to terminate the trial at any time for any reason.  The 
Sponsor may stop this trial at a particular site for any of the following reasons: 
• The site cannot enroll an adequate number of participants 
• Serious and/or persistent non-compliance with the protocol or clinical trial conduct 
• Careless or premeditated false documentation in the electronic case report form (eCRF) 
• Inadequate cooperation with the investigator 
• Non-compliance with GCP and/or regulatory requirements 
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15.7. CHANGES TO THE PROTOCOL  
Changes in any portion of this protocol must be documented in the form of an amendment from 
the Sponsor and must be approved by the investigational site’s IRB/EC and regulatory 
authorities, as required, before the amendment is implemented.  However, in the event of 
apparent immediate hazard to a participant, a deviation from the protocol is allowed to eliminate 
the hazard.  In this case, the deviation and the reason for it must be promptly reported as required 
by regional regulations to the applicable IRB/EC and regulatory authorities, along with a 
proposed protocol amendment if appropriate. 
Protocol amendments may only be made with prior written approval of the Sponsor and/or its 
representative and documented approval or favorable opinion from applicable regulatory 
authorities or regional IRB/EC, as required.  The investigator must send a copy of the 
documented approval to the Sponsor and/or its representative. 
15.8. OTHER CHANGES IN TRIAL CONDUCT  
Changes in trial conduct are not permitted.  Any unforeseen changes in trial conduct will be 
recorded in the clinical study report. 
15.9. USE OF INFORMATION AND PUBLICATION  
The data and information generated in this trial are the exclusive property of the Sponsor and are 
confidential.  Written approval from the Sponsor is required prior to disclosing any information 
related to this trial.  Publication of the results will be based on appropriate analyses and review of 
the complete data.  Authorship will be determined based on ICMJE criteria.  Publication of any 
data of this trial without prior Sponsor approval is not permitted. 
16. ETHICAL AND LEGAL CONSIDERATIONS  
This trial will be conducted in accordance with the following: 
• Protocol-related and trial-related documents 
• Declaration of Helsinki 
• GCPs as outlined in ICH E6 (R2) and regional regulations 
• Regional participant data protection laws and regulations 
• Other applicable regional and local regulations 
• US Federal Regulations, as applicable 
16.1. DATA MONITORING COMMITTEE  
An independent Data Monitoring Committee (DMC) will attend each DMC meeting to provide 
recommendations on: (A) the action to be taken (i.e. proceed to the next dose level as planned, 
modify the dose of the next cohort, or stop dose escalation); and (B) the escalation of dose for 
cohorts in the extension based on review of unblinded data.  The DMC may request to invite 
guests (on an as-needed basis) to DMC meetings for their expertise or may request advice from 
an ad hoc expert related to a specific safety concern. A guest/expert may be a specialist in a field 
where expertise is required.  Refer to the DMC Charter for further details. 


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In addition, ad hoc DMC meetings may be called by the Sponsor at any time for review of newly 
identified safety concerns. 
16.2. INFORMED CONSENT  
The draft ICF must be reviewed by the Sponsor and/or its representative prior to submission to a 
regional IRB/EC for approval.  A copy of the ICF approved by the review board must be 
forwarded to the Sponsor and/or its representative. 
The ICF (and Participant Information Sheet, if applicable) documents the trial-specific 
information the investigator provides to the participant and the participant’s agreement to 
participate.  The investigator or designee will fully explain in layman’s terms the nature of the 
trial along with the aims, methods, anticipated benefits, potential risks, and any discomfort 
participation may entail.  The ICF and Participant Information Sheet must be appropriately 
signed and dated before the participant undergoes any trial-related procedure.  The original and 
any amended signed and dated ICFs and participant information sheets must be retained at the 
trial site with a copy of each provided to the participant. 
16.2.1. Subject Identification Card  
Participants will be provided with a Subject Identification Card containing the following 
information: 
• Subject number 
• Participation status: that he/she is participating in a clinical study. 
• That the study includes a treatment regimen with TransCon CNP. 
• The name and phone number of the Investigator. 
• Name of main Sponsor / local Sponsor / CRO (note: as required by local regulations) 
The participant will be instructed to carry the card at all times during the participation in the 
study and asked to return the Subject Information Card at the end-of-trial visit. 
16.3. IRB/EC APPROVALS  
The Principal Investigator at each site is responsible for obtaining approval from the appropriate 
regional IRB/EC for the final protocol, Sponsor-approved ICF and participant information sheet 
(if applicable), and any advertisements to recruit participants.  Written approval of these 
documents must be obtained from the committee before any participant is enrolled at a trial site.  
The IRB/EC must comply with all applicable ICH E6 GCP requirements, as well as all regional 
and local requirements. 
The Principal Investigator is also responsible for the following interactions with the regional 
IRB/EC: 
1. Obtaining review board approval for any protocol amendments and ICF revisions before 
implementing the changes 
2. Providing the review board with any required information before or during the trial 


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3. Submitting progress reports to the review board as required during the conduct of the trial, 
requesting continuing review and approval of the trial as needed and providing copies of all 
review board re-approvals and relevant communication to the Sponsor and/or its 
representative 
4. Notifying the review board of all serious and unexpected AEs related to the study drug 
reported by the Sponsor and/or its representative, as required 
5. Notifying the review board of the end of trial participation, in accordance with regional 
guidelines and regulations. End of trial is defined as last subject last visit. 


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17. 
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Krejci P, Masri B, Fontaine V, et al. Interaction of fibroblast growth factor and C-natriuretic 
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SIGNATURE OF AGREEMENT 
In signing this protocol, the investigator agrees to: 
1. Conduct the trial in accordance with the relevant, current protocol and make changes only 
after notifying the Sponsor or its representative, except where necessary to eliminate 
apparent immediate hazards to human participants 
2. Comply with the International Conference on Harmonization Tripartite Guideline on Good 
Clinical Practice plus appropriate regional regulatory laws and requirements, including US 
Federal Regulations, as applicable 
3. Personally conduct or supervise the described investigation 
4. Inform any participants or persons used as controls that the study drugs are being used for 
investigational purposes 
5. Ensure requirements relating to obtaining informed consent and regional ethical or 
institutional review board approval have been met 
6. Report to the Sponsor or its representative any AEs that occur in the course of the 
investigations, as specified in Section 12  
7. Read and understand the Investigator’s Brochure, including potential risks and side effects of 
the study drug 
8. Ensure all associates, colleagues, and employees assisting in the conduct of the trial are 
informed of their obligations in meeting their commitments 
9. Maintain adequate and accurate records and make these available for inspection by the 
Sponsor and/or its representative or any regulatory agency authorized by law 
10. Promptly report to the regional ethical or institutional review board all changes in research 
activity and all unanticipated problems involving risks to human participants or others 
11. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements 
12. Administer study drug only to participants who meet trial entry criteria and are enrolled in 
the trial and only according to the guidelines set forth in this protocol 
13. Sign a Form 1572, as applicable 
 


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SIGNATURE OF AGREEMENT  
I have read and understand the information in this clinical trial protocol, including the potential 
risks and side effects of the study drug, and agree to personally conduct or supervise the 
described investigation(s) in accordance with the relevant, current protocol(s) and will not 
deviate from the protocol, except when necessary to protect the safety, rights, or welfare of 
participants.  I agree to inform all participants that the study drug is being used for experimental 
purposes, and I will ensure that the requirements related to obtaining informed consent are met.  I 
agree to report to the Sponsor any adverse events that occur in the course of the investigation(s). 
1. I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
trial are informed about their obligations in meeting the above commitments. 
2. I will not make any changes in the research without IRB/EC approval, except where 
necessary to eliminate apparent immediate hazards to human participants. 
3. I agree to maintain all information in this document and regarding the stud(ies) as 
confidential and to use it only for the purpose of conducting the stud(ies).  I agree not to 
forward this document to any other party without the prior written authorization of the 
Sponsor. 
Investigator:  
 
Printed Name and Title: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 


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18. 
APPENDICES  
Appendix 1 Schedule of Events in the Randomized Period 
Appendix 2 Schedule of Events in the Open-label Period 
Appendix 3 Tanner Staging Criteria 
Appendix 4 Blood Volume Drawn at Each Visit for the Randomized and Open-Label Extension 
Period 
Appendix 5 Definition of High Doses of Inhaled Corticosteroids 
Appendix 6 Definition of Childbearing Potential and Contraceptive Requirements  


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APPENDIX 1. 
SCHEDULE OF EVENTS IN THE RANDOMIZED PERIOD  
Visit 
Screen 
1 
Phonea 
2b 
3 
4 
5b 
6 
7/ETb 
Follow-Upc 
Week 
 
0 
2 
4 
8 
12 
26 
39 
52 
57 
Window 
-4 to -1 
weeks 
 
±3 days 
±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Verification of eligibility, including genetic test for 
ACHd 
X 
 
 
 
 
 
 
 
 
 
Medical historye 
X 
X 
 
 
 
 
 
 
 
 
Prior/Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events reviewf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Limited, symptom-directed physical examinationg 
 
X 
 
X 
X 
X 
 
X 
 
 
Full physical examinationh 
X 
 
 
 
 
 
X 
 
X 
 
Thorough skeletal physical exami 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Assessment of pubertal statusj 
X 
 
 
 
 
 
X 
 
X 
 
Vital signsk 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Standing height and sitting height 
X 
 
 
X 
X 
X 
 
X 
 
 
All anthropometric measurements 
 
X 
 
 
 
 
X 
 
X 
 
12-lead ECG 
X 
Xl 
 
X 
X 
 
X 
 
X 
 
Hand and Wrist X-ray 
 
Xm 
 
 
 
 
 
 
Xm 
 
DXAn 
 
Xm 
 
 
 
 
 
 
Xm 
 
AP standing lower extremity X-ray 
 
Xm 
 
 
 
Xo 
 
 
Xm 
 
AP and lateral Spine X-ray 
 
Xm 
 
 
 
Xo 
 
 
Xm 
 
Qualitative assessment of sleep and snoring pattern 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetics 
 
Xp 
 
X 
X 
X 
X 
X 
X 
 
Blood chemistry 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Lipid panel 
X 
 
 
 
X 
 
 
X 
X 
 
25(OH) Vitamin D 
X 
 
 
 
 
 
X 
 
X 
 


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Visit 
Screen 
1 
Phonea 
2b 
3 
4 
5b 
6 
7/ETb 
Follow-Upc 
Week 
 
0 
2 
4 
8 
12 
26 
39 
52 
57 
Window 
-4 to -1 
weeks 
 
±3 days 
±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
Biomarkers 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Anti-drug antibodies 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Urine collection 
X 
 
 
 
 
X 
X 
X 
X 
 
PRO/ObsRO Validation Batteryq 
X 
 
 
 
 
 
 
 
X 
 
Subset of PRO/ObsRO Validation Batteryq 
 
X 
 
 
X 
X 
X 
X 
 
 
r 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Dispensing of study drug and diary 
 
X 
 
X 
X 
X 
X 
X 
 
 
Study drug administration on site 
 
X 
 
 
 
 
 
 
 
 
a All participants will be contacted by phone during Week 2 for follow up.  During the call, the study staff will ask the caregiver about the general well-being of 
the child, inquire regarding correct administration of study drug procedures, record any AEs, record any concomitant medication changes and answer any 
questions. 
b Visit 2 (Week 4), Visit 5 (Week 26), and Visit 7 (Week 52) labs are drawn at trough. Therefore, study drug cannot be administered within 6 days prior to these 
visits. The last dose of study drug will be administered at least 6 days prior to Visit 7 
c Only for participants not proceeding to the Open-Label Extension Period. 
d Previous genetic testing will be accepted.  The documented lab result should be reviewed by the investigator to confirm the result along with the specific 
FGFR3 mutation. If not available in medical record, Screening will include testing for G380R mutation, but further testing may be pursued on an individual 
basis as indicated. 
e Medical history should elicit all major illnesses, diagnoses, and surgeries that the participant has ever had, and any prior or existing medical conditions that 
might interfere with study participation or safety. Medical history includes historical anthropometric measurements, as available. 
f Includes review of ACH comorbidities based on age, including risk of sleep apnea and CMC. 
g Limited, symptom-directed physical examination should be performed as needed at the discretion of the investigator to provide appropriate medical care to the 
participants and to verify no clinically relevant changes have occurred since the Screening Visit. On Visit 1, injection site must be visually inspected prior to 
dosing and at 1 hour and 2 hours after injection of study drug.  For participants that undergo blood collection for pharmacokinetic analyses at 8, 24, and 48 
hours following first dose, injection site will be inspected at the time of each blood collection. All subsequent visits should also include a visual inspection of 
injection sites. 
h Includes assessments of all major body systems including general appearance, HEENT, Neck (including thyroid), Lung/pulmonary, Chest, CV, Abdomen, 
Back, GU, Neurological, Extremities, and Skin. All visits, except at the Screening Visit, should also include a visual inspection of injection sites. 
i Thorough skeletal physical exam will be performed by palpating the bone structure and joints for tenderness and mobility and other abnormal changes not 
normally found in children with ACH. Special attention will be paid to the hip exam, which will include a supine assessment of abduction and adduction of 
hips to assess for pain and any limitation of range of motion. If changes are noted further evaluation will be required as clinically indicated, including imaging 
and/or orthopedic consultation. DMC will be apprised of any safety findings. 
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j Boys will be assessed for testis volumes, and girls for breast development according to Tanner stages (Tanner 1976).  Pubic hair rating will also be recorded 
according to Tanner stages but will not be used to assess eligibility.  All participants must be Tanner Stage 1 for breast development (girls) - no glandular 
development/breast buds, and Tanner Stage 1 for gonadal development (boys) - testicular volume < 4 mL (Emmanuel 2019).  Tanner stage progression during 
the course of the trial will not impact study treatment.  See Appendix 3 for details.  
k Participants should rest for at least 5 minutes before vital sign measurement and vital signs are to be taken before blood samples are drawn. Temperature 
measured in degrees Celsius (°C) or Fahrenheit (°F), blood pressure, and heart rate must be measured at Screening Visit and Visit 1.  Orthostatic HR and 
systolic/diastolic BP will also be measured at Visit 1 prior to administration of study drug following first dose when the participant is at rest for 5 minutes 
(preferably supine) and again after standing at 3 minutes for assessment of orthostatic hypotension. Additionally, at Visit 1, all vital signs must be monitored at 
1 hour and 2 hours post injection of the study drug. For participants that undergo blood collection for pharmacokinetic analyses at 8, 24, and 48 hours 
following first dose, orthostatic vital signs (HR, and BP) will also be measured prior to each PK blood collection.  At all other visits, resting heart rate and 
blood pressure must be measured.  
l At approximately 48 hours after the first dose for participants that undergo PK blood collection for PK analysis at that time. 
m Radiographic assessments may not be required, with Medical Monitor approval, if the same assessments were conducted within approximately 3 months prior 
to the visit. If radiographic assessments cannot be completed prior to study drug administration at Visit 1 due to scheduling conflicts, the assessments may be 
completed at up to 24 hours after study drug administration. 
n DXA scan are at Visit 1 and Visit 7 for children aged 5 years and older only. 
o Scheduled radiographic assessments may be performed within 1 week prior to or after the visit if all scheduled assessments cannot be completed within the 
same day. 
p PK blood collection will be performed for all participants prior to injection of study drug. For participants who weigh ≥11 kg, blood collection will be 
performed at approximately 8, 24, and 48 hours after injection at Visit 1 for pharmacokinetic analyses. Allowances will be made for accommodation.  
Exceptions to the extended PK blood collection will be considered on an individual basis (e.g. if travel creates an undue hardship for a family). 
q PRO/ObsRO validation batteries must be completed by the caregiver without assistance and should be completed prior to conducting any clinical assessments.  
The same caregiver should complete all PRO/ObsRO validation batteries throughout participation in the trial. If the same caregiver is unable to attend a 
particular visit, an alternate caregiver may complete the PRO/ObsRO validation batteries at the visit. 
r The 
 must be completed by the investigator who medically assessed the participant at the visit after all clinical assessments are completed.  The same 
assessor should assess the participant at every visit. 
 
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APPENDIX 2. 
SCHEDULE OF EVENTS IN THE OPEN-LABEL PERIOD  
Visit 
7 
Phonea 
8 
9 
10 
11 
12 
13 
14 
15 
16/ET 
Follow-
Up OLEq 
Week 
52 
54 
56 
65 
78 
91 
104 
117 
130 
143 
156 
161 
Window 
 
±3 days 
±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events reviewb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsc 
Xd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Limited physical examinatione 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
Full physical examinationf 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Thorough skeletal physical examg 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of pubertal status and 
childbearing potentialh 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Standing height and sitting height  
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
All anthropometric measurements 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
12-lead ECG 
Xi 
 
X 
Xp 
X 
Xp 
X 
 
X 
 
X 
 
Hand and Wrist X-rayj 
 
 
 
 
 
 
X 
 
 
 
X 
 
DXAj, k 
 
 
 
 
 
 
X 
 
 
 
X 
 
AP standing lower extremity X-rayj 
 
 
 
X 
 
 
X 
X 
 
 
X 
 
AP and lateral Spine X-rayj 
 
 
 
X 
 
 
X 
X 
 
 
X 
 
Qualitative assessment of sleep and 
snoring pattern 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetics 
Xl 
 
X 
Xp 
X 
Xp 
X 
 
X 
 
X 
 
Blood chemistry 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lipid panel 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
25(OH) Vitamin D 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Anti-drug antibodies 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarkers 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine collection 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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TCC-201, Version 5.0, 28 December 2022 
 
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CONFIDENTIAL 
Visit 
7 
Phonea 
8 
9 
10 
11 
12 
13 
14 
15 
16/ET 
Follow-
Up OLEq 
Week 
52 
54 
56 
65 
78 
91 
104 
117 
130 
143 
156 
161 
Window 
 
±3 days 
±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
Urine collection for hCG testing for 
females of childbearing potentialm 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PRO and ObsRO Validation 
Batteryn 
 
 
 
 
 
 
X 
 
 
 
X 
 
Subset of PRO/ObsRO Validation 
Batteryn 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispensing of study drug and diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug administration on site 
X 
 
 
 
 
 
 
 
 
 
 
 
a All participants will be contacted by phone during Week 54 for follow up.  During the call, the study staff will ask the caregiver about the general well-being of the 
child, inquire regarding correct administration of study drug procedures, record any AEs, record any concomitant medication changes and answer any questions. 
b Includes review of ACH comorbidities based on age, including risk of sleep apnea and CMC. 
c Participants should rest for at least 5 minutes before vital sign measurement and vital signs are to be taken before blood samples are drawn. Temperature measured 
in degrees Celsius (°C) or Fahrenheit (°F). 
d Orthostatic HR and systolic/diastolic BP will be measured at Visit 7 following first dose when the participant is at rest for 5 minutes (preferably supine) and again 
after standing at 3 minutes for assessment of orthostatic hypotension. Additionally, at Visit 7, all vital signs must be monitored at 1 hour and 2 hours post injection 
of the study drug. For participants that undergo blood collection for pharmacokinetic analyses at 8, 24, and 48 hours following first dose, orthostatic vital signs (HR, 
and BP) will also be measured prior to each PK blood collection. 
e Limited, symptom-directed physical examination should be performed as needed at the discretion of the investigator to provide appropriate medical care to the 
participants and to verify no clinically relevant changes have occurred since the last visit. On Visit 7, injection site must be visually inspected prior to dosing and at 
1 hour and 2 hours after injection of study drug.  For participants that undergo blood collection for pharmacokinetic analyses at 8, 24, and 48 hours following first 
dose, injection site will be inspected at the time of each blood collection. All subsequent visits should also include a visual inspection of injection sites. 
f Includes assessments of all major body systems including general appearance, HEENT, Neck (including thyroid), Lung/pulmonary, Chest, CV, Abdomen, Back, 
GU, Neurological, Extremities, and Skin. All visits should also include a visual inspection of injection sites. 
g Thorough skeletal physical exam will be performed by palpating the bone structure and joints for tenderness and mobility and other abnormal changes not normally 
found in children with ACH. Special attention will be paid to the hip exam, which will include a supine assessment of abduction and adduction of hips to assess for 
pain and any limitation of range of motion. If changes are noted further evaluation will be required as clinically indicated, including imaging and/or orthopedic 
consultation. DMC will be apprised of any safety findings. 
h Boys will be assessed for testis volumes, and girls for breast development according to Tanner stages (Tanner 1976).  Pubic hair rating will also be recorded 
according to Tanner stages but will not be used to assess eligibility.  Tanner stage progression during the course of the trial will not impact study treatment.  See 
Appendix 3. During the open-label period, the Investigator should ascertain an individual’s risk for becoming pregnant or fathering a child and take appropriate 
steps. Pregnancy prevention counseling and pregnancy testing should be provided as appropriate and can be tailored per the Investigator’s judgement based on 
maturity and cultural norms. See Appendix 6 for details on childbearing potential in females, wherever applicable.  
i At approximately 48 hours after the first dose for participants that undergo PK blood collection for PK analysis at that time. 
CCI


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CONFIDENTIAL 
j Scheduled radiographic assessments may be performed within 1 week prior to or after the visit if all scheduled assessments cannot be completed within the same 
day. Radiographic assessments may not be required, with Medical Monitor approval, if the same assessments were conducted within approximately 3 months prior 
to the visit for Visit 16/ET. 
k For children aged 5 years and older only. 
l For participants who weigh ≥11 kg, blood collection will be performed at approximately 8, 24, and 48 hours after injection at Visit 7 for pharmacokinetic analyses. 
Allowances will be made for accommodation.  Exceptions to the extended PK blood collection will be considered on an individual basis (e.g. if travel creates an 
undue hardship for a family). 
m Urinary hCG test for females of childbearing potential according to Appendix 6 will be performed for all visits. 
n PRO/ObsRO measures must be completed by the caregiver without assistance and should be completed prior to conducting any clinical assessments.  The same 
caregiver should complete all PRO/ObsRO measures throughout participation in the trial.  The PRO/ObsRO measures must be completed at the visit. If the same 
caregiver is unable to attend a particular visit, an alternate caregiver may complete the PRO/ObsRO measures at the visit. 
o The 
 must be completed by the study staff who medically assessed the participant at the visit after all clinical assessments are completed.  The same assessor 
should assess the participant at every visit. 
p ECG and blood collection for pharmacokinetics should be performed prior to study drug administration and only at visits where the dose is escalated 
q    Only for participants not proceeding to the separate Long-Term Open-Label Extension Study (ASND0039). 
 
CCI


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CONFIDENTIAL 
APPENDIX 3. 
TANNER STAGING CRITERIA  
(From Emmanuel 2019) 
Below are the Tanner Stages described in detail for clinical reference. For all three sites of 
development, Tanner Stage 1 corresponds to the prepubertal form with progression to Tanner 
Stage 5, the final adult form. Breast and genital staging, as well as other physical markers of 
puberty such as height velocity, should be relied on more than pubic hair staging to assess 
pubertal development because of the independent maturation of adrenal axis.  
Pubic Hair Scale (both males and females) 
• 
Stage 1: No hair 
• 
Stage 2: Downy hair 
• 
Stage 3: Scant terminal hair 
• 
Stage 4: Terminal hair that fills the entire triangle overlying the pubic region 
• 
Stage 5: Terminal hair that extends beyond the inguinal crease onto the thigh 
Female Breast Development Scale 
• 
Stage 1: No glandular breast tissue palpable  
• 
Stage 2: Breast bud palpable under areola (1st pubertal sign in females) 
• 
Stage 3: Breast tissue palpable outside areola; no areolar development 
• 
Stage 4: Areola elevated above contour of the breast, forming “double scoop” appearance 
• 
Stage 5: Areolar mound recedes back into single breast contour with areolar 
hyperpigmentation, papillae development and nipple protrusion 
Male External Genitalia Scale 
• 
Stage 1: Testicular volume < 4 ml or long axis < 2.5 cm 
• 
Stage 2: 4 ml-8 ml (or 2.5-3.3 cm long), 1st pubertal sign in males 
• 
Stage 3: 9 ml-12 ml (or 3.4-4.0 cm long) 
• 
Stage 4: 15-20 ml (or 4.1-4.5 cm long) 
• 
Stage 5: > 20 ml (or > 4.5 cm long)  


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CONFIDENTIAL 
APPENDIX 4. 
BLOOD VOLUME DRAWN AT EACH VISIT  
1. Blood Volume Drawn at Each Visit in the Randomized Period 
 
Blood Volume Drawn (ml) 
 
Visit 
Weight (kg) 
Screening 
(Week -4 to -1) 
1 at Predose 
(W 0) 
1 at 8h 
(W 0) 
1 at 24h 
(W 0) 
1 at 48h 
(W 0) 
2 
(W 4) 
3 
(W 8) 
4 
(W 12) 
5 
(W 26) 
6 
(W 39) 
7 
(W 52) 
F-U Visit 
(W 57)a  
Cumulative 
6.0-9.9 
5.5 
5.0 
0 
0 
0 
5.0 
6.0 
5.0 
5.5 
5.0 
5.0 
2.0 
44 
10.0-10.9 
9.5 
9.0 
0 
0 
0 
9.0 
6.0 
9.0 
9.5 
9.0 
9.0 
2.0 
72 
11.0-13.9 
9.5 
9.0 
2 
2 
3 
10.0 
6.0 
10.0 
10.5 
10.0 
10.0 
2.0 
84 
14.0-15.9 
12.5 
9.0 
2 
2 
3 
13.0 
6.0 
13.0 
13.5 
13.0 
13.0 
2.0 
102 
16.0-16.9 
12.5 
10.0 
2 
2 
3 
13.0 
6.0 
13.0 
13.5 
13.0 
13.0 
2.0 
103 
17.0-17.9 
12.5 
10.0 
2 
3 
3 
13.0 
6.0 
13.0 
13.5 
13.0 
13.0 
2.0 
104 
18.0-20.9 
12.5 
10.0 
3 
3 
3 
13.0 
6.0 
13.0 
13.5 
13.0 
13.0 
2.0 
105 
≥21.0 
12.5 
13.0 
3 
3 
3 
13.0 
6.0 
13.0 
13.5 
13.0 
13.0 
2.0 
108 
a Only for participants who are not continuing in the Open-Label Extension Period 
2. Blood Volume Drawn at Each Visit in the Open-Label Extension Period 
Weight 
(kg) 
7 at 8h 
(W 52) 
7 at 24h 
(W 52) 
7 at 48h 
(W 52) 
8 
(W 56) 
9a 
(W 65) 
10 
(W 78) 
11 
(W 91) 
12 
(W 104) 
13 
(W 117) 
14 
(W 130) 
15 
(W 143) 
16/ET 
(W 156) 
F-U Visit OLE 
(W 161) 
Cumulative 
6.0-9.9 
0 
0 
0 
5.0 
5.0 
(3.0) 
5.5 
5.0 
(3.0) 
5.5 
3.0 
5.5 
3.0 
5.5 
2.0 
45 
10.0-10.9 
0 
0 
0 
9.0 
9.0 
9.5 
9.0 
9.5 
7.0 
9.5 
7.0 
9.5 
2.0 
81 
11.0-13.9 
2 
2 
3 
10.0 
10.0 
(9.0) 
10.5 
10.0 
(9.0) 
10.5 
7.0 
10.5 
7.0 
10.5 
2.0 
95 
14.0-15.9 
2 
2 
3 
13.0 
13.0 
13.5 
13.0 
13.5 
10.0 
13.5 
10.0 
13.5 
2.0 
122 
16.0-16.9 
2 
2 
3 
13.0 
13.0 
13.5 
13.0 
13.5 
10.0 
13.5 
10.0 
13.5 
2.0 
122 
17.0-17.9 
2 
3 
3 
13.0 
13.0 
13.5 
13.0 
13.5 
10.0 
13.5 
10.0 
13.5 
2.0 
123 
18.0-20.9 
3 
3 
3 
13.0 
13.0 
13.5 
13.0 
13.5 
10.0 
13.5 
10.0 
13.5 
2.0 
124 
≥21.0 
3 
3 
3 
13.0 
13.0 
13.5 
13.0 
13.5 
10.0 
13.5 
10.0 
13.5 
2.0 
124 
a In case of dose escalation at Visit 9 or 11, total blood volume includes additional blood sampling for pharmacokinetics. In case dose escalation is not done at the 
visits, the total blood volume is indicated in parenthesis 


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CONFIDENTIAL 
APPENDIX 5. 
DEFINITION OF HIGH DOSES OF INHALED 
CORTICOSTEROIDS  
Dose of inhaled corticosteroids listed in the table below are considered high doses of inhaled 
corticosteroids and are not allowed to be used during participation in the TCC-201 trial. 
Medication 
Daily Dose (µg) 
Beclometasone (CFC) 
>400 
Declometasone (HFA) 
>200 
Budesonide (DPI) 
>400 
Budesonide (nebules) 
>1,000 
Ciclesonide 
>160 
Fluticasone propionate (DPI) 
>400 
Fluticasone propionate (HFA) 
>500 
Mometasone 
≥440 
Triamcinolone 
>1,200 
 
 


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TCC-201, Version 5.0, 28 December 2022 
 
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CONFIDENTIAL 
APPENDIX 6. 
DEFINITION OF CHILDBEARING POTENTIAL AND 
CONTRACEPTIVE REQUIREMENTS  
Participants are not expected to attain reproductive potential during the first year of the trial 
because progression from Tanner stage 1 to menarche within 12 months would be considered 
pathological and would lead to study drug discontinuation under Stopping Criteria #8. Abnormal 
pubertal development would be detected via full physical examination scheduled at Week 26, 
which includes Tanner staging, and such findings will be further investigated by the Investigator 
as clinically indicated.  
However, during the open-label period, the Investigator should ascertain an individual’s risk for 
becoming pregnant or fathering a child and take appropriate steps. This should be captured in the 
eCRF. Pregnancy prevention counseling and pregnancy testing should be provided as appropriate 
and can be tailored per the Investigator’s judgement based on maturity and cultural norms. 
If contraception is indicated, highly effective methods with a failure rate <1% per year are 
required. Abstinence is only considered an acceptable method of contraception if it is a 
pre-existing part of a participant’s lifestyle. Symptom-thermal methods (basal body temperature 
in degrees Celsius (°C) or Fahrenheit (°F), cervical mucous, or calendar/rhythm) or withdrawal 
are not considered adequate forms of contraception for the purposes of this trial (Heads of 
Medicine Agencies CTFG 2020) 
1) 
Definition of Female of Childbearing Potential and Fertility in Males 
Female participants who are post-menarchal, regardless of amenorrhea of any duration, will be 
considered to be of childbearing potential unless they have had a hysterectomy, bilateral 
oophorectomy, or medically documented ovarian failure.   
Male participants at Tanner Stage 3 will be considered fertile, unless they have medically 
documented infertility.  
2) 
Contraceptive Requirements for Females 
Female participants requiring contraception must use a recommended highly effective method 
consistently during the trial and at least 5 weeks after the last dose of TransCon CNP (equal to 
5 half-lives of TransCon CNP).  Acceptable highly effective methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
• with inhibition of ovulation: oral, intravaginal or transdermal  
• Progestogen-only hormonal contraception associated with inhibition of ovulation1: oral, 
injectable, or implantable  
• Intrauterine device (IUD)  
• Intrauterine hormone-releasing system (IUS)  
• Bilateral tubal occlusion  


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VV-SUB-011508 – 8.0 
 
CONFIDENTIAL 
• Vasectomised partner1 
• Sexual abstinence2 
1 
Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment 
of the surgical success.  
2 
In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the participant. 
3) 
Contraceptive Requirements for Male Participants (and their female partners) 
Male participants requiring contraception must agree to consistently and correctly use a condom 
until 5 weeks after administration of the last dose of study medication. If their female partner is 
of childbearing potential (as defined above), their female partner must use 1 of the methods of 
birth control listed above from the date of Screening until 5 weeks after administration of the last 
dose of study medication. 
If applicable, male participants must agree to refrain from sperm donation for at least 5 weeks 
after the last dose of study medication.  
4) 
Procedures to be Followed in the Event of Pregnancy 
Participants will be instructed to notify the Investigator if they or their partner become pregnant 
at any time during the study, or if they become pregnant within 5 weeks of the last dose of study 
medication. Participants who become pregnant or who suspect that they are pregnant must report 
the information to the Investigator. Participants whose partner has become pregnant or suspects 
she is pregnant must report the information to the Investigator. All pregnancies (participants and 
their partners) should be followed up until resolution if possible. 
 


   Approval Signatures
Document Name:
TCC-201 Protocol
Document Number:
VV-SUB-011508
Version:
8.0
This is a representation of an electronic record that was signed electronically in Veeva Vault. This page is
the manifestation of the electronic signature(s) used in compliance with the organizations electronic
signature policies and procedures.
 Approved
SIGNATURE INFORMATION:
11-Jan-2023 12:54:08 GMT+0000
 Approved
SIGNATURE INFORMATION:
11-Jan-2023 13:06:31 GMT+0000
 Approved
SIGNATURE INFORMATION:
12-Jan-2023 06:32:50 GMT+0000
 Approved
SIGNATURE INFORMATION:
12-Jan-2023 16:15:39 GMT+0000
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

SAP_001.pdf: 
Official Title: 
ACcomplisH: A Phase 2, multicenter, double-blind, 
randomized, placebo-controlled, dose escalation trial 
evaluating safety, efficacy, and pharmacokinetics of 
subcutaneous doses of TransCon CNP administered once 
weekly for 52 weeks in prepubertal children with 
achondroplasia followed by an Open-Label Extension Period 
NCT Number: 
NCT04085523 
Document Date:  SAP Version 2: 11 October 2022 


TCC-201  
Statistical Analysis Plan  
11 October 2022, Version 2.0 
Proprietary and Confidential 
Page 1 
STATISTICAL ANALYSIS PLAN 
Title 
ACcomplisH: A Phase 2, multicenter, double-blind, 
randomized, placebo-controlled, dose escalation trial 
evaluating safety, efficacy, and pharmacokinetics of 
subcutaneous doses of TransCon CNP administered 
once weekly for 52 weeks in prepubertal children with 
achondroplasia followed by an Open-Label Extension 
Period 
Protocol: 
TransCon CNP TCC-201 Version 4.0 
Investigational Product: TransCon CNP 
Phase: 
2 
Sponsor: 
Ascendis Pharma Bone Diseases A/S  
Tuborg Boulevard 12, DK-2900, Hellerup, Denmark 
Author: 
Date: 
11 October, 2022 
Version Number: 
Version 2.0 
1&7
PPD


TCC-201  
Statistical Analysis Plan  
11 October 2022, Version 2.0 
 
 
Proprietary and Confidential 
Page 2 
TABLE OF CONTENTS 
1 INTRODUCTION ...............................................................................................................7 
2 STUDY DESIGN.................................................................................................................7 
2.1 Blinding and Randomization Methods .......................................................................8 
3 STUDY OBJECTIVES ........................................................................................................9 
3.1 Primary Objectives ......................................................................................................9 
3.2 Secondary Objectives ..................................................................................................9 
3.3 Exploratory Objectives ...............................................................................................9 
4 SAMPLE SIZE CALCULATION .....................................................................................10 
5 PLANNED ANALYSIS ....................................................................................................10 
6 DATA MONITORING COMMITTEE .............................................................................10 
7 ANALYSIS ENDPOINTS ................................................................................................11 
7.1 Efficacy endpoints.....................................................................................................11 
7.1.1 
Primary Endpoint ........................................................................................11 
7.1.2 
Secondary Endpoint ....................................................................................11 
7.1.3 
Exploratory Endpoints .................................................................................11 
7.2 Safety Endpoints: ......................................................................................................12 
7.3 Pharmacokinetic Endpoints: .....................................................................................13 
8 DEFINITIONS ...................................................................................................................13 
8.1 Baseline .....................................................................................................................13 
8.2 Duration of exposure .................................................................................................13 
8.3 Total number of planned doses and Total/Average Weekly actual dosage ..............14 
8.4 Dose Compliance ......................................................................................................14 
8.5 Study Day ..................................................................................................................15 
8.6 Age ............................................................................................................................15 
8.7 Annualized Height Velocity......................................................................................15 
8.8 6-month Annualized Height Velocity .......................................................................15 


TCC-201  
Statistical Analysis Plan  
11 October 2022, Version 2.0 
 
 
Proprietary and Confidential 
Page 3 
8.9 3-month Annualized Height Velocity .......................................................................16 
8.10 Height Standard Deviation Score ..............................................................................16 
9 ANALYSIS POPULATIONS ...........................................................................................17 
9.1 Screened Population ..................................................................................................17 
9.2 Randomized Population ............................................................................................17 
9.3 Full Analysis Set .......................................................................................................17 
9.4 Safety Analysis Set ...................................................................................................17 
9.5 Pharmacokinetic Population .....................................................................................17 
10 DATA SCREENING AND ACCEPTANCE ....................................................................17 
10.1 General Principles .....................................................................................................17 
10.2 Handling of Missing and Incomplete Data ...............................................................17 
10.2.1 Missing Birth Dates .....................................................................................18 
10.2.2 Missing Date Imputation for Historical Anthropometric 
measurements ..............................................................................................18 
10.2.3 Missing Date Imputation for Adverse Events and Concomitant 
Medications .................................................................................................18 
10.2.4 Missing Causal Relationship to Investigational Product for Adverse 
Events ..........................................................................................................19 
10.2.5 Missing Primary Endpoint ...........................................................................19 
10.3 Visit Time Windows .................................................................................................19 
10.4 Software ....................................................................................................................20 
11 STATISTICAL METHODS OF ANALYSES ..................................................................20 
11.1 General Principles .....................................................................................................20 
11.2 Subject Accountability ..............................................................................................21 
11.3 Protocol Deviations ...................................................................................................21 
11.4 Investigational Product Administration ....................................................................21 
11.4.1 Extent of Exposure ......................................................................................21 
11.4.2 Measurement of Treatment Compliance .....................................................22 


TCC-201  
Statistical Analysis Plan  
11 October 2022, Version 2.0 
 
 
Proprietary and Confidential 
Page 4 
11.4.3 Demographic and Baseline Characteristics .................................................22 
11.4.4 Medical History ...........................................................................................22 
11.4.5 Prior and Concomitant Medication .............................................................22 
11.5 Efficacy Analysis ......................................................................................................23 
11.5.1 Analysis of Primary Efficacy Endpoint .......................................................23 
11.5.1.1 
Primary Analysis ..........................................................................23 
11.5.1.2 
Sensitivity Analysis .....................................................................24 
11.5.2 Analysis of Secondary Efficacy Endpoint ...................................................24 
11.5.3 Sequential Testing Procedure for Primary and Secondary Efficacy 
Endpoint ......................................................................................................25 
11.5.4 Analysis of Exploratory Efficacy Endpoints ...............................................25 
11.5.4.1 
PRO/ObsRO Measures ................................................................26 
11.6 Safety Analysis .........................................................................................................26 
11.6.1 Adverse Events ............................................................................................27 
11.6.2 Clinical Laboratory Parameters ...................................................................28 
11.6.3 Vital Signs ...................................................................................................29 
11.6.4 Physical Examination ..................................................................................29 
11.6.5 Electrocardiogram .......................................................................................30 
11.6.6 Radiographic findings .................................................................................30 
11.6.7 Antibody Parameters ...................................................................................30 
11.7 Pharmacokinetic Analysis .........................................................................................31 
12 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................31 
13 CHANGES TO PREVIOUS SAP .....................................................................................32 
14 REFERENCES ..................................................................................................................32 
15 APPENDICES ...................................................................................................................34 
Appendix 1. Schedule of Events in the Randomized Period .............................................34 
Appendix 2. Schedule of Events in the Open-Label Period ..............................................37 
Appendix 3. Multiple Imputation for Missing Data in Primary Endpoint .........................40 


TCC-201  
Statistical Analysis Plan  
11 October 2022, Version 2.0 
Proprietary and Confidential 
Page 5 
ABBREVIATIONS 
μg
Microgram 
 
 
ACH 
Achondroplasia 
ADA 
Anti-drug Antibodies 
AE 
Adverse event 
AHV 
Annualized height velocity 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AP 
Anthropometric 
 
 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
 
 
cm 
Centimeter 
CNP 
C-type natriuretic peptide
CRF 
Case report form 
CV 
Coefficient of variation 
DMC 
Data Monitoring Committee 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
HDL 
High-density lipoprotein 
IWRS 
Interactive web response system 
Kg 
Kilogram 
LDL 
Low-density lipoprotein 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCS 
Mental component score 
mPEG 
Methoxypolyethylene glycol 
ObsRO 
Observer-reported outcome 
OLE 
Open-Label Extension 
PCS 
Physical component score 
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PedsQL 4.0 
Pediatric Quality of Life Inventory Version 4.0 
PEG 
Polyethylene glycol 
 
 
PINP 
Propeptide of type I procollagen, N-terminal 
PK 
Pharmacokinetics 
PR 
PR interval of ECG 
PRO 
Patient-reported outcome 
PT 
Preferred term 
 
 
QRS 
Duration of ventricular muscle depolarization of ECG 
QT 
Duration of ventricular depolarization and repolarization of ECG 
QTcF 
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)⅓) 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SDS 
Standard Deviation Score 
SE 
Standard error 
 
 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WBC 
White blood cell 
WHO 
World Health Organization 
 
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1 INTRODUCTION  
The purpose of this Statistical Analysis Plan (SAP) is to provide a more technical and 
detailed elaboration of the statistical analyses of efficacy and safety data as outlined and/or 
specified in the study protocol (version dated 12August2021).  A population PK analysis plan 
for pharmacokinetic (PK) data was prepared separately (MODCNP001). 
2 STUDY DESIGN  
Study TCC-201 is a multicenter trial consisting of two treatment periods: A 52 week double-
blind, randomized, placebo controlled, dose escalation trial evaluating up to 5 different dose 
levels of weekly TransCon CNP administered subcutaneously in prepubertal children 2 to 10 
years old, inclusive, with ACH. For this part of the trial participants are randomized into 2 
treatment groups for each cohort in a 3:1 TransCon CNP: placebo ratio, with approximately 
≥9 participants on TransCon CNP and ≥3 participants on placebo in each cohort.  
Participants are to remain on the same dose of study drug throughout the entire 52-week 
Randomized Treatment Period. 
After completing 52 weeks of their assigned cohort dose (or placebo), participants who fulfill 
the rollover criteria can continue into the 104 weeks Open-Label Extension Period. In the 
extension period, participants may receive the highest dose level of TransCon CNP that has 
passed safety review and is recommended by the Data Monitoring Committee (DMC) (trial 
design scheme below).      
The study is expected to enroll approximately 60 subjects from approximately 35 sites 
worldwide.  
The total duration of the trial for an individual participant is up to approximately 165 weeks. 
Duration includes up to approximately 4 weeks of screening, plus 156 weeks of treatment (52 
weeks of treatment in the Randomized Period and an additional 104 weeks of treatment in 
the Open-Label Extension Period) and a 5-week follow-up period.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Trial design scheme 
 
 
 
 
Visit Schedule diagram in the Randomized and Open-Label Extension Periods 
 
 
 
 
2.1 
BLINDING AND RANDOMIZATION METHODS  
Eligible subjects will be enrolled in the study and assigned an identification number. A 
randomization schedule will be developed by an independent party to maintain blinding. 
Overall, approximately 60 subjects will be randomized TransCon CNP to Placebo in a 3:1 
ratio to one of the following via an Interactive Web Randomization System (IWRS): 


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Cohort 
Planned Dose Level 
Approximate Number of Participants** 
1 
6 μg CNP/kg/week 
9 on TransCon CNP, 3 on placebo 
2 
20 μg CNP/kg/week 
≥9 on TransCon CNP, ≥3 on placebo 
3 
50 μg CNP/kg/week 
≥9 on TransCon CNP, ≥3 on placebo 
4 
100 μg CNP/kg/week 
≥9 on TransCon CNP, ≥3 on placebo 
5 
> 100 μg CNP/kg/week* 
≥9 on TransCon CNP, ≥3 on placebo 
 *At a dose to be determined based on emerging data  
**Minimum of 12 participants per cohort will be enrolled. Plan to enroll approximately 14 
participants per cohort to account for potential drop-outs due to COVID-19. 
The Randomized Period will be double-blind so that neither the sponsor, subject, or site 
personnel involved in study conduct will know the identity of a subject’s treatment. The 
Randomized Period will be followed by a 104-week Open-Label Extension treatment period 
where all participants will receive TransCon CNP. 
3 STUDY OBJECTIVES  
3.1 
PRIMARY OBJECTIVES  
In prepubertal children with achondroplasia (ACH) at 52 weeks: 
x To determine the safety of once weekly subcutaneous (SC) doses of TransCon CNP  
x To evaluate the effect of once weekly SC doses of TransCon CNP on annualized height 
velocity (AHV) 
3.2 
SECONDARY OBJECTIVES  
x To evaluate the effect of once weekly SC doses of TransCon CNP on body 
proportionality (upper to lower body segment ratio) in prepubertal children with ACH at 
52 weeks 
x To evaluate the pharmacokinetic (PK) properties of once weekly SC doses of TransCon 
CNP 
x To assess the potential immunogenic response to once weekly SC doses of TransCon 
CNP 
3.3 
EXPLORATORY OBJECTIVES  
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4 SAMPLE SIZE CALCULATION  
A sample size of 9 in active groups (per cohort) and 12 in the placebo group (combined 
across cohorts) will provide 97% power to detect a treatment difference of 2 cm/year in 12-
month AHV at a 2-sided significance level of 5%, assuming the SD is 1.1 cm/yr. 
5 PLANNED ANALYSIS  
Planned Analysis will include the following: 
x DMC analysis: Summary analysis for DMC meetings are planned to monitor safety and 
determine dose escalation (the analysis scope and frequency will be specified in the DMC 
charter). 
x Interim by-cohort analysis: In each cohort, after all participants have completed or 
withdrawn from the Randomized Period and the database for the Randomized Period has 
been locked and unblinded for the same cohort, interim by-cohort analysis will be 
performed.  
x Primary analysis: The primary analysis will be performed after all participants have 
completed or withdrawn from the Randomized Period and the database for the 
Randomized Period has been locked and unblinded. 
x Final analysis: The final analysis will be performed after all participants have completed 
or withdrawn from the study and the clinical trial database has been locked.  
6 DATA MONITORING COMMITTEE  
DMC meetings will be held by the Sponsor upon review of the following data to assess 
whether the next cohort should be initiated as planned: 
x Initiation of Cohort 2: Cohort 1 data with a minimum of 12 weeks of follow up for all 
participants 
x Initiation of Cohort 3: Cohort 2 data with a minimum of 12 weeks of follow up for all 
participants and available data from all other cohorts 
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x Initiation of Cohort 4: Cohort 3 data with a minimum of 12 weeks of follow up for all 
participants and available data from all other cohorts 
Following the DMC meeting, the Sponsor will take into consideration the recommendation 
of the DMC to decide to either proceed to the next dose cohort as planned, modify the dose 
of the next cohort, or stop dose escalation.  If available data are inadequate to decide on the 
action to be taken, the decision may be deferred until after data through Visit 5 (Week 26) of 
the highest dosed cohort are available, at which time the DMC meeting will be reconvened.  
A DMC meeting will also be held when all participants in Cohort 4 have a minimum of 12 
weeks of follow up. If 100 μg CNP/kg/week is deemed safe at this meeting, then participants 
in the Open-Label Period may have their dose increased to 100 μg CNP/kg/week.   
Upon completion of 26 weeks of treatment (Visit 5) for all participants in Cohort 4, a DMC 
meeting will be held. After review of the data and consultation with the DMC, the Sponsor 
will decide whether a higher dose level should be investigated (up to 200 μg CNP/kg/week).  
The DMC will make the recommendation regarding dose escalation for cohorts in the Open-
Label Extension Period, which could be up to the highest dose level of TransCon CNP that 
has been reviewed by the DMC for safety and has passed DMC safety review. Dose 
escalation for the individual participant should be implemented at the next scheduled visit 
(except Visit 8) in the Open-Label Extension Period. After discussion with the Medical 
Monitor, an Investigator may choose to not increase the dose for an individual participant or 
may decrease to a prior dose. 
In addition, ad hoc DMC meetings may be called by the Sponsor at any time for review of 
newly identified safety concerns. 
The detailed roles and responsibilities of the DMC are specified in the DMC Charter. 
7 ANALYSIS ENDPOINTS  
7.1 
EFFICACY ENDPOINTS  
7.1.1 
Primary Endpoint  
x AHV as measured at 52 weeks of weekly TransCon CNP treatment or placebo. 
7.1.2 
Secondary Endpoint  
x Change in upper to lower body segment ratio as measured at 52 weeks of weekly 
TransCon CNP treatment or placebo 
7.1.3 
Exploratory Endpoints  
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7.2 
SAFETY ENDPOINTS:  
The following safety endpoints will be assessed for both Randomized Period and Open-Label 
Extension Period: 
x Incidence of AEs 
x All blood chemistry, hematology, lipid panel, and urinalysis parameters 
x Vital sign measurements and physical examination assessments 
x 12-lead ECG 
x Radiographic findings from: 
 Bone age X-ray 
 DXA 
 Anterior-posterior standing lower extremity X-ray  
 Anterior-posterior and lateral spine X-ray 
x Incidence of anti-drug antibodies 
 
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7.3 
PHARMACOKINETIC ENDPOINTS:  
• Plasma concentration of Total CNP 
• Plasma concentration of Free CNP  
• Plasma concentration of methoxypolyethylene glycol (mPEG) and mPEG-linker  
8 DEFINITIONS  
8.1 
BASELINE  
The initial baseline is defined as the last non-missing assessment prior to the initiation of the 
first dose of investigational product (CNP or Placebo). 
OLE Baseline is defined as the last non-missing assessment prior to the initiation of the first 
dose of CNP in OLE Period. 
For radiographic assessment of bone, the initial baseline is defined as the last non-missing 
assessment prior to or on visit 1, and the OLE baseline is defined as the last non-missing 
assessment prior to or on visit 7. 
Historical height measurement will be used to calculate baseline for AHV. Among all 
available historical height measurements taken between 6 months and 15 months prior to the 
first dose of investigational product, the measurement that is closest to the time of 12 months 
will be considered. If there are two measurements with equal distance to one year prior to the 
first dose of investigational product, the earlier one will be used to calculate baseline AHV 
and the baseline AHV will be calculated as follows, 
[Height (Baseline) - Height (Historical Measurement)] * 365.25/[Date (Baseline) - Date 
(Historical Measurement)+1] 
8.2 
DURATION OF EXPOSURE  
During the Randomized Period, duration of exposure to investigational product (Placebo or 
CNP), in days, is defined as last date of investigational product in the Randomized Period – 
first date of investigational product in the Randomized Period + 7 days. 
During the OLE Period, duration of exposure to CNP, in days, is defined as last dose date of 
CNP in the OLE Period – First OLE Dose Date + 7 days. 
Total duration of exposure to CNP, in days, is defined as last dose date of CNP – First dose 
date of CNP + 7 days. 


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8.3 
TOTAL NUMBER OF PLANNED DOSES AND TOTAL/AVERAGE 
WEEKLY ACTUAL DOSAGE  
For each dose, the last non-missing weight prior to the initiation of current dosing will be 
used to calculate the actual dosage. 
Total number of actual doses will be counted based on exposure recorded on eCRF. Multiple 
injections administered within 24 hours will be counted as one dose.  
During the Randomized Period,  
Total number of planned doses is defined as (last dose date in the Randomized Period – first 
dose date in the Randomized Period + 7)/7 truncated to the nearest integer. 
Total actual dosage (μg/kg) is defined as Sum (concentration (mg/mL) x volume 
(mL)*1000/weight(kg)) over all injections during the Randomized Period. 
Average weekly actual dosage (μg/kg/week) is defined as total actual dosage/total number of 
actual doses. 
During the OLE Period,  
Total number of planned doses is defined as (last dose date in the OLE Period – first OLE 
dose date + 7)/7 truncated to the nearest integer. 
Total actual dosage (μg/kg) is defined as Sum (concentration (mg/mL) x volume 
(mL)*1000/weight(kg)) over all injections during the OLE Period. 
Average weekly actual dosage (μg/kg/week) is defined as total actual dosage/total number of 
actual doses. 
TransCon CNP Overall 
Total number of planned CNP doses is (last dose date of CNP during the study – first dose 
date of CNP during the study + 7)/7 truncated to the nearest integer. 
Total actual CNP dosage is the sum of total actual CNP dosage in the Randomized Period 
and OLE Period. 
Average weekly actual CNP dosage (μg/kg/week) is defined as total actual CNP dosage/total 
number of actual CNP doses during the study including Randomized and OLE Periods. 
8.4 
DOSE COMPLIANCE  
Dosing compliance (%) during the Randomized Period or OLE Period is defined as the 
(Total number of actual doses/total number of planned doses during the specific period) * 
100. 


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CNP Dosing compliance (%) is defined as the (Total number of actual CNP doses/total 
number of planned CNP doses) * 100. 
8.5 
STUDY DAY  
The study day for all assessments is calculated as the difference between the date of the event 
(visit date, assessment date, etc.) and the start of study treatment plus one day if on or after 
first dose of investigational product:  
Study day = (event date – date of the first dose of investigational product + 1) 
If the event date is prior the first dose of investigational product: 
Study day = event date – date of the first dose of investigational product 
8.6 
AGE  
Unless specified, the age will be derived based on the first dose date of investigational 
product: Age = (First Dose Date – Birth Date+1)/365.25. When date of birth is missing, the 
age recorded on electronic case report forms (eCRF) will be used. 
If birth date is missing and age recorded on eCRF is also missing, the birth date will be 
imputed to calculate (See Section 10.2.1 the algorithm to impute birth date) age. 
8.7 
ANNUALIZED HEIGHT VELOCITY  
During the Randomized Period, the AHV at visit x will be derived based on the height at the 
initial baseline**: 
[Height (Visit x) - Height (Initial Baseline)] * 365.25/[Date (Visit x) - Date (Baseline)+1] 
** Refer to Section 8.1 for definition of initial baseline height.  
The height velocity will be calculated for Randomization period and OLE period separately. 
During the OLE Period, the OLE baseline value will be used for each successive AHV 
calculation until Week 104. And starting from Week 117 until end of study, the baseline 
value used for each successive AHV calculation will be the subject’s height measured 52 
weeks prior, e.g. height at Week 65 served as the baseline value to determine AHV at Week 
117. If height at visit 52 weeks prior is missing then the most recent height prior to that visit 
will be used. 
8.8 
6-MONTH ANNUALIZED HEIGHT VELOCITY  
6- Month AHV will be derived based on height measured 26 weeks prior during the study: 


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[Height (Visit x) - Height (Visit 26 week prior)] * 365.25/[Date (Visit x) - Date (Visit 26 
week prior)+1] 
During the Randomized Period, the 6-Month AHV at Week 26 will be calculated using initial 
baseline height as defined in Section 8.1. Starting from Week 39 until end of Randomized 
Period, the baseline value used for each successive AHV calculation will be the subject’s 
height measured 26 weeks prior, e.g. height at Week 12 served as the baseline value to 
determine AHV at Week 39. If height at the visit 26 weeks prior is missing then the most 
recent height prior to that visit will be used. 
The 6-Month AHV will be calculated for Randomization period and OLE period separately. 
During the OLE Period, the 6-Month AHV at Week 78 will be calculated using OLE baseline 
height. And starting from Week 91 until end of study, the baseline value used for each 
successive 6-Month AHV calculation will be the subject’s height measured 26 weeks prior 
during the OLE Period. If height at the visit 26 weeks prior is missing then the most recent 
height prior to that visit will be used. 
8.9 
3-MONTH ANNUALIZED HEIGHT VELOCITY  
The 3-Month AHV will be derived based on height measured approximately 12 weeks apart 
during the study: 
[Height (Visit x) - Height (Visit 12 week prior)] * 365.25/[Date (Visit x) - Date (Visit 12 
week prior)+1]. 
Similar to the 6-month annualized height velocity, the 3-Month AHV during Randomized 
Period and OLE Period will be calculated using the corresponding baseline height. If height 
at the visit 12 weeks prior is missing (or not available) then the most recent height prior to 
that visit will be used. 
8.10 
HEIGHT STANDARD DEVIATION SCORE  
Height expressed in Standard Deviation Score (SDS) is derived using CDC 2000 (United 
States of America)/Kuczmarski method as, 
(((Height/M)^L)-1)/(L x S) 
Where M=median, S= generalized coefficient of variation, and L= power in the Box-Cox 
transformation. The M, S, L values are obtained from the CDC website; Percentile Data Files 
with LMS Values. M, L, and S need to be interpolated based on the next lower age category, 
and the next upper age category. Age at the corresponding visit with height measurement will 
be used for the derivation. 
In addition, ACH specific height SDS is derived using age and gender specific mean and 
(upper or lower, depending on whether the height value is larger or smaller than its age and 


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sex specific mean height) standard deviations from ACH population [1], as follows: (Height 
– mean)/standard deviation. 
9 ANALYSIS POPULATIONS  
9.1 
SCREENED POPULATION  
The Screened Population will consist of all subjects who underwent a Screening Visit and 
received a subject identification number. 
9.2 
RANDOMIZED POPULATION  
The Randomized Population will include all subjects who were randomized to a treatment 
group in the trial.  
9.3 
FULL ANALYSIS SET  
The Full Analysis Set will include all randomized subjects who have received at least one 
dose of investigational product and have a non-missing baseline height as well as at least one 
post-baseline height measurement. Subjects will be analyzed according to study treatment as 
randomized. 
9.4 
SAFETY ANALYSIS SET  
The Safety Analysis Set will include all randomized subjects who have received at least one 
dose of investigational product. Subjects will be analyzed according to study treatment as 
treated. 
9.5 
PHARMACOKINETIC POPULATION  
The PK Population includes all subjects in the Full Analysis Set who have the primary PK 
data that are considered sufficient and interpretable.   
10 DATA SCREENING AND ACCEPTANCE  
10.1 GENERAL PRINCIPLES  
Data will be reviewed periodically. Any questionable data will be reported to the clinical data 
manager promptly for query and resolution.  
10.2 HANDLING OF MISSING AND INCOMPLETE DATA  
Missing clinical outcome data can occur for multiple reasons, including missed subject visits 
and scales or measures with missing item scores. Missing and incomplete data will be 
identified through the data quality review plan for this study. Missing and incomplete data 
will be identified for investigation, and possible resolution, by Data Management prior to the 
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Unless specified otherwise, only the observed data (not imputed data) will be presented in 
listings. 
10.2.1 
Missing Birth Dates  
To impute missing birth date, the following rules will be applied: 
• If day is missing, impute 15. 
• If month is missing, impute June. 
• If year is missing, then no imputation will be done; the date will be missing.  
If the imputed date is later than any study visit date/observed adverse event start date/ 
observed concomitant medication start date, then earliest available visit date/adverse event 
start date/concomitant medication start date will be used without changing observed 
information. 
10.2.2 
Missing Date Imputation for Historical Anthropometric measurements  
Imputation will be done if only day is missing and month and year are present in 
historical/rollover measurements.  If day is missing impute 15, unless the imputed date is 
later than screening date then screening date will be the imputed date. 
10.2.3 
Missing Date Imputation for Adverse Events and Concomitant Medications  
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications.  Note that the imputed values outlined here may not 
always provide the most conservative date.   
Missing Start Dates 
• If the day is unknown, then: 
o If the month and year match the first dose of investigational product start date 
month and year in this study, then impute the day of the first dose date. 
o Otherwise, assign the first day of the month. 
• If both day and month are unknown, then: 
o If the year matches the year of the first dose of investigational product date in 
this trial, then impute the day and month of the first dose date in this trial. 
o Otherwise, assign ‘January 01’.  
• If the year is unknown, then the date will not be imputed and will be assigned a 
missing value.  
If the imputed date is earlier than birth date, then birth date will be used. If the imputed start 
date is later than the end date, then the start date will be set as the same date as the end date. 


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Missing End Dates for “not ongoing” CM  
• If the day is unknown, then assign the last day of the month. 
• If both day and month are unknown, then assign ‘December 31.’ 
• If the year is unknown, then the date will not be imputed and will be assigned a missing 
value, and the event will be considered ongoing.  
If the resulting end date is after the date of study completion / discontinuation/ data cutoff, 
set the imputed end date to the date of study completion / discontinuation/ data cutoff, 
whichever is earlier. 
10.2.4 
Missing Causal Relationship to Investigational Product for Adverse Events  
If the causal relationship to the investigational product is missing for an AE that started on or 
after the date of the first dose of investigational product, a causality of “related” will be 
assigned. The imputed values for causal relationship to investigational product will be used 
for the incidence summary; the values will be shown as missing in the data listings. 
10.2.5 
Missing Primary Endpoint  
Subjects with missing primary endpoint will have height value imputed using a multiple 
imputation model that contains the following variables:  gender, baseline age, baseline height 
SDS, and height values at post-baseline visits. The multiple imputation will be stratified by 
treatment ([4-5]), which is detailed in Appendix 3.    
10.3 VISIT TIME WINDOWS  
Unscheduled visit (occurred after the date of initiation of the first dose) or end of study visit 
will be mapped to the closet scheduled visit. If the unscheduled visit is in the middle of two 
scheduled visits, map it to the later one. 
After mapping, if there are more than one visits in the same window, the scheduled visit will 
be used if available; if there is no scheduled visit in the same window, the mapped visit 
closer to the target assessment day will be used. If more than one visits have the equal 
distance to the target day then the later one will be used, if more than one visits on the same 
day, use the time or the sequence number to select the later record. For listings and shift 
tables, all data points will be included. 
Table 10.3–1 presents the visit window assigned for assessments scheduled and the 
corresponding range of treatment days (window) during which an actual visit may occur.  
 
 


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Table 10.3–1:  Analysis Window to Map Unscheduled and Early Termination Visits 
Period 
Visit 
Week 
Scheduled Visit Day Window 
Randomized 
Period 
Visit 1 
Baseline 
Day 1 
Days ≤ 1 
Visit 2 
Week 4 
Day 29 
Days [2, 43] 
Visit 3 
Week 8 
Day 57 
Days [44, 71] 
Visit 4 
Week 12 
Day 85 
Days [72, 134] 
Visit 5 
Week 26 
Day 183 
Days [135, 228] 
Visit 6 
Week 39 
Day 274 
Days [229, 319] 
Visit 7 
Week 52 
Day 365 
[320, study day of first 
OLE dose date*] 
OLE Period 
Visit 8 
Week 56 
Day 393 
[study day of first OLE 
dose date + 1, 424] 
Visit 9 
Week 65 
Day 456 
Days [425, 501] 
Visit 10 
Week 78 
Day 547 
Days [502, 592] 
Visit 11 
Week 91 
Day 638 
Days [593, 684] 
Visit 12 
Week 104 
Day 730 
Days [685, 775] 
Visit 13 
Week 117 
Day 821 
Days [776, 866] 
Visit 14 
Week 130 
Day 912 
Days [867, 957] 
Visit 15 
Week 143 
Day 1003 
Days [958,1049] 
Visit 16 
Week 156 
Day 1095 
Days ≥ 1050 
*If a subject entered into OLE Period, the date of OLE first dose will be used. Otherwise, the 
last visit date during the Randomized Period will be used. 
10.4 SOFTWARE  
SAS® software version 9.4 or higher will be used to perform statistical analyses unless 
otherwise specified. 
11 STATISTICAL METHODS OF ANALYSES  
11.1 
GENERAL PRINCIPLES  
Efficacy analyses will be based on the Full Analysis Set and safety analyses will be based on 
Safety Analysis Set. PK analysis will be based on the PK population. Continuous variables 
will be presented using number of subjects, mean, standard deviation (SD), standard error 


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(SE), median, minimum and maximum. Categorical data will be presented using counts and 
percentages of subjects.  
In general, analyses will be done by dose levels, and placebo subjects will be pooled as 
placebo group. Results for the Randomization Period and OLE Period will be summarized by 
treatment group assigned during the Randomized Period. In addition, by-cohort analysis will 
also be performed after each cohort completes Randomized Period and Database is locked 
and unblinded for that cohort. 
All statistical tests will be two-sided and tested at statistical significance level of 0.05. 
Confidence intervals will be 2-sided 95% confidence intervals, unless stated otherwise. 
11.2 
SUBJECT ACCOUNTABILITY  
The number and percentage of subjects in each of the study populations (Screened, 
Randomized, Full Analysis Set, Safety Analysis Set and PK) will be summarized. Subjects 
excluded from the analysis set will be listed. 
Screen-failure subjects (i.e., subjects screened but not randomized) and the associated 
reasons for failure to randomize will be listed.  
The number and percentage of subjects who complete the treatment period and of subjects 
who prematurely discontinue will be presented for each treatment group for the Randomized 
Population. The reasons for premature discontinuation from treatment and/or the study as 
recorded on eCRFs will be summarized. Disposition data will be listed by subject for the 
Randomized Population. 
11.3 
PROTOCOL DEVIATIONS  
Important protocol deviations will be summarized by type in each treatment group for the 
Randomized Population. Both important and non-important deviations will be listed. 
Deviations related to COVID-19 pandemic, if applicable, will be listed. 
11.4 
INVESTIGATIONAL PRODUCT ADMINISTRATION  
11.4.1 
Extent of Exposure  
Exposure to the investigational product for the Safety Analysis Set will be summarized by 
treatment group. 
For the Randomized Period, the following parameters will be presented: 
• Duration of exposure 
• Total number of planned doses 
• Total number of actual doses 
• Total actual dosage 
• Average actual weekly dosage  


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For the OLE Period, the following parameters will be presented: 
• Duration of exposure 
• Total number of planned doses 
• Total number of actual doses 
• Total actual dosage 
• Average actual weekly dose  
 
In additional, overall TransCon CNP exposure will be summarized for the following 
parameters: 
• Duration of exposure to TransCon CNP 
• Total number of planned CNP doses 
• Total number of actual CNP doses 
• Total actual CNP dosage 
• Average actual weekly CNP dosage 
 
Duration of exposure to actual dose of investigational product throughout Randomized 
Period and OLE Period will be summarized for each treatment group assigned during the 
Randomized Period.  
 
11.4.2 
Measurement of Treatment Compliance  
Descriptive statistics for investigational product compliance will be presented by treatment 
group for the Safety Analysis Set. Treatment compliance will be calculated as defined in 
Section 8.4. 
11.4.3 
Demographic and Baseline Characteristics  
Demographic parameters (age, age group, race/ethnicity, sex, height, height SDS, weight, 
BMI) and other baseline characteristics (age at ACH diagnosis, type of mutation, and 
baseline AHV) will be summarized descriptively by treatment group for the Full Analysis 
Set. 
11.4.4 
Medical History  
Medical history will also be summarized by system organ class (SOC) and preferred term 
(PT) for the Full Analysis Set by treatment group.  
11.4.5 
Prior and Concomitant Medication  
Prior medication is defined as any medication started before the date of the first dose of 
investigational product (medication start date prior to the first dose date).  
Concomitant medication is defined as any medication taken on or after the date of the first 
dose of investigational product (medication end date on or after first dose date [or ongoing], 


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and medication start date prior or on the last dose date). Any concomitant medications started 
after the date of the last dose of investigational product will not be presented in the summary 
tables but will be included in the subject data listings. 
Both prior and concomitant medications will be coded by drug name and therapeutic class 
using World Health Organization (WHO) Drug Dictionary. Both prior and concomitant 
medications will be summarized by treatment group for the Full Analysis Set. 
If a subject took a specific medication multiple times or took multiple medications within a 
specific therapeutic class, that subject will be counted only once for the coded drug name or 
therapeutic class. 
11.5 
EFFICACY ANALYSIS  
The efficacy analysis will be performed using the Full Analysis Set.  
For the Randomized Period, Analysis of Covariance (ANCOVA) model will be used as the 
primary analysis for the primary and secondary efficacy endpoint to compare different dose 
levels of TransCon CNP groups vs. pooled placebo group (combined across cohort). 
During the OLE Period, the efficacy endpoints and applicable change from baseline will be 
summarized descriptively and in general, OLE baseline will be used. 
11.5.1 
Analysis of Primary Efficacy Endpoint  
11.5.1.1 
Primary Analysis  
The estimand formulation is as follows, 
The following primary hypothesis will be tested (two-tailed):  
 
H0: Difference in mean AHV at Week 52 between CNP treatment group and the placebo 
group = 0  
H1: Difference in mean AHV at Week 52 between CNP treatment group and the placebo 
group ≠ 0 
Population:  
Full Analysis Set 
Variable 
AHV as measured at 52 weeks of weekly TransCon CNP treatment or placebo. 
Intercurrent events and their handling rules are as follows: 
Subjects who discontinue study treatment due to any reason will have their data collected 
after discontinuation of study treatment (up to Visit 7 if discontinued during the Randomized 


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Period), and included in the study database and analysis, whenever possible (Treatment 
Policy). 
For subjects with missing primary efficacy endpoint will have the height value imputed using 
the multiple imputation method as specified in Section 10.2.5 and Appendix 3, will be used.  
Analysis: 
The primary analysis is ANCOVA model with the AHV at Week 52 as the response variable, 
treatment (dose groups and placebo) and sex as factors, baseline age and baseline height SDS 
as covariates.  
Population-level Summary: 
Difference in estimated means between the CNP treatment group and placebo. 
11.5.1.2 
Sensitivity Analysis  
To assess the robustness of the primary analysis, following sensitivity analyses of the 
primary endpoint will be performed on Full Analysis Set. 
Sensitivity Analysis 1  
ANCOVA model with the AHV at Week 52 as the response variable, covariates including 
treatment, sex, baseline age group (<5 vs. ≥ 5 years), and baseline height SDS. 
Sensitivity Analysis 2 
Piecewise ANCOVA model with the AHV at Week 52 as the response variable, covariates 
including treatment, sex, baseline age for age <5 years and age ≥ 5 years, and baseline height 
SDS. 
Sensitivity Analysis 3  
The change from baseline to Week 52 in AHV will be analyzed using ANCOVA model with 
treatment and sex as factors, baseline age, baseline height SDS, and baseline AHV as 
covariates. 
Sensitivity Analysis 4 
The 6-month AHV at Week 52 will be analyzed using ANCOVA model with 6-month AHV 
at Week 52 as the response variable, treatment (dose groups and placebo) and sex as factors, 
baseline age and baseline height SDS as covariates. 
11.5.2 
Analysis of Secondary Efficacy Endpoint  
To analyze change from baseline to Week 52 in upper to lower body segment ratio, 
ANCOVA model will be performed with treatment and sex as factors, baseline age, and 
baseline upper to lower body segment ratio as covariates.  


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11.5.3 
Sequential Testing Procedure for Primary and Secondary Efficacy Endpoint  
Once the highest tolerated dose is established, the following multiplicity adjustment schema 
will be used for the comparison between the highest tolerated dose group and pooled placebo 
group. 
The primary analysis for AHV at Week 52 will be performed first. If the p-value for 
comparing the highest tolerated dose group and pooled placebo is <0.05, then the formal 
hypothesis test for upper to lower body segment ratio will be performed. 
11.5.4 
Analysis of Exploratory Efficacy Endpoints  
An ANCOVA model with treatment and sex as factors, baseline age and corresponding 
baseline endpoint measurements as covariates, will be used to analyze the following 
exploratory endpoints, 
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11.5.4.1 
PRO/ObsRO Measures  
PRO/ObsRO measures for the trial consist of the following scales: 
To analyze change from baseline to Week 52 in above PRO/ObsRO measures, ANCOVA 
model will be performed with treatment and sex as factors, baseline age and corresponding 
baseline PRO/ObsRO measures as covariates. The observed values and change from baseline 
at each timepoint of the above PRO/ObsRO scales, will be summarized descriptively by 
treatment group, for both Randomized Period and OLE Period.   
11.6 
SAFETY ANALYSIS  
The safety analysis will be performed using the Safety Analysis Set for Randomization 
Period and OLE Period. The safety parameters include AEs, clinical laboratory, vital sign, 
physical examinations, ECG parameters, radiographic findings and antibody parameters.  
For safety endpoints, all analyses will be based on the observed data (i.e., with no imputation 
of missing data), unless otherwise stated. 
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11.6.1 
Adverse Events  
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA). The investigator will grade an AE as mild, 
moderate or severe. 
An AE (classified by preferred term) will be considered a treatment emergent adverse event 
(TEAE) in the Randomized Period, if the AE start date occurs or worsens in severity on or 
after the first dose of study drug in the Randomized Period, or before the first dose of study 
drug in the OLE Period, if subjects continue to OLE Period. 
 
An AE (classified by preferred term) will be considered a TEAE in the OLE Period, if the 
AE start date occurs or worsens in severity on or after the first dose of study drug in the OLE 
Period. 
An AE that occurs within 30 days after the last dose of study drug in the last treatment period 
(Randomized Period or OLE Period) will be assigned to the last treatment period as TEAE. 
Subject incidence of TEAEs will be tabulated by treatment group as the following Summary 
of TEAEs    
• TEAEs by SOC and PT (preferred term)  
• Related TEAEs by SOC and PT  
• Serious TEAEs by SOC and PT 
• Serious Related TEAEs by SOC and PT 
• Grade 3 or Higher TEAEs by SOC and PT 
• Comorbidity of ACH TEAE by SOC and PT 
• Related to Study Procedures TEAE by SOC and PT 
• TEAEs leading to Deaths by SOC and PT 
• TEAEs leading to discontinuation of study by SOC and PT 
• TEAEs leading to discontinuation of treatment by SOC and PT 
• TEAEs by PT 
• Related TEAEs by PT 
• Serious TEAEs by PT  


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• TEAEs leading to Deaths by PT 
Detailed listings for all AEs, serious TEAEs, AEs leading to the discontinuation of study, 
AEs leading to the discontinuation of treatment, and death will also be generated.  
In addition, subject incidence of TEAEs by actual dose of investigational product throughout 
Randomized Period and OLE Period will be summarized for the following: 
• TEAEs by SOC and PT by Grade 
• Related TEAEs by SOC and PT  
• Serious TEAEs by SOC and PT 
• Serious Related TEAEs by SOC and PT 
• Serious Related TEAEs by SOC and PT 
• TEAEs by PT 
11.6.2 
Clinical Laboratory Parameters  
Descriptive statistics for clinical laboratory values (in conventional and SI units) and changes 
from the baseline values at each assessment time point will be presented by treatment group 
and treatment period for the following laboratory parameters: 
• Chemistry 
 Sodium 
 Potassium 
 Chloride 
 Bicarbonate 
 Magnesium 
 Phosphate 
 Calcium 
 Glucose 
 Alkaline Phosphatase 
 Aspartate Aminotransferase (AST) 
 Alanine Aminotransferase (ALT) 
 Creatinine 
 Creatine Phosphokinase 
 Albumin 
 Direct Bilirubin 
 Total Bilirubin 
 Blood urea nitrogen (BUN) 
 Gamma Glutamyl Transferase 


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 Lactate Dehydrogenase 
 Total Protein 
 Uric Acid 
• Hematology 
 Hemoglobin 
 Hematocrit 
 Red blood cell (RBC) Count 
 White blood cell (WBC) Count 
 Differential Cell Count 
 Platelet Count 
• Lipid panel 
 Total cholesterol 
 Low-density lipoprotein (LDL) 
 High-density lipoprotein (HDL) 
 Triglycerides 
• Urine Chemistry 
 Urine Calcium 
 Urine Creatinine 
 Urine Phosphate 
Data listings for laboratory will be provided. Listings of clinically significant laboratory 
findings will be provided separately. 
11.6.3 
Vital Signs  
Descriptive statistics for vital signs (systolic and diastolic blood pressures, heart rate, and 
temperature) and changes from baseline values at each assessment time point will be 
presented by treatment group and treatment period. 
Descriptive statistics for orthostatic changes for vital signs (systolic and diastolic blood 
pressures and heart rate) and changes from baseline values at each assessment time point will 
be presented by treatment group, as appropriate. 
Data listings for vital signs will be provided.   
11.6.4 
Physical Examination  
For sleep and snoring patterns, the number and percentage of subjects with abnormal findings 
at Screening will be summarized by treatment group. Changes from Screening and from last 
visits at each assessment time point will be summarized by treatment group and treatment 
period. 
Descriptive statistics for pubertal status will be provided by sex and treatment group. 


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Data listings for physical examination will be provided. 
11.6.5 
Electrocardiogram  
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS duration, 
QT interval, and QTcF) and changes from baseline values at each assessment time point will 
be presented by treatment group and treatment period.  
Data listings for ECG parameters will be provided. 
11.6.6 
Radiographic findings  
Results from the following radiographic assessments will be summarized.  
• Bone age X-ray 
• dual-energy X-ray absorptiometry (DXA) 
• Anterior-posterior standing lower extremity X-ray 
• Anterior-posterior and lateral spine X-ray 
The change in bone age, the ratio of bone age over chronical age, and delay in bone age will 
be calculated and summarized by treatment group and treatment period.  
 
Data listings for radiographic findings will be provided. 
 
11.6.7 
Antibody Parameters  
The appropriateness of the approach taken to analyze and report anti-drug antibody data 
should be evaluated on a case-by-case basis [2], following recent regulatory guidance and 
white papers [3].  Statistical analysis of antibodies against drug (ADA) will include (but not 
be limited to) the following tabulated summaries of antibody frequencies and population 
percentages: 
1. Incidence of pre-existing anti-CNP-38 binding antibodies (positive baseline) 
2. Incidence of treatment induced anti- CNP-38 binding antibodies by positive types 
(treatment emergent positive and treatment boosted positive) and overall 
3. Incidence of persistent anti-CNP-38 binding antibodies by positive types and overall 
4. Incidence of transient anti-CNP-38 binding antibodies by positive types and overall 
5. Incidence of pre-existing anti-CNP-22 binding antibodies (positive baseline) 
6. Incidence of treatment induced anti- CNP-22 binding antibodies by positive types and 
overall 
7. Incidence of persistent anti-CNP-22 binding antibodies by positive types and overall 
8. Incidence of transient anti-CNP-22 binding antibodies by positive types and overall 
9. Incidence of treatment induced anti-CNP neutralizing antibodies1 by positive types 
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10. Incidence of persistent anti-CNP neutralizing antibodies by positive types and overall 
11. Incidence of transient anti-CNP neutralizing antibodies by positive types and overall 
12. Incidence of pre-existing anti-prodrug antibodies (positive baseline) 
13. Incidence of treatment induced anti-prodrug binding antibodies by positive types and 
overall 
14. Incidence of persistent anti-prodrug antibodies by positive types and overall 
15. Incidence of transient anti-prodrug antibodies by positive types and overall 
Neutralizing antibodies are defined as confirmed binding anti-CNP antibodies that are 
confirmed positive in a cell-based neutralizing antibody assay. 
Treatment induced ADA will include two positive types: 
• Treatment emergent positive: if baseline (pre-treatment sample) is negative for ADA 
and at least 1 post-treatment sample is positive for ADA 
• Treatment boosted positive: if baseline (pre-treatment sample) is positive and at least 
1 post-treatment sample has a titer which is at least 4-fold higher than the pre-
treatment sample. 
Transient ADA is defined as treatment-induced ADA detected only at one sampling time 
point during study, or when there is less than 16 weeks between the first and the last ADA 
positive post-treatment samples.  
Persistent ADA is defined as when there is more than (or equal to) 16 weeks between the 
first and the last ADA positive post-treatment samples.  
For Randomized Period, antibody data will be summarized by treatment group. In addition, 
antibody data for overall CNP treatment period (both Randomized and OLE Period for CNP 
treatment group; OLE Period for placebo treatment group) will also be summarized 
separately, and the initial baseline will be used for antibody analysis. 
11.7 
PHARMACOKINETIC ANALYSIS  
Summary statistics will be provided for plasma concentration of Total CNP, Free CNP and 
mPEG and mPEG-linker at scheduled visits/time points.  Plasma concentration values below 
the limit of quantitation will be treated as zero in the descriptive statistics calculations. 
Missing values will be treated as if the sample was not taken. The summary tables will 
include the number of subjects, number of samples with values below the limit of 
quantitation, mean, standard deviation, standard error, percent coefficient of variation 
(%CV), 95% CI, median, minimum, maximum geometric mean, and geometric %CV. 
Plasma concentration data versus visit/time points will be presented in figures. 
12 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL  
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13 CHANGES TO PREVIOUS SAP  
Section Number Section 
Changes 
8.9 
3-Month 
Annualized Height 
Velocity 
Added details for 3-Month AHV calculation.  
8.10 
Height Standard 
Deviation Score 
Added details on the calculation of ACH specific 
height SDS. 
11.3 
Protocol Deviations 
Changed major and minor protocol deviations to 
important and non-important protocol 
deviations.  
11.4.1 
Extent of Exposure 
Added summaries for duration of exposure to 
actual dose of investigational product. 
11.5.1.2 
Sensitivity Analysis Added additional sensitivity analyses. 
11.5.4 
Analysis of 
Exploratory 
Efficacy Endpoints 
11.6.1 
Adverse Events 
Added summaries of TEAEs by actual dose of 
investigational product. 
 
14 REFERENCES  
[1] Hoover-Fong, J.E., Schulze, K.J., Alade, A.Y. et al. Growth in achondroplasia including 
stature, weight, weight-for-height and head circumference from CLARITY: achondroplasia 
natural history study—a multi-center retrospective cohort study of achondroplasia in the US. 
Orphanet J Rare Dis 16, 522 (2021). https://doi.org/10.1186/s13023-021-02141-4 
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[2] Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein 
Products (Draft Guidance), April 2016: 
https://www.fda.gov/downloads/Drugs/Guidances/UCM192750.pdf 
[3] Shankar et al. (2014) Assessment and reporting of the clinical immunogenicity of 
therapeutic proteins and peptides-harmonized terminology and tactical recommendations, 
AAPS J. 2014 Jul;16(4):658-73 
[4] Schafer JL. Analysis of incomplete multivariate data. New York: Chapman and Hall 
1997. 
[5] Schafer JL. Multiple imputation: A Primer. Statistical Methods in Medical Research 
1999;8: 3-15. 
[6] Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height 
velocity, weight velocity, and stages of puberty. Arch Dis Child. 1976;51(3):170-179. 
[7] Emmanuel M, Bokor BR. Tanner Stages. [Updated 2019 May 13]. In: StatPearls 
[Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK470280/ 
[8] Little RJA and Rubin DB. Statistical analysis with missing data. Second Edition, New 
York: John Wiley & Sons 2002. 
 
 
 


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15 APPENDICES  
APPENDIX 1. SCHEDULE OF EVENTS IN THE RANDOMIZED PERIOD  
Visit 
Screen 
1 
Phonea 
2b 
3 
4 
5b 
6 
7/ETb 
Follow-Upc 
Week 
 
0 
2 
4 
8 
12 
26 
39 
52 
57 
Window 
-4 to -1 
weeks 
 
±3 days 
±3 days 
±7 days 
±7 
days 
±7 days 
±7 days 
±7 days 
±7 days 
Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Verification of eligibility, including genetic test 
for ACHd 
X 
 
 
 
 
 
 
 
 
 
Medical historye 
X 
X 
 
 
 
 
 
 
 
 
Prior/Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events reviewf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Limited, symptom-directed physical 
examinationg 
 
X 
 
X 
X 
X 
 
X 
 
 
Full physical examinationh 
X 
 
 
 
 
 
X 
 
X 
 
Thorough skeletal physical exami 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Assessment of pubertal statusj 
X 
 
 
 
 
 
X 
 
X 
 
Vital signsk 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Standing height and sitting height 
X 
 
 
X 
X 
X 
 
X 
 
 
All anthropometric measurements 
 
X 
 
 
 
 
X 
 
X 
 
12-lead ECG 
X 
Xl 
 
X 
X 
 
X 
 
X 
 
Bone age X-ray 
 
Xm 
 
 
 
 
 
 
Xm 
 
DXAn 
 
Xm 
 
 
 
 
 
 
Xm 
 
AP standing lower extremity X-ray 
 
Xm 
 
 
 
Xo 
 
 
Xm 
 
AP and lateral Spine X-ray 
 
Xm 
 
 
 
Xo 
 
 
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Qualitative assessment of sleep and snoring 
pattern 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetics 
 
Xp 
 
X 
X 
X 
X 
X 
X 
 
Blood chemistry 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Lipid panel 
X 
 
 
 
X 
 
 
X 
X 
 
25(OH) Vitamin D 
X 
 
 
 
 
 
X 
 
X 
 
Biomarkers 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Anti-drug antibodies 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Urine collection 
X 
 
 
 
 
X 
X 
X 
X 
 
PRO/ObsRO Validation Batteryq 
X 
 
 
 
 
 
 
 
X 
 
Subset of PRO/ObsRO Validation Batteryq 
 
X 
 
 
X 
X 
X 
X 
 
 
r 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Dispensing of study drug and diary 
 
X 
 
X 
X 
X 
X 
X 
 
 
Study drug administration on site 
 
X 
 
 
 
 
 
 
 
 
Error! Reference source not found. 
All participants will be contacted by phone during Week 2 for follow up.  During the call, the study staff will ask the 
caregiver about the general well-being of the child, inquire regarding correct administration of study drug procedures, record any AEs, record any concomitant 
medication changes and answer any questions. 
b Visit 2 (Week 4), Visit 5 (Week 26), and Visit 7 (Week 52) labs are drawn at trough. Therefore, study drug cannot be administered within 6 days prior to these 
visits. The last dose of study drug will be administered at least 6 days prior to Visit 7 
c Only for participants not proceeding to the Open-Label Extension Period. 
d Previous genetic testing will be accepted.  The documented lab result should be reviewed by the investigator to confirm the result along with the specific 
FGFR3 mutation. If not available in medical record, Screening will include testing for G380R mutation, but further testing may be pursued on an individual 
basis as indicated. 
e Medical history should elicit all major illnesses, diagnoses, and surgeries that the participant has ever had, and any prior or existing medical conditions that 
might interfere with study participation or safety. Medical history includes historical anthropometric measurements, as available. 
f Includes review of ACH comorbidities based on age, including risk of sleep apnea and CMC. 
g Limited, symptom-directed physical examination should be performed as needed at the discretion of the investigator to provide appropriate medical care to the 
participants and to verify no clinically relevant changes have occurred since the Screening Visit. On Visit 1, injection site must be visually inspected prior to 
dosing and at 1 hour and 2 hours after injection of study drug.  For participants that undergo blood collection for pharmacokinetic analyses at 8, 24, and 48 
hours following first dose, injection site will be inspected at the time of each blood collection. All subsequent visits should also include a visual inspection of 
injection sites. 
h Includes assessments of all major body systems including general appearance, HEENT, Neck (including thyroid), Lung/pulmonary, Chest, CV, Abdomen, 
Back, GU, Neurological, Extremities, and Skin. All visits, except at the Screening Visit, should also include a visual inspection of injection sites. 
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i Thorough skeletal physical exam will be performed by palpating the bone structure and joints for tenderness and mobility and other abnormal changes not 
normally found in children with ACH. Special attention will be paid to the hip exam, which will include a supine assessment of abduction and adduction of 
hips to assess for pain and any limitation of range of motion. If changes are noted further evaluation will be required as clinically indicated, including imaging 
and/or orthopedic consultation. DMC will be apprised of any safety findings. 
j Boys will be assessed for testis volumes, and girls for breast development according to Tanner stages ([6]).  Pubic hair rating will also be recorded according to 
Tanner stages but will not be used to assess eligibility.  All participants must be Tanner Stage 1 for breast development (girls) - no glandular 
development/breast buds, and Tanner Stage 1 for gonadal development (boys) - testicular volume < 4 mL ([7]).  Tanner stage progression during the course of 
the trial will not impact study treatment.  See Protocol Appendix 3 for details.  
k Participants should rest for at least 5 minutes before vital sign measurement and vital signs are to be taken before blood samples are drawn. Temperature 
measured in degrees Celsius (°C) or Fahrenheit (°F), blood pressure, and heart rate must be measured at Screening Visit and Visit 1.  Orthostatic HR and 
systolic/diastolic BP will also be measured at Visit 1 prior to administration of study drug following first dose when the participant is at rest for 5 minutes 
(preferably supine) and again after standing at 3 minutes for assessment of orthostatic hypotension. Additionally, at Visit 1, all vital signs must be monitored at 
1 hour and 2 hours post injection of the study drug. For participants that undergo blood collection for pharmacokinetic analyses at 8, 24, and 48 hours 
following first dose, orthostatic vital signs (HR, and BP) will also be measured prior to each PK blood collection.  At all other visits, resting heart rate and 
blood pressure must be measured.  
l At approximately 48 hours after the first dose for participants that undergo PK blood collection for PK analysis at that time. 
m Radiographic assessments may not be required, with Medical Monitor approval, if the same assessments were conducted within approximately 3 months prior 
to the visit. If radiographic assessments cannot be completed prior to study drug administration at Visit 1 due to scheduling conflicts, the assessments may be 
completed at up to 24 hours after study drug administration. 
n DXA scan are at Visit 1 and Visit 7 for children aged 5 years and older only. 
o Scheduled radiographic assessments may be performed within 1 week prior to or after the visit if all scheduled assessments cannot be completed within the 
same day. 
p PK blood collection will be performed for all participants prior to injection of study drug. For participants who weigh ≥11 kg, blood collection will be 
performed at approximately 8, 24, and 48 hours after injection at Visit 1 for pharmacokinetic analyses. Allowances will be made for accommodation.  
Exceptions to the extended PK blood collection will be considered on an individual basis (e.g. if travel creates an undue hardship for a family). 
q PRO/ObsRO validation batteries must be completed by the caregiver without assistance and should be completed prior to conducting any clinical assessments.  
The same caregiver should complete all PRO/ObsRO validation batteries throughout participation in the trial. If the same caregiver is unable to attend a 
particular visit, an alternate caregiver may complete the PRO/ObsRO validation batteries at the visit. 
r The 
 must be completed by the investigator who medically assessed the participant at the visit after all clinical assessments are completed.  The same 
assessor should assess the participant at every visit. 
 
 
 
 
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APPENDIX 2. SCHEDULE OF EVENTS IN THE OPEN-LABEL PERIOD  
Visit 
7 
Phonea 
8 
9 
10 
11 
12 
13 
14 
15 
16/ET 
Follow-
Up OLE 
Week 
52 
54 
56 
65 
78 
91 
104 
117 
130 
143 
156 
161 
Window 
 
±3 days 
±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events reviewb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsc 
Xd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Limited physical examinatione 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
Full physical examinationf 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Thorough skeletal physical examg 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of pubertal status and 
childbearing potentialh 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Standing height and sitting height  
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
All anthropometric measurements 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
12-lead ECG 
Xi 
 
X 
Xp 
X 
Xp 
X 
 
X 
 
X 
 
Bone X-rayj 
 
 
 
 
 
 
X 
 
 
 
X 
 
DXAj, k 
 
 
 
 
 
 
X 
 
 
 
X 
 
AP standing lower extremity X-rayj 
 
 
 
X 
 
 
X 
X 
 
 
X 
 
AP and lateral Spine X-rayj 
 
 
 
X 
 
 
X 
X 
 
 
X 
 
Qualitative assessment of sleep and 
snoring pattern 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetics 
Xl 
 
X 
Xp 
X 
Xp 
X 
 
X 
 
X 
 
Blood chemistry 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lipid panel 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
25(OH) Vitamin D 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Anti-drug antibodies 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarkers 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


TCC-201  
Statistical Analysis Plan  
11 October 2022, Version 2.0 
 
 
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Visit 
7 
Phonea 
8 
9 
10 
11 
12 
13 
14 
15 
16/ET 
Follow-
Up OLE 
Week 
52 
54 
56 
65 
78 
91 
104 
117 
130 
143 
156 
161 
Window 
 
±3 days 
±3 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
±7 days 
Urine collection 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine collection for hCG testing for 
females of childbearing potentialm 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PRO and ObsRO Validation 
Batteryn 
 
 
 
 
 
 
X 
 
 
 
X 
 
Subset of PRO/ObsRO Validation 
Batteryn 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispensing of study drug and diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug administration on site 
X 
 
 
 
 
 
 
 
 
 
 
 
a All participants will be contacted by phone during Week 54 for follow up.  During the call, the study staff will ask the caregiver about the general well-being of the 
child, inquire regarding correct administration of study drug procedures, record any AEs, record any concomitant medication changes and answer any questions. 
b Includes review of ACH comorbidities based on age, including risk of sleep apnea and CMC. 
c Participants should rest for at least 5 minutes before vital sign measurement and vital signs are to be taken before blood samples are drawn. Temperature measured 
in degrees Celsius (°C) or Fahrenheit (°F). 
d Orthostatic HR and systolic/diastolic BP will be measured at Visit 7 following first dose when the participant is at rest for 5 minutes (preferably supine) and again 
after standing at 3 minutes for assessment of orthostatic hypotension. Additionally, at Visit 7, all vital signs must be monitored at 1 hour and 2 hours post injection 
of the study drug. For participants that undergo blood collection for pharmacokinetic analyses at 8, 24, and 48 hours following first dose, orthostatic vital signs (HR, 
and BP) will also be measured prior to each PK blood collection. 
e Limited, symptom-directed physical examination should be performed as needed at the discretion of the investigator to provide appropriate medical care to the 
participants and to verify no clinically relevant changes have occurred since the last visit. On Visit 7, injection site must be visually inspected prior to dosing and at 
1 hour and 2 hours after injection of study drug.  For participants that undergo blood collection for pharmacokinetic analyses at 8, 24, and 48 hours following first 
dose, injection site will be inspected at the time of each blood collection. All subsequent visits should also include a visual inspection of injection sites. 
f Includes assessments of all major body systems including general appearance, HEENT, Neck (including thyroid), Lung/pulmonary, Chest, CV, Abdomen, Back, 
GU, Neurological, Extremities, and Skin. All visits should also include a visual inspection of injection sites. 
g Thorough skeletal physical exam will be performed by palpating the bone structure and joints for tenderness and mobility and other abnormal changes not normally 
found in children with ACH. Special attention will be paid to the hip exam, which will include a supine assessment of abduction and adduction of hips to assess for 
pain and any limitation of range of motion. If changes are noted further evaluation will be required as clinically indicated, including imaging and/or orthopedic 
consultation. DMC will be apprised of any safety findings. 
h Boys will be assessed for testis volumes, and girls for breast development according to Tanner stages ([6]).  Pubic hair rating will also be recorded according to 
Tanner stages but will not be used to assess eligibility.  Tanner stage progression during the course of the trial will not impact study treatment.  See Protocol 
Appendix 3. During the open-label period, the Investigator should ascertain an individual’s risk for becoming pregnant or fathering a child and take appropriate 
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Statistical Analysis Plan  
11 October 2022, Version 2.0 
 
 
Proprietary and Confidential 
Page 39 
steps. Pregnancy prevention counseling and pregnancy testing should be provided as appropriate and can be tailored per the Investigator’s judgement based on 
maturity and cultural norms. See Protocol Appendix 6 for details on childbearing potential in females, wherever applicable.  
i At approximately 48 hours after the first dose for participants that undergo PK blood collection for PK analysis at that time. 
j Scheduled radiographic assessments may be performed within 1 week prior to or after the visit if all scheduled assessments cannot be completed within the same 
day. Radiographic assessments may not be required, with Medical Monitor approval, if the same assessments were conducted within approximately 3 months prior 
to the visit for Visit 16/ET. 
k For children aged 5 years and older only. 
l For participants who weigh ≥11 kg, blood collection will be performed at approximately 8, 24, and 48 hours after injection at Visit 7 for pharmacokinetic analyses. 
Allowances will be made for accommodation.  Exceptions to the extended PK blood collection will be considered on an individual basis (e.g. if travel creates an 
undue hardship for a family). 
m Urinary hCG test for females of childbearing potential according to Protocol Appendix 6 will be performed for all visits. 
n PRO/ObsRO measures must be completed by the caregiver without assistance and should be completed prior to conducting any clinical assessments.  The same 
caregiver should complete all PRO/ObsRO measures throughout participation in the trial.  The PRO/ObsRO measures must be completed at the visit. If the same 
caregiver is unable to attend a particular visit, an alternate caregiver may complete the PRO/ObsRO measures at the visit. 
o The 
 must be completed by the study staff who medically assessed the participant at the visit after all clinical assessments are completed.  The same assessor 
should assess the participant at every visit. 
p ECG and blood collection for pharmacokinetics should be performed prior to study drug administration and only at visits where the dose is escalated 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
11 October 2022, Version 2.0 
 
 
Proprietary and Confidential 
Page 40 
APPENDIX 3. MULTIPLE IMPUTATION FOR MISSING DATA IN PRIMARY ENDPOINT  
Imputation of missing data will be conducted under a working assumption of missing at random (MAR).  Missing at random means 
that the missing data mechanism is assumed not to depend on unobserved missing values but may depend on any other available 
information collected in the trial. 
The imputations will be performed for post-baseline visits. The Markov Chain Monte Carlo (MCMC) method will be used under the 
multivariate normality assumption to impute the missing height values by treatment group. The variable list for imputations will 
include gender, baseline age, baseline height SDS, as well as all available post-baseline height values. The SAS procedure PROC MI 
will be used in the multiple simulation.  The MCMC method will impute 100 datasets.  Multiple imputation replaces each missing 
value with a set of m = 100 plausible possibilities.  The set of these possibilities represent the uncertainty about the unobserved ‘true’ 
value that was imputed.   
Step I:  Imputation of Missing Data 
Default EM algorithm will be used to derive a set of initial parameter estimates for MCMC method.  A non-informative prior (default 
Jeffreys’ prior) will be used to derive the posterior distribution of the parameters. Trace plots and autocorrelation plots of the variables 
will be examined.  The number of burn-in iterations may be modified (the default is 200 burn-in iterations) to ensure the iterations 
converge to the stationary distribution before the imputation. 
Step II: Inference 
For each of the 100 imputed datasets, height velocity will be recalculated based on the multiply imputed height values. The primary 
efficacy analysis will then be performed using an ANCOVA model with the AHV at Week 52 as the response variable, treatment 
(dose groups and placebo) and sex as factors, baseline age and baseline height SDS as covariates.  
The estimates from the 100 fitted models for each of the 100 imputed datasets will be combined to provide an overall estimate of the 
least square mean with a corresponding confidence interval for each treatment group and an overall estimate of the difference in least 
square means between the CNP treatment vs. the placebo group and a p-value ([8]).  
 


   Approval Signatures
Document Name:
CNP TCC-201 SAP
Document Number:
VV-SUB-015442
Version:
2.0
This is a representation of an electronic record that was signed electronically in Veeva Vault. This page is
the manifestation of the electronic signature(s) used in compliance with the organizations electronic
signature policies and procedures.
 Approved
SIGNATURE INFORMATION:
11-Oct-2022 15:39:19 GMT+0000
 Approved
SIGNATURE INFORMATION:
11-Oct-2022 16:24:29 GMT+0000
 Approved
SIGNATURE INFORMATION:
11-Oct-2022 17:06:06 GMT+0000
PPD
PPD
PPD
PPD
PPD
PPD