PaTHway TRIAL: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial, With an Open-Label Extension, Investigating the Safety, Tolerability and Efficacy of TransCon PTH Administered Subcutaneously Daily in Adults With Hypoparathyroidism
Phase: PHASE3
Conditions: Hypoparathyroidism, Endocrine System Diseases, Parathyroid Diseases
Sponsor: Ascendis Pharma Bone Diseases A/S

Official Title: 
PaTHway Trial: A Phase 3, Multicenter, Randomized, Double-
Blind, Placebo-Controlled, Parallel Group Trial, with an Open-
Label Extension, Investigating the Safety, Tolerability and 
Efficacy of TransCon PTH Administered Subcutaneously 
Daily in Adults with Hypoparathyroidism 
NCT Number: 
 NCT04701203 
Document Date:   Protocol Version 7.0, 25 May 2023 

Clinical Trial Protocol 
Ascendis Pharma 
TCP-304, Version 7.0 
Page 1 of 125 
VV-SUB-023233-12.0
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
Product Name: 
TransCon PTH (Palopegteriparatide) 
Protocol Number: 
TCP-304 
IND Number: 
133469 
EUDRACT Number: 
2020-003380-26 
Phase: 
3 
Protocol Title: 
PaTHway TRIAL: A Phase 3, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Parallel Group Trial, with an Open-Label Extension, 
Investigating the Safety, Tolerability and Efficacy of TransCon PTH 
Administered Subcutaneously Daily in Adults with Hypoparathyroidism 
Protocol Date: 
V1.0, 23 SEP 2020 
V2.0, 16 MAR 2021 
V3.0, 10 JUN 2021 
V4.0, 03 AUG 2021 
V5.0, 20 DEC 2021 
V6.0, 13 DEC 2022 
V7.0, 25 May 2023 
Protocol Version: 
V7.0 
Sponsored By: 
Ascendis Pharma Bone Diseases A/S 
Tuborg Boulevard 12, DK-2900, Hellerup, Denmark 
Sponsor Medical 
Monitors:  
, MD 
Ascendis Pharma, Inc. 
1000 Page Mill Road, Palo Alto, 
California 94034, United States 
Phone: 
email: 
, MD 
Ascendis Pharma, Inc. 
1000 Page Mill Road, Palo Alto, 
California 94304, United States 
Phone: 
email:
 MD 
Ascendis Pharma, Inc. 
1000 Page Mill Road, Palo Alto, 
California 94304, United States 
Phone: 
Cell: 
email:
CONFIDENTIAL 
This document contains proprietary and confidential information of Ascendis Pharma Bone Diseases 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Acceptance of this document constitutes agreement by the recipient that no previously unpublished information contained herein 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 Bone Diseases 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 Bone Diseases A/S or its affiliates shall be promptly notified of 
any such disclosure.  
1&7
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 2 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
SUMMARY OF CHANGES – VERSION 6.0 TO VERSION 7.0  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
This amendment to the protocol is being issued to add precaution in case of use of digoxin 
during the open-label extension period based on authority feedback and to add administrative 
updates.     
Note that added text is highlighted in bold character. When the only change consists of a deletion 
or the replacement of a single term, the deleted or replaced text is marked with a horizontal line 
(strikethrough), leaving the deleted/replaced text legible. 
Section(s) 
Description of Change (s) 
Brief Rationale 
Title Page 
Remove 
 as Medical Monitor, Add 
 
 as Medical Monitor, Update 
 
title 
 
MD 
 
Ascendis Pharma, Inc. 
1000 Page Mill Road, Palo Alto, California 94304, 
United States 
Phone: 
 
Cell: 
 
email: 
 
 
, MD 
, 
 
Ascendis Pharma, Inc. 
1000 Page Mill Road, Palo Alto, 
California 94304, United States 
Phone: 
 
email:
 
 
, MD 
 
Administrative 
changes 
Section 9.6.1 
Dose changes and 
Treatment 
Interruptions 
x 
Persistent severe hypercalcemia with albumin-
corrected serum calcium >≥12.0 mg/dL4 for 
>7 days despite: 
 
Footnote 4: Thresholds for albumin-corrected serum 
calcium: > ≥12.0 mg/dL (>≥3.00 mmol/L), or ionized 
calcium: > ≥1.50 mmol/L 
Correction for 
consistency 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 3 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
Section 9.9.2 
Prohibited 
Therapies 
Added following precaution:  
 
TransCon PTH increases calcium, and therefore 
concomitant use with digoxin (which has a narrow 
therapeutic index) may predispose patients to 
digitalis toxicity if hypercalcemia develops. When 
TransCon PTH is used concomitantly with digoxin, 
measure serum calcium and digoxin levels, and 
monitor for signs and symptoms of digoxin toxicity. 
The use of digoxin is 
permitted in the open 
label extension period 
if clinically indicated 
and should be used 
with caution as 
hypercalcemia may 
predispose the subject 
to digoxin toxicity. 
 
The protocol is 
updated with the 
precaution based on 
authority feedback to 
protocol version 6.0 
Section 12.1.5 
Special Situation 
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 
Subjects participating 
in the trial will not be 
treated off-label 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 4 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
SUMMARY OF CHANGES – VERSION 5.0 TO VERSION 6.0  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
This amendment to the protocol is being issued to clarify the use of prohibited medications  
during the open-label extension period, to add an efficacy endpoint for extension period and to 
provide clarification on the trial. 
Note that added text is highlighted in bold character. When the only change consists of a deletion 
or the replacement of a single term, the deleted or replaced text is marked with a horizontal line 
(strikethrough), leaving the deleted/replaced text legible. 
Section(s) 
Description of Change (s) 
Brief Rationale 
Title Page 
Update address of Ascendis Pharma, Inc 
Administrative 
Change 
Title Page 
Add 
 and Remove 
 as 
Medical Monitor 
Administrative 
Change 
Section 9.5.2.1. 
SoC Dose 
Adjustments during 
Blinded Treatment 
Period 
 
Section 11.14. 
Laboratory 
Assessments 
SoC adjustments should be made preferably within 48 
hours of blood collection.   
 
 
Investigators must be able to receive local laboratory results 
within a time frame sufficent to allow instructions to 
subjects on dose adjustments preferably within 48 hours of 
blood collection 
Clarification of 
time frame for 
titration  
Section 9.9.2. 
Prohibited 
Therapies 
The following therapies are prohibited during the blinded 
phase: throughout the trial 
 
For the open-label extension period, these medications 
are allowed only if deemed necessary by the investigator 
for patient safety considerations. Use of 
bisphosphonates or denosumab requires consultation 
with the Medical Monitor to determine potential impact 
on integrity of relevant endpoints. 
Clarification of 
use of these 
medications 
during open-label 
extension period 
Section 12.4.2. 
Recording 
Procedures for All 
Adverse Events 
AEs will be documented at the maximum intensity 
experienced. If a previously recorded and closed AE or 
condition recorded as part of medical history increases 
in severity or frequency, it will be recorded as a new 
AE. 
Language updated 
to clarify 
collection of AEs 
Section 12.5.2. 
Reporting 
All SAEs, AESIs, and Special Situations (including follow-
up information) must be reported to e-mail: 
ascendis@pharmalex.com 
OR 
fax: 003497 620 4402using the Safety report form or the 
Pregnancy report form provided. A completed Safety 
report form / Pregnancy report form must be uploaded 
to the Safety Reporting Portal at: 
Updated safety 
reporting process 
from email/fax to 
online safety 
reporting portal to 
be compliant to 
data privacy 
regulation  
PPD
PPD

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 5 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Safety.ascendispharma.com 
Specific instructions regarding completion of the form 
and reporting details are provided on the Safety report 
form. 
Synopsis 
Section 15.2.1.2.2. 
Other Secondary 
Efficacy Endpoints 
The primary and key secondary efficacy endpoints and the 
following efficacy endpoint will be measured evaluated at 
predefined timepoints during the Extension Period.  
• 
The proportion of subjects that meet the following 
criteria:  
− 
Albumin-adjusted sCa measured within the 
normal range (8.3-10.6 mg/dL); and  
− 
Independence from active vitamin D (i.e., 
standing dose of active vitamin D equal to 
zero on the day prior to the Week 52 visit 
or other visits of interest); and  
− 
Independence from therapeutic doses of 
calcium (i.e., standing dose of elemental 
calcium ≤ 600 mg on the day prior to the 
Week 52 visit or other visits of interest). 
Add an efficacy 
endpoint for 
Extension Period 
Synopsis 
Section 15.3. 
Statistical Analysis 
All efficacy endpoints will be summarized descriptively 
in Extension Period analysis. 
Specify how 
analysis will be 
done for efficacy 
endpoints for 
Extension Period 
 

Clinical Trial Protocol 
Ascendis Pharma 
TCP-304, Version 7.0 
Page 6 of 125 
VV-SUB-023233-12.0
CONFIDENTIAL 
SUMMARY OF CHANGES – VERSION 4.0 TO VERSION 5.0 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
This amendment to the protocol is being issued to address comments and recommendation from 
the Food and Drug Administration (FDA).  
Note that added text is highlighted in bold character. When the only change consists of a deletion 
or the replacement of a single term, the deleted or replaced text is marked with a horizontal line 
(strikethrough), leaving the deleted/replaced text legible. 
Section(s) 
Description of Change (s) 
Brief Rationale 
Synopsis 
Section 15.2.1.1 
Primary Efficacy 
Endpoints 
x
Independence from therapeutic doses of calcium (i.e.,
taking calcium supplements ≤600 mg/day). This dose
of calcium ≤600 mg/day in the form of tablets, powder,
liquid suspension, or transdermal patch is considered as
“supplemental” to meeting recommended daily intake
for general health, as opposed to a “therapeutic” dose
to treat hypoparathyroidism*** and
x
No increase in prescribed study drug within 4
weeks prior to Week 26 visit****
**** Dose decrease permitted for safety reasons
Synopsis 
Section 15.2.1.2.1 
Key Secondary 
Efficacy Endpoints 
Change from baseline at 26 weeks of treatment: 
x
HPES symptom – Total Physical domain score
x
HPES Symptom –Cognitive domain score
x
HPES Impact - Physical functioning domain Total
score
x
HPES Impact – Daily life domain score
x
36-Item Short Form Survey (SF-36) Physical
component functioning subscale score
x
SF-36 Mental component score
In addition, HPES domains scores (Physical, Cognitive,
Physical Functioning, Daily Life, Psychological Well-
being, Social life and Relationships) and SF-36 subscale
scores (Physical Functioning, Role Limitations due to
Physical Health Problems, Bodily Pain, General Health,
Vitality, Social Functioning, Role Limitations due to
Emotional Problems and Mental Health) will be analyzed.
Synopsis 
Section 15.2.1.2.2 
Other Secondary 
Efficacy Endpoints 
x
HPES: HPES Impact domain scores (Psychological
Well-being and Social life and Relationships) and
HPES Symptom and Impact total scores
x
SF-36 subscale scores (Role Limitations due to
Physical Health Problems, Bodily Pain, General
Health, Vitality, Social Functioning, Role
Limitations due to Emotional Problems, and Mental
Health) and SF-36 component scores (Physical
component score and Mental component score)
CCI
CCI
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 7 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
Synopsis 
Section 15.3 
Statistical Analysis  
Gatekeeping testing procedure Sequential testing will be 
applied to control the family-wise type-1 error rate for the 
primary and key secondary endpoints. Details will be 
specified in the SAP. 
In general, continuous endpoints during Blinded 
Treatment Period will be analyzed using ANCOVA model 
with unequal covariance.  The model will include the 
change from baseline for the endpoint of interest as a 
response variable, treatment assignment and etiology of 
hypoparathyroidism as fixed factor and baseline value of 
the endpoint will be entered as a covariate, unless 
otherwise specified in the SAP.  The key secondary PRO 
efficacy endpoints will be analyzed as continuous and in 
terms of change from baseline using the described 
ANCOVA model with multiple imputation for missing 
post-baseline assessments.   
 
Appendix 2. 
Titration Algorithm 
Footnote 5 
Through Week 52: cCheck sCa within 7-14 days after any 
changes in study drug dose; standing calcium, standing 
vitamin D doses; or sCa outside the normal range. A 
scheduled visit or LV within 7-14 days meets this 
requirement. When scheduled study visits occur less 
frequently (e.g. 13 weeks apart) then an ULV should be 
pursued. After Week 52 of the trial check sCa within 7-31 
days after any changes in study drug dose. 
Appendix 2. 
Titration Algorithm 
Note 
At all times during the trial, subjects with symptoms of 
hypocalcemia may take PRN doses of calcium (preferred) 
and/or active vitamin D, and/or do an ULV visit to measure 
sCa. Subjects with symptoms of hypercalcemia may 
hold doses of study drug for 1 day and/or do an ULV to 
measure sCa. An ULV must be performed within 7 
days of a PRN supplement dose or a held dose. An ULV 
must be performed within 7 days of a PRN supplement 
dose.  
At all times during the trial, subjects with symptoms of 
hypercalcemia may hold doses of study drug for 1 day 
and/or do an ULV to measure sCa. An ULV must be 
performed within 7 days of a held dose. If due to 
symptoms >2 PRN doses of SoC  are taken or >2 doses 
of SoC and/or study drug are held within those 7 days, 
an ULV is required within 2 days of the third PRN or 
held dose. 
 
CCI
CCI
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 8 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
SUMMARY OF CHANGES - VERSION 3.0 TO VERSION 4.0  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Note that added text is highlighted in bold character. When the only change consists of a deletion 
or the replacement of a single term, the deleted or replaced text is marked with a horizontal line 
(strikethrough), leaving the deleted/replaced text legible. 
Section(s) 
Description of Change (s) 
Brief Rationale 
Section 9.6.1 
Dose changes and 
Treatment 
Interruptions 
x 
maximum protocol permitted dose of study drug  
x 
study drug dose ≥30 μg/day  
Administrative 
correction. Updated to 
reflect the maximum dose 
of study drug in the 
protocol 
Section 11.9.4 36-
Item Short-Form 
Survey 
The 36-Item Short-Form Survey (SF-36) V2 Health 
Survey (1-week recall) is a multipurpose short-
form health survey with 36 questions that yields 
an eight-scale profile of functional health and 
general well-being, as well as two 
psychometrically based physical and mental 
health summary measures and a preference-
based health utility index.   
Synopsis  
Section 15.2.1.1 
Primary Efficacy 
endpoints 
At 26 weeks of treatment, the proportion of subjects 
with:  
x 
Albumin-adjusted sCa measured within 4 
weeks prior to and on the Week 26 visit are 
within the normal range (8.3-10.6mg/dL) *; and  
x 
Independence from active vitamin D** and  
x 
Independence from therapeutic doses of calcium 
(i.e., taking calcium supplements ≤600 mg/day). 
This dose of calcium ≤600 mg/day in the form 
of tablets, powder, liquid suspension, or 
transdermal patch is considered as 
“supplemental” to meeting recommended daily 
intake for general health, as opposed to a 
“therapeutic” dose to treat 
hypoparathyroidism*** 
* Except for at the Week 26 visit, confirmation 
that an albumin-adjusted sCa is “abnormal” 
requires 2 consecutive results outside the normal 
range within 4 weeks prior to the Week 26 visit. 
**Independence from active vitamin D will be 
defined as a daily standing dose equal to zero on 
all days AND use of any PRN vitamin D ≤7 days 
within 4 weeks prior to the Week 26 visit.  
***Independence from therapeutic calcium will 
be defined as average daily standing dose ≤600 
mg AND use of PRN doses on ≤7 days within 4 
weeks prior to the Week 26 visit.  
CCI
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 9 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
* Daily calcium and active vitamin D doses are 
calculated as the sum of standing and PRN doses on 
a calendar day.  Independence from therapeutic 
calcium is defined as daily elemental calcium dose 
≤600 mg on the calendar day of and day prior to the 
week 26 visit.  Independence from active vitamin D 
is defined as receiving no active vitamin D in the 
same 2-day period.  
Synopsis 
Section 15.2.1.2  
Secondary efficacy 
endpoints 
Change from baseline at 26 weeks of treatment: 
At 26 weeks of treatment: 
x 
Change from baseline in HPES 
x 
Change from baseline in 36-Item Short Form 
Survey (SF-36) 
x 
HPES Symptom - Total score 
x 
HPES Impact - Total score 
x 
36-Item Short Form Survey (SF-36) Physical 
component score  
x 
SF-36 Mental component score  
In addition, HPES domains scores (Physical, 
Cognitive, Physical Functioning, Daily Life, 
Psychological Well-being, Social life and 
Relationships) and SF-36 subscale scores 
(Physical Functioning, Role Limitations due to 
Physical Health Problems, Bodily Pain, General 
Health, Vitality, Social Functioning, Role 
Limitations due to Emotional Problems and 
Mental Health) will be analyzed.  
Section 15.3 
Statistical Analysis 
Subjects with no Week 26 albumin-adjusted sCa 
OR with >25% (i.e., >7 days) missing diary data 
of active vitamin D or calcium during the 4 weeks 
will be considered as non-responders. 
Subjects who have missing data on one or more of 
the criteria for the primary endpoint at time of the 
analysis will be considered as non-responders 
Clarification of handling 
of missing data 
Appendix 2 
Decrease calcium supplements by ≥1500 mg/day6 
Clarification of PI’s 
discretion to continue 
calcium supplementation 
to meet nutritional 
requirements if clinically 
warranted 
Appendix 2 
Footnote 5 
 
Through Week 52: Check sCa within 7-14 31 days 
after any changes in study drug dose; standing 
calcium, standing vitamin D doses; or sCa 
outside the normal range. A scheduled visit or LV 
within 7-14 31 days meets this requirement. When 
scheduled study visits occur less frequently e.g. 13 
weeks apart) then an ULV should be pursued. After 
CCI
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 10 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
Week 52 of the trial check sCa within 7-31 days 
after any changes in study drug dose.  
Appendix 2  
Notes 
Adjustments of study drug, calcium and/or active 
vitamin D will be made per the titration 
algorithm based on the results of the most recent 
laboratory results whether scheduled or 
unscheduled.  When central and local calcium 
values are obtained concurrently, local values 
should be used to guide titration. 
Clarification regarding 
use of titration algorithm 
after scheduled and 
unscheduled laboratory 
visit calcium values 
Appendix 3 
Weekly diary activation dispensing  
Updated to reflect the use 
of paper weekly diary 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 11 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
SUMMARY OF CHANGES - VERSION 2.0 TO VERSION 3.0  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
This amendment to the protocol is being issued to provide clarification on the trial. Comments 
from the National Security Agency of Medicine and Health Products (ANSM) were also taken 
into consideration.    
Note that added text is highlighted in bold character. When the only change consists of a deletion 
or the replacement of a single term, the deleted or replaced text is marked with a horizontal line 
(strikethrough), leaving the deleted/replaced text legible. 
Section(s) 
Description of Change (s) 
Brief Rationale 
Synopsis 
8.1.1 Inclusion 
Criteria 
8.1.2 Exclusion 
Criteria 
Standardized units as milli-international units per 
liter (mIU/L) 
mIU/mL 
mIU/L 
Correction. Updated to 
denote TSH units as 
milli-international units 
per liter (mIU/L). 
Synopsis 
8.1.1 Inclusion 
Criteria 
* Excluding individuals receiving PTH-like drugs 
within 12 weeks of the screening visit, who need 
only demonstrate a stable requirement for 
elemental calcium and active vitamin D above 
minimum thresholds for 5 weeks prior to the 
screening visit. 
Prior PTH treatment 
considered equivalent to 
requirements for high 
dose SoC 
supplementation. 
Synopsis 
8.1.2 Exclusion 
Criteria 
Note: Male subjects must use a condom, or his 
female partner of childbearing potential must use an 
effective form of contraception (as per CTFG 
definition) as described in Appendix 1, from the 
beginning of screening to the last trial visit  
Clarification regarding 
definition of effective 
contraception use in male 
participants with female 
partners of childbearing 
age. 
Synopsis 
 
Sequential testing Gatekeeping procedure will be 
applied to control the family wise type 1 error rate 
between the multiplicity for the primary and key 
secondary endpoint. Additional multiplicity control 
will be applied for the key secondary endpoints. 
Update multiplicity 
control method 
11.5 
Electrocardiogram 
Appendix 3. 
Schedule of Events 
Standard 12-lead ECG, which includes QT interval 
and Heart Rate, will be recorded when the subject 
is in a resting state, prior to blood collection if 
performed at the same visit.   
A historical ECG performed within the 6 months 
prior to Screening is acceptable if the report includes 
QT interval and Heart Rate. For the UK only: A 
study specific ECG reporting heart rate and QT 
interval must be performed at screening.  
As per ANSM request 
11.12 Subject 
Diary 
Paper diary might be used as back-up solution. 
Back-up solution 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 12 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
11.8 Dietary 
Calcium 
Questionnaire 
Update of hyperlink 
https://www.osteoporosis.foundation/educational-
hub/topic/calcium-calculator 
Correction 
11.10 Local 
Tolerability 
Assessment 
(See section 12.4.3.4 for ISR reporting) 
An ISR is defined as a reaction at the site of 
administration that is deemed abnormal from those 
ordinarily observed in SC injections (including pain 
intensity, pruritus, swelling, induration, ulceration, 
lipoatrophy, lipodystrophy, and infection).  
Asymptomatic erythema is not considered an ISR 
but can be captured as an AE of erythema.  In 
general, occasional mild pain or bleeding is 
expected with all daily SC injections, and should not 
be captured as AEs unless the frequency or severity 
is greater than expected or normally seen with SC 
injections. 
Clarification of rationale 
and intentions for 
reporting and AE 
determination of injection 
site reactions.   
12.1.1 Adverse 
Event 
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: 
An AE is defined as any untoward medical 
occurrence in a clinical investigation 
subject administered a pharmaceutical product 
and which does not necessarily have a causal 
relationship with the treatment. An Adverse 
event can therefore be any of the following: 
Clarification of 
definitions, in accordance 
with ICH E6 GCP and 
ICH E2A guidance 
 
12.1.2 Serious 
Adverse Events 
An SAE is any untoward medical occurrence at 
any dose that meets any of the following criteria:  
An AE should be classified as an SAE if any of the 
following criteria are met: 
Clarification of 
definitions, in accordance 
with ICH E6 GCP and 
ICH E2A guidance 
12.4.3.1 Abnormal 
Laboratory Values 
Abnormal serum calcium values will not be 
considered AEs unless associated with a sign or 
symptom* 
Results in a medical intervention (e.g., potassium 
supplementation for hypoccalmia hypokalemia or a 
change in concomitant therapy. 
* Abnormal serum calcium values - whether or not 
associated with titration of study drug, calcium, or 
active vitamin D doses - will not be considered AEs 
unless associated with a sign or symptom. Serum 
calcium is a pharmacodynamic marker of study 
drug therapy and thus used to guide titration of 
study drug, calcium, and active vitamin D doses 
(per Appendix 2). 
Clarification of rationale 
and intentions for AE 
reporting due to calcium 
abnormalities. These do 
not constitute AEs unless 
symptomatic – to remain 
consistent with protocol 
V1.0. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 13 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
12.4.3.3 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 hypercalcemia heart 
failure rather than abdominal pain, nausea, polyuria, 
dyspnea, orthopnea and high serum calcium 
extremity edema). 
Clarification 
12.4.3.4 Injection 
Site Reactions 
12.4.3.4 Injection Related Site Reactions  
Each sign or symptoms will be recorded as a 
separate AE on the AE eCRF. 
Local reaction ISRs that occur during or after 
study drug administration and that are judged to 
be related to study drug injection are deemed to 
be AEs. These AEs at the site of injection 
administration should be captured as a unified 
diagnosis rather than as individual signs and 
symptoms on the AE eCRF (e.g. adverse event 
reportingas an “injection site reaction” rather than 
capturing “injection site bleeding” or and “injection 
site induration” as separate adverse events). The 
diagnosis is at the discretion of the investigator. 
Signs, symptoms, and features of the injection 
site reaction should be recorded on a dedicated 
corresponding eCRF. 
Clarification of rationale 
and intentions for 
reporting and AE 
determination of injection 
site reactions.   
12.5 Safety 
Reporting 
Requirements 
12.5 Safety Reporting Requirements 
12.5 Serious adverse events (SAE) and suspected 
unexpected serious adverse reactions (SUSAR) 
Heading updated for 
reader clarity 
15.1 General 
Data from clinical assessments will be summarized 
using descriptive statistics.  Numerical variables will 
be summarized by mean, median, standard deviation 
(SD), standard error (SE), minimum, and maximum 
while categorical variables will be summarized by 
counts and proportions.   
The primary analysis will use the Cochran-Mantel-
Haenszel (CMH) test stratified by etiology of 
hypoparathyroidism (post-surgical vs other) to 
compare the proportion of subjects meeting the 
listed criteria of the primary endpoint (responders 
vs. non-responders) in the TransCon PTH vs. 
placebo groups. Sequential testing will be applied to 
control the family-wise type-1 error rate between the 
primary and key secondary endpoints. Additional 
multiplicity control will be applied for the key 
secondary endpoints. Details will be specified in the 
SAP. 
Redundant paragraph 
deleted 
15.3 Statistical 
Analysis 
• 
Analysis: CMH test stratified by etiology of 
hypoparathyroidism (post-surgical vs. other) is 
the primary analysis method and will be used to 
Update multiplicity 
control method 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 14 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
compare the proportion of subjects meeting the 
listed criteria of the primary endpoint 
(responders vs. non-responders) in the TransCon 
PTH vs. placebo groups  
Sensitivity analyses be performed, and the details 
will be provided in SAP.  
Gatekeeping testing procedure will be applied to 
control the family-wise type-1 error rate for the 
primary and key secondary endpoints. Details 
will be specified in the SAP. 
The model will include the change from baseline for 
the endpoint of interest as a response variable, 
treatment assignment and etiology of 
hypoparathyroidism as fixed factor and baseline 
value of the endpoint will be entered as a covariate, 
unless otherwise specified in the SAP. 
Appendix 1. 
Contraception 
Methods of contraception with a failure rate of more 
than 1% per year with consistent adherence are not 
permitted for female participants of childbearing 
potential. 
Clarification 
Appendix 3. 
Schedule of Events 
Footnote 5:  
COAs: PRO measures must be completed by the 
subject without assistance and prior to conducting 
any clinical assessments or supplement dose 
adjustments. On visit 6, 9 and 10/ET, additional 
 needs to be completed 
by the subject. The CGI-S should be completed by 
the investigator after all clinical assessments are 
completed. 
Change in 
 
collection format 
Appendix 3. 
Schedule of Events 
Footnote 17: 
A single Repeat TSH may be performed during the 
Screening Period if the baseline measurement is out 
of the allowable range.  
Clarification 
 
CCI
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 15 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
SUMMARY OF CHANGES - VERSION 1.0 TO VERSION 2.0  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
This amendment to the protocol is being issued to address comments and recommendation from 
the Food and Drug Administration (FDA) and provide clarification on the trial. Comments from 
the Federal Institute for Drugs and Medical Devices (BfArM), Medicine and Healthcare products 
Regulatory Agency (MHRA) and National Security Agency of Medicine and Health Products 
(ANSM) were also taken into consideration.  
Note that added text is highlighted in bold character. When the only change consists of a deletion 
or the replacement of a single term, the deleted or replaced text is marked with a horizontal line 
(strikethrough), leaving the deleted/replaced text legible. 
Section(s) 
Description of Change (s) 
Brief Rationale 
Title page 
Change title from 
 to 
 
for 
 
Added 
 MD as Medical 
Monitor 
, MD as Medical Monitor 
Implemented as an 
Administrative 
amendment  
Throughout the 
protocol and added in 
Section 4.0. List of 
Abbreviations and 
Definitions  
Change “rescue” to “PRN” (as needed) 
Clarification of 
abbreviation and 
definition  
Section 4.0. List of 
Abbreviations and 
Definitions 
Revised to capture current protocol status 
CMH: Cochran-Mantel-Haenszel 
DMC: Data Monitoring Committee 
ISC – Independent Safety Committee 
Administrative 
change 
Section 5.1.3. Current 
Standard Therapy for 
Hypoparathyriodism 
Table 1 deleted 
Administrative 
change 
Throughout the 
protocol  
Please refer to the current version of the TransCon 
PTH Investigator’s Brochure, for example, Section 4 
– Nonclinical Studies for a full summary discussion 
of the nonclinical data 
To include reference 
to the specific 
sections in the IB 
Section 5.3. Clinical 
Experience 
Figure 3 shows a dose-dependent increase in Free 
PTH, with a half-life of ~60 hours, resulting in an 
infusion-like profile in the lower half of the normal 
range at approximate steady-state (after the 10th 
daily dose), with a low peak-to-trough ratio of ~1.27 
to 1.55 over 24 hours.  Phase 1 data demonstrate 
that the effective half-life of Free PTH released 
from the prodrug is ~60 hours, with Free PTH 
approaching steady-state by Day 8 after dosing. 
This is further supported by sparse PK sampling 
performed in the Phase 2 trial (TransCon PTH 
TCP-201). The normal physiologic range for intact 
Introductory section 
was revised to capture 
the most updated 
information on 
TransCon PTH 
PPD
PPD
PPD
PPD
PPD

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 16 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
PTH(1-84) is 10-65 pg/mL; as PTH(1-34) and 
PTH(1-33) comprise about 40% of the molecular 
mass of the intact hormone, the calculated normal 
range is about 4-26 pg/mL. 
A total of 59 male and female subjects with HP of at 
least 26 weeks duration treated with a stable dose of 
≥ 0.25 μg BID active vitamin D (or ≥ 1.0 μg/day of 
alfacalcidol) and ≥400 mg BID calcium for at least 
12 weeks prior to Screening were randomized 
1:1:1:1 to TransCon PTH 15, 18 or 21 μg/day or to 
placebo for 4 weeks, followed by an ongoing 
open-label extension for an additional 12 months.  
Preliminary data up to 26 weeks of follow up are 
presently available. 
Analysis of 26 week data from the Phase 2 open 
label extension confirm these findings, with 91% 
of participants requiring no vitamin D and ≤500 
mg/d elemental calcium.  Participants required 
TransCon PTH doses between 6 and 39 μg/day. 
No TEAEs related to abnormal serum calcium 
have required urgent medical attention.  No 
TEAEs have resulted in discontinuation of study 
drug, withdrawal from the trial or death.  There 
have been no SUSARs as of February 2021.  A 
single participant opted to withdraw consent 
from the Phase 2 trial in open label Extension 
Period due to the requirements for contraception.  
Synopsis 
Section 6.2. 
Secondary Objectives 
Secondary Objectives: 
To assess the treatment effect of daily TransCon 
PTH on pharmacodynamic markers (including sCa 
and urine calcium [uCa]) 
To assess the treatment effect of daily TransCon 
PTH on serum phosphate (sP), serum calcium x 
phosphate product (CxP) (albumin adjusted sCa x sP 
product), and serum magnesium (sMg), urine 
phosphate (uP) and urine creatinine clearance) 
Secondary objectives 
have been adjusted to 
reflect the endpoints. 
Synopsis 
Section 7.2. Overall 
Trial Design and Plan  
Randomization will be stratified by etiology of 
hypoparathyroidism (post-surgical vs other). 
Synopsis 
Section 7.2. Overall 
Trial Design and Plan 
incl. Figure 7 
Section 10.1. Trial 
Duration 
Appendix 3. Schedule 
of Events 
Blinded Treatment Period (study drug stable with 
and SoC optimization): 26 weeks 
Titration Period: up to 10 weeks 
Individualized Dosing Period: up to 16 weeks 
Deleted Section 10.1.4. and 10.1.5. 
Clarification to no 
longer distinguish 
between titration and 
individualized dosing 
in the Blinded 
Treatment Period 
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 17 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
Section 7.2 Overall 
Trial Design and Plan 
Subsequently, at every clinic visit (every 2 weeks) 
up to and including Visit 6 in the Blinded Titration 
Period, subjects Study drug, calcium and active 
vitamin D will be titrated according to the 
Titration Algorithm (Appendix 2) on each 
occasion serum calcium is measured.    to their 
optimal TransCon PTH/placebo dose.  Starting at 
Visit 6, all subjects are expected to remain on a 
stable dose of TransCon PTH or corresponding 
placebo. 
Clarification 
Section 7.2. Overall 
Trial Design and Plan 
Figure 7 
Added a footnote 
**Target Week for visits between V16 and V26: 
See Appendix 3 Extension Period  
Clarification 
Synopsis 
8.1.1. Inclusion 
Criteria  
No.2  
Subjects with postsurgical chronic HP, or auto-
immune, genetic, or idiopathic HP for at least 
26 weeks. Diagnosis of HP is established based on a 
history of hypocalcemia in the setting of 
inappropriately low serum PTH levels. 
(Hypocalcemia is defined as a value below the 
reference range for normal at the performing 
laboratory.  Inappropriately low serum PTH 
levels are defined as at or below the median value 
of the reference range for normal at the 
performing laboratory while the concomitant 
serum calcium is low.  If specific lab results at the 
time of original diagnosis are not available, as 
historical diagnosis affirming these two 
components is adequate for inclusion) 
Clarification on 
hypocalcemia was 
added to Inclusion 
Criteria No.2  
No 4. 
Optimization of supplements prior to randomization 
to achieve the target serum levels of:  
• 
25(OH) vitamin D levels of 20-80 ng/mL 
(49-200 nmol/L) and 
• 
Magnesium level in the normal range, or just 
below the normal range i.e.: ≥1.3 mg/dL 
(0.53 mmol/L) and 
• 
Albumin-adjusted or ionized sCa level in the 
normal range, or *just below the normal 
range, i.e.: 
− 
Albumin-adjusted sCa 7.8-10.6 mg/dL (or 
1.95-2.64 mmol/L) 
− 
Ionized sCa 4.40-5.29 mg/dL (or 1.10-1.32 
mmol/L) 
*Just below the normal range implies the 
numerical range of 7.8-8.2 mg/dL (or 1.95-2.06 
mmol/L) for albumin-adjusted sCa and the 
Inclusion No.4 was 
updated to define 
“just below normal 
range” in bullet 3 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 18 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
numerical range of 4.40-4.636 mg/dL (or 1.10-
1.159 mmol/L) for ionized sCa. 
No. 13 
For France only: The subject is obligated to be 
affiliated with, or beneficiary of a social security 
system or assimilated. 
Updated to reflect a 
local French 
requirement  
Synopsis 
Section 8.1.2. 
Exclusion criteria 
No. 2 
Any disease that might affect calcium metabolism or 
calcium-phosphate homeostasis or PTH levels other 
than HP, such as active hyperthyroidism; Paget 
disease of bone; severe hypomagnesemia; 
type 1 diabetes mellitus or poorly controlled type 2 
diabetes mellitus (HbA1C >9%, documented 
HbA1C result drawn within 12 weeks prior to 
Screening is acceptable); severe and chronic liver, or 
renal disease; Cushing syndrome; multiple myeloma; 
active pancreatitis; malnutrition; rickets; recent 
prolonged immobility; active malignancy (other than 
low-risk well differentiated thyroid cancer or basal 
cell non-melanoma skin cancer); active 
hyperparathyroidism; parathyroid carcinoma within 
5 years prior to Screening; acromegaly; or multiple 
endocrine neoplasia types 1 and 2  
No. 11 
Pregnant or lactating women  
Note: Acceptable highly effective contraception (see 
Appendix 1) is required for sexually active women 
of childbearing potential during the trial and for 
2 weeks after the last dose of study drug, and 
pregnancy testing will be performed throughout the 
trial.  Sexually active women of childbearing 
potential who are unwilling to use acceptable highly 
effective contraception are excluded from the trial 
Clarification 
Section 9.3. Selection 
of Trial Doses 
Old text 
The 4-week blinded treatment period of the 
Phase 2 trial (TransCon PTH TCP-201) with 
fixed doing of TransCon PTH (15, 18, and 21 
µg/day) demonstrated that a dose of 18 µg/day 
was both effective and well-tolerated, with less 
hypercalcemia compared to a dose of 21 µg/day 
and without meaningful hypocalcemia. The Phase 
2 trial is ongoing as an open-label extension and 
overall, based on the preliminary data, the safety 
profile of 18 µg/day appears to be similar 
compared to 15 µg/day. During the open-label 
extension period the dose distribution across 
subjects has been approximately 6-30 µg/day, 
titrated to achieve normocalcemia. The 
Trial dose section was 
revised to capture the 
most updated 
information on 
TransCon PTH doses 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 19 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
preliminary data shows no safety concern on 
TransCon PTH doses <15µg/day or >21µg/day 
(doses below and above, respectively, the fixed 
doses of the 4-week blinded treatment period) 
with no meaningful difference in adverse events 
(AE) including the AEs related to hypo- or 
hypercalcemia.  Therefore, the starting dose for 
the Blinded Treatment Period this trial will be 18 
µg/day, followed by titration to 6-60 µg/day to 
ideally achieve normocalcemia and independence 
from conventional therapy.  
New text 
The 4-week blinded treatment period of the Phase 
2 trial - with fixed dosing of TransCon PTH 15, 
18, and 21 µg/day - demonstrated that a dose of 
18 µg/day was both effective and well-tolerated, 
with less hypercalcemia compared to a dose of 21 
µg/day and without meaningful hypocalcemia. 
Preliminary data from the open label extension of 
the Phase 2 trial as of February 2021 
demonstrates comparable safety profiles at doses 
of both 15 and 18 µg/day. The dose distribution 
during the open label extension has been 6-39 
µg/day, titrated to achieve normocalcemia. Phase 
2 data demonstrates no meaningful difference in 
AEs, including those related to hypo- or 
hypercalcemia, on TransCon PTH doses 
<15µg/day or >21µg/day. 5-10% of participants 
are anticipated to require doses >30µg/d to 
achieve normocalcemia in the present trial. 
Therefore, the starting dose for the Blinded 
Treatment Period will be 18 µg/day, followed by 
titration to 6-60 µg/day to achieve normocalcemia 
and independence from conventional therapy.  
Synopsis 
Section 9.4.2. 
Treatment 
Assignment During 
Open-Label 
Extension Period 
At Visit 10 (Week 26), subjects will be assigned to 
open-label treatment as follows: 
Administrative 
change 
Section 9.5.2.1. SoC 
Dose Adjustments 
during Blinded 
Treatment Period 
Subsequently, active vitamin D and/or calcium doses 
should be titrated as per Appendix 2. The target 
vitamin D range during treatment phases of this 
trial is 30-80 ng/mL 
Clarification of 
maintenance range 
Section 9.5.2.2. Study 
Drug Dose 
Adjustments During 
Added 
Serum calcium results from local laboratory 
analysis will be used to guide titration of study 
Administrative 
change 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 20 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
Blinded Treatment 
Period 
drug.  Central laboratory results will be definitive 
for data analysis. 
Section 9.5.3.1. SoC 
Dose Adjustments 
during Extension 
Period 
Added 
Start the new SoC regimen: 
• 
On the day of Visit 10 for those subjects who 
are still taking active vitamin D at the time of 
Visit 10 
• 
On the day after Visit 10 for those subjects 
who are off active vitamin D and taking study 
drug ≥30 µg/day at Visit 10 
Clarification of start 
of the new SoC 
regimen at Visit 10 
Section 9.6. Study 
Drug Dose Changes, 
Interruptions or 
Stopping 
9.6.1. Dose changes and Possible 
StoppingTreatment Interruptions 
A discussion between tThe investigator and medical 
monitor will occur to determine dose changes and/or 
study drug holding/stopping for the following 
situations 
Footnote 2 
Thresholds for albumin-corrected serum calcium: 
<7.0 mg/dL (><1.75 mmol/L), or ionized calcium: 
<0.95 mmol/L 
Title adjusted to 
reflect the content in 
the section better  
 
Deleted medical 
monitor to make it 
clear that the 
investigator is 
responsible for all 
trial-related medical 
decisions 
 
Corrected typo in 
footnote 2 
Section 9.6.2. 
Required Stopping 
Pregnancy, unless the benefit exceeds the perceived 
risks 
Ascendis medical monitors will immediately 
notify the Data Monitoring Committee (DMC) 
and Ascendis pharmacovigilance of any such 
events for evaluation of potential broader safety 
concerns 
Updated to clarify that 
pregnancy must result 
in permanent 
discontinuation of 
study drug 
Section 9.9.1. 
Required HP 
Therapies 
Subjects may also be on cholecalciferol (vitamin D3) 
and magnesium supplements as part of their HP 
treatment or to achieve the recommended daily 
allowance (RDA), as needed to maintain target 
ranges of each. The 25 (OH) vitamin D target 
range is 30-80 ng/mL during trial 
participation.treatment phases of the trial. long as 
doses are expected to remain stable throughout the 
trial.   
Subjects should receive calcium supplementation 
in the form of calcium citrate in case of 
concomitant use of proton pump inhibitors or 
anti-acid therapies. 
Clarification of 
maintenance range 
Section 9.9.2. 
Prohibited Therapies 
The following therapies are prohibited throughout 
the trial: 
• 
PTH therapies other than TransCon PTH 
Clarification to guide 
the investigator 
without a requirement 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 21 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
• 
Thiazide or loop diuretics, unless otherwise 
agreed with the Medical Monitor  
• 
Phosphate binders (other than calcium 
supplements) 
• 
Digoxin, lithium, methotrexate 
• 
Systemic corticosteroids (other than as 
replacement therapy).  Short course use of 
steroids (≤2 weeks/year) ≤40mg/day is 
permitted 
• 
Bisphosphonates  
• 
Denosumab 
• 
Biotin >30 µg/day 
If the administration of a prohibited concomitant 
medication becomes necessary any time after 
randomization, contact the Medical Monitor. 
to discuss with the 
medical monitor 
 
Section 10.1. Trial 
Duration  
Section 11.9.7. Phone 
Exit Interviews 
Appendix 3. Schedule 
of Events 
Deleted Section 10.1.4. and 10.1.5.  
and moved/added 
In selected English speaking countries/sites, 
approximately 2 weeks prior to the final Blinded 
Treatment Period visit (Visit 10), subjects will be 
contacted to set up a one-hour phone interview to 
occur within 2 weeks after the final Blinded 
Treatment Period visit (Visit 10) to discuss their 
experience in the trial. In case of subject 
discontinuation before or at Visit 10, the phone 
interview will be scheduled to be completed within 2 
weeks after the Early Termination Visit. The phone 
interview will be conducted by an external vendor 
(see Section 11.9.7). 
Clarification that 
phone interview will 
only take place in 
English speaking 
countries/sites  
Section 11.5. 
Electrocardiogram 
Appendix 3. Schedule 
of Events  
For the UK only: A study specific ECG reporting 
heart rate and QT interval must be performed at 
screening 
Clarification that UK 
only accept ECGs 
performed at 
screening not 
historical 
Section 11.15.3. 
Contraception 
Irrespectively, acceptable highly effective 
contraception during the trial and for 2 weeks after 
the last dose of study drug is required for women of 
childbearing potential if sexually active, and 
pregnancy testing for women of childbearing 
potential will be performed throughout the trial.  
See Appendix 1 for further guidance on acceptable 
highly effective contraception. 
Updated to align with 
Exclusion criteria 11  
Section 12. Adverse 
Event Assessment 
and Reporting  
Section 12 was revised to implement new standard 
text  
Minor corrections were done in Section 12.3.1.2. 
regarding “Outcome Assessment” and its 
classifications. 
Added section 12.1.5. 
The Adverse Event 
Assessment and 
Reporting Section 
incl. outcome 
assessment were 
updated to new 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 22 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
Special Situation  
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 AE 
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.  
Added section 12.4.3.9.  
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. 
In this study, the TransCon PTH delivery system 
consists of a multi-use cartridge integrated into a 
device to constitute a pre-filled injection pen 
which is considered a medical device.  The 
investigator must report all medical device 
complaints to the Sponsor.  The investigator 
should document as much information as possible 
including the product batch number and forward 
the information to the Sponsor immediately 
(refer to the pharmacy manual for further 
details).  If the medical device results in an 
adverse event to the study patient, the event must 
be reported on the AE eCRF and submitted 
through the EDC system.  If the event is serious, 
the AE eCRF must be completed immediately 
(i.e., no more than 24 hours after learning of the 
event), as outlined in Section 12.5.2. 
standard text for 
alignment across 
Ascendis Pharma 
clinical trial  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 23 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
Section 13. Safety 
Monitoring 
Replaced with new standard text 
Safety monitoring was 
updated to new 
standard text for 
alignment across 
Ascendis Pharma 
clinical trial 
Synopsis 
Section 15.1. 
Statistics – General 
Section 15.3. 
Statistical Analysis 
The primary analysis will use the Fisher’s 
exactCMH (Cochran-Mantel-Haenszel) test 
stratified by etiology of hypoparathyroidism 
(post-surgical vs other) to compare the proportion 
of subjects meeting the listed criteria of the primary 
endpoint (responders vs. non-responders) in the 
TransCon PTH vs. placebo groups. 
Analysis: Fisher’s exactCMH test stratified by 
etiology of hypoparathyroidism is the primary 
analysis method and will be used to compare the 
proportion of subjects meeting the listed criteria of 
the primary endpoint (responders vs. non-
responders) in the TransCon PTH vs. placebo groups  
Categorical endpoints during Blinded 
Treatment Period will be analyzed using Fisher’s 
exactCMH test stratified by etiology of 
hypoparathyroidism. 
Updated statistical 
analysis method 
Implemented as an 
administrative 
amendment 
Synopsis 
Section 15.2.1.1. 
Primary Efficacy 
Endpoint 
Added text  
*Daily calcium and active vitamin D doses are 
calculated as the sum of standing and PRN doses 
on a calendar day. Independence from 
therapeutic calcium is defined as daily elemental 
calcium dose ≤600 mg on the calendar day of and 
day prior to the week 26 visit. Independence from 
active vitamin D is defined as receiving no active 
vitamin D in the same 2-day period.  
Clarification of the 
primary endpoint 
Synopsis 
Section 15.2.1.2.1. 
Key Secondary 
Efficacy Endpoints 
Key Secondary Efficacy Endpoints 
At 26 weeks of treatment, the proportion of subjects 
with:  
Albumin-adjusted sCa within the normal range (8.3-
10.6mg/dL); and  
Independence from active vitamin D and  
Independence from therapeutic doses of calcium 
(i.e., taking calcium supplements ≤600 mg/day) and 
Normal 24-hour urine calcium excretion (≤250 
mg/24h for females, ≤300 mg/24h for males) or ≥ 
50% reduction from baseline 
sP levels at 26 weeks 
HPES domain scores at 26 weeks 
x 
Change from baseline in HPES  
x 
Change from baseline in 36-Item Short Form 
Survey (SF-36)   
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 24 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
Synopsis 
Section 15.2.1.2.2. 
Other Secondary 
Efficacy Endpoints 
The primary and key secondary efficacy endpoints 
will be measured at predefined timepoints during the 
Extension period.  
The following endpoints will be evaluated after 26 
weeks at predefined timepoints during the of 
Blinded Treatment and at predefined timepoints 
during the Extension Period:  
Calcium and active vitamin D doses every 26 weeks 
Daily “pill burden” of active vitamin D and calcium 
(as oral tablets, powder, liquid solutions, liquid 
suspensions, or transdermal patches) assessed every 
26 weeks 
Normal 24-hour uCa excretion (≤250 mg/24h for 
females, ≤300 mg/24h for males), or ≥50% reduction 
from baseline at 52, 104, 156 and 182 weeks 
sP every 26 weeks 
Albumin-adjusted sCa x sP product, including 
proportion of subjects with albumin-adjusted sCa x 
sP product ≤55 mg2/dL2, ≤52 mg2/dL2, and ≤44 
mg2/dL2 every 26 weeks 
Albumin-adjusted sCa every 26 weeks 
24-hour uP at 26, 52, 104, 156 and 182 weeks 
BMD and TBS by DXA at52, 104 and 182 weeks  
Bone turnover markers (serum P1NP and CTx) at 
52, 104 and 182 weeks 
sMg every 26 weeks 
SF-36 
EQ-5D 
CGI-S 
Synopsis 
Section 15.2.2. Safety 
Endpoints 
Safety Endpoints 
The following safety endpoints will be assessed 
during the Blinded Treatment and Extension 
Periods:  
Incidence of AEs, AESI and SAEs 
24- hour uCa excretion 
Serum chemistry and hematology, and 
24-hour urine chemistry (including urine calcium 
and urine creatinine clearance) at prespecified 
timepoints including Week 26 
Clinical events of hypo- or hypercalcemia 
(emergency/urgent care visits and hospitalizations)  
Injection site tolerability (based on AEs) 
Evaluation of anti-PTH, anti-TransCon PTH and 
anti-PEG antibody responses 
Vital signs 
Updated to reflect the 
change in safety 
endpoints  
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 25 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
Section 15.3. 
Statistical Analysis 
Pharmacokinetic Analysis  
The PK parameters and their statistical evaluation 
will be included in the Clinical Study Report. PK 
data will be used to describe plasma concentration at 
steady-state. Potential impact of any anti-PTH, anti-
TransCon PTH and anti-PEG antibodies detected 
will be included in the evaluation. The Free PTH 
results will additionally be added to the 
population PK analysis. 
Clarification for Free 
PTH results 
Section 16.6. Trial 
Termination or 
Completion 
The Sponsor must also terminate the trial 
prematurely for any of the following reasons: 
Unjustifiable risk and/or toxicity in risk-benefit 
analysis (occurrence of new adverse events 
unknown to date in respect of their nature, 
severity, duration or frequency in relation to the 
current established safety profile of the study 
drug) 
New scientific evidence becomes available during 
the study that could affect the subject’s safety 
Premature termination 
criteria has been 
specified 
Section 17. Ethical 
and Legal 
Considerations 
Previous Section 17.1. Data Safety Monitoring 
Committee/Independent Safety Committee updated 
Independent oversight of this trial may be provided 
by a data safety monitoring committee/independent 
safety committee, if deemed appropriate.   
17.1. Data Monitoring Committee 
Independent oversight of this trial will be 
provided by a DMC.  Its duty is to regularly 
review the progress of the trial and assess the 
accumulating safety data.  After each meeting it 
will advise the Sponsor on the continuing safety 
of current subjects in the trial and on the 
continuing validity and scientific merit of the 
trial.  All decisions about the conduct of the trial 
will rest solely with the Sponsor.  The DMC will 
consist of members, all with experience in clinical 
studies, and who will operate based on the 
Charter agreed upon.  The Charter will define 
data content, format, and review frequency.  The 
Sponsor may attend the DMC meetings. 
Clarification 
Appendix 1. 
Contraception 
Due to the lack of genotoxic or teratogenic or 
reproductive toxicity with any component of 
TransCon PTH, acceptable effective contraception 
are methods that result in a failure rate of more than 
1% per year when used consistently and correctly 
are permitted in this trial.  Following the Clinical 
Trial Facilitation Group recommendations 
(CTFG 2014), such methods include: 
Updated to align 
global requirement for 
highly effective forms 
of contraception 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 26 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
• 
Progestogen-only oral hormonal contraception, 
where inhibition of ovulation is not the primary 
mode of action 
• 
Male or female condom with or without 
spermicide 
• 
Cap, diaphragm or sponge with spermicide  
Subjects of child-bearing potential can also use h 
Highly effective contraception are methods that can 
achieve a failure rate of less than 1% per year when 
used consistently and correctly, following the CTFG 
2014 recommendations, such methods include:   
• 
Combined (estrogen and progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation: 
− 
Oral 
− 
Intravaginal 
− 
Transdermal 
• 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation: 
− 
Oral 
− 
Injectable 
− 
Implantable 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion/ligation 
• 
Vasectomized partner 
• 
Sexual abstinence, defined as refraining from 
heterosexual intercourse during the entire period 
of risk associated with the study treatments 
• 
Postmenopausal.  A postmenopausal state is 
defined as no menses for 12 months without an 
alternative medical cause  
Methods of contraception with a failure rate of 
more than 1% per year with consistent adherence 
are not permitted. Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM) are not acceptable 
methods of contraception. Female condoms and 
male condoms should not be used together.  
Appendix 2. Titration 
Algorithm 
4If albumin-adjusted sCa ≥12.0 mg/dL (3.00 
mmol/L) or ionized calcium ≥1.50 mmol/L, hold 
study drug for approximately 2-3 days. Remember to 
resume study drug therapy afterwards. Also reduce 
study drug, active vitamin D, or calcium as per 
algorithm. 
Clarification of sCa 
level and ULV 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 27 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Section(s) 
Description of Change (s) 
Brief Rationale 
Notes: 
At all times during the trial, subjects with symptoms 
of hypocalcemia may take rescue PRN doses of 
calcium (preferred) and/or active vitamin D, and/or 
do an ULV visit to measure sCa. An ULV must be 
performed within 7 days of a PRN supplement 
dose.  
At all times during the trial, subjects with symptoms 
of hypercalcemia may hold doses of study drug for 1 
day and/or do an ULV to measure sCa. An ULV 
must be performed within 7 days of a held dose.  
Appendix 3. Footnote 
17  
Multiple local laboratory assessments over the 
approximate 4 weeks of the Screening Period are 
expected in order to optimize both the albumin-
adjusted or ionized sCa to the normal range, as well 
as normalize the sMg and vitamin D level. A single 
repeat TSH may be performed during the 
Screening Period if the baseline measurement is 
out of the allowable range. 
Clarification  
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 28 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
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 Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 (R2) and regional 
regulations 
• Regional subject data protection laws and regulations 
• Other applicable regional and local regulations 
• US Federal Regulations, as applicable 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 29 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
1. 
APPROVAL SIGNATURES  
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 Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 (R2) and regional 
regulations 
x Regional subject 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: 
PaTHway TRIAL: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group Trial, with an Open-Label Extension, Investigating the Safety, Tolerability and 
Efficacy of TransCon PTH Administered Subcutaneously Daily in Adults with 
Hypoparathyroidism  
 
 
 
 
 
See Appended Electronic Signature 
 
 
 
, MD 
 
Ascendis Pharma, Inc. 
 
Date 
PPD
PPD

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 30 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
2. 
SYNOPSIS  
NAME OF 
SPONSOR/COMPANY 
Ascendis Pharma Bone Diseases A/S 
PRODUCT 
NUMBER/NAME 
TransCon PTH (Palopegteriparatide) 
PROTOCOL NUMBER 
TCP-304 
IND NUMBER 
133469 
EUDRACT NUMBER 
2020-003380-26 
DEVELOPMENT 
PHASE 
3 
PROTOCOL TITLE 
PaTHway TRIAL: A Phase 3, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Parallel Group Trial, with an Open-Label 
Extension, Investigating the Safety, Tolerability and Efficacy of 
TransCon PTH Administered Subcutaneously Daily in Adult Subjects 
with Hypoparathyroidism 
INDICATION 
Hypoparathyroidism (HP) in Adults 
OBJECTIVES 
Primary: 
To assess the treatment effect of daily TransCon PTH on serum calcium 
(sCa) levels, and therapeutic doses of active vitamin D (i.e., calcitriol or 
alfacalcidol) and calcium at 26 weeks of treatment.  
Secondary: 
x 
To assess the safety and tolerability of daily TransCon PTH 
x 
To assess the treatment effect of daily TransCon PTH on 
hypoparathyroidism patient experience scale (HPES) domain scores  
x 
To assess the treatment effect of daily TransCon PTH on 
pharmacodynamic markers (including sCa) and active vitamin D and 
calcium doses  
x 
To assess the treatment effect of daily TransCon PTH on serum 
phosphate (sP), serum calcium x phosphate product (CxP) (albumin-
adjusted sCa x sP product) and serum magnesium (sMg) 
x 
To assess anti-parathyroid hormone (PTH), anti-TransCon PTH and 
anti-polyethylene glycol (PEG) antibody responses 
x 
To assess the treatment effect during Extension Period 
x 
To assess the treatment effect of daily TransCon PTH on 
 
Bone mineral density (BMD) and trabecular bone score 
(TBS) by Dual-energy X-ray absorptiometry (DXA)  
 
Bone turnover markers (serum procollagen type 1 amino-
terminal propeptide [P1NP] and c-telopeptide of type 1 
collagen [CTx]) 
To assess the impact of treatment on patient-reported health related 
quality of life (QOL) and a clinician-reported outcome (ClinRO) 
assessment 
Exploratory: 
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 31 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
PLANNED TRIAL 
SITES  
Up to approximately 40 sites worldwide 
PLANNED NUMBER OF 
SUBJECTS 
Approximately 76 
TRIAL POPULATION 
Male and female adults with postsurgical chronic HP or autoimmune, 
genetic, or idiopathic HP, for at least 26 weeks; treated with either 
calcitriol ≥0.5 μg/day or alfacalcidol ≥1.0 μg/day and elemental calcium 
≥800 mg/day for at least 12 weeks prior to Screening; and have a 24-
hour urine calcium (uCa) excretion ≥125 mg/24h. 
Note: The thresholds for calcitriol, alfacalcidol, and calcium are 
provided above in total daily doses. Acknowledging that the total 
daily doses may be taken in divided doses throughout the day, the 
corresponding thresholds would be calcitriol ≥0.25 μg twice daily 
[BID]; alfacalcidol ≥0.50 μg BID; calcium ≥400 mg BID. 
ELIGIBILITY 
CRITERIA 
Inclusion Criteria: 
1. Males and females, ≥18 years of age 
2. Subjects with postsurgical chronic HP, or auto-immune, genetic, or 
idiopathic HP for at least 26 weeks. Diagnosis of HP is established 
based on historic hypocalcemia in the setting of inappropriately low 
serum PTH levels (Hypocalcemia is defined as a value below the 
reference range for normal at the performing laboratory.  
Inappropriately low serum PTH levels are defined as at or below the 
median value of the reference range for normal at the performing 
laboratory while the concomitant serum calcium is low.  If specific 
lab results at the time of original diagnosis are not available, as 
historical diagnosis affirming these two components is adequate for 
inclusion) 
3. Requirement for doses of standard of care (SoC) (e.g., calcitriol, 
alfacalcidol, calcium supplements) at or above a minimum threshold:  
• 
For countries other than Japan: requirement for a dose of calcitriol 
≥0.5 μg/day, or alfacalcidol ≥1.0 μg/day and (elemental) calcium 
≥800 mg/day (e.g., calcium citrate, calcium carbonate etc.) for at 
least 12 weeks prior to Screening*. In addition, the dose of calcitriol, 
or alfacalcidol, or calcium should be stable** for at least 5 weeks 
prior to Screening 
• 
For Japan: requirement for a dose of calcitriol ≥1.0 µg/day, or 
alfacalcidol ≥2.0 µg/day for at least 12 weeks prior to Screening*.  
In addition, the dose of calcitriol or alfacalcidol should be stable** 
for at least 5 weeks prior to Screening.  In Japan only (due to local 
practice and dietary patterns), there is no requirement to exceed a 
minimum dose of calcium supplements 
* Excluding individuals receiving PTH-like drugs within 12 weeks of the 
screening visit, who need only demonstrate a stable requirement for 
elemental calcium and active vitamin D above minimum thresholds for 5 
weeks prior to the screening visit. 
** Does not preclude occasional (≤2/week) PRN doses of calcium 
and/or active vitamin D for symptomatic hypocalcemia 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 32 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
4. Optimization of supplements prior to randomization to achieve the 
target serum levels of:  
• 
25(OH) vitamin D levels of 20-80 ng/mL (49-200 nmol/L) and 
• 
Magnesium level in the normal range, or just below the normal 
range i.e.: ≥1.3 mg/dL (0.53 mmol/L) and 
• 
Albumin-adjusted or ionized sCa level in the normal range, 
or*just below the normal range, i.e.: 
− 
Albumin-adjusted sCa 7.8-10.6 mg/dL (or 1.95-2.64 
mmol/L) 
− 
Ionized sCa 4.40-5.29 mg/dL (or 1.10-1.32 mmol/L) 
* Just below the normal range implies the numerical range of 
7.8-8.2 mg/dL (or 1.95-2.06 mmol/L) for albumin-adjusted sCa and the 
numerical range of 4.40-4.636 mg/dL (or 1.10-1.159 mmol/L) for ionized 
sCa 
5. The subject demonstrates a 24-hour uCa excretion of ≥125 mg/24h 
(on a sample collected within 52 weeks prior to Screening or during 
the Screening Period)  
Note: Although 24-hour urine samples prior to Screening may 
be done on or off thiazide therapy, thiazide therapy is prohibited 
during the trial; and the 24-hour urine collection scheduled 
prior to Visit 1 must be done while off thiazides for at least 4 
weeks prior to collection   
6. Body mass index (BMI) 17- 40 kg/m2 at Screening  
7. If ≤25 years of age, radiological evidence of epiphyseal closure 
based on X-ray of non-dominant wrist and hand 
8. Thyroid-stimulating hormone (TSH) within normal laboratory limits 
within the 6 weeks prior to Visit 1; if on suppressive therapy for a 
history of thyroid cancer, TSH level must be ≥0.2 mIU/L 
9. If treated with thyroid hormone replacement therapy, the dose must 
have been stable for at least 5 weeks prior to Screening 
10. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 
during Screening 
11. Able to perform daily subcutaneous (SC) self-injections of study 
drug (or have a designee to perform injections) via a pre-filled 
injection pen 
12. Able and willing to provide written and signed Informed Consent 
Form (ICF) in accordance with Good Clinical Practice (GCP) 
13. For France only: The subject is obligated to be affiliated with, or 
beneficiary of a social security system or assimilated. 
Exclusion Criteria: 
1. Impaired responsiveness to PTH (pseudohypoparathyroidism) which 
is characterized as PTH-resistance, with elevated PTH levels in the 
setting of hypocalcemia 
2. Any disease that might affect calcium metabolism or calcium-
phosphate homeostasis or PTH levels other than HP, such as active 
hyperthyroidism; Paget disease of bone; severe hypomagnesemia; 
type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus 
(HbA1C >9%, documented HbA1C result drawn within 12 weeks 
prior to Screening is acceptable); severe and chronic liver, or renal 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 33 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
disease; Cushing syndrome; multiple myeloma; active pancreatitis; 
malnutrition; rickets; recent prolonged immobility; active 
malignancy (other than low-risk well differentiated thyroid cancer or 
non-melanoma skin cancer); active hyperparathyroidism; 
parathyroid carcinoma within 5 years prior to Screening; 
acromegaly; or multiple endocrine neoplasia types 1 and 2  
3. High risk thyroid cancer within 2 years, requiring suppression of 
TSH <0.2 mIU/L 
4. Use of loop diuretics, phosphate binders (other than calcium 
supplements), digoxin, lithium, methotrexate, biotin >30 µg/day, or 
systemic corticosteroids (other than as replacement therapy) 
5. Use of thiazide diuretic within 4 weeks prior to the 24-hour urine 
collection scheduled to occur within 1 week prior to Visit 1 
6. Use of PTH-like drugs (whether commercially available or through 
participation in an investigational trial), including PTH(1-84), 
PTH(1-34), or other N-terminal fragments or analogs of PTH or 
PTH-related protein, within 4 weeks prior to Screening 
7. Use of other drugs known to influence calcium and bone 
metabolism, such as calcitonin, fluoride tablets (>0.5 mg/day), 
strontium, or cinacalcet hydrochloride, within 12 weeks prior to 
Screening 
8. Use of osteoporosis therapies known to influence calcium and bone 
metabolism, i.e., bisphosphonate (oral or intravenous [IV]), 
denosumab, raloxifene, or romosozumab therapies within 2 years 
prior to Screening 
9. Non-hypocalcemic seizure disorder with a history of a seizure within 
26 weeks prior to Screening 
Note: History of seizures that occur in the setting of 
hypocalcemia is not exclusionary 
10. Increased risk for osteosarcoma, such as those with Paget’s disease 
of bone or unexplained elevations of alkaline phosphatase, 
hereditary disorders predisposing to osteosarcoma, or with a prior 
history of substantial external beam or implant radiation therapy 
involving the skeleton 
11. Pregnant or lactating women  
Note: Acceptable highly effective contraception (see Appendix 1) 
is required for sexually active women of childbearing potential 
during the trial and for 2 weeks after the last dose of study drug, 
and pregnancy testing will be performed throughout the trial. 
Sexually active women of childbearing potential who are 
unwilling to use acceptable highly effective contraception are 
excluded from the trial 
12. Male who has a female partner who intends to become pregnant or is 
of childbearing potential and is unwilling to use adequate 
contraceptive methods during the trial 
Note: Male subjects must use a condom, or his female partner of 
childbearing potential must use an effective form of 
contraception (as per CTFG definition), from the beginning of 
screening to the last trial visit  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 34 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
13. Diagnosed drug or alcohol dependence within 3 years prior to 
Screening 
14. Disease processes that adversely affect gastrointestinal absorption, 
including but not limited to short bowel syndrome, significant small 
bowel resection, gastric bypass, tropical sprue, active celiac disease, 
active ulcerative colitis, active Crohn’s disease, gastroparesis and 
autoimmune regulator (AIRE) gene mutations with malabsorption  
15. Chronic or severe cardiac disease within 26 weeks prior to Screening 
including but not limited to congestive heart failure, myocardial 
infarction, severe or uncontrolled arrhythmias, bradycardia (resting 
heart rate <48 beats/minute, unless chronic and asymptomatic), 
symptomatic hypotension or systolic blood pressure (BP) <80 mm 
Hg or diastolic <40 mm Hg, or poorly controlled hypertension 
(systolic BP >165 mm Hg or diastolic >95 mm Hg). In the absence 
of a prior history of hypertension, an isolated BP >165/95 in the 
setting of white coat hypertension/anxiety may not be exclusionary 
and a measurement can be repeated prior to randomization 
16. Cerebrovascular accident within 5 years prior to Screening 
17. Within 26 weeks prior to Screening: acute colic due to 
nephrolithiasis, or acute gout. Subjects with asymptomatic renal 
stones are permitted 
18. Participation in any other interventional trial in which receipt of 
investigational drug or device occurred within 8 weeks or within 
5.5 times the half-life of the investigational drug (whichever comes 
first) prior to Screening 
19. Any disease or condition that, in the opinion of the investigator, may 
require treatment or make the subject unlikely to fully complete the 
trial, or any condition that presents undue risk from the 
investigational product or procedures, including treated malignancies 
that are likely to recur within the approximate 3.5-year duration of 
the trial 
20. Known allergy or sensitivity to PTH or any of the excipients 
[metacresol, mannitol, succinic acid, NaOH/(HCl)] 
21. Likely to be non-compliant with respect to trial conduct 
22. Any other reason that in the opinion of the investigator would 
prevent the subject from completing participation or following the 
trial schedule 
TRIAL DESIGN 
This is a Phase 3, multicenter, randomized, double-blind, placebo-
controlled, parallel group, 26-week trial, with an open-label extension of 
3 years of daily TransCon PTH in male and female adults with either 
postsurgical chronic HP or autoimmune, genetic, or idiopathic HP for at 
least 26 weeks, treated with calcitriol (an active vitamin D) ≥0.5 μg/day, 
or alfacalcidol (an active vitamin D) ≥1.0 μg/day and elemental calcium 
≥800 mg/day for at least 12 weeks prior to Screening. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 35 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Screening Period (Week -6 to Week -2): 
The Screening Period consists of determining eligibility (including 
determining on a historical test within 52 weeks prior to Screening or a 
test during Screening that 24-hour uCa excretion is ≥125 mg/24 hr), and 
optimizing vitamin D, calcium and magnesium levels, and doses of SoC 
(active vitamin D and calcium) prior to study drug (TransCon PTH or 
placebo) dosing to achieve the following target serum levels:  
• 
25(OH) vitamin D: 20-80 ng/mL (49-200 nmol/L) 
• 
Magnesium: within the normal range, or just below the normal range 
i.e.: ≥1.3 mg/dL (0.53 mmol/L) 
• 
Albumin-adjusted or ionized sCa: within the normal range, or just 
below the normal range, i.e.: 
− 
Albumin-adjusted sCa 7.8-10.6 mg/dL (or 1.95-2.64 mmol/L) 
− 
Ionized sCa 4.40-5.29 mg/dL (or 1.10-1.32 mmol/L)  
Therapeutic doses of calcitriol, alfacalcidol, calcium, magnesium and 
Vitamin D3 are adjusted only after initial Screening laboratory results 
are received. Follow-up laboratory assessments of the above values, with 
the exception of 25(OH) vitamin D levels, are performed approximately 
3 days after every dose adjustment during the Screening Period; the 
25(OH) vitamin D level may be rechecked ≥7 days from any dose 
change. If required, additional dose adjustments, with follow-up 
laboratory assessments approximately 3 days later may be performed 
throughout the Screening Period. For additional guidance see 
Section 9.5.1. 
When laboratory results are within the above optimization ranges and all 
other entry criteria are met, the subject is eligible to move to the Blinded 
Treatment Period and be randomized following confirmation by the 
Medical Monitor or designee. Following randomization, it is 
recommended to start the treatment period (Visit 1) within 2 weeks from 
the time of randomization. 
The Screening Period may be extended with Medical Monitor approval 
for subjects who fail to achieve values within the target laboratory 
ranges within the Screening window. 
Blinded Treatment Period (Visit 1 - 10; Week 0-26): 
Subjects will be randomized 3:1 to receive either TransCon PTH or 
placebo: 
• 
TransCon PTH 18 μg/day*, co-administered with SoC 
• 
Placebo for TransCon PTH (excipient solution) 18 μg/day, 
co-administered with SoC 
* Dose of TransCon PTH refers to dose of PTH(1-34) administered 
Randomization will be stratified by etiology of hypoparathyroidism 
(post-surgical vs other). 
All subjects will start with study drug 18 µg/day and will be individually 
and progressively titrated to an optimal dose in dose increments of 
3 μg/day. 
Blinded Treatment Period Visit 1-10 (Weeks 0-26): 
Visit 1: Start study drug 18 µg/day and decrease active vitamin D dose 
by 33-50% (e.g., skip 2nd dose of the day if taking BID, skip final dose 
of the day if taking three times daily (TID), or reduce once daily dose of 
alfacalcidol ≥1.0 µg by 50% (≥0.5 µg). 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 36 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Subsequently, subjects will attend frequent clinic visits and laboratory 
visits (LV) (LV1, LV2, LV3) to measure sCa levels. Assuming albumin-
adjusted or ionized sCa remains ≥ the lower limit of normal (LLN) and ≤ 
the upper limit of normal (ULN), SoC doses will be progressively 
withdrawn. 
Complete guidance on SoC titration during the Blinded Treatment 
Period is provided in Section 9.5.2.1 and Appendix 2.  
Because this trial is assessing the potential for TransCon PTH to be a 
parathyroid hormone replacement therapy, a goal is for subjects to 
achieve independence from standing doses of calcitriol, alfacalcidol, and 
calcium supplements.  
Note: In case needed to meet recommended dietary intake of 
calcium, it is permitted to take calcium supplements ≤600 mg/day as 
a nutritional supplement for the sake of reaching the recommended 
dietary intake. The calcium dose of ≤600 mg/day is considered as 
“supplemental” to meeting recommended daily intake for general 
health, as opposed to a “therapeutic” dose to treat 
hypoparathyroidism. The progressive cessation of calcitriol, 
alfacalcidol, and calcium should occur while increasing the dose of 
TransCon PTH to achieve normocalcemia. 
Meanwhile, study drug doses can be increased by 3 µg/day as long as 
≥7 days have elapsed since a prior dose adjustment in study drug. 
Gradual increases in study drug doses may facilitate gradual reduction 
and eventual cessation of SoC. Alternatively, study drug doses can be 
decreased by 3 µg/day for serum calcium levels that continue to be high 
even after all SoC has been withdrawn.  The study drug dose range for 
this trial is 6-60 µg/day, and will be supported by 3 pen presentations 
delivering discrete doses of 6, 9, and 12 µg/day; 15, 18, and 21 µg/day; 
and 24, 27, and 30 µg/day, respectively.  
Complete guidance on study drug titration during the Blinded Treatment 
Period is provided in Section 9.5.2.2 and Appendix 2.  
Per the Schedule of Events, initial clinic visits and LVs occur relatively 
frequently to accommodate dose titration of study drug, and occur less 
frequently later on (see Appendix 3 and Appendix 4).  
Open-Label Extension Period (Visits 10+; Weeks 26+): 
At Visit 10 (Week 26), all subjects will be assigned to open-label 
treatment as follows: 
• 
If still taking active vitamin D: Start TransCon PTH at a dose of 
18 µg/day, and subsequently follow the titration algorithm as per 
Appendix 2 
• 
If NOT taking active vitamin D:  
− 
And taking study drug ≥ 30 µg/day: Start TransCon PTH 
at a dose of 18 µg/day, and subsequently follow the 
titration algorithm per Appendix 2 
− 
And taking study drug dose < 30 µg/day: Start TransCon 
PTH at the same dose of study drug taken at the end of the 
Blinded Treatment Period. Exception: In cases of an out-of-
range sCa level at Visit 10, adjust the TransCon PTH 
and/or calcium doses as per Appendix 2 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 37 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
TransCon PTH doses can be increased by 3 µg/day as long as ≥7 days 
have elapsed - since a prior dose adjustment in study drug.  Gradual 
increases in study drug doses may facilitate gradual reduction and 
eventual cessation of SoC. Alternatively, study drug doses can be 
decreased by 3 µg/day for sCa levels that continue to be high even after 
all SoC has been withdrawn. Note: At all times during the trial, 
subjects with symptoms of hypocalcemia may take PRN doses of 
calcium (preferred) and/or active vitamin D, and/or do an 
Unscheduled Laboratory Visit (ULV) to measure sCa levels. Based 
on the sCa level, the investigator may titrate the SoC and/or study 
drug dose per Appendix 2. Due to the long half-life of TransCon 
PTH, the full effect of a dose level occurs by approximately 7 days 
after a dose change. 
INVESTIGATIONAL 
PRODUCT 
Name: TransCon PTH 
TransCon PTH drug product is supplied as a solution with a 
concentration of 0.3 mg PTH(1-34)/mL in a single-patient-use prefilled 
pen intended for SC injection. Excipients include metacresol, mannitol, 
succinic acid, and NaOH/(HCl).   
The TransCon PTH delivery system consists of a multi-use cartridge 
integrated into a device to constitute a prefilled injection pen. The 
cartridge contains compounded solution of TransCon PTH or placebo 
TransCon PTH.  
Three presentations of the prefilled pen containing TransCon PTH drug 
product for 14 days usage at room temperature below 86°F (30°C) are 
available. The three pen presentations are 6, 9, and 12 µg/day; 15, 18, 
and 21 µg/day; and 24, 27 and 30 µg/day, respectively. The TransCon 
PTH drug product concentration is 0.3 mg PTH(1-34)/mL, so the 
delivered volume across the dose range of 6 to 30 µg/day is 20 to 100 
µL.  
REFERENCE 
PRODUCT(S) 
Placebo for TransCon PTH drug product (excipient solution in the pens) 
in three pen presentations to mimic dose ranges of 6, 9, and 12 µg/day; 
15, 18, and 21 µg/day; and 24, 27 and 30 µg/day within the Blinded 
Treatment Period. 
TREATMENT 
REGIMEN 
Daily treatment with TransCon PTH or placebo for TransCon PTH 
(excipient solution) delivered by a modified Ypsomed UnoPen Fix pen 
injector using 31G x5 mm pen needles to deliver doses of 6-30 µg/day in 
a volume of ≤100 µL, to either abdomen or anterior thigh, rotating 
injection sites. 
The TransCon PTH allowed dose range will be 6-60 µg/day. All doses 
>30 µg/day will be delivered in the form of two single doses injected 
one after another at different injection sites using two pens. 
All treatment groups may continue to take doses of magnesium and 
vitamin D3 to maintain the defined ranges. 
BLINDING 
This trial consists of a 26-week randomized, double-blind, placebo-
controlled treatment period followed by an open-label Extension Period 
of up to 156 weeks. 
To maintain the double-blind during the Blinded Treatment Period, the 
subjects will be randomized 3:1 to either receive initially 18 μg/day of 
TransCon PTH or placebo for TransCon PTH (excipient solution). 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 38 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
TRIAL AND 
TREATMENT 
DURATION 
The total duration of the trial for an individual subject is expected to be 
up to approximately 190 weeks including up to approximately 4 weeks 
of Screening, a 182-week treatment period and a 2 weeks of follow up 
period after last study drug administration (plus a recommended period 
of up to approximately 2 weeks between randomization and Visit 1). 
• 
Blinded Treatment Period: 26 weeks  
• 
Extension Period (open-label TransCon PTH treatment): 
156 weeks 
Only subjects who successfully complete the Blinded Treatment Period 
on blinded study drug may enter the open-label Extension Period 
(TransCon PTH only). 
STOPPING RULES 
Study drug may be temporarily held for symptomatic hypercalcemia. 
The study drug may be discontinued for severe intractable hypo- or 
hypercalcemia for 2 weeks that cannot be corrected with dose 
adjustments of SoC and/or TransCon PTH. Reinstitution of the study 
drug, in such cases requires prior approval by the Medical Monitor. In 
case the study drug is permanently discontinued prior to Visit 10, 
subjects are expected to continue in the trial without taking study drug 
until Visit 10. If the study drug is permanently discontinued after Visit 
10, subjects are withdrawn from the study following an Early 
Termination Visit. 
ENDPOINTS 
Primary Efficacy Endpoint: 
At 26 weeks of treatment, the proportion of subjects with:  
• 
Albumin-adjusted sCa measured within 4 weeks prior to and on the 
Week 26 visit are within the normal range (8.3-10.6mg/dL) *; and  
• 
Independence from active vitamin D** and  
• 
Independence from therapeutic doses of calcium (i.e., taking calcium 
supplements ≤600 mg/day). This dose of calcium ≤600 mg/day in 
the form of tablets, powder, liquid suspension, or transdermal patch 
is considered as “supplemental” to meeting recommended daily 
intake for general health, as opposed to a “therapeutic” dose to treat 
hypoparathyroidism*** and 
• 
No increase in prescribed study drug within 4 weeks prior to Week 
26 visit**** 
* Except for at the Week 26 visit, confirmation that an albumin-adjusted 
sCa is “abnormal” requires 2 consecutive results outside the normal 
range within 4 weeks prior to the Week 26 visit. 
**Independence from active vitamin D will be defined as a daily 
standing dose equal to zero on all days AND use of any PRN vitamin D 
≤7 days within 4 weeks prior to the Week 26 visit.  
***Independence from therapeutic calcium will be defined as average 
daily standing dose ≤600 mg AND use of PRN doses on ≤7 days within 
4 weeks prior to the Week 26 visit.  
• 
****Dose decrease permitted for safety reasons. 
Key Secondary Efficacy Endpoints: 
Change from baseline at 26 weeks of treatment: 
• 
HPES symptom – Physical domain score 
• 
HPES Symptom – Cognitive domain score 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 39 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
• 
HPES Impact - Physical functioning domain score 
• 
HPES Impact – Daily life domain score 
• 
36-Item Short Form Survey (SF-36) Physical  functioning subscale 
score 
Other Secondary Efficacy Endpoints: 
The key secondary efficacy endpoints and the following efficacy 
endpoint will be evaluated at predefined timepoints during the Extension 
Period.   
• 
The proportion of subjects that meet the following criteria:  
− 
Albumin-adjusted sCa measured within the normal range 
(8.3-10.6 mg/dL); and  
− 
Independence from active vitamin D (i.e., standing dose of 
active vitamin D equal to zero on the day prior to the Week 
52 visit or other visits of interest); and  
− 
Independence from therapeutic doses of calcium (i.e., 
standing dose of elemental calcium ≤ 600 mg on the day 
prior to the Week 52 visit or other visits of interest). 
The following endpoints will be evaluated at predefined timepoints 
during the Blinded Treatment and the Extension Period:  
• 
Calcium and active vitamin D doses 
• 
Daily “pill burden” of active vitamin D and calcium (as oral tablets, 
powder, liquid solutions, liquid suspensions, or transdermal patches) 
• 
sP  
• 
Albumin-adjusted sCa x sP product, including proportion of subjects 
with albumin-adjusted sCa x sP product ≤55 mg2/dL2, ≤52 mg2/dL2, 
and ≤44 mg2/dL2  
• 
Albumin-adjusted sCa  
• 
BMD and TBS by DXA 
• 
Bone turnover markers (serum P1NP and CTx)  
• 
sMg 
• 
EuroQol 5-Dimensional Questionnaire (EQ-5D) 
• 
Clinical Global Impression of Severity (CGI-S) 
• 
HPES: HPES Impact domain scores (Psychological Well-being and 
Social life and Relationships) and HPES Symptom and Impact total 
scores  
• 
SF:36: SF-36 subscale scores (Role Limitations due to Physical 
Health Problems, Bodily Pain, General Health, Vitality, Social 
Functioning, Role Limitations due to Emotional Problems, and 
Mental Health) and SF-36 component scores (Physical component 
score and Mental component score) 
Safety Endpoints: 
The following safety endpoints will be assessed during the Blinded 
Treatment and Extension Periods:  
• 
Incidence of adverse events (AEs), adverse events of special interest 
(AESI) and serious adverse events (SAEs) 
• 
Serum chemistry, hematology  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 40 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
x 
24-hour urine chemistry (including urine calcium and urine 
creatinine clearance) at prespecified timepoints including at Week 
26 
x 
Clinical events of hypo- or hypercalcemia (emergency/urgent care 
visits and hospitalizations)  
x 
Injection site tolerability (based on AEs) 
x 
Evaluation of anti-PTH, anti-TransCon PTH and anti-PEG antibody 
responses 
x 
Vital signs 
Exploratory Endpoints: 
END OF TRIAL 
The end of trial (EOT) is defined as the last subject last visit. 
STATISTICAL 
METHODS 
Details of applicable statistical methods will be provided in a Statistical 
Analysis Plan (SAP) which will be finalized before trial unblinding and 
database lock of the Blinded Treatment Period. 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. 
The Intent-To-Treat (ITT) Population consists of all subjects who were 
randomized and received at least one dose of blinded study drug. All 
efficacy analysis will be based on ITT and treatment assignment per 
randomization. The Safety Analysis Population consists of all 
randomized subjects who received at least one dose of study drug. The 
safety analyses will be based on the Safety Analysis Population and 
actual treatment received. 
In general, data from clinical assessments will be summarized using 
descriptive statistics. Categorical data will be presented using counts and 
percentages of subjects. Continuous variables will be presented using 
number of subjects, mean, standard deviation (SD)/standard error (SE), 
median, minimum and maximum. 
All statistical tests will be two-sided and tested at the statistically 
significant level of 0.05. Confidence intervals will be 2-sided 95% 
confidence intervals, unless stated otherwise.  
The primary analysis will use the CMH (Cochran-Mantel-Haenszel) test 
stratified by etiology of hypoparathyroidism (post-surgical vs other) to 
compare the proportion of subjects meeting the listed criteria of the 
primary endpoint (responders vs. non-responders) in the TransCon PTH 
vs. placebo groups.  Sequential testing will be applied to control the 
multiplicity for the primary and key secondary endpoints. Details will be 
specified in the SAP. 
All efficacy endpoints will be summarized descriptively in Extension 
Period analysis.  
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 41 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
SAMPLE SIZE 
DETERMINATION 
The sample size is determined based on considerations from both 
statistical power and adequate safety exposure perspectives. Assuming  
that the response rate is 70% for TransCon PTH and 15% for placebo for 
the primary endpoint at 26 weeks, 68 subjects randomized 3:1 to 
active TransCon PTH vs. placebo will have approximate statistical 
powers of 99% at alpha = 0.05, and 95%  at alpha = 0.01 (two-sided) to 
demonstrate statistically significant difference between TransCon PTH 
and placebo. Taking into account of approximately 10% dropout, a total 
sample size of 76 is targeted.   
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 42 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
3. 
TABLE OF CONTENTS 
SUMMARY OF CHANGES – VERSION 6.0 TO VERSION 7.0 .................................................2 
SUMMARY OF CHANGES – VERSION 5.0 TO VERSION 6.0 .................................................4 
SUMMARY OF CHANGES – VERSION 4.0 TO VERSION 5.0 .................................................6 
SUMMARY OF CHANGES - VERSION 3.0 TO VERSION 4.0..................................................8 
SUMMARY OF CHANGES - VERSION 2.0 TO VERSION 3.0................................................11 
SUMMARY OF CHANGES - VERSION 1.0 TO VERSION 2.0................................................15 
STATEMENT OF COMPLIANCE ...............................................................................................28 
1. 
APPROVAL SIGNATURES .....................................................................................29 
2. 
SYNOPSIS .................................................................................................................30 
3. 
TABLE OF CONTENTS ...........................................................................................42 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS .................................................49 
5. 
INTRODUCTION ......................................................................................................52 
5.1. 
Background and Rationale ..........................................................................................52 
5.1.1. 
Parathyroid Hormone ..................................................................................................52 
5.1.2. 
Hypoparathyroidism ...................................................................................................52 
5.1.3. 
Current Standard Therapy for Hypoparathyroidism ...................................................53 
5.2. 
Relevant Findings from Nonclinical Studies ..............................................................55 
5.3. 
Clinical Experience .....................................................................................................55 
5.4. 
Trial Rationale ............................................................................................................60 
5.5. 
Summary of Potential Risks and Benefits ..................................................................60 
5.5.1. 
Potential Risks ............................................................................................................60 
5.5.2. 
Potential Benefits ........................................................................................................61 
6. 
OBJECTIVES .............................................................................................................61 
6.1. 
Primary Objectve ........................................................................................................61 
6.2. 
Secondary Objectives .................................................................................................62 
6.3. 
Exploratory Objectives ...............................................................................................62 
7. 
TRIAL DESIGN .........................................................................................................62 
7.1. 
Trial Design Discussion ..............................................................................................62 
7.2. 
Overall Trial Design and Plan ....................................................................................63 
7.2.1. 
Measures Taken to Maximize Study Integrity and Minimize Bias ............................64 
7.3. 
Trial Sites ....................................................................................................................65 
8. 
TRIAL POPULATION ..............................................................................................65 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 43 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
8.1. 
Trial Entry Criteria .....................................................................................................65 
8.1.1. 
Inclusion Criteria ........................................................................................................65 
8.1.2. 
Exclusion Criteria .......................................................................................................66 
8.2. 
Subject WithdrawaL/discontinuation .........................................................................68 
8.2.1. 
Study Drug Discontinuation .......................................................................................69 
8.2.1.1. 
Study Drug Discontinuation during Blinded Treatment Period .................................69 
8.2.1.2. 
Study Drug Discontinuation during Extension Period ...............................................69 
9. 
TREATMENTS ..........................................................................................................69 
9.1. 
Investigational Product ...............................................................................................69 
9.1.1. 
Reference Product .......................................................................................................70 
9.1.2. 
Labeling ......................................................................................................................70 
9.1.3. 
Accountability, Storage, and Dispensing ....................................................................70 
9.1.4. 
Post-trial Treatment ....................................................................................................70 
9.2. 
Treatment Administered .............................................................................................71 
9.3. 
Selection of Trial Doses ..............................................................................................72 
9.4. 
Treatment Assignment ................................................................................................72 
9.4.1. 
Treatment Assignment During Blinded Treatment Period .........................................72 
9.4.2. 
Treatment Assignment During Open-Label Extension Period ...................................72 
9.5. 
Dose Adjustments .......................................................................................................72 
9.5.1. 
Screening Period Supplement Dose Adjustments ......................................................72 
9.5.2. 
Blinded Treatment Period (Visits 1-10; Weeks 0-26) Dose Adjustments ..................73 
9.5.2.1. 
SoC Dose Adjustments during Blinded Treatment Period .........................................73 
9.5.2.2. 
Study Drug Dose Adjustments During Blinded Treatment Period ............................73 
9.5.3. 
Extension Period (Visits 10+; Weeks 26+) Dose Adjustments ..................................74 
9.5.3.1. 
SoC Dose Adjustments during Extension Period .......................................................74 
9.5.3.2. 
TransCon PTH Dose Adjustments during Extension Period ......................................74 
9.6. 
Study Drug Dose Changes, Interuptions, or Stopping ................................................75 
9.6.1. 
Dose changes and Treatment Interruptions ................................................................75 
9.6.2. 
Required Stopping ......................................................................................................77 
9.7. 
Treatment Compliance ................................................................................................77 
9.8. 
Standard of Care .........................................................................................................77 
9.9. 
Prior and Concomitant Therapies ...............................................................................78 
9.9.1. 
Required HP Therapies ...............................................................................................78 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 44 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
9.9.2. 
Prohibited Therapies ...................................................................................................78 
10. 
TRIAL PROCEDURES..............................................................................................79 
10.1. 
Trial Duration .............................................................................................................79 
10.1.1. 
Trial Periods and Visits ..............................................................................................79 
10.1.2. 
Screening Period (Week -6 to -2, Day -42 to -14) ......................................................79 
10.1.3. 
Blinded Treatment Period (Visit 1 - 10, Day 1 to Week 26) ......................................80 
10.1.4. 
Extension Period (Visit 10 - 26 (End of Trial visit), Week 26 to 182) .......................80 
10.1.5. 
Unscheduled Visits .....................................................................................................81 
10.1.6. 
Unscheduled Lab Visits ..............................................................................................81 
10.1.7. 
Home Visits/Virtual Visits .........................................................................................81 
10.1.8. 
Early Termination Visits .............................................................................................81 
10.1.9. 
Follow up Telephone Contact .....................................................................................81 
11. 
ASSESSMENTS.........................................................................................................82 
11.1. 
Medical History ..........................................................................................................82 
11.2. 
Vital Sign Measurements ............................................................................................82 
11.2.1. 
Post-Dose Orthostatic Measurements .........................................................................82 
11.3. 
Physical Examination .................................................................................................82 
11.4. 
Prior and Concomitant Medication .............................................................................82 
11.5. 
Electrocardiogram .......................................................................................................83 
11.6. 
X-Ray of Non-Dominant Wrist and Hand ..................................................................83 
11.7. 
Dual-Energy X-Ray Absorptiometry and Trabecular Bone Score .............................83 
11.8. 
Dietary Calcium Questionnaire ..................................................................................83 
11.9. 
Clinical Outcome Assessments ...................................................................................83 
11.9.1. 
Hypoparathyroidism Patient Experience Scale ..........................................................83 
..................................84 
11.9.3. 
EuroQol 5-dimensional questionnaire ........................................................................84 
11.9.4. 
36-Item Short-Form Survey ........................................................................................84 
.............................................................................84 
11.9.6. 
Clinical Global Impression of Severity ......................................................................85 
11.9.7. 
Phone Exit Interviews .................................................................................................85 
11.10. 
Local Tolerability Assessment ...................................................................................85 
..........................................................................85 
11.12. 
Subject Diary ..............................................................................................................85 
CCI
CCI
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 45 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
11.13. 
Adverse Event Assessments .......................................................................................86 
11.14. 
Laboratory Assessments .............................................................................................86 
11.15. 
Lifestyle Modification ................................................................................................87 
11.15.1. 
Dietary Modifications .................................................................................................87 
11.15.2. 
Exercise Modifications ...............................................................................................87 
11.15.3. 
Contraception ..............................................................................................................87 
11.15.4. 
Study Drug Administration.........................................................................................88 
11.15.4.1. Blinded Treatment Period Administration..................................................................88 
11.15.4.2. Extension Period Administration ................................................................................88 
11.15.5. 
Hypo- or Hypercalcemia Symptom Management ......................................................88 
12. 
ADVERSE EVENT ASSESSMENT AND REPORTING ........................................88 
12.1. 
Definition ....................................................................................................................88 
12.1.1. 
Adverse Event .............................................................................................................88 
12.1.2. 
Serious Adverse Events ..............................................................................................89 
12.1.3. 
Adverse Events of Special Interest (AESIs) ...............................................................89 
12.1.4. 
TransCon PTH Adverse Events of Special Interest ....................................................89 
12.1.5. 
Special Situation .........................................................................................................90 
12.2. 
Methods and Timing for Assessing and Recording Safety Variables ........................90 
12.3. 
Adverse Event Reporting Period ................................................................................90 
12.3.1. 
Assessment of Severity of Adverse Events ................................................................90 
12.3.1.1. 
Causality Rating ..........................................................................................................91 
12.3.1.2. 
Outcome Assessment ..................................................................................................91 
12.4. 
Procedures for Eliciting, Recording and Reporting Adverse Events .........................92 
12.4.1. 
Eliciting Adverse Events ............................................................................................92 
12.4.2. 
Recording Procedures for All Adverse Events ...........................................................92 
12.4.3. 
Specific Instructions for Recording Adverse Events ..................................................93 
12.4.3.1. 
Abnormal Laboratory Values .....................................................................................93 
12.4.3.2. 
Abnormal Vital Sign Values .......................................................................................94 
12.4.3.3. 
Diagnosis vs. Signs and Symptoms ............................................................................94 
12.4.3.4. 
Injection Site Reactions ..............................................................................................94 
12.4.3.5. 
Deaths .........................................................................................................................95 
12.4.3.6. 
Hospitalizations for Medical or Surgical Procedures .................................................95 
12.4.3.7. 
Preexisting Medical Conditions ..................................................................................95 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 46 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
12.4.3.8. 
Pregnancy ...................................................................................................................95 
12.4.3.9. 
Product Complaints ....................................................................................................95 
12.5. 
Safety Reporting Requirements ..................................................................................96 
12.5.1. 
Non-Serious Adverse Events Leading to Discontinuation .........................................96 
12.5.2. 
Reporting ....................................................................................................................96 
13. 
SAFETY MONITORING ..........................................................................................97 
14. 
DEVICE ASSOCIATED HAZARDS, RISKS, AND ADVERSE EVENTS ............97 
15. 
STATISTICS ..............................................................................................................98 
15.1. 
General ........................................................................................................................98 
15.2. 
Endpoints ....................................................................................................................99 
15.2.1. 
Efficacy Endpoints ......................................................................................................99 
15.2.1.1. 
Primary Efficacy Endpoint .........................................................................................99 
15.2.1.2. 
Secondary Efficacy Endpoints ....................................................................................99 
15.2.2. 
Safety Endpoints .......................................................................................................100 
15.2.3. 
Exploratory Endpoints ..............................................................................................101 
15.3. 
Statistical Analysis ....................................................................................................101 
15.4. 
Power Calculation .....................................................................................................102 
15.5. 
Significance ..............................................................................................................102 
15.6. 
Accountability ...........................................................................................................102 
15.7. 
Deviation Reporting ..................................................................................................102 
15.8. 
Unblinding Procedures .............................................................................................103 
16. 
TRIAL CONDUCT ..................................................................................................103 
16.1. 
Site Initiation ............................................................................................................103 
16.2. 
Data Handling and Record Keeping .........................................................................103 
16.2.1. 
Collection of Data .....................................................................................................103 
16.2.2. 
Coding Dictionaries ..................................................................................................104 
16.2.3. 
Data Handling ...........................................................................................................104 
16.2.4. 
Direct Access to Source Data/Documents ................................................................104 
16.2.5. 
Record Keeping ........................................................................................................104 
16.3. 
Data Quality Control .................................................................................................105 
16.3.1. 
Monitoring Procedures .............................................................................................105 
16.3.2. 
Data Management .....................................................................................................105 
16.4. 
Auditing Procedures .................................................................................................105 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 47 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
16.5. 
Laboratory Quality Standards ...................................................................................106 
16.6. 
Trial Termination or Completion..............................................................................106 
16.7. 
Changes to the Protocol ............................................................................................107 
16.8. 
Other Changes in Trial Conduct ...............................................................................107 
16.9. 
Clinical Study Report ...............................................................................................107 
16.10. 
Use of Information and Publication ..........................................................................107 
17. 
ETHICAL AND LEGAL CONSIDERATIONS ......................................................107 
17.1. 
Data Monitoring Committee .....................................................................................108 
17.2. 
Informed Consent .....................................................................................................108 
17.3. 
Institutional Review Board/Ethics Committee Approvals .......................................108 
18. 
REFERENCES .........................................................................................................110 
19. 
SIGNATURE OF AGREEMENT ............................................................................112 
20. 
APPENDICES ..........................................................................................................114 
APPENDIX 1. CONTRACEPTION .........................................................................................114 
APPENDIX 2. TITRATION ALGORITHM ............................................................................115 
APPENDIX 3. SCHEDULE OF EVENTS ...............................................................................117 
APPENDIX 4. SCHEDULE OF LABORATORY ASSESSMENTS ......................................123 
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 48 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
LIST OF TABLES  
Table 1: 
Recommended Dosing Schemes >30 µg PTH(1-34)/Day or Placebo ........................71 
Table 2: 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
WHO Toxicity Grading Scale ....................................................................................91 
Table 3: 
Severity Ratings Applied in Risk Evaluation .............................................................98 
 
LIST OF FIGURES  
Figure 1: 
Structure of TransCon PTH ........................................................................................54 
Figure 2: 
Illustration of the TransCon PTH Technology and the Release of Active 
PTH .............................................................................................................................55 
Figure 3: 
Arithmetic Mean Plasma Concentrations of Free PTH on Day 10 ............................56 
Figure 4: 
Spot Fractional Excretion of Calcium: MAD Cohorts ...............................................57 
Figure 5: 
Albumin adjusted sCa: Absolute Value by Visits ......................................................58 
Figure 6: 
Serum Phosphate: Change from Baseline Value by Visits .........................................59 
Figure 7: 
Trial Design ................................................................................................................64 
Figure 8: 
Decision Tree for TransCon PTH Dose Selection at Visit 10 (Week 26) ..................75 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 49 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS  
Abbreviation 
Definition 
AC 
arterial calcification 
AE 
adverse events 
AESI 
adverse events of special interest 
AIRE 
autoimmune regulator 
BID 
twice daily 
BMD 
bone mineral density 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CGI-S 
clinical global impression of severity 
ClinRO 
clinician-reported outcome 
Cmax 
maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
COA 
clinical outcome assessment 
CRO 
contract research organization 
CTFG 
Clinical Trial Facilitation Group 
CTx 
c-telopeptide of type 1 collagen 
CxP 
calcium-phosphate product 
DMC 
Data Monitoring Committee 
DXA 
dual-energy X-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR  
estimated glomerular filtration rate 
EOT 
end of trial 
EQ-5D 
euroQol 5-dimensional 
EQ-5D-5L 
euroQol 5-dimensional five-level 
EQ-VAS 
euroQol visual analogue scale 
EC 
ethics committee 
FDA 
Food and Drug Administration 
FECa 
fractional excretion of calcium  
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 50 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Abbreviation 
Definition 
hCG 
human chorionic gonadotropin 
HP 
hypoparathyroidism 
HPES 
hypoparathyroidism patient experience scale 
ICF 
informed consent form 
ICH 
International Council for Harmonisation Technical Requirements for  
Pharmaceuticals for Human Use 
IFU 
instructions for use 
IM 
investigator meeting 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
Intent-To-Treat 
ISR 
injection site reaction 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
LAM 
lactational amenorrhoea method 
LLN 
lower level of normal 
LV 
Laboratory Visit 
MAD 
multiple ascending dose 
MedDRA 
medical dictionary for regulatory activities 
mPEG 
methoxypolyethylene glycol 
MTD 
maximum tolerated dose 
NIH 
National Institutes of Health 
NOAEL 
no-observed-adverse-effect level 
P1NP 
procollagen type 1 amino-terminal propeptide 
 
 
PD 
pharmacodynamics 
PEG 
polyethylene glycol 
PI 
principal investigator 
PK 
pharmacokinetics 
pQCT 
peripheral quantitative computed tomography 
PTH 
parathyroid hormone 
PRN 
As needed. Used interchangeably with “rescue” 
PRO 
patient-reported outcome 
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 51 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Abbreviation 
Definition 
QOL 
quality of life 
RDA 
recommended daily allowance 
SAD 
single ascending dose  
SAE 
serious adverse events 
SD 
standard deviation 
SE 
standard error 
SAP 
statistical analysis plan 
SC 
subcutaneous 
sCa 
serum calcium 
SF-36 
36-item short form survey 
SIV 
site initiation visit 
sMg 
serum magnesium 
SoC 
standard of care (active vitamin D plus calcium) 
SOP 
standard operating procedure 
sP 
serum phosphate 
SUSAR 
suspected unexpected serious adverse reaction 
TBS 
trabecular bone score 
TEAE 
treatment-emergent adverse event 
TID 
three times daily 
TPTx 
thyroparathyroidectomized 
TSH 
thyroid-stimulating hormone 
uCa 
urine calcium 
uP 
urine phosphate 
ULN 
upper level of normal 
ULV 
unscheduled laboratory visit 
UV 
unscheduled visit 
 
 
 
Definition Used 
Explanation 
Study Drug 
Refers to TransCon PTH or Placebo 
Active vitamin D 
Refers to therapeutic calcitriol (1,25-dihydroxyvitamin D3) or alfacalcidol (1α-
hydroxyvitamin D3, an analogue of active vitamin D) 
Standard of Care 
(SoC) 
Is equivalent to conventional therapy, i.e., active vitamin D and calcium supplements 
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 52 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
5. 
INTRODUCTION  
5.1. 
BACKGROUND AND RATIONALE  
5.1.1. 
Parathyroid Hormone  
Parathyroid hormone (PTH) is a product of endocrine secretion from the four parathyroid glands.  
It is synthesized by chief cells as a prohormone peptide, eventually cleaved to 84 amino acids, 
i.e., PTH(1-84), which is secreted.  Although PTH(1-84) is the biologically active form of PTH, 
receptor-mediated activities require only the 34 amino acid N-terminus fragment, PTH(1-34).  
PTH(1-84) is fairly quickly cleaved to PTH(1-34) both by the parathyroid glands and by hepatic 
Kuppfer cells (Hamilton 1983).  PTH(1-33) appears to equipotent to PTH(1-34) (Morley 1999). 
PTH maintains the body’s extracellular calcium and phosphate homeostasis, the former within a 
very narrow range.  When serum calcium (sCa) levels drop, PTH is released from the 
parathyroid glands.  An important effect of PTH at the renal PTH/PTHrP receptor is to increase 
calcium reabsorption, decrease phosphate reabsorption, and convert the prohormone 
25-hydroxyvitamin D (25OHD) to the fully active steroid hormone, 1,25-dihydroxyvitamin D 
[1,25D(OH)2 vitamin D3 or calcitriol].  Active vitamin D increases calcium and phosphate 
absorption in the small intestine.  Another direct action of PTH is to increase osteoclast activity 
causing calcium and phosphate to increase and potentially osteocyte activity, increasing ionized 
calcium. 
5.1.2. 
Hypoparathyroidism  
Hypoparathyroidism (HP) is a rare disease of impaired PTH production or activity.  The majority 
of cases (≥75%) are acquired, occurring secondary to anterior neck surgery in which 
approximately 0.12-4.6% of procedures cause the parathyroid gland(s) to be inadvertently 
injured or destroyed (Brandi 2016, Clarke 2016).  Of these, 3-30% result in chronic HP, i.e., 
features of HP lasting more than 6 months after the surgery (Mannstadt 2013, Brandi 2016, 
Shoback 2016).  Autoimmune diseases are the second most common cause of acquired HP while 
less common causes include intrinsic genetic defects of the parathyroid glands, 
hemochromatosis, magnesium deficiency, as well as idiopathic disease (Brandi 2016, 
Clarke 2016). 
The US prevalence rate of HP is estimated to range from 60,000-115,000, thus meeting orphan 
disease status (Brandi 2016).  Given the predominance of cases secondary to anterior neck 
surgery, HP incidence rates depend on the number of anterior neck surgeries performed in a 
given locale, the expertise of the surgeons, and underlying pathology. 
In HP, the sCa level drops and there is a lack of compensatory PTH secretion, so 
calcium-phosphate homeostasis is disrupted.  The kidneys decrease calcium reabsorption, 
phosphate excretion, and conversion of 25OHD to active 1,25(OH)2D.  Given decreased 
1,25(OH)2D conversion in the kidneys, intestinal absorption of calcium and phosphate decline 
and due to deficient PTH the bone osteoclast activity is decreased, further decreasing sCa and 
resulting in over-mineralized bone and higher-than-normal bone mineral density (BMD).  
Despite decreased gastrointestinal absorption of phosphate from decreased 1,25(OH)2D 
production, patients with HP typically show either elevated or high-normal levels of serum 
phosphate (sP) due to decreased renal phosphate excretion. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 53 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
5.1.3. 
Current Standard Therapy for Hypoparathyroidism  
Current Standard of Care (SoC) for HP – specifically active vitamin D and high doses of calcium 
– may improve hypocalcemia, particularly in patients with mild/moderate HP; active vitamin D 
stimulates calcium and phosphate absorption from the intestines and calcium supplements 
increase sCa (Brandi 2016). Yet, chronic calcium and vitamin D therapy may also produce 
adverse effects beyond the original problems of HP because active vitamin D and calcium do not 
restore PTH-dependent renal calcium reabsorption, correct the elevated sP in HP, or correct 
diminished bone turnover (Winer 2012, Mannstadt 2017).  Patients on SoC may become 
hypercalciuric, with a subsequent risk for nephrolithiasis, nephrocalcinosis, and chronic kidney 
disease (Winer 2012, Mannstadt 2017). Decreased PTH activity also leads to decreased bone 
resorption, i.e., a low bone turnover – high bone mass state.  Finally, as SoC increases both sCa 
(which is low in HP) and sP (which is elevated in HP), SoC can also result in an increased 
calcium-phosphate product (CxP), thereby increasing the risk for ectopic calcifications, including 
in the vascular system, the renal parenchyma, the lens of the eye, and the basal ganglia of the 
central nervous system (Abate 2017).  
Based on the current SoC, there have been six goals of chronic HP therapy: 1) prevent signs and 
symptoms of hypocalcemia; 2) maintain sCa concentration slightly below or within the 
low-normal range; 3) maintain the CxP below 55 mg2/dL2 (4.4 mmol2/L2); 4) avoid 
hypercalciuria;  5) avoid hypercalcemia; and 6) avoid renal (nephrocalcinosis/nephrolithiasis) 
and other extra-skeletal calcifications (Bilezikian 2016, Brandi 2016). 
In the absence of a true PTH replacement therapy that replaces active PTH within the normal 
physiologic range 24 hours per day, achieving all six goals of HP therapy is a challenge.  
Furthermore, given that active vitamin D and calcium may cause paradoxical long-term 
morbidity and mortality, replacing the missing hormone in HP patients has long been desired.  In 
1996, Winer et al established the experimental basis for using biologically active PTH(1-34) to 
treat HP (Winer 1996).  Since then, twice daily (BID) administration has been shown to achieve 
better calcemic control than daily, and continuous infusion has been shown to achieve better 
control than BID (Winer 1998, Winer 2008, Winer 2012).  In addition to normalizing both sCa, 
sP, and serum magnesium (sMg), PTH by continuous infusion has also demonstrated less sCa 
fluctuations, a reduction in urine calcium (uCa), and normalized bone turnover compared to BID 
PTH(1-34) administration, despite a 65% lower dose of infused vs BID PTH(1-34) 
(Winer 2012). While intermittent PTH administration results in high hormone fluctuations, with 
an initial supraphysiological PTH level [high maximum concentration (Cmax)] followed by a 
rapid decline to subtherapeutic levels, continuous infusion maintains PTH levels in the 
physiological range throughout the day.  Although PTH(1-34) is currently only approved for 
osteoporosis, these studies provided proof of concept for its use in HP.  Thus, with a treatment 
that provides active PTH within the lower half of the normal range for 24 hours per day, it 
should be possible to change the 2nd goal to maintaining a sCa concentration within the normal 
range, while achieving the remaining 5 goals. 
Recombinant PTH(1-84) (Natpara, trademark owned by Takeda) was approved as an adjunct to 
active vitamin D and calcium by the Food and Drug Administration (FDA) in 2015 
(BLA #125511 2015) using PTH to treat HP. In its Advisory Meeting Briefing Document, the 
FDA noted that “This [lack of control of urinary calcium excretion] is primarily due to the short 
half-life (~ 3 hours) of Natpara, which results in PTH concentrations returning to baseline by 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 54 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
10-12 hours”, and also noted that Natpara did not reduce the clinical episodes of either 
hypocalcemia or hypercalcemia compared to placebo plus SoC (Briefing Document 2014, 
Khurana 2019).  Using a calcium homeostasis systems pharmacology model, the FDA simulated 
effects following 100 µg daily or BID dosing of 50 µg and compared these regimens against a 
theoretical slow-release model.  It concluded that PTH replacement therapy requires a 
physiologic profile, specifically a dosing regimen that is either more frequent than daily dosing 
or daily dosing with a slow-release formulation that achieves an infusion-like exposure within 
the physiological normal range; both of which the model predicted would decrease renal calcium 
excretion (Khurana 2019).  In April 2017, once-daily subcutaneous (SC) injection administration 
of recombinant PTH(1-84) (Natpar) was approved in Europe as a new therapy and recommended 
for adult patients with HP who cannot be well controlled on conventional therapy alone 
(CHMP 2017).  However, CHMP noted that this treatment has not demonstrated the ability to 
reduce the incidence of hypocalcemia, hypercalcemia, or hypercalciuria relative to the 
conventional therapy of oral calcium and active vitamin D analogues, due to its relatively short 
half-life of 3 hours (CHMP 2017).  On 9/5/2019, FDA removed Natpara from the US market 
due to safety concerns about rubber particles from the vial septum; it remains not commercially 
available in the US. 
TransCon PTH is a prodrug consisting of PTH(1-34) transiently conjugated to a branched 
40 kDa methoxypolyethylene glycol (mPEG) moiety through a proprietary TransCon Linker as 
illustrated in Figure 1. 
Figure 1: 
Structure of TransCon PTH  
 
 
TransCon PTH is administered as a once-daily SC and is designed to maintain a steady 
concentration of PTH in the blood stream within the normal physiological range for 24 hours per 
day. After SC injection, auto-cleavage of TransCon PTH occurs in a controlled manner by 
first-order kinetics, whereby active PTH is released as either PTH(1-34) or PTH(1-33) (major 
metabolite) from the TransCon Linker at a rate proportional to the prodrug concentration. The 
carrier inactivates PTH and shields it from clearance and receptor binding and uptake.  
Following release from the prodrug, active PTH retains the original mode of action (i.e., binding 
to the PTH receptor 1) and the TransCon Linker-mPEG is cleared primarily by renal excretion 
(see Figure 2).   

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 55 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Figure 2: 
Illustration of the TransCon PTH Technology and the Release of Active PTH  
 
 
5.2. 
RELEVANT FINDINGS FROM NONCLINICAL STUDIES  
Please refer to the current version of the TransCon PTH Investigator’s Brochure 
Section 4 – Nonclinical Studies for a full summary of the nonclinical data.  
A comprehensive nonclinical development program has been conducted for TransCon PTH to 
support clinical development.  The testing strategy involved a range of in silico, in vitro and in 
vivo studies in Sprague Dawley rats, cynomolgus monkeys, and New Zealand White rabbits to 
characterize the pharmacokinetics (PK), TK, PD, and safety profile of TransCon PTH.  
Bioanalytical assays, including immunogenicity assays were developed and validated according 
to relevant guidelines. 
In vivo safety assessment was based on standard toxicological endpoints and assessment of bone 
turnover markers, peripheral quantitative computed tomography (pQCT), dual-energy X-ray 
absorptiometry (DXA), and histomorphometry. 
The pharmacological effect of TransCon PTH was demonstrated in single-dose PK/PD and in 
repeat-dose toxicity studies in rats, monkeys, and rabbits.  The pharmacological effect was 
further confirmed in thyroparathyroidectomized (TPTx) rats, a disease model for HP. 
In repeat-dose toxicity studies the no-observed-adverse-effect level (NOAEL) for SC daily 
administrations of TransCon PTH for up to 26 weeks was 10 μg PTH(1-34)/kg in rats and 0.5 μg 
PTH(1-34)/kg in monkeys.  The adverse findings considered related to TransCon PTH were all 
considered exaggerated pharmacological effects of continuous administration of PTH resulting in 
sustained hypercalcemia.  TransCon PTH did not induce any adverse effects on the central 
nervous, pulmonary, or cardiovascular system, and was not considered genotoxic as assessed in 
specific genotoxicity studies.  Furthermore, the reproductive and developmental toxicity studies 
conducted so far have not identified any adverse effects on embryofetal development or fertility. 
5.3. 
CLINICAL EXPERIENCE  
A Phase 1 clinical trial [a randomized, placebo-controlled, single ascending dose (SAD) and 
multiple ascending dose (MAD) trial to evaluate the safety, tolerability, pharmacodynamics 
(PD), and PK of TransCon PTH in healthy adult subjects] conducted under good clinical practice 
(GCP), ethics committee (EC), and Declaration of Helsinki guidelines has been completed. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 56 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
A total of 132 male and female normal healthy subjects were randomized and received study 
treatment; 69 subjects in 7 SAD cohorts [56 received TransCon PTH and 13 placebo (3.5, 12, 32, 
48, 72, 100, and 124 μg/day PTH)] with a maximum tolerated dose (MTD) of 124 μg PTH and 
63 subjects in 6 MAD cohorts [50 received TransCon PTH and 13 placebo (3.5, 7.0, 12, 16, 20, 
and 24 μg/day PTH)] with a MTD of 20 μg PTH/day. 
The primary goal of the trial was to identify the clinically effective dose range for the 
Phase 2 clinical trial (based on change in albumin-adjusted sCa from baseline), the effect of 
treatment on the fractional excretion of calcium (FECa), and to assess the PK profile, safety, 
tolerability, and immunogenicity of TransCon PTH. 
In healthy volunteers in SAD cohorts, TransCon PTH demonstrated dose-dependent increases in 
Free PTH, corresponding to the sum of active Free PTH [intact Free PTH(1-34)] and the main 
metabolite Free PTH(1-33) in the calculated normal range, which correlated with dose-dependent 
increases in albumin-adjusted sCa and suppression of intact PTH(1-84) at all single doses of 
≥32 μg.  Despite mild hypercalcemia over 3 days in the cohorts receiving single doses of 
TransCon ≥100 μg PTH, at the time of greatest sCa (mean ±SD of 10.3±0.23 to 
10.97±0.56 mg/dL on Day 2), the urine FECa remained well-controlled below the upper level of 
normal (ULN) of the normal range (2%), demonstrating that active PTH within the normal range 
continuously over 24 hours can enhance the renal handling of calcium.   
Figure 3 shows a dose-dependent increase in Free PTH, with a low peak-to-trough ratio of 
~1.27 to 1.55 over 24 hours.  Phase 1 data demonstrate that the effective half-life of Free PTH 
released from the prodrug is ~60 hours, with Free PTH approaching steady-state by Day 8 after 
dosing. This is further supported by sparse PK sampling performed in the Phase 2 trial 
(TransCon PTH TCP-201). The normal physiologic range for intact PTH(1-84) is 10-65 pg/mL; 
as PTH(1-34) and PTH(1-33) comprise about 40% of the molecular mass of the intact hormone, 
the calculated normal range is about 4-26 pg/mL. 
Figure 3: 
Arithmetic Mean Plasma Concentrations of Free PTH on Day 10  
 
Note: Negative SE bars less than 0 are shown as 0 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 57 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Figure 4 presents spot FECa for subjects in the MAD cohorts.  Overall, in the MAD cohorts, 
mean spot FECa remained stable over the trial.  Despite the moderate hypercalcemia in the 
cohorts receiving doses of TransCon ≥20 μg PTH/day, at the time of greatest sCa (~10.5 to 
11.2 mg/dL) on Day 11, the urine FECa remained well-controlled below the ULN of the normal 
range (2%), demonstrating that active PTH within the normal range continuously over 24 hours 
can enhance the renal handling of calcium.  
Detailed information is given in the Investigator’s Brochure Section 5 – Effects in Humans. 
Figure 4: 
Spot Fractional Excretion of Calcium: MAD Cohorts  
 
1 Syed 2001 
 
TransCon PTH was generally well tolerated across the clinical dose range proposed for the 
Phase 2 clinical trial.  There were no drug-related serious adverse events (SAEs) or severe 
adverse events. 
In summary, TransCon PTH demonstrated a potent serum calcemic and renal calcium 
reabsorption effect in normal subjects, predicting control of both sCa and uCa in patients with 
HP.  The effect of TransCon PTH on bone formation markers was consistent with results 
reported for continuous infusion of PTH(1-34) (Horwitz 2011, Winer 2012, Winer 2014) and 
lacked an anabolic effect. 
A Phase 2 clinical trial [a randomized, placebo-controlled trial to evaluate the safety, tolerability, 
PD, and PK of TransCon PTH] in patients with HP conducted under GCP, EC, and Declaration 
of Helsinki guidelines is currently ongoing. 
A total of 59 male and female subjects with HP of at least 26 weeks duration treated with a stable 
dose of ≥0.25 µg BID active vitamin D (or ≥ 1.0 µg/day of alfacalcidol) and ≥400 mg BID 
calcium for at least 12 weeks prior to Screening were randomized 1:1:1:1 to TransCon PTH 15, 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 58 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
18 or 21 µg/day or to placebo for 4 weeks, followed by an ongoing open-label extension for an 
additional 12 months.  Preliminary data up to 26 weeks of follow up are presently available. 
In the per protocol analysis (n=57) at four weeks, 22/44 subjects (50%) in the TransCon PTH 
group met the primary endpoint vs. 2/13 subjects (15%) in the placebo group with a statistically 
significant response (p=0.0308).  82% of subjects in the TransCon PTH group were able to come 
off SoC (i.e., off active vitamin D and ≤ 500 mg/day of calcium supplements) vs 15% of subjects 
in the placebo group (p<0.0001), and 50% of the TransCon PTH group were able to completely 
stop active vitamin D and all calcium supplements vs. 0% in the placebo group (p=0.0008).  The 
results demonstrated that TransCon PTH increased sCa levels (see Figure 5), enabled 
discontinuation of active vitamin D and continuous reduction of calcium supplements over the 
four-week period.  TransCon PTH reduced urinary calcium excretion (as measured by FECa) 
despite increased sCa resulted in sustained reductions in sP and CxP (see Figure 6).   
Figure 5: 
Albumin adjusted sCa: Absolute Value by Visits  
 
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 59 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Figure 6: 
Serum Phosphate: Change from Baseline Value by Visits  
 
 
All doses were well tolerated within the 4-week Blinded Treatment Period, and no serious or 
severe adverse events were shown at any point.  No treatment-emergent adverse events (TEAEs) 
led to discontinuation of study drug or early discontinuation of the trial, and the overall incidence 
of TEAEs was comparable between TransCon PTH and placebo. 
Intensive PK assessments (including Free PTH) were analyzed in the Phase 1 trial (TransCon 
CT-103), showing that the dose range of 12-24 µg/day resulted in Free PTH levels within the 
lower half of the normal range.  Confirmatory PK (including Free PTH in a subset of subjects) 
was analyzed in the Phase 2 trial (TransCon PTH TCP-201), and again showed that dosing over 
4 weeks at doses of 15-21 µg/day resulted in Free PTH levels within the lower half of the normal 
range.     
Thus, the double-blind portion of the Phase 2 trial (TransCon PTH TCP-201) in patients with HP 
confirms the results of the Phase 1 trial in normal human volunteers, as well as the results of the 
National Institutes of Health (NIH) PTH-infusion studies (Winer 2012, Winer 2014); namely, 
that TransCon PTH by providing stable levels of active Free PTH within the physiologic range 
24/7 effectively treats all of the acute symptoms and signs of HP more effectively than SoC. 
Analysis of data from the Phase 2 open label extension confirm these findings, with 91% of 
participants requiring no vitamin D and ≤500 mg/d elemental calcium.  Participants required 
TransCon PTH doses between 6 and 39 µg/day.  No TEAEs related to abnormal serum calcium 
have required urgent medical attention.  No TEAEs have resulted in discontinuation of study 
drug, withdrawal from the trial or death.  There have been no suspected unexpected serious 
adverse reactions (SUSARs) as of February 2021.  A single participant opted to withdraw 
consent from the Phase 2 trial in open label Extension Period due to the requirements for 
contraception.  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 60 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
5.4. 
TRIAL RATIONALE  
A NIH trial with once-daily SC administration of PTH(1-34) maintained the mean sCa level 
within the normal range over a 24-hour period and reduced uCa excretion (Winer 1996).  
Another trial in adults demonstrated that twice-daily PTH(1–34), at a significantly lower daily 
dose, provides improved metabolic control compared with once-daily PTH(1–34) therapy 
(Winer 1998).  Long term effect of PTH(1–34) was further studied in patients with HP of various 
etiologies.  The trial demonstrated that long-term BID PTH administration maintained mean sCa 
within or just below the normal range over a 3-year period with concurrent normalization of 
mean urinary calcium excretion (Winer 2003).  Further on, a trial comparing continuous 
PTH(1-34) delivery, by insulin pump, with BID SC injection in adult HP patients showed that 
continuous exposure to PTH restored bone turnover to normal levels while avoiding the anabolic 
overstimulation from daily or twice-daily injection (Winer 2012).  In addition, pump delivery led 
to a 65% reduction in the PTH(1-34) dose needed to maintain normal sCa levels in the HP 
patients.  The trial also hypothesized that pump delivery of PTH(1-34) would provide more 
physiological control of sCa and uCa (compared with conventional treatment or intermittent PTH 
delivery), would reduce symptoms of HP, improve quality of life (QOL), and lower the long-
term risk of renal damage, without adverse effect on bone (Winer 2012). 
Recombinant PTH(1-84) (Natpara) was approved as an adjunct to active vitamin D and calcium 
by the FDA in 2015 to treat HP.  But in the Advisory Committee Natpara Briefing Document, 
the FDA also concluded that due to its short half-life (~ 3 hours), PTH concentrations returns to 
baseline by 10-12 hours and there is a lack of control of urinary calcium excretion.  In addition, 
Natpara did not reduce the clinical episodes of either hypocalcemia or hypercalcemia compared 
to placebo plus SoC (Briefing Document 2014).  FDA recently published these data 
(Khurana 2019). Similar comments were made by CHMP (CHMP 2017). 
5.5. 
SUMMARY OF POTENTIAL RISKS AND BENEFITS  
5.5.1. 
Potential Risks  
In comparison to short-lived PTH molecules that show supraphysiological PTH levels at tmax 
followed by a rapid decline to undetectable levels after 10-12 hours, TransCon PTH is designed 
for sustained-release of PTH with a t½ of ~ 60 hours, ensuring a stable systemic concentration of 
the hormone with a flat, infusion-like profile within the physiological normal concentration 
range.  The ability of TransCon PTH to maintain circulating PTH levels in the normal range has 
been confirmed in a Phase 1 clinical trial (TransCon PTH CT-103) and in the Phase 2 trial 
(TransCon PTH TCP-201), as well as a lack of an anabolic effect seen with short-lived PTH 
molecules.   
The following risks have been seen in either the TransCon PTH Phase 1 clinical trial or have 
been reported for approved PTH medications, and thus considered to be potential risks for 
TransCon PTH: 
• Hypercalcemia 
• Injection site erythema 
• Orthostatic hypotension/presyncope/syncope/dizziness/tachycardia (palpitations) 
• Headache 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 61 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
• Fatigue 
• Nausea 
Osteosarcoma is listed as a potential risk with short-acting PTH analogs, but is not considered to 
be a risk with TransCon PTH, due to the absence of an anabolic effect based on no increase in 
procollagen type 1 amino-terminal propeptide (P1NP) over 4 weeks in the Phase 2 trial.  
Please refer to the current version of the TransCon PTH Investigator’s Brochure 
Section 6.4 – Anticipated Risks for further details.  
During the Blinded Treatment Period, there is a potentially increased risk of hypocalcemia if the 
starting dose of 18 µg/day is sub-optimal, or hypercalcemia if the starting dose of 18 µg/day is 
higher than optimal for a subject.  However, this risk is limited to no more than about 6 days (in 
the event of hypercalcemia) and about 9 days (in the event of hypocalcemia), when the dose can 
be held or adjusted up or down, and is also reduced due to the laboratory visits (LVs) over the 
time between visits.  Additionally, acute hypocalcemia can be managed in most situations by 
PRN doses of active vitamin D and calcium, and acute hypercalcemia can be managed by 
stopping SoC or by holding the dose of TransCon PTH. 
During the reduction in SoC following initiation of study drug (TransCon PTH or placebo) at 
Visit 1 (and for those subjects on active vitamin D at Visit 10), there is a higher risk of 
hypocalcemia.  However, the following have been included in the protocol to limit the extent of 
this risk: 
• Step-wise decreases of SoC occurring only after sCa levels are confirmed to be within 
appropriate pre-defined ranges and the subject is asymptomatic  
• Returning subjects with symptomatic hypocalcemia to their previous SoC dose 
• Allowing subjects who experience hypocalcemic symptoms during this period (and 
throughout the trial) to use PRN doses of SoC, and to increase their dose of TransCon PTH 
≥7 days 
5.5.2. 
Potential Benefits  
In the Phase 2 trial, TransCon PTH at doses of 15-21 µg/day allowed subjects with HP to safely 
discontinue their SoC without experiencing meaningful hypo- or hypercalcemic symptoms, 
mostly after 2 weeks, along with reductions in FECa by 4 weeks. 
6. 
OBJECTIVES  
6.1. 
PRIMARY OBJECTVE  
The primary objective is to assess the treatment effect of daily TransCon PTH on sCa levels, and 
therapeutic doses of active vitamin D (i.e., calcitriol or alfacalcidol) and calcium at 26 weeks of 
treatment.  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 62 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
6.2. 
SECONDARY OBJECTIVES  
The secondary objectives are  
x To assess the safety and tolerability of daily TransCon PTH 
x To assess the treatment effect of daily TransCon PTH on hypoparathyroidism patient 
experience scale (HPES) domain scores  
x To assess the treatment effect of daily TransCon PTH on PD markers (including sCa) and 
active vitamin D and calcium doses  
x To assess the treatment effect of daily TransCon PTH on sP, CxP (albumin-adjusted sCa x sP 
product) and sMg 
x To assess anti-PTH, anti-TransCon PTH and anti-polyethylene glycol (PEG) antibody 
responses 
x To assess the treatment effect during Extension Period 
x To assess the treatment effect of daily TransCon PTH on 
 
BMD and trabecular bone score (TBS) by DXA  
 
Bone turnover markers (serum P1NP and CTx) 
x To assess the impact of treatment on patient-reported health-related QOL and a clinician-
reported outcome (ClinRO) assessment 
6.3. 
EXPLORATORY OBJECTIVES  
7. 
TRIAL DESIGN  
7.1. 
TRIAL DESIGN DISCUSSION  
The trial design is a randomized, parallel-group, double-blind, placebo-controlled design. 
Randomization introduces a deliberate element of chance into the assignment of treatment in a 
clinical trial. During subsequent analysis of the trial data, it provides a sound statistically basis 
for the quantitative evaluation of the evidence relating to treatment effect.  
A double-blind set-up has been chosen to minimize the potential biases resulting from 
differences in management, treatment, or assignment of subject or interpretation of results that 
could arise as a result of subjects or investigator knowledge of the assigned treatment. 
A placebo group will be used as a control-group. It is considered ethically justifiable since the 
subjects in both treatment groups can continue taking SoC and PRN medication to treat their 
hypocalcemic symptoms. Furthermore, subjects will be medically monitored during the trial and 
the expenses related to SoC may be reimbursed, always following national legislation and/or 
guidance. 
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 63 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
7.2. 
OVERALL TRIAL DESIGN AND PLAN  
The double-blind, placebo-controlled, parallel group treatment period of this trial is expected to 
enroll approximately 76 subjects from up to approximately 40 sites worldwide.  
Subjects will be randomized in a 3:1 ratio into 2 treatment groups: 
• TransCon PTH 18 μg/day*, co-administered with SoC 
• Placebo for TransCon PTH (excipient solution) 18 μg/day, co-administered with SoC 
* Dose of TransCon PTH refers to dose of PTH(1-34) administered 
Randomization will be stratified by etiology of hypoparathyroidism (post-surgical vs other).  
All subjects will start with study drug 18 µg/day of and will be individually and progressively 
titrated to an optimal dose in dose increments of 3 μg/day. 
Study drug, calcium and active vitamin D will be titrated according to the Titration Algorithm 
(Appendix 2) on each occasion serum calcium is measured.     
Dose range for the trial will be supported by 3 pen presentations delivering discrete doses of 6, 9, 
and 12 µg/day; 15, 18, and 21 µg/day; and 24, 27 and 30 µg/day, respectively. The TransCon 
PTH allowed dose range will be 6-60 µg/day. 
Following successful completion of the Blinded Treatment Period, subjects will be allowed to 
enter the open-label Extension Period when all subjects will receive TransCon PTH. 
Because the potential for TransCon PTH to be a hormone replacement therapy is being assessed 
in this trial, a goal is for subjects to achieve independence from standing doses of calcitriol and 
alfacalcidol, and to progressively reduce calcium supplements to ≤600 mg/day (a dose 
considered as “supplemental” to meeting recommended daily intake for general health, as 
opposed to a “therapeutic” dose to treat HP).  The progressive cessation of calcitriol, 
alfacalcidol, and calcium should occur while increasing the dose of TransCon PTH to achieve 
normocalcemia. 
Per the Schedule of Events, initial study visits and LVs occur relatively frequently to 
accommodate dose titration of TransCon PTH, and occur less frequently later on (see 
Appendix 3 and Appendix 4). 
The trial consists of: 
• Screening Period (supplement optimization): Up to approximately 4 weeks (plus a 
recommended period of up to approximately 2 weeks between randomization and Visit 1) 
• Blinded Treatment Period (study drug and SoC optimization): 26 weeks 
• Extension Period (open-label TransCon PTH treatment): 156 weeks  
The total duration of participation for each subject is expected to last up to approximately 
190 weeks (including follow up telephone contact 2 weeks after last study drug administration). 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 64 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Figure 7: 
Trial Design  
 
 
7.2.1. 
Measures Taken to Maximize Study Integrity and Minimize Bias  
Subject visits should be performed at approximately the same time of day, and preferably in the 
morning hours.  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 subject retention 
• Investigators will be instructed to encourage subjects to complete all trial visits, including 
any subjects who discontinue the study drug early 
• The Informed Consent Form (ICF) will include a statement educating subjects about the 
scientific importance of their data even if the subject discontinues study drug early 
• Special efforts will be made to provide assistance to subjects/families who might discontinue 
due to travel or cost barriers, such as offers of free transportation to the clinic 
• All trial visits have visit windows to allow flexibility for clinic attendance (see Schedule of 
Events, Appendix 3) 
• Every effort will be made to contact subjects or other family members to maintain contact 
with the clinic  
• To minimize individual investigator bias, Appendix 2 provide standardized guidelines for 
withdrawal/adjustment of SoC and titration of TransCon PTH based on objective laboratory 
tests and subjects’ experience of hypo- or hypercalcemic symptoms.  Additionally, the 
Medical Monitor will perform timely review of albumin-adjusted sCa and/or ionized sCa 
results and prescribed dosing to confirm investigator compliance with Appendix 2  
* Plus a maximum of 2 weeks between randomization and VI 
** Target Week for visits between v 16 and V26: See Appendix 3 
Extension Period 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 65 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
7.3. 
TRIAL SITES  
The trial will be conducted at up to approximately 40 sites.  All centers will be specialized 
treatment centers in the management of HP. 
8. 
TRIAL POPULATION  
Approximately 76 male and female adults with postsurgical chronic HP or autoimmune, genetic, 
or idiopathic HP, for at least 26 weeks; treated with either calcitriol ≥0.5 μg/day or alfacalcidol 
≥1.0 μg/day and elemental calcium ≥800 mg/day for at least 12 weeks prior to Screening; and 
have a 24-hour uCa excretion ≥125 mg/24 hr, may enter the Screening Period. 
Note: The thresholds for calcitriol, alfacalcidol, and calcium are provided above in total 
daily doses. Acknowledging that the total daily doses may be taken in divided doses 
throughout the day, the corresponding thresholds would be calcitriol ≥0.25 μg BID; 
alfacalcidol ≥0.50 μg BID; calcium ≥400 mg BID. 
8.1. 
TRIAL ENTRY CRITERIA  
8.1.1. 
Inclusion Criteria  
1. Males and females, ≥18 years of age 
2. Subjects with postsurgical chronic HP, or auto-immune, genetic, or idiopathic HP for at least 
26 weeks. Diagnosis of HP is established based on a history of hypocalcemia in the setting of 
inappropriately low serum PTH levels (Hypocalcemia is defined as a value below the 
reference range for normal at the performing laboratory.  Inappropriately low serum PTH 
levels are defined as at or below the median value of the reference range for normal at the 
performing laboratory while the concomitant serum calcium is low.  If specific lab results at 
the time of original diagnosis are not available, as historical diagnosis affirming these two 
components is adequate for inclusion) 
3. Requirement for doses of SoC (e.g., calcitriol, alfacalcidol, calcium supplements) at or above 
a minimum threshold:  
• For countries other than Japan: requirement for a dose of calcitriol ≥0.5 μg/day, or 
alfacalcidol ≥1.0 μg/day and (elemental) calcium ≥800 mg/day (e.g., calcium citrate, 
calcium carbonate etc.) for at least 12 weeks prior to Screening*. In addition, the dose of 
calcitriol, or alfacalcidol, or calcium should be stable for at least 5 weeks prior to 
Screening 
• For Japan: requirement for a dose of calcitriol ≥1.0 µg/day, or alfacalcidol ≥2.0 µg/day 
for at least 12 weeks prior to Screening*.  In addition, the dose of calcitriol or alfacalcidol 
should be stable** for at least 5 weeks prior to Screening.  In Japan only (due to local 
practice and dietary patterns), there is no requirement to exceed a minimum dose of 
calcium supplements    
* Excluding individuals receiving PTH-like drugs within 12 weeks of the screening visit, who 
need only demonstrate a stable requirement for elemental calcium and active vitamin D above 
minimum thresholds for 5 weeks prior to the screening visit. 
** Does not preclude occasional (≤2/week) PRN doses of calcium and/or active vitamin D for 
symptomatic hypocalcemia 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 66 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
4. Optimization of supplements prior to randomization to achieve the target serum levels of:  
• 25(OH) vitamin D levels of 20-80 ng/mL (49-200 nmol/L) and 
• Magnesium level in the normal range, or just below the normal range i.e.: ≥1.3 mg/dL 
(0.53 mmol/L) and 
• Albumin-adjusted or ionized sCa level in the normal range, or *just below the normal 
range, i.e.: 
− 
Albumin-adjusted sCa 7.8-10.6 mg/dL (or 1.95-2.64 mmol/L) 
− 
Ionized sCa 4.40-5.29 mg/dL (or 1.10-1.32 mmol/L) 
* Just below the normal range implies the numerical range of 7.8-8.2 mg/dL (or 1.95-2.06 mmol/L) for 
albumin-adjusted sCa and the numerical range of 4.40-4.636 mg/dL (or 1.10-1.159 mmol/L) for 
ionized sCa. 
5. The subject demonstrates a 24-hour uCa excretion of ≥125 mg/24h (on a sample collected 
within 52 weeks prior to Screening or during the Screening Period)  
Note: Although 24-hour urine samples prior to Screening may be done on or off 
thiazide therapy, thiazide therapy is prohibited during the trial; and the 24-hour urine 
collection scheduled prior to Visit 1 must be done while off thiazides for at least 4 weeks 
prior to collection   
6. BMI 17- 40 kg/m2 at Screening  
7. If ≤25 years of age, radiological evidence of epiphyseal closure based on X-ray of 
non-dominant wrist and hand 
8. Thyroid-stimulating hormone (TSH) within normal laboratory limits within the 6 weeks prior 
to Visit 1; if on suppressive therapy for a history of thyroid cancer, TSH level must be 
≥0.2 mIU/L 
9. If treated with thyroid hormone replacement therapy, the dose must have been stable for at 
least 5 weeks prior to Screening 
10. eGFR ≥30 mL/min/1.73 m2 during Screening 
11. Able to perform daily SC self-injections of study drug (or have a designee to perform 
injections) via a pre-filled injection pen 
12. Able and willing to provide written and signed ICF in accordance with GCP 
13. For France only: The subject is obligated to be affiliated with, or beneficiary of a social 
security system or assimilated. 
8.1.2. 
Exclusion Criteria  
1. Impaired responsiveness to PTH (pseudohypoparathyroidism) which is characterized as 
PTH-resistance, with elevated PTH levels in the setting of hypocalcemia 
2. Any disease that might affect calcium metabolism or calcium-phosphate homeostasis or PTH 
levels other than HP, such as active hyperthyroidism; Paget disease of bone; severe 
hypomagnesemia; type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus 
(HbA1C >9%, documented HbA1C result drawn within 12 weeks prior to Screening is 
acceptable); severe and chronic liver, or renal disease; Cushing syndrome; multiple 
myeloma; active pancreatitis; malnutrition; rickets; recent prolonged immobility; active 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 67 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
malignancy (other than low-risk well differentiated thyroid cancer or non-melanoma skin 
cancer); active hyperparathyroidism; parathyroid carcinoma within 5 years prior to 
Screening; acromegaly; or multiple endocrine neoplasia types 1 and 2  
3. High risk thyroid cancer within 2 years, requiring suppression of TSH <0.2 mIU/L 
4. Use of loop diuretics, phosphate binders (other than calcium supplements), digoxin, lithium, 
methotrexate, biotin >30 µg/day, or systemic corticosteroids (other than as replacement 
therapy) 
5. Use of thiazide diuretic within 4 weeks prior to the 24-hour urine collection scheduled to 
occur within 1 week prior to Visit 1 
6. Use of PTH-like drugs (whether commercially available or through participation in an 
investigational trial), including PTH(1-84), PTH(1-34), or other N-terminal fragments or 
analogs of PTH or PTH-related protein, within 4 weeks prior to Screening 
7. Use of other drugs known to influence calcium and bone metabolism, such as calcitonin, 
fluoride tablets (>0.5 mg/day), strontium, or cinacalcet hydrochloride, within 12 weeks prior 
to Screening 
8. Use of osteoporosis therapies known to influence calcium and bone metabolism, i.e., 
bisphosphonate (oral or intravenous [IV]), denosumab, raloxifene, or romosozumab therapies 
within 2 years prior to Screening 
9. Non-hypocalcemic seizure disorder with a history of a seizure within 26 weeks prior to 
Screening 
Note: History of seizures that occur in the setting of hypocalcemia is not exclusionary 
10. Increased risk for osteosarcoma, such as those with Paget's disease of bone or unexplained 
elevations of alkaline phosphatase, hereditary disorders predisposing to osteosarcoma, or 
with a prior history of substantial external beam or implant radiation therapy involving the 
skeleton 
11. Pregnant or lactating women  
Note: Acceptable highly effective contraception (see Appendix 1) is required for sexually 
active women of childbearing potential during the trial and for 2 weeks after the last 
dose of study drug, and pregnancy testing will be performed throughout the trial.  
Sexually active women of childbearing potential who are unwilling to use acceptable 
highly effective contraception are excluded from the trial 
12. Male who has a female partner who intends to become pregnant or is of childbearing 
potential and is unwilling to use adequate contraceptive methods during the trial 
Note: Male subjects must use a condom, or his female partner of childbearing potential 
must use an effective form of contraception (as per CTFG definition), from the 
beginning of screening to the last trial visit  
13. Diagnosed drug or alcohol dependence within 3 years prior to Screening 
14. Disease processes that adversely affect gastrointestinal absorption, including but not limited 
to short bowel syndrome, significant small bowel resection, gastric bypass, tropical sprue, 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 68 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
active celiac disease, active ulcerative colitis, active Crohn’s disease, gastroparesis and AIRE 
gene mutations with malabsorption  
15. Chronic or severe cardiac disease within 26 weeks prior to Screening including but not 
limited to congestive heart failure, myocardial infarction, severe or uncontrolled arrhythmias, 
bradycardia (resting heart rate <48 beats/minute, unless chronic and asymptomatic), 
symptomatic hypotension or systolic BP <80 mm Hg or diastolic <40 mm Hg or poorly 
controlled hypertension (systolic BP >165 mm Hg or diastolic >95 mm Hg).  In the absence 
of a prior history of hypertension, an isolated BP >165/95 in the setting of white coat 
hypertension/anxiety may not be exclusionary and a measurement can be repeated prior to 
randomization 
16. Cerebrovascular accident within 5 years prior to Screening 
17. Within 26 weeks prior to Screening: acute colic due to nephrolithiasis, or acute gout. 
Subjects with asymptomatic renal stones are permitted 
18. Participation in any other interventional trial in which receipt of investigational drug or 
device occurred within 8 weeks (or within 5.5 times the half-life of the investigational drug) 
(whichever comes first) prior to Screening 
19. Any disease or condition that, in the opinion of the investigator, may require treatment or 
make the subject unlikely to fully complete the trial, or any condition that presents undue risk 
from the investigational product or procedures, including treated malignancies that are likely 
to recur within the approximate 3.5-year duration of the trial 
20. Known allergy or sensitivity to PTH or any of the excipients [metacresol, mannitol, succinic 
acid, NaOH/(HCl)] 
21. Likely to be non-compliant with respect to trial conduct 
22. Any other reason that in the opinion of the investigator would prevent the subject from 
completing participation or following the trial schedule 
8.2. 
SUBJECT WITHDRAWAL/DISCONTINUATION  
A subject may withdraw from the study at any time at his/her own request or may be 
discontinued at any time at the discretion of the investigator for safety, behavioral, or compliance 
reasons. This is expected to be uncommon. 
Additionally, the investigator may discontinue the treatment of a subject at any time if 
considered to be in the subject's best interest. 
In the case of subject discontinuation, the investigator should schedule an Early Termination 
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, see Section 10.1.8.  Individual assessments may 
be waived if the subject refuses to participate, if they have been done recently and/or are not 
deemed appropriate or required. Such instances shall be discussed with the Medical Monitor.  
For subjects that discontinue study drug for reasons related to safety, unblinding of the treatment 
assignment for the subject 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 subject. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 69 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
The investigator/site staff should make every attempt to contact the subject via phone to arrange 
the appropriate follow-up assessment(s) for such subjects. 
Data obtained until trial discontinuation will be used in the statistical analyses. 
See Section 10.1.8 for details on Early Termination Visit. 
8.2.1. 
Study Drug Discontinuation  
8.2.1.1. 
Study Drug Discontinuation during Blinded Treatment Period  
Unless informed consent is withdrawn*, subjects who permanently discontinue study drug 
during the Blinded Treatment Period should:  
• Attend all subsequent visits within the Blinded Treatment Period 
• Complete an Early Termination Visit in place of Visit 10  
• Not continue into the Extension Period   
All efforts should be made for subject to continue in the Blinded Treatment Period even if study 
drug is discontinued.  
* If the subject is not willing to attend all subsequent trial visits within the Blinded Treatment 
Period, this should be considered a withdrawal of consent and an Early Termination Visit should 
be scheduled.  
See Section 10.1.8 on Early Termination Visit.  
8.2.1.2. 
Study Drug Discontinuation during Extension Period  
Subjects who permanently discontinue study drug during the Extension Period should be 
withdrawn from the trial and an Early Termination Visit should be scheduled immediately. 
See Section 10.1.8 for details on Early Termination Visit.  
9. 
TREATMENTS  
9.1. 
INVESTIGATIONAL PRODUCT  
TransCon PTH drug product is supplied as a solution with a concentration of 0.3 mg 
PTH(1-34)/mL in a single-patient-use prefilled pen intended for SC injection.  Excipients include 
metacresol, mannitol, succinic acid, and NaOH/(HCl).  The prefilled pens are stored in the 
refrigerator until first use; the TransCon PTH drug product is stable at room temperature below 
86°F (30°C) for the 14 days in-use period when dosing with the pre-filled pen. 
Three presentations of the prefilled pen containing TransCon PTH drug product and the three 
pen presentations are 6, 9, and 12 µg/day; 15, 18, and 21 µg/day; and 24, 27 and 30 µg/day, 
respectively.  
Refer to the Investigator’s Brochure Section 3 – Physical, Chemical, and Pharmaceutical 
Properties and Formulations for details on the composition and characteristics of TransCon PTH 
and the Pharmacy Manual and instructions for use (IFU) for complete details on storage and 
handling. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 70 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
9.1.1. 
Reference Product  
The placebo for TransCon PTH drug product (excipient solution in the pens) are in three pen 
presentations to mimic dose ranges of 6, 9, and 12 µg/day; 15, 18, and 21 µg/day; and 24, 27 and 
30 µg/day within the Blinded Treatment Period. 
9.1.2. 
Labeling  
All study drug will be labeled according to current Good Manufacturing Practice and local 
regulatory requirements.  The labels carry unique identification pack numbers.  Subjects will be 
provided with dosing and storage instructions. 
9.1.3. 
Accountability, Storage, and Dispensing  
Investigator or delegated site staff 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 access limited to designated trial staff and stored according to its labeling.  Investigator or 
dedicated trial staff must evaluate the storage temperature and inform Sponsor immediately if 
study drug has been stored outside the specified conditions on the label.  The trial will use an 
internet-based interactive response technology (IRT) system as source to capture drug inventory 
and accountability data, including receipt of drug inventory and supplies by the site, treatment 
assignment for each subject, dispensing to subjects, return to the site from subjects, and return to 
the contracted parties (or destruction with the Sponsor’s approval).  The IRT 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]. 
Direct-to-subject shipments of study drug from investigational sites will be allowed in 
exceptional cases in which subjects might not be able to attend on-site visits and risk continued 
access to study drug for subjects. 
Investigator or delegated site staff will be responsible for study drug/pen accountability and 
reconciliation of study drug. 
Site staff will provide training on proper storage and study drug administration to each subject at 
Visit 1.  This training will include a review of the IFU and on-site administration of the first dose 
of study drug by the subject.  A copy of the IFU will be provided to the subject for reference at 
home. 
Note: Under no circumstances will the investigator allow study drugs to be used other than 
as directed by this protocol. 
See Pharmacy Manual and IFU for further details. 
9.1.4. 
Post-trial Treatment  
After the end of the trial, the investigator must advice trial subject on access to appropriate and 
available treatment. Such treatment will not be funded by Sponsor. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 71 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
9.2. 
TREATMENT ADMINISTERED  
The TransCon PTH delivery system consists of a multi-use cartridge integrated into a modified 
Ypsomed UnoPen Fix pen injector using 31Gx5 mm pen needles.  The cartridge contains 
compounded solution of TransCon PTH or placebo for TransCon PTH with a fill volume 
sufficient for 14 doses.  Each study drug administration is in a volume ≤100 μL (6 µg/day in 
volumes of 20 µL, 9 µg/day in volumes of 30 µL, 12 µg/day in volumes of 40 µL, 15 µg/day in 
volumes of 50 µL, 18 µg/day in volumes of 60 µL, 21 µg/day in volumes of 70 µL, 24 µg/day in 
volumes of 80 µL, 27 µg/day in volumes of 90 µL, or 30 µg/day in volumes of 100 µL), and is to 
be self-administered (following training by study staff).  There is a total of 4 possible injection 
areas: right abdomen, left abdomen, right anterior thigh, and left anterior thigh, and multiple 
sub-areas within each area.  Subjects should be instructed to rotate injection sites. Refer to the 
IFU for complete instructions on administration. 
Although the starting dose is 18 µg PTH or placebo (using the mid-dose pen), throughout the 
entire trial (including Blinded and Open Label Treatment Period), all three pen presentations are 
available for TransCon PTH or corresponding placebo allowing for dose increments of 3 µg (6, 
9, and 12 µg; 15, 18, and 21 µg; and 24, 27 and 30 µg, respectively). 
The study drug allowed dose range will be 6-60 µg/day. All doses >30 µg/day will be delivered 
in the form of two single doses injected one after another at different injection sites using two 
pens of the same pen presentation, except for the 45 µg/day dose which will be delivered as a 
combination of the mid-dose and high-dose pen presentations as shown in Table 1. Based on the 
design verification data for the pen presentations (at standard atmosphere conditions), dose 
accuracy data for a given combination of doses from two pens has been evaluated against the 
acceptance criteria for dose accuracy. The combinations presented in Table 1 will deliver the 
desired doses within the specifications for dose accuracy. Two injections will be given shortly 
after each other and the dose can therefore be considered the sum of the two injections. 
Table 1: 
Recommended Dosing Schemes >30 µg PTH(1-34)/Day or Placebo  
Dose 
Dosing Scheme 
Pen Combination 
33 µg/day 
18 µg/day + 15 µg/day 
Two mid-dose pens 
36 µg/day 
18 µg/day + 18 µg/day 
Two mid-dose pens 
39 µg/day 
21 µg/day + 18 µg/day 
Two mid-dose pens 
42 µg/day 
21 µg/day + 21 µg/day 
Two mid-dose pens 
45 µg/day 
24 µg/day + 21 µg/day 
Mid-dose and high-dose pens 
48 µg/day 
24 µg/day + 24 µg/day 
Two high-dose pens 
51 µg/day 
27 µg/day + 24 µg/day 
Two high-dose pens 
54 µg/day 
27 µg/day + 27 µg/day 
Two high-dose pens 
57 µg/day 
30 µg/day + 27 µg/day 
Two high-dose pens 
60 µg/day 
30 µg/day + 30 µg/day 
Two high-dose pens 
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 72 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
9.3. 
SELECTION OF TRIAL DOSES  
The 4-week Blinded Treatment Period of the Phase 2 trial - with fixed dosing of TransCon PTH 
15, 18, and 21 µg/day -  demonstrated that a dose of 18 µg/day was both effective and well-
tolerated, with less hypercalcemia compared to a dose of 21 µg/day and without meaningful 
hypocalcemia. Preliminary data from the open label extension of the Phase 2 trial as of February 
2021 demonstrates comparable safety profiles at doses of both 15 and 18 µg/day. The dose 
distribution during the open label extension has been 6-39 µg/day, titrated to achieve 
normocalcemia. Phase 2 data demonstrates no meaningful difference in AEs, including those 
related to hypo- or hypercalcemia, on TransCon PTH doses <15 µg/day or >21 µg/day. 5-10% of 
participants are anticipated to require doses >30 µg/d to achieve normocalcemia in the present 
trial. Therefore, the starting dose for the Blinded Treatment Period will be 18 µg/day, followed 
by titration to 6-60 µg/day to achieve normocalcemia and independence from conventional 
therapy.   
9.4. 
TREATMENT ASSIGNMENT  
9.4.1. 
Treatment Assignment During Blinded Treatment Period  
Subjects will be randomized 3:1 into TransCon PTH or placebo. 
• TransCon PTH 18 µg/day, co-administered with SoC 
• Placebo for TransCon PTH, co-administered with SoC  
− 
Mimicking dose of 18 µg/day 
All subjects will start with study drug 18 µg/day and will be individually and progressively 
titrated to an optimal dose in dose increments of 3 μg/day. 
9.4.2. 
Treatment Assignment During Open-Label Extension Period  
At Visit 10 (Week 26), subjects will be assigned to open-label treatment as follows: 
• If still taking active vitamin D: Start TransCon PTH at a dose of 18 µg/day, and 
subsequently follow the titration algorithm as per Appendix 2  
• If NOT taking active vitamin D:  
− 
And taking study drug ≥30 µg/day: Start TransCon PTH at a dose of 18 µg/day, 
and subsequently follow the titration algorithm per Appendix 2 
− 
And taking study drug <30 µg/day: Start TransCon PTH at the same dose of study 
drug taken at the end of the Blinded Treatment Period. Exception: in cases of an out-
of-range sCa level at Visit 10, adjust the TransCon PTH and/or calcium doses as per 
Appendix 2 
9.5. 
DOSE ADJUSTMENTS  
9.5.1. 
Screening Period Supplement Dose Adjustments  
During the Screening Period, adjustments to doses of HP-related supplements [SoC (active 
vitamin D – calcitriol, alfacalcidol – and calcium), magnesium, vitamin D] will be made to 
achieve the following laboratory levels: 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 73 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
• 25(OH) vitamin D: 20-80 ng/mL (49-200 nmol/L) 
• Magnesium within the normal range or just below the normal range i.e.: ≥1.3 mg/dL 
(0.53 mmol/L)  
• Albumin-adjusted or ionized sCa: within the normal range, or just below the normal range, 
i.e.: 
− 
Albumin-adjusted sCa 7.8-10.6 mg/dL (or 1.95-2.64 mmol/L) 
− 
Ionized sCa 4.40-5.29 mg/dL (or 1.10-1.32 mmol/L)  
Therapeutic doses of calcitriol, alfacalcidol, calcium, magnesium and vitamin D3 are adjusted 
only after initial Screening laboratory results are received.  Follow-up laboratory assessments of 
the above values, with exception of 25(OH) vitamin D levels, are performed approximately 
3 days after every dose adjustment during the Screening Period.  25(OH) vitamin D level may be 
rechecked ≥7 days from any dose change.  If required, additional dose adjustments, with 
follow-up laboratory assessments approximately 3 days later, may be performed throughout the 
Screening Period.  
9.5.2. 
Blinded Treatment Period (Visits 1-10; Weeks 0-26) Dose Adjustments  
9.5.2.1. 
SoC Dose Adjustments during Blinded Treatment Period  
Visit 1: Start study drug 18 µg/day and decrease active vitamin D dose by 33-50% (e.g., skip 
2nd dose of the day if taking BID, skip final dose of the day if taking three times daily (TID), or 
reduce once daily dose of alfacalcidol ≥1.0 µg by 50% (≥0.5 µg). 
Subsequently, active vitamin D and/or calcium doses should be titrated as per Appendix 2. The 
target vitamin D range during treatment phases of this trial is 30-80 ng/mL 
SoC adjustments should be made preferably within 48 hours of blood collection.   
Because this trial is assessing the potential for TransCon PTH to be a parathyroid hormone 
replacement therapy, a goal is for subjects to achieve independence from standing doses of 
calcitriol, alfacalcidol, and calcium supplements.  
Note: In case needed to meet recommended dietary intake of calcium, it is permitted to 
take calcium supplements ≤600 mg/day as a nutritional supplement for the sake of reaching 
the recommended dietary intake. The calcium dose of ≤600 mg/day is considered as 
“supplemental” to meeting recommended daily intake for general health, as opposed to a 
“therapeutic” dose to treat hypoparathyroidism. The progressive cessation of calcitriol, 
alfacalcidol, and calcium should occur while increasing the dose of TransCon PTH to 
achieve normocalcemia. 
9.5.2.2. 
Study Drug Dose Adjustments During Blinded Treatment Period  
All subjects will start with 18 µg/day of study drug. The study drug dose will be individually and 
progressively titrated in dose increments of 3μg/day with the goal to achieve normocalcemia as 
shown in Appendix 2.  
Study drug doses can be increased by 3 µg/day as long as ≥7 days have elapsed since a prior 
dose adjustment in study drug.  Gradual increases in study drug doses may facilitate gradual 
reduction and eventual cessation of SoC. Alternatively, study drug doses can be decreased by 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 74 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
3 µg/day for serum calcium levels that continue to be high even after all SoC has been 
withdrawn.   
Serum calcium results from local laboratory analysis will be used to guide titration of study drug.  
Central laboratory results will be definitive for data analysis. 
9.5.3. 
Extension Period (Visits 10+; Weeks 26+) Dose Adjustments  
9.5.3.1. 
SoC Dose Adjustments during Extension Period  
At Visit 10 (Week 26), the following categories of subjects will start TransCon PTH 18 µg/day. 
• Those still taking active vitamin D (this group may be enriched with subjects initially 
randomized to placebo) 
• Those off active vitamin D and taking study drug ≥30 µg/day  
As such, when selecting the appropriate doses of SoC (active vitamin D and calcium 
supplements) to accompany the TransCon PTH 18 µg/day, investigators are advised to: 
• Consider the doses of active vitamin D and calcium required at trial baseline (before 
exposure to the study drug)  
AND 
• Reduce the active vitamin D (taken before exposure to study drug) by 33-50% when starting 
TransCon PTH 18 µg/day at Visit 10 
Start the new SoC regimen: 
• On the day of Visit 10 for those subjects who are still taking active vitamin D at the time of 
Visit 10 
• On the day after Visit 10 for those subjects who are off active vitamin D and taking study 
drug ≥30 µg/day at Visit 10 
9.5.3.2. 
TransCon PTH Dose Adjustments during Extension Period  
For subjects still taking active vitamin D at Visit 10: Start TransCon PTH at a dose of 18 µg/day 
at Visit 10, and subsequently follow the titration algorithm as per Appendix 2. 
For subjects not taking active vitamin D at Visit 10 and taking study drug dose ≥ 30 µg/day: 
Start TransCon PTH at a dose of 18 µg/day at Visit 10, and subsequently follow the titration 
algorithm per Appendix 2. 
For subjects not taking active vitamin D at Visit 10 and taking study drug dose < 30 µg/day: 
Start TransCon PTH at Visit 10 at the same dose of study drug taken at the end of the Blinded 
Treatment period. Exception: in cases of an out-of-range sCa level at Visit 10, adjust the 
TransCon PTH and/or calcium doses as per Appendix 2.  
The TransCon PTH dose selection at Visit 10 is also demonstrated in the decision tree below in 
Figure 8. 
TransCon PTH doses can be increased by 3 µg/day as long as ≥7 days have elapsed since a prior 
dose adjustment in study drug.  Gradual increases in TransCon PTH doses may facilitate gradual 
reduction and eventual cessation of SoC. Alternatively, TransCon PTH doses can be decreased 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 75 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
by 3 µg/day for serum calcium levels that continue to be high even after all SoC has been 
withdrawn. 
Figure 8: 
Decision Tree for TransCon PTH Dose Selection at Visit 10 (Week 26)  
 
 
9.6. 
STUDY DRUG DOSE CHANGES, INTERUPTIONS, OR STOPPING  
9.6.1. 
Dose changes and Treatment Interruptions  
The investigator may change the dose, and/or temporarily hold the study drug for an individual 
subject as per the dose titration algorithm (Appendix 2). 
The investigator will determine dose changes and/or study drug holding/stopping for the 
following situations: 
• Persistent hypocalcemia with albumin-corrected serum calcium <8.3 mg/dL1 for >7 days 
despite all of the following: 
− 
increases in doses of (and adherence to) study drug, calcium supplements, and active 
vitamin D  
− 
maximum protocol permitted dose of study drug  
                                                 
1 Thresholds for albumin-corrected serum calcium: <8.3 mg/dL (<2.07 mmol/L), or ionized calcium: <1.16 mmol/L 
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 76 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
• Persistent severe hypocalcemia with albumin-corrected serum calcium <7.0 mg/dL2 for 
>7 days despite: 
− 
increases in (and adherence to) study drug, calcium supplements, and active vitamin 
D 
− 
medical intervention (e.g. intravenous calcium infusions, urgent/emergency care, 
hospitalization) as needed and at the discretion of the investigator 
• Persistent hypercalcemia with albumin-corrected serum calcium >10.6 mg/dL3 for >7 days 
despite all of the following: 
− 
cessation of active vitamin D and calcium supplements 
− 
study drug dose 6 µg/day 
• Persistent severe hypercalcemia with albumin-corrected serum calcium ≥12.0 mg/dL4 for 
>7 days despite: 
− 
cessation of active vitamin D and calcium supplements 
− 
decreases in/cessation of study drug 
− 
oral hydration 
− 
medication intervention (e.g. intravenous fluids, urgent/emergency care, 
hospitalization) as at the discretion of the investigator 
• Persistent vasodilatory symptoms that cannot be corrected with adjustments to study drug 
• Any other study-drug related severe adverse event, or serious adverse event, that warrants 
holding or discontinuing study drug at the discretion of the investigator and/or medical 
monitor 
• “Non-responders” to TransCon PTH may be evaluated for discontinuation of TransCon PTH 
therapy, after a discussion between the investigator and medical monitor during the open 
label Extension Period of the trial 
− 
A “non-responder” to TransCon PTH is a subject taking the maximum dose of 
TransCon PTH 60 µg/day for at least 39 weeks, who is unable to reduce standing or 
as-needed doses of SoC as compared to his/her baseline requirements for 
conventional therapy (i.e. has symptoms and/or low serum calcium if conventional 
therapy is reduced below study baseline requirements).  If reduction in conventional 
therapy remains impossible at the end of 39 weeks, the patient may discontinue 
TransCon PTH. The selection of a 39-week duration recognizes there may be rare 
instances where subjects temporarily have significantly accelerated clearance of 
TransCon PTH that is expected to spontaneously resolve by approximately 26-35 
weeks (and thus be associated with a reduction in a subject’s dose requirement of 
TransCon PTH)  
                                                 
2 Thresholds for albumin-corrected serum calcium: <7.0 mg/dL (<1.75 mmol/L), or ionized calcium: <0.95 mmol/L 
3 Thresholds for albumin-corrected serum calcium: >10.6 mg/dL (>2.64 mmol/L), or ionized calcium: >1.32 mmol/L 
4 Thresholds for albumin-corrected serum calcium: ≥12.0 mg/dL (≥3.00 mmol/L), or ionized calcium: ≥1.50 mmol/L 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 77 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Persistent severe hypocalcemia and persistent severe hypercalcemia (as defined above) will be 
reported to the regulatory authorities, based on local requirements.  
See Section 8.2.1 for further guidance on study drug discontinuation. 
9.6.2. 
Required Stopping  
The investigator, with Sponsor medical monitor notification, must stop the study drug for an 
individual subject at any time during the trial in the presence of the following: 
• Evidence of a severe hypersensitivity to TransCon PTH  
• Confirmed neutralizing anti-PTH antibodies that correlate with reduced PD response  
• Suspicion of osteosarcoma (e.g., persistent localized pain or occurrence of a new soft tissue 
mass tender to palpation that could be consistent with osteosarcoma, in association with an 
elevation of bone-specific alkaline phosphatase)  
• Pregnancy  
Ascendis medical monitors will immediately notify the Data Monitoring Committee (DMC) and 
Ascendis pharmacovigilance of any such events for evaluation of potential broader safety 
concerns 
9.7. 
TREATMENT COMPLIANCE  
Compliance of both study drug and SoC doses will be assessed based on review of the subject 
diary and returned pens at every clinic visit.  
9.8. 
STANDARD OF CARE  
SoC will not be provided by the Sponsor acknowledging the preferred and prescribed type of 
calcium salt, active vitamin D analog, and ratio of calcium to active vitamin D may differ among 
prescriber, patient, and global region (Babey 2018).  For example, the prescribed active vitamin 
D or analog and calcium salt may be based on prescriber/individual subject/local preference and 
availability.  The calcium salts are known to differ with respect to ease of absorption, 
requirement of gastric acid for absorption, content (percentage) of elemental calcium - and thus 
size of tablet.  Finally, the proportions of active vitamin D to calcium supplements may also 
differ based on local practice and diet patterns, and effects on individual subject.  Thus, calcium 
and active vitamin D regimens are highly individualized around the world. Therefore, the trial 
permits subjects to continue taking the SoC they were taking prior entering into the trial. 
However, SoC may be reimbursed by the Sponsor; handling of reimbursement for such expenses 
should follow national legislation and/or guidance. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 78 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
9.9. 
PRIOR AND CONCOMITANT THERAPIES  
9.9.1. 
Required HP Therapies  
Prior to Screening, subjects must be taking doses of the following SoC HP treatments for at least 
12 weeks with a minimum of 5 weeks being stable on these doses: 
• Calcitriol ≥0.5 µg/day or alfacalcidol ≥1.0 µg/day and 
• Elemental calcium ≥800 mg/day (e.g., calcium citrate, calcium carbonate, etc.)   
Note: The thresholds for calcitriol, alfacalcidol, and calcium are provided above in total 
daily doses. Acknowledging that the total daily doses may be taken in divided doses 
throughout the day, the corresponding thresholds would be calcitriol ≥0.25 μg BID; 
alfacalcidol ≥0.50 μg BID; calcium ≥400 mg BID 
Subjects should receive calcium supplementation in the form of calcium citrate in case of 
concomitant use of proton pump inhibitors or anti-acid therapies. 
Subjects may also be on cholecalciferol (vitamin D3) and magnesium supplements as part of 
their HP treatment or to achieve the recommended daily allowance (RDA), as needed to maintain 
target ranges of each. The 25 (OH) vitamin D target range is 30-80 ng/mL during treatment 
phases of the trial. Subjects are to be instructed to take their HP-related supplements at 
approximately the same time every day throughout the trial. Subjects taking a thiazide diuretic 
should discontinue at least 4 weeks prior to the baseline Screening 24-hour urine collection 
scheduled during the week prior to Visit 1.   
9.9.2. 
Prohibited Therapies  
The following therapies are prohibited during the blinded phase: 
• PTH therapies other than TransCon PTH 
• Thiazide or loop diuretics  
• Phosphate binders (other than calcium supplements) 
• Digoxin, lithium, methotrexate 
• Systemic corticosteroids (other than as replacement therapy).  Short course use of steroids 
(≤2 weeks/year) ≤40mg/day is permitted 
• Bisphosphonates  
• Denosumab 
• Biotin >30 µg/day 
For the open-label extension period, these medications are allowed only if deemed necessary by 
the investigator for patient safety considerations. Use of bisphosphonates or denosumab requires 
consultation with the Medical Monitor to determine potential impact on integrity of relevant 
endpoints. 
TransCon PTH increases calcium, and therefore concomitant use with digoxin (which has a 
narrow therapeutic index) may predispose patients to digitalis toxicity if hypercalcemia develops. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 79 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
When TransCon PTH is used concomitantly with digoxin, measure serum calcium and digoxin 
levels, and monitor for signs and symptoms of digoxin toxicity. 
See Section 8.1.2  Exclusion Criteria for prohibited prior therapies during the Screening Period.  
10. 
TRIAL PROCEDURES  
10.1. TRIAL DURATION  
Each subject’s participation is expected to last up to approximately 190 weeks including up to 
approximately 4 weeks of Screening, a 182-week treatment period and a 2 weeks of follow up 
period after last study drug administration (plus a recommended period of up to approximately 
2 weeks between randomization and Visit 1). 
10.1.1. Trial Periods and Visits  
See Appendix 3 for Schedule of Events. 
10.1.2. Screening Period (Week -6 to -2, Day -42 to -14)  
The Screening Period will last up to approximately 4 weeks during which clinical data will be 
collected and Screening procedures will be performed to determine eligibility and optimize 
subjects on their HP-related supplements prior to enrollment.  
Prior to any protocol related activities, Screening procedures, or assignment of a Subject 
Number, informed consent will be obtained from each potential subject in accordance with GCP 
and regional regulatory requirements.  The format and content of the ICF must be approved by 
the appropriate institutional review board (IRB)/EC prior to implementation. 
The procedures that must be performed and collected during the Screening Period prior to 
enrollment/randomization are listed within the Schedule of Events (see Appendix 3). 
Multiple local laboratory assessments over the approximate 4 weeks of the Screening Period are 
expected to optimize both the albumin-adjusted or ionized sCa into the normal range, as well as 
the sMg and vitamin D level.  Once the laboratory results are within the optimization ranges and 
all other entry criteria are met, the subject is eligible to move to the Blinded Treatment Period 
and be randomized following confirmation by the Medical Monitor or designee.  Following 
randomization, it is recommended to start the treatment period (Visit 1) within 2 weeks from the 
time of randomization. 
The 24-hour urine collection during Screening can be based on a historic 24-hour uCa performed 
within 52 weeks prior to Screening.  Subjects may have been on thiazides, however, subjects 
must discontinue thiazides at least 4 weeks prior to the baseline 24-hour urine collection 
scheduled within one week prior to Visit 1.  
Investigators are encouraged to provide historical PTH (1-84) values, if available, since HP 
diagnosis of the subjects.  
The Screening Period may be extended with Medical Monitor approval for subjects who fail to 
optimize to the target laboratory ranges within the Screening window. 
Subjects who appear to already be optimized to the target laboratory ranges based on historical 
laboratory results within 4 weeks prior to Screening and show a 24-hour uCa excretion within 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 80 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
the upper portion of the normal range within 52 weeks of Screening require only a 24-hour urine 
collection scheduled within 1 week prior to Visit 1.   
See Section 11 for further details on procedures and assessments listed in the Schedule of Events.  
See Appendix 4 for further details on laboratory assessments to be performed.  
Subjects who sign the ICF 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 subject ID, demography and reason for screen 
failure (eligibility criteria or any other reason as applicable). 
The decision to rescreen will be made on a case by case basis after discussion with the Medical 
Monitor, including which Screening procedures may not need to be repeated.  Documentation for 
rescreening must include date and reason for initial exclusion. 
10.1.3. Blinded Treatment Period (Visit 1 - 10, Day 1 to Week 26)  
Subjects will be randomized in a 3:1 ratio into 2 treatment groups: 
• TransCon PTH 18 μg/day*, co-administered with SoC 
• Placebo for TransCon PTH (excipient solution) 18 μg/day, co-administered with SoC 
* Dose of TransCon PTH refers to dose of PTH(1-34) administered 
See Appendix 3 for assessments to be performed within the Blinded Treatment Period. 
Multiple local laboratory assessments between Visits 2 and 6 may be necessary to guide 
TransCon PTH/placebo and potentially SoC dose adjustment. 
In selected countries, home visits/virtual visits may be performed at Visits 3, 4, 5, 7 and 8 instead 
of on-site visits.  See Section 10.1.7 for further details. 
In selected English speaking countries/sites, approximately 2 weeks prior to the final Blinded 
Treatment Period visit (Visit 10), subjects will be contacted to set up a one-hour phone interview 
to occur within 2 weeks after the final Blinded Treatment Period visit (Visit 10) to discuss their 
experience in the trial. In case of subject discontinuation before or at Visit 10, the phone 
interview will be scheduled to be completed within 2 weeks after the Early Termination Visit. 
The phone interview will be conducted by an external vendor (see Section 11.9.7). 
See Section 11 for further details of procedures and assessments listed in the Schedule of Events.  
See Appendix 4 for further details on laboratory assessments to be performed.  
10.1.4. Extension Period (Visit 10 - 26 (End of Trial visit), Week 26 to 182)  
See Appendix 3 for assessments to be performed within the Extension Period. 
See Section 11 for further details of procedures and assessments listed in the Schedule of Events.  
See Appendix 4 for further details on laboratory assessments to be performed.  
In selected countries, home visits/virtual visits may be performed at Visits 13, 14, 15, 17, 19, 21, 
23, and 25 instead of on-site visits.  See Section 10.1.7 for further details. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 81 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Subjects that show a treatment induced response for either anti-PTH, anti-TransCon or anti-PEG 
antibodies should be followed 4 to 6 weeks after the treatment ends to determine if antibody 
levels revert to baseline. Blood samples may be collected every 3 to 6 months, until antibodies 
can no longer be detected or have a sustained decline. 
10.1.5. Unscheduled Visits  
Unscheduled visits (UVs) are those visits that occur at the clinic between regularly scheduled 
visits at investigator discretion to assess a potential AE, manage an already documented AE, 
and/or confirm an abnormal laboratory value requiring Central Laboratory testing.  Only focused 
assessments (guided by the reason for the visit) will occur at these visits.  Unscheduled local 
laboratory visits (ULVs) do not constitute UVs. 
10.1.6. Unscheduled Lab Visits  
ULVs are those visits that occur at the local laboratory between regularly scheduled visits at 
subject or investigator discretion to assess a potential AE, follow-up on an already documented 
AE, confirm an abnormal laboratory value requiring Local Laboratory testing.  This includes 
assessment of albumin-adjusted or ionized sCa levels if clinical symptoms of hypo- or 
hypercalcemia occur at any time during the trial.  
10.1.7. Home Visits/Virtual Visits  
Home visits/virtual visits may be conducted in place of in-person on-site visits for visits which 
do not require assessments to be performed on site.  Necessary assessments may be performed by 
a home nurse and the investigational site staff may have a telephone/televideo call with the 
subject to follow up on general health, AEs, concomitant medications etc.  A physical 
assessment will be performed by the home nurse under the remote supervision of the 
Investigator. 
10.1.8. Early Termination Visits  
If a subject discontinue the trial prematurely an Early Termination Visit should be performed, if 
possible.   
If the subject discontinuation occur prior to Visit 10, the structure and assessments of the Early 
termination Visit should be as similar as possible to Visit 10.  
If the subject discontinuation occurs after Visit 10, the structure and assessments of the Early 
termination Visit should be as similar as possible to Visit 26.  
10.1.9. Follow up Telephone Contact  
A telephone contact must take place 2 weeks (+7 days) after last study drug administration to 
evaluate AEs that were ongoing at the final trial visit and to evaluate the subject for any further 
AEs during the 2 weeks since last study drug administration.  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 82 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
11. 
ASSESSMENTS  
11.1. MEDICAL HISTORY  
Medical history should include any medical condition, signs, symptoms and illnesses ongoing at 
the time of Informed Consent and must be recorded in the eCRF.  The medical history should 
also capture a detailed description of any prior or ongoing kidney stone, renal insufficiency, 
cataract, and seizure. 
11.2. VITAL SIGN MEASUREMENTS  
Subjects should rest for at least 5 minutes before vital sign measurement.  The following vital 
signs should be measured: 
• Respiratory Rate 
• Body Temperature 
• Orthostatic Blood Pressure (BP) & Heart Rate  
Assure subjects are well hydrated prior to assessing orthostatic changes. 
BP and heart rate are measured while the subject is sitting. The subject is then asked to stand up 
and, within 2 minutes of doing so, BP and heart rate are measured again.  
Orthostasis is defined as a ≥ 20 mmHg decrease in systolic BP, or a ≥10 mmHg decrease in 
diastolic BP, or an increase in heart rate > 20 bpm after standing. Orthostatic hypotension or 
orthostatic tachycardia should be captured as an adverse event of special interest 
(Section 12.1.3 and Section 12.1.4). 
11.2.1. Post-Dose Orthostatic Measurements  
At Visit 1, a set of orthostatic BP and heart rate should be taken 30 minutes after study drug 
administration.  
At Visit 10, a set of orthostatic BP and heart rate should be taken 30 minutes after TransCon 
PTH administration for subjects on active vitamin D at Visit 10 or subjects off active vitamin D 
at Visit 10 and taking study drug ≥ 30 µg/day at the end of the Blinded Treatment Period. 
11.3. PHYSICAL EXAMINATION  
A complete physical examination should be performed at Screening. Subsequent physical 
examinations should be performed according to Schedule of Events (see Appendix 3) and may 
be symptom-directed with the specific components performed at Investigator’s discretion. Height 
and weight will also be measured and recorded at screening.   
11.4. PRIOR AND CONCOMITANT MEDICATION  
Prior and concomitant therapies include all prescription or over-the-counter medications, 
vitamins and herbal/nutritional supplements taken within 26 weeks prior to Visit 1 and through 
the end of the trial, which should be documented with the name of the medication/supplement, 
dosage information including dose, route, and frequency, dates of administration including start 
and end dates, and reason for use.  Past use of PTH compounds within 5 years will be captured. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 83 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
11.5. ELECTROCARDIOGRAM  
An electrocardiogram (ECG) must be performed and read locally during Screening prior to 
Visit 1.  Standard 12-lead ECG, which includes QT interval and Heart Rate, will be recorded 
when the subject is in a resting state, prior to blood collection if performed at the same visit.   
11.6. X-RAY OF NON-DOMINANT WRIST AND HAND  
To confirm epiphyseal closure, an X-ray of the non-dominant wrist and hand must be performed 
and read locally prior to Visit 1 for subjects 25 years old or younger (as of Screening).  A 
historical X-ray showing epiphyseal closure is acceptable.  
11.7. DUAL-ENERGY X-RAY ABSORPTIOMETRY AND TRABECULAR BONE 
SCORE  
To evaluate bone density and quality, a DXA scan of the spine, hip, and forearm, as well as TBS 
scoring must be performed.  TBS scoring will not be performed for subjects 18 to 20 years of 
age.  The DXA images will be read centrally by an external vendor. See the DXA Manual for 
complete details.  The same DXA machine should be used throughout the trial. 
A historical DXA performed within 6 months prior to Screening is acceptable for Screening 
purposes if the same DXA machine will be used throughout the trial and meets the requirements 
outlined in the DXA Manual.  If the historical DXA did not include TBS, TBS analysis should 
be performed. 
11.8. DIETARY CALCIUM QUESTIONNAIRE  
Dietary Calcium Questionnaire is a subject-completed assessment of the subject’s daily dietary 
calcium intake.  After the questionnaire is completed, site will enter data into the International 
Osteoporosis Foundation’s Dietary Calcium Calculator  
(https://www.osteoporosis.foundation/educational-hub/topic/calcium-calculator) and print out the 
calculated results as source documentation to be entered into the electronic data capture (EDC) 
system by the site staff.  Based on the results, site staff will also review and counsel subject to 
maintain a reasonably stable dietary calcium intake during the trial, potentially optimizing their 
nutritional calcium intake to get close to the RDA, as well as avoiding unhealthy intake of 
sodium that can contribute to hypercalciuria.  
11.9. CLINICAL OUTCOME ASSESSMENTS  
Five subject-completed patient-reported outcome (PRO) measures, and a ClinRO measure will 
be used in this trial.  In countries where the HPES and other measures are available, all 
participants will be expected to complete the HPES and the other available measures.  
Note: All PROs must be completed by the subject without assistance and prior to 
conducting any clinical assessments.   
11.9.1. Hypoparathyroidism Patient Experience Scale  
The HPES measures are disease-specific PROs that were developed and validated by the 
Sponsor to assess relevant patient-reported symptom and disease impacts.  The HPES-Symptom 
assesses the key HP-related physical and cognitive symptoms from the patient perspective.  The 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 84 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
HPES-Impact assesses the key impacts of these symptoms on patient functioning and well-being 
(physical functioning, daily life, psychological well-being, social life and relationships).   
The HPES takes approximately 5-10 minutes to complete.   
11.9.3. EuroQol 5-dimensional questionnaire  
The EuroQol 5-dimensional (EQ-5D) questionnaire is a widely used generic health measure that 
can be applied to a wide range of health conditions.  This measure is used to quantify health 
related QOL and measures a patient’s health across five different domains: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression.  The measure consists of two 
components: health state description and evaluation.  In the description part, health status is 
measured in terms of the five dimensions.  The respondents rate the level of severity for each 
dimension using a five-level (EQ-5D-5L) scale.  In the evaluation part, the respondents evaluate 
their overall health status using a EuroQol visual analogue scale (EQ-VAS).   
The EQ-5D-5L takes approximately 5 minutes to complete. 
11.9.4. 36-Item Short-Form Survey  
The 36-Item Short-Form Survey (SF-36) V2 Health Survey (1-week recall) is a multipurpose 
short-form health survey with 36 questions that yields an eight-scale profile of functional health 
and general well-being, as well as two psychometrically based physical and mental health 
summary measures and a preference-based health utility index.  It is a practical, reliable and 
valid measure of physical and mental health.  The SF-36 is a generic health survey as it can be 
used across age (18 and older), disease, and treatment group, as opposed to a disease-specific 
health survey, which focuses on a particular condition or disease.  
The SF-36 can be completed in 5-10 minutes.  
CCI
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 85 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
11.9.6. Clinical Global Impression of Severity  
The Clinical Global Impression of Severity (CGI-S) is a ClinRO measure.  It should be 
completed by the investigator after all clinical assessments are completed. The CGI-S consists of 
3 questions that ask the investigator to assess - on a 6-point scale - the subject’s overall 
symptoms, physical symptoms, and cognitive symptoms based on the investigator’s clinical 
judgement, and their impression of the subject’s disease from the summary of all assessments 
and information collected at the visit.  The CGI-S provides a clinician’s view of the subject’s 
disease status, which is valuable in correlating the subject’s self-assessment of their disease 
status.  
The CGI-S takes approximately 1-2 minutes to complete. 
11.9.7. Phone Exit Interviews  
Phone interviews after the Blinded Treatment Period, in selected English speaking countries/sites 
are used to assess the subject’s experience in the trial in their own words and supply a qualitative 
view to complement the quantitative clinical outcome assessments (COAs).  The exit interviews 
will collect information on subject’s evaluation of treatment received, and the subject’s 
experience of taking part in the clinical trial, and aid in the interpretation of changes in clinical 
and PRO scores, including the HPES-Symptom and HPES-Impact measures, to determine what 
constitutes meaningful change for patients with HP. 
11.10. LOCAL TOLERABILITY ASSESSMENT  
Local Tolerability is assessed based on the presence of an injection site reaction (ISRs) captured 
as an AE (see section 12.4.3.4 for ISR reporting).   
At Visit 1, assessment of local tolerability including redness, itching and swelling is performed 
by trial staff at the time of the first study drug injection and at least 15 minutes post-dose.  
At Visit 10, the first dose of open-label TransCon PTH is administered on-site only for subjects 
still taking active vitamin D or subjects off active vitamin D and taking study drug dose 
≥30 μg/day at the end of Blinded Treatment Period.  An assessment of local tolerability 
including redness, itching and swelling is performed by trial staff using the Local Tolerability 
Scale at the time of the TransCon PTH injection and at least 15 minutes post-dose.   
As part of the local tolerability assessment at Visit 1 and 10, the subject will complete the Wong-
Baker FACES® Pain Rating Scale to assess the pain at the injection site that the subject is 
experiencing after the injection.  
11.12. SUBJECT DIARY  
Subjects are trained on the diary during Screening and the diary should be reviewed at the visit 
by trial staff as part of study drug compliance and SoC/PRN medication doses review.  
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 86 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
An eDiary solution will be used with subject’s own device or with a provision device.  
Subjects will be required to complete a daily diary until Visit 13 to capture the following:  
• Study drug, starting at Visit 1 (administration date and time, dose, location of injection site) 
• SoC (administration date, name and dose), including PRN medication doses 
Subjects will be required to complete a weekly diary starting from Visit 13 to Visit 18 to capture 
TransCon PTH administration and any SoC/PRN medication doses.  
Paper diary might be used as back-up solution.  
Diary completion during the Screening Period assists in tracking SoC optimization.  The 
minimum 7 days between the Screening Period and Visit 1 should be used as an opportunity for 
subjects who are already optimized on HP-related supplements prior to Screening to become 
acquainted with the diary prior to enrollment/randomization.   
11.13. ADVERSE EVENT ASSESSMENTS  
At each visit, the subject 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  
• Hypo- or hypercalcemic symptoms since the previous visit 
• Vasodilatory symptoms as adverse events of special interest (AESI) 
• Emergency/urgent care visits or hospitalizations since the previous visit 
Additionally, the site staff will review subject diary data to determine if diary entries reflect any 
AEs with a reference to the AE section and at applicable visits, changes from baseline noted 
during a physical examination should be assessed for potential AEs. 
At the investigator’s discretion, additional assessments, including an examination of injection 
sites, a physical examination, or additional laboratory assessment, may be performed even if not 
required at the specific trial visit or if an UV or ULV must be scheduled.   
See Section 12.3 for details on reporting AEs. 
11.14. LABORATORY ASSESSMENTS  
Samples will be obtained at a minimum for both central and local laboratory tests to be 
performed as outlined in Appendix 4. 
Note:  
• Blood collection must occur prior to on-site study drug administration, when applicable 
• On the day of lab assessments, subjects should avoid exercise prior to blood collection 
• On the day of lab assessments, subjects should be instructed to take their SoC (as 
applicable) and eat their usual breakfast prior to blood collection 
Investigators must be able to receive local laboratory results within a time frame sufficent to 
allow instructions to subjects on dose adjustments preferably within 48 hours of blood collection.  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 87 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
All local laboratory results required by this protocol will be entered into the EDC system by the 
site staff. 
Data from samples obtained for analysis of antibodies against PTH, TransCon PTH and PEG 
will be used to support evaluation of post-dose antibody detection.  Blood samples may be used 
for additional exploratory characterization of anti-drug antibody responses. 
Subjects that show a treatment induced response for either anti-PTH, anti-TransCon or anti-PEG 
antibodies should be followed 4 to 6 weeks after the treatment ends to determine if antibody 
levels revert to baseline.  Blood samples may be collected every 3 to 6 months, until antibodies 
can no longer be detected or have a sustained decline. 
If a subject experience a suspected anaphylactic reaction (excluding anaphylactic reactions due 
to confirmed exposure to an allergen known to be a trigger for an individual subject), blood 
should be drawn as soon as possible (ideally within 48 hours) for tryptase and total IgE.  The 
subject should also be further evaluated (by the investigator and/or an allergist or similar 
specialist) to confirm/refute an anaphylactic reaction through a thorough history, with 
consideration given to interval testing of tryptase, total IgE, and a re-challenge with study drug. 
Samples for measuring Free PTH will be collected in a subset of subjects at selected sites.  The 
aim is to obtain samples from as many subjects as possible but expect a minimum of 
approximately 30% of the subjects. 
11.15. LIFESTYLE MODIFICATION  
11.15.1. Dietary Modifications  
Subjects should be advised to consume approximately the same amount of calcium from their 
diet every day to minimize the effect of dietary calcium on fluctuation in sCa level.  The 
Investigator or site staff will counsel the subjects about their dietary calcium intake based on the 
dietary calcium questionnaire and counseled to avoid excessive sodium intake. 
11.15.2. Exercise Modifications  
Subjects should be advised to avoid exercise prior to visits which include blood collection. 
11.15.3. Contraception  
TransCon PTH did not induce adverse effects on male or female fertility in dedicated fertility 
studies conducted in rats.  Further, TransCon PTH did not induce adverse effects on embryofetal 
developmental in pregnant rats and rabbits (see Investigator’s Brochure 
Section 4.4.4 – Reproductive Performance and Developmental Toxicity Studies).  
Irrespectively, acceptable highly effective contraception during the trial and for 2 weeks after the 
last dose of study drug is required for women of childbearing potential if sexually active, and 
pregnancy testing for women of childbearing potential will be performed throughout the trial.  
See Appendix 1 for further guidance on acceptable highly effective contraception. 
See Appendix 4 for further details on pregnancy testing schedule.  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 88 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
11.15.4. Study Drug Administration  
11.15.4.1. Blinded Treatment Period Administration  
The first dose of study drug will be administered by the subject in the clinic, and the subject will 
be observed for at least 30 minutes for local tolerability assessment and adverse reactions, 
including orthostatic hypotension and orthostatic tachycardia.  Subjects will inject subsequent 
doses of study drug daily at home. 
It is recommended that subjects inject the study drug every day in the evenings before bedtime 
(starting at day 2). 
11.15.4.2. Extension Period Administration  
For the subjects still on active vitamin D at Visit 10 or the subjects off active vitamin D at Visit 
10 and taking TransCon PTH/placebo dose ≥30 µg/day at the end of Blinded Treatment Period, 
the first dose of open-label TransCon PTH is administered by the subject in the clinic, and the 
subjects will be observed for at least 30 minutes for local tolerability assessment and adverse 
reactions, including orthostatic hypotension and orthostatic tachycardia.   
The subjects should get back to the evening dosing as before the day after Visit 10. 
11.15.5. Hypo- or Hypercalcemia Symptom Management  
Most HP subjects are able to recognize their symptoms of hypocalcemia, and many can 
recognize symptoms of hypercalcemia.  Just as in normal management of patients with HP, if 
hypo- or hypercalcemic symptoms develop any time in between trial visits, subjects should 
contact the site and visit the local laboratory (i.e., ULV) to assess albumin-adjusted or ionized 
sCa.  Additionally, as in normal management of patients with HP, all subjects will be permitted 
to take extra active vitamin D and/or calcium supplements as PRN medications to resolve 
symptoms of hypocalcemia, and reduce calcium and/or active vitamin D supplements (or 
hold/reduce their dose of Transcon PTH if off SoC) to resolve acute symptoms of hypercalcemia.  
Subjects should be encouraged to visit the local laboratory for assessment of sCa and albumin, or 
ionized calcium levels for symptoms of hypercalcemia.  
12. 
ADVERSE EVENT ASSESSMENT AND REPORTING  
12.1. DEFINITION  
12.1.1. Adverse Event  
An AE is defined as any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with the treatment. An Adverse event can therefore be any of the following: 
• 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. 
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with hypoparathyroidism that were 
not present prior to the AE reporting period.  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 89 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
• 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.  
12.1.2. Serious Adverse Events  
An SAE is any untoward medical occurrence at any dose that meets any of the following criteria: 
• 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 subject 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 12.4.3.6). 
• It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions).  
• 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 subject 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 AE 
(e.g., rated as mild, moderate, or severe; see Section 12.3.1; 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 AE recorded on the eCRF. 
Serious AEs 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 12.5.2 for reporting instructions). 
12.1.3. Adverse Events of Special Interest (AESIs)   
AESIs are a subset of Events to Monitor (EtMs) of scientific and potential medical concern 
specific to the product, for which ongoing monitoring and reported by the Investigator within 
24 hours to the Sponsor is required. Such an event might require further investigation in order to 
characterize and understand it. Depending on the nature of the event, rapid communication by 
the trial Sponsor to other parties (e.g. Regulatory Authorities) may also be warranted. 
12.1.4. TransCon PTH Adverse Events of Special Interest  
AEs of special interest for this study include the following: 
• Vasodilatory signs and symptoms which may include orthostatic dizziness, lightheadedness, 
weakness, blurring of vision, pre-syncope, syncope, headache, orthostatic hypotension, 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 90 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
orthostatic tachycardia/palpitations. Such symptoms are usually transient in nature and can be 
managed by dosing at bedtime, while reclining. PTH is known to have vasodilatory effects 
(Rambausek 1982) 
• Persistent severe hypocalcemia (as defined in Section 9.6.1) 
• Persistent severe hypercalcemia (as defined in Section 9.6.1) 
12.1.5. Special Situation  
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 
AE or medical condition. Examples of special situations include and should all be captured in the 
eCRF: 
• Pregnancy 
• Breastfeeding 
• Overdose 
• Drug abuse 
• Misuse 
• Occupational exposure 
• Lack of therapeutic efficacy 
• Medication error 
The Medical Monitor will review all safety information on an ongoing basis.  
12.2. METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES  
The investigator is responsible for ensuring that all AEs, AESIs 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. 
12.3. ADVERSE EVENT REPORTING PERIOD  
The Adverse Event Reporting Period is the period requiring reporting of AEs, AESIs and SAEs 
for any subjects exposed to IMP product and or any study related procedures.  Reporting period 
begins from the time when the informed consent is obtained and ends 2 weeks following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier. 
After this period, investigators should only report SAEs that are attributed to prior study 
treatment Severity, Causality, and Outcome Assessment. 
12.3.1. Assessment of Severity of Adverse Events  
The World Health Organization (WHO) toxicity grading scale will be used for assessing AE 
severity.  Table 2 will be used for assessing severity for AEs that are not specifically listed in the 
WHO toxicity grading scale. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 91 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Table 2: 
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 AE (see 
Section 12.1.2). 
 
12.3.1.1. Causality Rating  
All AEs, AESIs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other means 
must be reported appropriately. 
Each reported AE, AESIs or SAE must be described by its duration (i.e., start and end dates), 
seriousness criteria if applicable, suspected relationship to the TransCon PTH (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 TransCon PTH.  The AE cannot be readily explained by the subject’s 
clinical state, intercurrent illness, or concomitant therapies.  The AE follows a known pattern 
of response to TransCon PTH or with similar treatments.  And/or the AE abates or resolves 
upon discontinuation of TransCon PTH or dose reduction and, if applicable, reappears upon 
re-challenge. 
Not Related (No) – Evidence exists that the AE has an etiology other than the TransCon PTH 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication).  The AE has no plausible temporal relationship to TransCon PTH 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
Expected AEs are those AEs that are listed or characterized in the current Investigator’s 
Brochure. 
Unexpected AEs are those not listed in the current IB or not identified.  This includes AEs for 
which the specificity or severity is not consistent with the description in the Investigator’s 
Brochure.  
12.3.1.2. Outcome Assessment  
Subjects will be followed until AEs have either resolved, subjects have returned to their baseline 
status, or subjects are deemed stable or commensurate with ongoing disease processes.  One of 
five outcomes listed below must be recorded: 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 92 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Recovered/Resolved – The event has stopped. The stop date of the event must be recorded. 
Recovering/Resolving – The subject 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 subject has died as a consequent of the event.  Date of death is recorded as stop 
date for the AE. 
Unknown – Unknown to investigator, e.g. subject lost to follow up. 
12.4. PROCEDURES FOR ELICITING, RECORDING AND REPORTING ADVERSE 
EVENTS  
12.4.1. Eliciting Adverse Events  
A consistent methodology for eliciting AEs at all subject 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?”  
12.4.2. Recording Procedures for All Adverse Events  
All AEs will be documented in response to question about the subject’s well-being and whether 
any possible changes in well-being have occurred since the previous visit. 
AEs, including AESIs and SAEs, will be documented through the end of the subject’s 
participation in the trial or Early Termination Visit.  All AEs must be recorded on the appropriate 
eCRF. AEs either observed by the investigator or reported by the subject must be recorded 
regardless of causality.  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 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 93 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
• Action taken 
• Determination of “seriousness criteria” (whether serious or not serious) 
Any medical history condition, signs, symptoms, and illnesses active during the Screening 
Period 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 documented as medical history unless the event is trial procedure–related, 
in which case it will be reported as a non–treatment-emergent AE.  Any new or worsening 
pretreatment event that occurs from the time of the first study drug administration until the EOT 
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, AESIs 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). 
AEs will be documented at the maximum intensity experienced. If a previously recorded and 
closed AE or condition recorded as part of medical history increases in severity or frequency, it 
will be recorded as a new AE.  
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 subject(s) monitored.  Since accidental overdoses with the study drug 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.  
12.4.3. Specific Instructions for Recording Adverse Events  
12.4.3.1. Abnormal Laboratory Values  
Not every laboratory abnormality qualifies as an AE.  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).  Abnormal serum calcium values will not be 
considered AEs unless associated with a sign or symptom* 
• 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 AE. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 94 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF. 
* Abnormal serum calcium values - whether or not associated with titration of study drug, 
calcium, or active vitamin D doses - will not be considered AEs unless associated with a sign or 
symptom. Serum calcium is a pharmacodynamic marker of study drug therapy and thus used to 
guide titration of study drug, calcium, and active vitamin D doses (per Appendix 2). 
12.4.3.2. Abnormal Vital Sign Values  
Not every vital sign abnormality qualifies as an AE.  A vital sign 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, treatment interruption, or 
treatment discontinuation) 
• Results in a medical intervention or a change in concomitant therapy 
• Is clinically significant in the investigator's judgment 
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 AE. 
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. 
12.4.3.3. 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 heart failure rather than dyspnea, orthopnea and extremity edema).  
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. 
12.4.3.4. Injection Site Reactions  
ISRs that occur during or after study drug administration and that are judged to be related to 
study drug injection are deemed to be AEs. These AEs should be captured as a unified diagnosis 
on the AE eCRF (e.g. as an “injection site reaction” rather than capturing “injection site 
bleeding” and “injection site induration” as separate adverse events). The diagnosis is at the 
discretion of the investigator. Signs, symptoms, and features of the injection site reaction should 
be recorded on a dedicated corresponding eCRF.  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 95 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
12.4.3.5. 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”. 
12.4.3.6. 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 subject 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 subject 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  
12.4.3.7. 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”).  
12.4.3.8. Pregnancy   
If a female subject becomes pregnant while receiving the study drug or within two weeks after 
the last dose of study drug, or if the female partner of a male study subject becomes pregnant 
while the study subject is receiving the study drug or within two weeks, a Pregnancy report 
should be completed and expeditiously submitted to Ascendis Pharma.  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 subject exposed to the study drug should be expeditiously reported as an SAE.  
12.4.3.9. 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, 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 96 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial. 
In this study, the TransCon PTH delivery system consists of a multi-use cartridge integrated into 
a device to constitute a pre-filled injection pen which is considered a medical device.  The 
investigator must report all medical device complaints to the Sponsor.  The investigator should 
document as much information as possible including the product batch number and forward the 
information to the Sponsor immediately (refer to the pharmacy manual for further details).  If the 
medical device results in an adverse event to the study patient, the event must be reported on the 
AE eCRF and submitted through the EDC system.  If the event is serious, the AE eCRF must be 
completed immediately (i.e., no more than 24 hours after learning of the event), as outlined in 
Section 12.5.2. 
12.5. SAFETY REPORTING REQUIREMENTS  
12.5.1. 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. 
12.5.2. Reporting  
All initial and follow-up information regarding SAEs, AESIs, and Special Situations 
reporting must be reported by the investigator to the Sponsor or its representatives within 
24 hours of discovery/awareness, including those related to protocol-mandated procedures and 
regardless of suspected causality.  
For each AE recorded on the AE eCRF, the investigator will make an assessment of seriousness 
(see Section 12.1.2 for seriousness criteria), severity (Section 12.3.1), and causality (see 
Section 12.3.1.1). 
Reporting must not be delayed by waiting for additional information.  The minimum information 
required for reporting an SAE, AESIs, 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, AESIs, and Special Situations (including follow-up information) must be reported using 
the Safety report form or the Pregnancy report form provided. A completed Safety report form / 
Pregnancy report form must be uploaded to the Safety Reporting Portal at: 
Safety.ascendispharma.com 
Specific instructions regarding completion of the form and reporting details are provided on the 
Safety report form.  
SAEs, AESIs, 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: 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 97 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
• 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 (in particular related to albumin adjusted serum calcium, ionized calcium), 
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  Section 6.8 – Reference Safety Information for Assessment of Expectedness of 
Serious Adverse Reactions. 
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. 
14. 
DEVICE ASSOCIATED HAZARDS, RISKS, AND ADVERSE EVENTS  
During the device development process, risk management activities have been performed 
according to ISO 14971.  Risk analyses have been performed using Failure Mode and Effects 
Analysis techniques to address risks related to design, use and manufacturing of the TransCon 
PTH prefilled pen.  The severity of hazards related to risks has been assessed and used to ensure 
appropriate risk mitigation and evaluation of residual risks.  The severity rating applied 
throughout the TransCon PTH prefilled pen risk management activities are listed in Table 3. 
An analysis of risks associated with the use of the TransCon PTH prefilled pen has been 
performed.  This analysis addressed 73 use related risks.  All these risks have been mitigated or 
reduced to an acceptable level by packaging design or by labeling (IFU).  The use related risk 
analysis of the TransCon PTH prefilled pen identifies three residual risks related to a potential 
hazard with a severity rating of S4 or above.  These three risks relate to swallowing of small 
parts (choking hazard), cross contamination between multiple users and infections.  These are 
class-related risks related to the single use needle or to the single patient use prefilled pen.  These 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 98 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
risks are common for marketed prefilled pen combination products and are therefore evaluated to 
be acceptable.  The TransCon PTH prefilled pens are delivered with Ypsomed Clickfine 
AutoProtect single use needles designed to reduce the potential risk associated with accidental 
needle stick injuries.  The remaining 70 use-related risks, including risks related to under-dosing, 
over-dosing or injection of a degraded drug product, relate to hazards rated S3 or lower.  The 
packaging and IFU have been developed and tested through a series of formative usability 
studies (one platform prefilled pen study and six TransCon PTH prefilled pen studies).  In 
conclusion the usability testing of the TransCon PTH prefilled pen, packaging and IFU supported 
the effectiveness of the risk mitigations as well as the safe and effective use for both untrained 
and trained intended users.  Finally, it is noted, that the risk analysis did not identify a need for 
cleaning of the device during its use period.  The risk evaluation including the assessment of the 
residual risks concludes that the use of the TransCon PTH prefilled pen is safe and effective. 
The Phase 2 trial (TransCon PTH TCP-201) has been conducted using the TransCon PTH 
prefilled pen configurations that are also intended to be used in the Phase 3 trial (TCP-304).  No 
AEs relating to the device constituent of the TransCon PTH prefilled pen has been reported.  
Less than ten complaints relating to the device constituent, IFU and needles have been registered 
during the clinical trial.  One complaint has led to a minor update of the IFU and the rest have 
not triggered any changes. 
Table 3: 
Severity Ratings Applied in Risk Evaluation  
Severity Rating 
Negligible (S1) 
Minor (S2) 
Serious (S3) 
Critical (S4) 
Catastrophic (S5) 
Inconvenience or 
momentary 
discomfort 
Temporary injury or 
impairment without 
requiring professional 
medical attention 
Temporary loss of 
efficacy 
Injury or impairment 
probably requiring 
professional medical 
treatment 
Long term loss of 
efficacy 
Permanent 
impairment or 
life-threatening 
injury 
Death 
 
15. STATISTICS  
15.1. GENERAL  
Details of applicable statistical methods will be provided in a statistical analysis plan (SAP) 
which will be finalized before trial unblinding and database lock of the Blinded Treatment 
Period.  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. 
All statistical tests will be two-sided and tested at the statistically significant level of 0.05. 
Confidence intervals will be 2-sided 95% confidence intervals, unless stated otherwise.  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 99 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
15.2. ENDPOINTS  
15.2.1. Efficacy Endpoints  
15.2.1.1. Primary Efficacy Endpoint  
At 26 weeks of treatment, the proportion of subjects with: 
• Albumin-adjusted sCa measured within 4 weeks prior to and on Week 26 visit are within the 
normal ranges (8.3-10.6mg/dL)*; and  
• Independence from active vitamin D** and  
• Independence from therapeutic doses of calcium (i.e., taking calcium supplements 
≤600 mg/day).  This dose of calcium ≤600 mg/day in the form of tablets, powder, liquid 
suspension, or transdermal patch is considered as “supplemental” to meeting recommended 
daily intake for general health, as opposed to a “therapeutic” dose to treat 
hypoparathyroidism*** and 
• No increase in prescribed study drug within 4 weeks prior to Week 26 visit**** 
* Except for at the Week 26 visit, confirmation that an albumin-adjusted sCa is “abnormal” 
requires 2 consecutive results outside the normal range within 4 weeks prior to the Week 26 
visit. 
** Independence from active vitamin D will be defined as a daily standing dose equal to zero on 
all days AND use of any PRN vitamin D ≤7 days within 4 weeks prior to the Week 26 visit.  
*** Independence from therapeutic calcium will be defined as average daily standing dose 
≤600 mg AND use of PRN doses on ≤7 days within 4 weeks prior to the Week 26 visit.  
**** Dose decrease permitted for safety reasons. 
15.2.1.2. Secondary Efficacy Endpoints  
15.2.1.2.1. Key Secondary Efficacy Endpoints  
Change from baseline at 26 weeks of treatment: 
• HPES Symptom – Physical domain score 
• HPES Symptom – Cognitive domain score 
• HPES Impact - Physical functioning domain score  
• HPES Impact – Daily life domain score 
• 36-Item Short Form Survey (SF-36) Physical functioning subscale score 
15.2.1.2.2. Other Secondary Efficacy Endpoints  
The key secondary efficacy endpoints and the following efficacy endpoint will be evaluated at 
predefined timepoints during the Extension Period.  
• 
The proportion of subjects that meet the following criteria:  
− 
Albumin-adjusted sCa measured within the normal range (8.3-10.6 mg/dL); and  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 100 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
− 
Independence from active vitamin D (i.e., standing dose of active vitamin D equal to 
zero on the day prior to the Week 52 visit or other visits of interest); and  
− 
Independence from therapeutic doses of calcium (i.e., standing dose of elemental 
calcium ≤ 600 mg on the day prior to the Week 52 visit or other visits of interest). 
The following endpoints will be evaluated at predefined timepoints during the Blinded Treatment 
and the Extension Period:  
• Calcium and active vitamin D doses 
• Daily “pill burden” of active vitamin D and calcium (as oral tablets, powder, liquid solutions, 
liquid suspensions, or transdermal patches) 
• sP  
• Albumin-adjusted sCa x sP product, including proportion of subjects with albumin-adjusted 
sCa x sP product ≤55 mg2/dL2, ≤52 mg2/dL2, and ≤44 mg2/dL2  
• Albumin-adjusted sCa  
• BMD and TBS by DXA 
• Bone turnover markers (serum P1NP and CTx)  
• sMg 
• EuroQol 5-Dimensional Questionnaire (EQ-5D) 
• Clinical Global Impression of Severity (CGI-S) 
• HPES: HPES Impact domain scores (Psychological Well-being and Social life and 
Relationships) and HPES Symptom and Impact total scores 
• SF-36: SF-36 subscale scores (Role Limitations due to Physical Health Problems, Bodily 
Pain, General Health, Vitality, Social Functioning, Role Limitations due to Emotional 
Problems, and Mental Health) and SF-36 component scores (Physical component score and 
Mental component score) 
15.2.2. Safety Endpoints  
The following safety endpoints will be assessed during the Blinded Treatment and Extension 
Periods:  
• Incidence of AEs, AESI and SAEs 
• Serum chemistry, hematology, and  
• 24-hour urine chemistry (including urine calcium and urine creatinine clearance) at 
prespecified timepoints including at Week 26 
• Clinical events of hypo- or hypercalcemia (emergency/urgent care visits and hospitalizations)  
• Injection site tolerability (based on AEs) 
• Evaluation of anti-PTH, anti-TransCon PTH and anti-PEG antibody responses 
• Vital signs 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 101 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
15.2.3. Exploratory Endpoints  
15.3. STATISTICAL ANALYSIS  
The Intent-To-Treat (ITT) Population consists of all subjects who were randomized and received 
at least one dose of blinded study drug.  All efficacy analysis will be based on ITT and treatment 
assignment per randomization.  The Safety Analysis Population consists of all randomized 
subjects who received at least one dose of study drug.  The safety analyses will be based on the 
Safety Analysis Population and actual treatment received. 
In general, descriptive statistics summary will be generated by double blind and extension 
phases. 
Categorical data will be presented using counts and percentages of subjects.  Continuous 
variables will be presented using number of subjects, mean, standard deviation (SD)/standard 
error (SE), median, minimum and maximum. 
Efficacy Analysis 
The primary estimand for the primary analysis is defined by the following components: 
x Population: Refer to Section 8 Trial Population, with inclusion/exclusion criteria considered. 
The efficacy analyses will be based on the ITT Population 
x Efficacy Endpoints: Refer to Section 15.2.1.1 
x Handling missing data (intercurrent events): Subjects may have missing data for primary 
endpoint assessments due to early discontinuation from study drug, missing lab visits, non-
evaluable lab values, etc. Such subjects will be included in primary analysis. Subjects with 
no Week 26 albumin-adjusted sCa OR with >25% (i.e., >7 days) missing diary data of active 
vitamin D or calcium during the 4 weeks will be considered as non-responders.  
x Analysis: CMH test stratified by etiology of hypoparathyroidism (post-surgical vs. other) is 
the primary analysis method and will be used to compare the proportion of subjects meeting 
the listed criteria of the primary endpoint (responders vs. non-responders) in the TransCon 
PTH vs. placebo groups  
x Population-level summary: Number and percentage of subjects meeting the primary endpoint 
criteria defined in Section 15.2.1.1 will be provided. 
Sequential testing will be applied to control the family-wise type-1 error rate for the primary and 
key secondary endpoints. Details will be specified in the SAP. 
In general, continuous endpoints during Blinded Treatment Period will be analyzed using 
ANCOVA model with unequal covariance.  The model will include the change from baseline for 
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 102 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
the endpoint of interest as a response variable, treatment assignment and etiology of 
hypoparathyroidism as fixed factor and baseline value of the endpoint will be entered as a 
covariate, unless otherwise specified in the SAP.  The key secondary PRO efficacy endpoints 
will be analyzed as continuous and in terms of change from baseline using the described 
ANCOVA model with multiple imputation for missing post-baseline assessments.   
Categorical endpoints during Blinded Treatment Period will be analyzed using CMH test 
stratified by etiology of hypoparathyroidism. 
All efficacy endpoints will be summarized descriptively in Extension Period analysis.  
Pharmacokinetic Analysis  
The PK parameters and their statistical evaluation will be included in the Clinical Study Report.  
PK data will be used to describe plasma concentration at steady-state.  Potential impact of any 
anti-PTH, anti-TransCon PTH and anti-PEG antibodies detected will be included in the 
evaluation.  The Free PTH results will additionally be added to the population PK analysis. 
Safety Analysis 
The reporting of the safety data is descriptive.  Descriptive analysis will include the incidence 
TEAEs, and changes in laboratory, vital signs, and pre-existing and treatment induced, anti-PTH, 
anti-TransCon PTH and anti-PEG antibodies responses.  Listings of all safety endpoints by 
treatment group will be presented.   
Interim Analysis 
The analysis of the Blinded Treatment Period will be conducted after database lock of the 
Blinded Treatment Period, which will occur prior to database lock of the Extension Period.  No 
interim analysis is planned. 
15.4. POWER CALCULATION  
The sample size is determined based on considerations from both statistical power and adequate 
safety exposure perspectives.  Assuming that the response rate is 70% for TransCon PTH and 
15% for placebo for the primary endpoint at 26 weeks, 68 subjects randomized 3:1 to active 
TransCon PTH vs. placebo will have approximate statistical powers of 99% at alpha = 0.05, and 
95% at alpha = 0.01 (two-sided) to demonstrate statistically significant difference between 
TransCon PTH and placebo.  Taking into account of approximately 10% dropout, a total sample 
size of 76 is targeted. 
15.5. SIGNIFICANCE  
Statistical significance is defined as P <0.05 (2-Sided).  
15.6. ACCOUNTABILITY  
Subjects with missing data, including missed assessments and early discontinuation will be 
summarized. 
15.7. DEVIATION REPORTING  
Major protocol deviations will be summarized. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 103 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
15.8. UNBLINDING PROCEDURES  
The Investigator and site personnel will remain blinded to the randomization code during the 
trial.  Treatment assignment for an individual subject should be unblinded by the Investigator 
only in an emergency (e.g., event concerning subject safety) and only if knowledge of the 
treatment assignment is urgently needed for the clinical management or welfare of the subject.  
The investigator is encouraged to notify the Medical Monitor or clinical program manager before 
unblinding, when possible, but priority should be given to treatment of the subject. 
The Investigator must record the date and reason for revealing the blinded treatment assignment 
for that subject within the IRT.  Treatment assignment may be unblinded by the Sponsor to 
satisfy expedited safety reporting requirements of regulatory authorities.  The system to unblind 
an assignment will be maintained and executed through the IRT, which will be available 
24 hours a day, 7 days a week. 
16. 
TRIAL CONDUCT  
16.1. 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 an Investigator Meeting (IM).  Protocol and GCP training must 
take place before any subjects 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 subject eligibility requirements. 
16.2. DATA HANDLING AND RECORD KEEPING  
16.2.1. 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 
subject status during the course of the trial.  Only a Subject Identification Number will be used to 
identify the subject.  The investigator must keep a separate Subject Identification Code List with 
subject names and medical record numbers (or other personal identifiers). 
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] 
to the same degree of confidence as is provided with paper systems.  Clinical investigators must 
retain either the original or a certified copy of all source, 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 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 104 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
provides a means to locate and read the prior information.  All changes to 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. 
16.2.2. Coding Dictionaries  
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system.  
Medical history for illnesses and AEs will be coded using the medical dictionary for regulatory 
activities (MedDRA).   
16.2.3. Data Handling  
eCRFs should be completed in a timely manner to enable the sponsor or designee to perform 
central monitoring of data. Subsequent to data entry, a study monitor may 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 his/her 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 read-only archive 
copy of the data entered by that site.  This archive must be stored in accordance with the records 
retention requirements outlined in Section 16.2.1. 
16.2.4. 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. 
16.2.5. 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 subject 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 
8. Normal laboratory values  

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 105 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
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. Subject Screening & Enrollment Log(s) 
15. Subject 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 
16.3. DATA QUALITY CONTROL  
16.3.1. 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 subjects 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. 
16.3.2. 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 Sponsor and/or 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. 
16.4. AUDITING PROCEDURES  
In addition to the routine monitoring procedures, a GCP Quality Assurance audit may be 
initiated by the Sponsor.  The investigator has to ensure that subjects/parents/legal guardians 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 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 106 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
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. 
16.5. LABORATORY QUALITY STANDARDS  
Laboratory tests or evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards as described in the SOPs of the local and central laboratories.  Some 
blood samples may be used for laboratory test validation.  
The laboratories will provide a list of reference ranges for applicable analyses before trial start.  
These will be held in the investigator site file and the trial master file.  The methods employed 
for each assay should be available upon 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. 
16.6. TRIAL TERMINATION OR COMPLETION  
The investigator should notify the IRB/EC in writing of the completion or early termination of 
the trial.  End of trial (EOT) is defined as last subject 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 
including insufficient efficacy and unanticipated safety concerns.  If the trial is prematurely 
terminated, the investigator should promptly inform the subjects and ensure appropriate therapy 
and follow-up. 
The Sponsor may stop this trial at a particular site for any of the following reasons:  
• The site cannot enroll an adequate number of subjects  
• Serious and/or persistent non-compliance with the protocol or clinical trial conduct  
• Careless or premeditated false documentation in the eCRF  
• Inadequate cooperation with the investigator  
• Non-compliance with GCP and/or regulatory requirements  
• The investigator requests discontinuation 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 107 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
The Sponsor must also terminate the trial prematurely for any of the following reasons: 
• Unjustifiable risk and/or toxicity in risk-benefit analysis (occurrence of new adverse events 
unknown to date in respect of their nature, severity, duration or frequency in relation to the 
current established safety profile of the study drug) 
• New scientific evidence becomes available during the study that could affect the subject’s 
safety 
16.7. 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 subject, a deviation from the protocol is allowed in order to 
eliminate the hazard.  In this case, the deviation and the reason for it must be 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. 
16.8. 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. 
16.9. CLINICAL STUDY REPORT  
Data will be reported in a clinical study report in compliance with requirements of the current 
version of ICH E3.  A signatory investigator will review and sign the clinical trial report.  The 
signatory coordinating investigator(s) for the clinical study report will be selected based on 
experience and knowledge in clinical trials, treatment of HP and involvement in this trial.  
16.10. 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 enrollment of eligible subjects or 
contribution to the design, conduct, or interpretation of the trial.  Publication of any data of this 
trial without prior Sponsor approval is not permitted. 
17. ETHICAL AND LEGAL CONSIDERATIONS  
This trial will be conducted in accordance with the following: 
• Protocol-related and trial-related documents 
• GCPs as outlined in ICH E6 (R2) and regional regulations 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 108 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
• Declaration of Helsinki 
• Regional required subject data protection laws and regulations 
• Applicable regional regulations 
• US Federal Regulations, as applicable  
17.1. DATA MONITORING COMMITTEE  
Independent oversight of this trial will be provided by a DMC.  Its duty is to regularly review the 
progress of the trial and assess the accumulating safety data.  After each meeting it will advise 
the Sponsor on the continuing safety of current subjects in the trial and on the continuing validity 
and scientific merit of the trial.  All decisions about the conduct of the trial will rest solely with 
the Sponsor.  The DMC will consist of members, all with experience in clinical studies, and who 
will operate based on the Charter agreed upon.  The Charter will define data content, format, and 
review frequency.  The Sponsor may attend the DMC meetings. 
17.2. INFORMED CONSENT  
The 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 Subject Information Sheet, if applicable) documents the trial-specific information 
the investigator provides to the subject and the subject’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 Subject Information Sheet must be appropriately signed and dated before the 
subject undergoes any trial-related procedure.  The original and any amended signed and dated 
ICFs and subject information sheets must be retained at the trial site with a copy of each 
provided to the subject. 
17.3. INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE APPROVALS  
The Principal Investigator (PI) at each site is responsible for obtaining approval from the 
appropriate regional IRB/EC for the final protocol, Sponsor-approved ICF and subject 
information sheet (if applicable), and any advertisements to recruit subjects.  Written approval of 
these documents must be obtained from the committee before any subject is enrolled at a trial 
site. 
The PI 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 
3. Submitting progress reports to the review board as required during the conduct of the trial, 
requesting re-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 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 109 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
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 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 110 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
18. 
REFERENCES  
Abate EG, Clarke BL. Review of hypoparathyroidism. Front Endocrinol (Lausanne). 
2017;7:172. 
Babey M, Brandi ML, Shoback D. Conventional Treatment of Hypoparathyroidism. Endocrinol 
Metab Clin North Am. 2018;47(4):889-900. 
Bilezikian JP, Cusano NE, Khan AA, et al. Primary hyperparathyroidism. Nat Rev Dis Primers. 
2016;2:16033. 
BLA #125511, Natpara. Center for Drug Evaluation and Research, Food & Drug Administration. 
2015. 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125511Orig1s000AdminCorres.pdf. 
Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary 
statement and guidelines.  J Clin Endocrinol Metab. 2016;101(6):2273-2283. 
Briefing Document, BLA #125511 Natpara. 2014. 
https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20Pink%20Sheet
%20DAILY/2014/September/Natpara_FDA_brfg.pdf. 
CHMP 24/04/2017. Natpar EMEA/H/C/0003861. 
Clarke BL, Brown EM, Collins MT, et al. Epidemiology and diagnosis of hypoparathyroidism. J 
Clin Endocrinol Metab. 2016;101(6):2284-2299. 
Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy 
testing in clinical trials. CTFG. 2014;1-13. 
Hamilton JW, Jilka RL, MacGregor RR. Cleavage of parathyroid hormone to the 1-34 and 35-84 
fragments by cathepsin D-like activity in bovine parathyroid gland extracts. Endocrinology 
1983;113(1):285–292. 
Horwitz MJ, Tedesco MB, Sereika SM, et al. A 7-day continuous infusion of PTH or PTHrP 
suppresses bone formation and uncouples bone turnover. J Bone Miner Res. 2011;26(9):2287-
2297. 
International Osteoporosis Foundation’s Dietary Calcium Calculator. 
https://www.osteoporosis.foundation/educational-hub/topic/calcium-calculator 
Khurana M, Zadezensky I, Lowy N, et al. Use of a Systems Pharmacology Model Based 
Approach Toward Dose Optimization of Parathyroid Hormone Therapy in Hypoparathyroidism. 
Clin Pharmacol Ther. 2019;105(3):710-718. 
Mannstadt M, Bilezikian JP, Thakker RV, et al. Hypoparathyroidism. Nat Rev Dis Primers. 
2017;3:17080. 
Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid 
hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, 
randomised, phase 3 study. Lancet Diabetes Endocrinol. 2013;1(4):275-283. 
Morley P, Whitfield JF, Willick GE. Design and applications of parathyroid hormone analogues. 
Curr Med Chem. 1999;6(11):1095-1106. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 111 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Rambausek M, Ritz E, Rascher W, et al. Vascular effects of parathyroid hormone (PTH). Adv 
Exp Med Biol. 1982;151:619-632. 
Shoback DM, Bilezikian JP, Costa AG, et al. Presentation of Hypoparathyroidism: Etiologies 
and Clinical Features. J Clin Endocrinol Metab. 2016;101(6):2300-2312. 
Syed MA, Horwitz MJ, Tedesco MB, et al. Parathyroid hormone-related protein-(1-36) 
stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the 
pathogenesis of humoral hypercalcemia of malignancy. J Clin Endocrinol Metab. 
2001;86(4):1525-1531. 
Winer KK, Fulton KA, Albert PS, et al. Effects of pump versus twice-daily injection delivery of 
synthetic parathyroid hormone 1-34 in children with severe congenital hypoparathyroidism. J 
Pediatr. 2014;165(3):556-563. 
Winer KK, Ko CW, Reynolds JC, et al. Long-term treatment of hypoparathyroidism: a 
randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and 
calcium. J Clin Endocrinol Metab. 2003;88(9):4214-4220. 
Winer KK, Sinaii N, Peterson D, et al. Effects of once versus twice-daily parathyroid hormone 1 
34 therapy in children with hypoparathyroidism. J Clin Endocrinol Metab. 2008;93(9):3389 
3395. 
Winer KK, Yanovski JA, Cutler GB Jr. Synthetic human parathyroid hormone 1-34 vs calcitriol 
and calcium in the treatment of hypoparathyroidism. JAMA. 1996;276(8):631-636. 
Winer KK, Yanovski JA, Sarani B, et al. A randomized, cross-over trial of once-daily versus 
twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism. J. Clin. Endocrinol. 
Metab. 1998;83(10):3480-3486. 
Winer KK, Zhang B, Shrader JA, et al. Synthetic human parathyroid hormone 1-34 replacement 
therapy: a randomized crossover trial comparing pump versus injections in the treatment of 
chronic hypoparathyroidism. J Clin Endocrinol Metab. 2012;97(2):391-399. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 112 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
19. 
SIGNATURE OF AGREEMENT  
In signing this protocol, the investigator agrees to: 
• 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 subjects 
• Comply with the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use Guideline on Good Clinical Practice plus appropriate 
regional regulatory laws and requirements 
• Personally conduct or supervise the described investigation 
• Inform any subjects or persons used as controls that the study drugs are being used for 
investigational purposes 
• Ensure requirements relating to obtaining informed consent and regional ethical or 
institutional review board approval have been met 
• Report to the Sponsor or its representative any adverse events that occur in the course of the 
investigations, as specified in Section 12 
• Read and understand the Investigator’s Brochure, including potential risks and side effects of 
the study drug 
• Ensure all associates, colleagues, and employees assisting in the conduct of the trial are 
informed of their obligations in meeting their commitments 
• 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 
• Promptly report to the regional ethical or institutional review board all changes in research 
activity and all unanticipated problems involving risks to human subjects or others 
• Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements 
• Administer study drug only to subjects who meet trial entry criteria and are enrolled in the 
trial and only according to the guidelines set forth in this protocol 
• Sign a Form 1572, as applicable 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 113 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
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 
subjects.  I agree to inform all subjects 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 risks to human subjects 
3. I agree to maintain all information in this document and regarding the study as confidential 
and to use it only for the purpose of conducting the study.  I agree not to forward this 
document to any third party without the prior written authorization of the Sponsor 
Investigator: 
 
Printed Name and Title: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 114 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
20. 
APPENDICES  
APPENDIX 1. 
CONTRACEPTION  
Highly effective contraception are methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly, following the CTFG 2014 recommendations, such 
methods include:   
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
− 
Oral 
− 
Intravaginal 
− 
Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− 
Oral 
− 
Injectable 
− 
Implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion/ligation 
• Vasectomized partner 
• Sexual abstinence, defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments 
• Postmenopausal.  A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause  
Methods of contraception with a failure rate of more than 1% per year with consistent adherence 
are not permitted for female participants of childbearing potential. Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM) are not acceptable methods of contraception.  
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 115 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
APPENDIX 2. 
TITRATION ALGORITHM  
Measure serum calcium3
Serum calcium LOW
Serum calcium NORMAL
Serum calcium HIGH
(If serum calcium ≥12 mg/dL [≥3.0 mmol/L], also 
see footnote 4.
≥7 days since started study drug, or 
changed study drug dose?
≥7 days since started study drug, or 
changed study drug dose?
Increase study drug 
dose by 3 µg/day5
Increase routine calcium supplement 
dose and/or active vitamin D dose.  
Increase toward prior doses and at 
investigator’s discretion.   
(Continue same dose study drug.)
Titration Algorithm1: Study Drug2, Active Vitamin D, and Calcium Supplements (Goal to Gain Independence from Conventional Therapy)
Still taking active vitamin D?
Decrease or discontinue active vitamin D.  
If decreasing, reduce by approximately 33-50% 
of dose taken at baseline (prior to study drug), 
and/or ≥0.25 µg/day for calcitriol and ≥0.5 µg/
day for alfacalcidol.
AND
Increase study drug by 3 µg/day5
Still taking calcium 
supplements?
Stay on same dose of 
study drug
Stay on same dose 
of study drug
Still taking active vitamin D?
Still taking calcium 
supplements?
Decrease study drug 
by 3 µg/day5
Decrease or discontinue active vitamin D.  
If decreasing, reduce by approximately 33-
50% of dose taken at baseline (prior to study 
drug), and/or ≥0.25 µg/day for calcitriol and 
≥0.5 µg/day for alfacalcidol.
Is calcium dose 
≥1500 mg/day?
Decrease calcium supplements by 
≥1500 mg/day6
AND
Increase study drug by 3 µg/day5
Discontinue calcium supplements6 
AND
Increase study drug by 3 µg/day5
Is calcium dose 
≥1500 mg/day?
Decrease calcium supplements by 
≥1500 mg/day6
Discontinue calcium 
supplements6
Yes
No
Yes
No
Yes
No
No
Yes
Yes
No
Yes
No
Yes
No
Yes
No
 
 
 
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 116 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
1 At Visit 1 (Week 0, Day 1), start study drug at 18 µg/day and decrease active vitamin D dose by 33-50% (e.g., skip second dose of the day if taking BID, and 
skip final dose of the day if taking TID). 
2 Study drug refers to TransCon PTH or placebo. 
3 sCa refers to either albumin-adjusted sCa and/or ionized calcium. For the purposes of this trial, the normal ranges are: albumin-adjusted sCa 8.3-10.6 mg/dL 
(2.07-2.64 mmol/L); ionized calcium 1.16-1.32 mmol/L. 
4 If albumin-adjusted sCa ≥12.0 mg/dL (3.00 mmol/L) or ionized calcium ≥1.50 mmol/L, hold study drug for approximately 2-3 days. Remember to resume 
study drug therapy afterwards. Also reduce study drug, active vitamin D, or calcium as per algorithm. 
5 Check sCa within 7-14 days after any changes in study drug dose; standing calcium, standing vitamin D doses; or sCa outside the normal range. A scheduled 
visit or LV within 7-14 days meets this requirement. When scheduled study visits occur less frequently (e.g. 13 weeks apart) then an ULV should be pursued.   
6 The goal is to demonstrate independence from therapeutic doses of calcium supplements. In case needed to meet recommended dietary intake of calcium, it is 
permitted to take calcium supplements ≤600 mg/day as a nutritional supplement for the sake of reaching the recommended dietary intake. 
Notes: 
Adjustments of study drug, calcium and/or active vitamin D will be made per the titration algorithm based on the results of the most recent laboratory results 
whether scheduled or unscheduled.  When central and local calcium values are obtained concurrently, local values should be used to guide titration. 
At all times during the trial, subjects with symptoms of hypocalcemia may take PRN doses of calcium (preferred) and/or active vitamin D, and/or do an ULV 
visit to measure sCa. Subjects with symptoms of hypercalcemia may hold doses of study drug for 1 day and/or do an ULV to measure sCa. An ULV must be 
performed within 7 days of a PRN supplement dose or a held dose. If due to symptoms >2 PRN doses of SoC  are taken or >2 doses of SoC and/or study drug are 
held within those 7 days, an ULV is required within 2 days of the third PRN or held dose. 
 
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 117 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
APPENDIX 3. 
SCHEDULE OF EVENTS  
Period 
Screening 
Supplement 
Optimization 
Blinded Treatment Period and Start of OLE 
Visit 
Screening1   
V1 
LV1 
LV2 
V2 
LV3 
V32 
V42 
V52 
V6 
V72 
V82 
V9 
V103/ET4 
Week 
-6 to -2 
0 
0 
1 
2 
3 
4 
6 
8 
10 
12 
16 
20 
26 
Day 
-42 to -14 
1 
3 
8 
15 
22 
29 
43 
57 
71 
85 
113 
141 
183 
Window 
 
 
+1 day 
+2 days 
± 2 days 
± 3 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
COAs5   
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X6 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight measurements 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurements7   
X 
X8 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X9 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & Concomitant medication  
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
12-lead ECG10   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
DXA11   
X 
 
 
 
 
 
 
 
 
 
 
 
 
X12 
X-ray of non-dominant wrist and left 
hand13   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
24-hour urine collection14   
X14 
X14 
 
 
 
 
 
 
 
 
X14 
 
 
X14 
Urine collection for local lab 
assessments15 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection for local lab 
assessments16   
X17 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Blood collection for central lab 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dietary calcium questionnaire18   
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Subject diary activation and training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject diary review 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
HP-related therapy optimization19  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SoC titration20   
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X20 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 118 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Period 
Screening 
Supplement 
Optimization 
Blinded Treatment Period and Start of OLE 
Visit 
Screening1   
V1 
LV1 
LV2 
V2 
LV3 
V32 
V42 
V52 
V6 
V72 
V82 
V9 
V103/ET4 
Week 
-6 to -2 
0 
0 
1 
2 
3 
4 
6 
8 
10 
12 
16 
20 
26 
Day 
-42 to -14 
1 
3 
8 
15 
22 
29 
43 
57 
71 
85 
113 
141 
183 
Window 
 
 
+1 day 
+2 days 
± 2 days 
± 3 days 
Treatment assignment 
X21   
 
 
 
 
 
 
 
 
 
 
 
 
X22 
Study drug training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug receipt & compliance 
review 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review23   
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
On site study drug administration 
 
X24   
 
 
 
 
 
 
 
 
 
 
 
X25 
Local tolerability assessment 
 
X26   
 
 
 
 
 
 
 
 
 
 
 
X27 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
TransCon PTH/placebo titration28   
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Following randomization, it is recommended to start Visit 1 within 2 weeks from the time of randomization. 
2 In selected countries, home/virtual visits can be performed instead of on-site visits at Visit 3, 4, 5, 7 and 8. 
3 Visit 10 marks the end of the Blinded Treatment Period. Subjects still taking active vitamin D, or subjects off active vitamin D and taking study drug ≥ 30 
μg/day entering this visit will start open-label TransCon PTH at a dose of 18 μg/day, with the 1st dose taken in clinic on Visit 10.  Subjects off active vitamin 
D and taking study drug < 30 μg/day will start TransCon PTH at the same dose of study drug taken at the end of the Blinded Treatment Period (Exception: in 
cases of out-of-range sCa level at Visit 10,  adjust the TransCon PTH dose and/or calcium doses as per Figure 8 and Appendix 2). 
4 Early Termination (ET) Visit for the Subjects who discontinue the trial prior to Visit 10. The structure and assessments of this ET visit should be as similar as 
possible to Visit 10. 
5 COAs: PRO measures must be completed by the subject without assistance and prior to conducting any clinical assessments or supplement dose adjustments.  
On visit 6, 9 and 10/ET, additional 
 needs to be completed by the subject. The CGI-S should be completed by the investigator after all 
clinical assessments are completed. 
6 In selected English speaking countries/sites, approximately 2 weeks prior to Visit 10, subjects will be contacted to set up a one-hour phone interview to occur 
within 2 weeks after Visit 10 to discuss their experience in the trial. Additionally, in case of subject discontinuation before or at Visit 10, the phone interview 
will be scheduled to be completed within 2 weeks after the early termination visit. The phone interview will be conducted by an external vendor, and not by the 
site or the sponsor. 
7 Subject should rest for at least 5 minutes before vital sign measurements, including respiratory rate, temperature, orthostatic BP and heart rate. BP and heart 
rate are performed while the subject is sitting. The subject is then asked to stand up, within 2 minutes of doing so, BP and heart rate are measured again. 
8 Orthostatic BP and heart rate should also be performed 30 minutes after study drug administration. 
CCI
CCI

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 119 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
9 Orthostatic BP and heart rate should also be performed 30 minutes after study drug administration only for subjects still taking active vitamin D or subjects off 
active vitamin D and taking study drug ≥ 30 µg/day at the end of the Blinded Treatment Period.  
10 Standard ECG must include QT interval and Heart Rate. 
11 A historical DXA may be utilized if it was performed within 6 months prior to Screening and report includes required elements per Section 11.7. 
12 A DXA is performed at or within one week prior to Visit 10. 
13 An X-ray of the non-dominant wrist and hand with evidence of epiphyseal closure is only required for subjects who are ≤ 25 years old as of Screening.  A 
historical X-ray may be utilized. 
14 24-hour urine collection is performed within 52 weeks prior to Screening or during the Screening Period. After the investigator has confirmed the subject is 
eligible to move into the Blinded Treatment Period, 24-hour urine collection is performed within one week prior to Visit 1. The subject should also perform 
this collection at home within one week prior to Visit 10 while the subject could perform this collection at home within one week (+/- one week) of Visit 7. 
15 Only for female subjects of childbearing potential. 
16 Local lab assessments may always be performed at investigator’s discretion e.g. for symptoms or to guide SoC or TransCon PTH/placebo titration if necessary, 
at any visits after Visit 6 during Blinded Treatment Period, or at any point in time as needed. 
17 Multiple local laboratory assessments over the approximate 4 weeks of the Screening Period are expected in order to optimize both the albumin-adjusted or 
ionized sCa to the normal range, as well as normalize the sMg and vitamin D level. Repeat TSH may be performed during the Screening Period if the baseline 
measurement is out of the allowable range.  
18 Based on review of dietary calcium questionnaire, subjects will be counseled to maintain a stable dietary calcium and to avoid unnecessary/excessive dietary 
sodium intake throughout the trial. 
19 During Screening, HP-related therapies (calcitriol, alfacalcidol, calcium, magnesium, and vitamin D3) will be optimized to achieve the protocol-specified 
ranges for sCa, 25(OH) vitamin D, and sMg. See Section 9.5.1. 
20 See Section 9.5.2.1, Section 9.5.3.1 (for Visit 10) and Appendix 2. 
21 Randomization may occur only after Medical Monitor or designee confirmation of eligibility. 
22 See Section 9.4.2.  At Visit 10, subjects still taking active vitamin D or subjects off active vitamin D and taking study drug ≥ 30 µg/day will start TransCon 
PTH at a dose of 18 µg/day while subjects off active vitamin D and taking study drug < 30 µg/day will continue their TransCon PTH dose taken at the end of 
the Blinded Treatment Period (Exception: in cases of out-of-range sCa level at Visit 10, adjust the TransCon PTH dose as per Appendix 2). 
23 Adverse event review includes questions about general well-being, changes to health or medications, hypo- or hypercalcemic symptoms, vasodilatory 
symptoms as AESI, emergency/urgent care visits or hospitalizations, and abnormal results from physical examination, examination of injection sites, and 
laboratory results, as applicable. 
24 On-site drug administration to include on-site observation for at least 30 minutes for local tolerability assessment and adverse reactions, including light 
headedness. 
25 On-site drug administration only for subjects still taking active vitamin D at Visit 10 or subjects off active vitamin D and taking study drug ≥ 30 µg/day 
entering Visit 10. 
26 Local tolerability assessment including redness, itching, swelling and pain assessment to be performed at Visit 1 at time of the first study drug injection and at 
least 15 minutes post dose. 
27 Local tolerability assessment including redness, itching, swelling and pain assessment to be performed at Visit 10 only for subjects still taking active vitamin D 
at Visit 10 or subjects off active vitamin D and taking study drug ≥ 30 µg/day entering Visit 10, at time of the study drug injection and at least 15 minutes post 
dose. 
28 See Section 9.5.2.2, Section 9.5.3.2 and Appendix 2.

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 120 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Period 
Extension 
Visit 
LV41 
LV51 
V11 
LV61 
LV71 
LV81 
V12 
V132 
V142 
V152 
V16 
V172 
V18 
V19 
to 
V252 
V26 
(EoT)/ET3 
Week 
26 
27 
28 
29 
30 
32 
34 
38 
42 
46 
52 
65 
78 
91 to 
1694 
182 
Day 
185 
190 
197 
204 
211 
225 
239 
267 
295 
323 
365 
456 
547 
638 
to 
1184 
1275 
 
2-3 
days 
post-
V10 
7-8 
days 
post-
V10 
14-16 
days 
post-
V10 
21-23 
days 
post-
V10 
28-30 
days 
post-
V10 
±2 days 
±3 days 
±7 days 
COAs5 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X6 
X 
Vital sign 
measurements7 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X8 
X 
Concomitant 
medication review 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X9 
X 
Physical examination 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X10 
X 
Weekly diary 
dispensing 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Subject diary review 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood Collection for 
local lab assessment11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Blood collection for 
central lab 
assessments 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X12 
X 
24-hour urine 
collection 
 
 
 
 
 
 
 
 
 
 
X13 
 
 
X13 
X13 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 121 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Period 
Extension 
Visit 
LV41 
LV51 
V11 
LV61 
LV71 
LV81 
V12 
V132 
V142 
V152 
V16 
V172 
V18 
V19 
to 
V252 
V26 
(EoT)/ET3 
Week 
26 
27 
28 
29 
30 
32 
34 
38 
42 
46 
52 
65 
78 
91 to 
1694 
182 
Day 
185 
190 
197 
204 
211 
225 
239 
267 
295 
323 
365 
456 
547 
638 
to 
1184 
1275 
 
2-3 
days 
post-
V10 
7-8 
days 
post-
V10 
14-16 
days 
post-
V10 
21-23 
days 
post-
V10 
28-30 
days 
post-
V10 
±2 days 
±3 days 
±7 days 
DXA 
 
 
 
 
 
 
 
 
 
 
X14 
 
 
X14 
X14 
TransCon PTH 
dispensing 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
TransCon PTH receipt 
& compliance review 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
review15 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X9 
X 
SoC titration16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TransCon PTH 
titration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 LV4-LV8 are performed for subjects who are still taking active vitamin D at Visit 10 or subjects off active vitamin D and taking TransCon PTH/placebo dose 
≥30 μg/day entering Visit 10. 
2 In selected countries, home/virtual visits may be performed at Visits 13, 14, 15, 17, 19, 21, 23, and 25. 
3 Early Termination (ET) Visit for the subjects who discontinue the trial after Visit 10. The structure and assessments of the ET visit should be as similar as 
possible to Visit 26. 
4 Visit 19 to 25 are performed in Week 91, 104, 117, 130, 143, 156 and 169. 
5 COAs: PRO measures must be completed by the subject without assistance and prior to conducting any clinical assessments. The CGI-S should be completed 
by the investigator after all clinical assessments are completed. 
6 COAs will be completed at Visits 20, 22, 24. 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 122 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
7 Subject should rest for at least 5 minutes before vital sign measurements, including respiratory rate, temperature, orthostatic BP and heart rate. BP and heart 
rate are performed while the subject is sitting. The subject is then asked to stand up, within 2 minutes of doing so, BP and heart rate are measured again. 
8 Vital sign measurements are performed at Visit 20, 22 and 24. 
9 Correspondence (e.g., telemedicine, phone call, email) with subject is required to perform concomitant medication review, including PRN doses of SoC, and 
adverse event review if visit is not performed on-site. 
10 Physical Examination is performed at Visit 20, 22 and 24. 
11 Local lab assessments may be performed at the clinic visits, or at any time at the investigator’s discretion e.g., for symptoms or to guide SoC or TransCon PTH 
titration. 
12 Blood Collection for central lab assessments only at Visit 19, 20 and every other visit after. 
13 24-hour urine collection is performed by the subject at home within one week (+/- one week) of Visit 16, 20, 24, and within one week prior to Visit 26. 
14 DXA is performed at or within one week (+/- one week) of Visit 16, 20, and at or within one week prior to Visit 26. 
15 Adverse event review includes a question about general well-being, changes to health or medications, hypo- or hypercalcemic symptoms, vasodilatory 
symptoms as AESI, emergency/urgent care visits or hospitalizations, and abnormal results from physical examination, examination of injection sites, and 
laboratory results, as applicable. Two weeks (+ 7 days) after last study drug administration, a telephone contact will take place to evaluate AEs that were 
ongoing at the final study visit and to evaluate the subject for any further AEs during the 2 weeks since last study drug administration. 
16 See Section 9.5.3.1 and Appendix 2. 
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 123 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
APPENDIX 4. 
SCHEDULE OF LABORATORY ASSESSMENTS  
Visit 
Screening 
1 
LV1-
LV2 
2 
LV3 
3 
4 
5 
6 
71 
8-101 
Week 
-6 to -2 
0 
0-1 
2 
3 
4 
6 
8 
10 
12 
16-26 
Laboratory 
Type 
Local 
Central 
Local 
Central 
Local 
ONLY 
Local 
Central 
Local 
ONLY 
Local 
Central 
Local 
Central 
Local 
Central 
Local 
Central 
Central 
Central 
Calcium & 
Albumin 
or Ionized 
Calcium1 
X 
Included 
in 
Chem. 
Panel 
 
Included  
in 
Chem. 
Panel 
X 
X 
Included 
in 
Chem. 
Panel 
X 
X 
Included 
in 
Chem. 
Panel 
X 
Included 
in 
Chem. 
Panel 
X 
Included 
in 
Chem. 
Panel 
X 
Included 
in 
Chem. 
Panel 
Included 
in 
Chem. 
Panel 
Included 
in 
Chem. 
Panel 
25(OH) 
Vitamin D 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X2 
1,25(OH)2 
Vitamin D 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X2 
Chemistry 
Panel3  
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Hematolog
y Panel4 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Free PTH5 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X5 
Antibodies 
against 
PTH, 
TransCon 
PTH & 
PEG6 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X6 
Bone 
Turnover 
markers 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X7 
Magnesiu
m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X2 
 
PTH(1-84) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 124 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
Visit 
Screening 
1 
LV1-
LV2 
2 
LV3 
3 
4 
5 
6 
71 
8-101 
Week 
-6 to -2 
0 
0-1 
2 
3 
4 
6 
8 
10 
12 
16-26 
Laboratory 
Type 
Local 
Central 
Local 
Central 
Local 
ONLY 
Local 
Central 
Local 
ONLY 
Local 
Central 
Local 
Central 
Local 
Central 
Local 
Central 
Central 
Central 
Serum 
FSH8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
hCG9 
X 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
hCG9 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
24-hour 
Urine 
Panel11 
 
X12 
 
X13 
 
 
 
 
 
 
 
 
 
 
 
 
X12 
X12 
1 Local lab assessments may be performed at the clinic visits, or at any time at the investigator’s discretion e.g., for symptoms or to guide SoC or study drug titration. 
2 25(OH) vitamin D, 1,25(OH)2 vitamin D and TSH are assessed at Visit 10. 
3 Including but not limited to: Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, Alkaline Phosphatase, ALT (SGPT), AST (SGOT), GGT, Urea Nitrogen, Creatinine, Uric Acid, Calcium, 
Phosphate, Total Protein, Albumin, Globulin, CK, Sodium, Potassium, Bicarbonate, Chloride, Magnesium. (At Screening only: also Glucose, Cholesterol and HbA1C [Documented 
HbA1C result drawn within 12 weeks prior to Screening is acceptable.]) 
4 Including but not limited to: Hemoglobin, Hematocrit, RBC, MCH, MCHC, RBC morphology & MCV, WBC, Neutrophils, Lymphocytes, Monocytes Eosinophils, Basophils, Platelets. 
5 Only for subjects at selected sites, where Free PTH assessment will be performed. Free PTH(1-34) and Free PTH(1-33) are assessed at Visit 1, 3, 5, 7 and 10. 
6 Anti-PTH, anti-TransCon PTH and anti-PEG antibodies are assessed at Visit 1, 3, 5, 7 and 10. 
7 Bone turnover markers are assessed at Visit 10. 
8 Follicle stimulating hormone (FSH) is assessed only for female subjects ≥ 45 years old as of Screening, without menses for at least 6 months prior to Screening without an alternative 
medical cause (e.g., surgically sterile) to determine if they are postmenopausal (i.e., do not require pregnancy testing). 
9 Human chorionic gonadotropin (hCG) (pregnancy test) is assessed only for female subjects of childbearing potential.  Female subjects are considered NOT to be of childbearing potential 
if they are surgically sterile or postmenopausal, defined as age >50 with absent menses for ≥12 months, or age ≥45 years old as of Screening, without menses for at least 6 months prior to 
Screening and FSH >30 mIU/mL). 
10 Local urine hCG (pregnancy test) results must confirm subject is not pregnant prior to first study drug dose administration at Visit 1. 
11 24-hour urine panel includes but not limited to: Creatinine, Calcium, Citrate, Uric Acid, Oxalate, Phosphate, Sodium, Potassium, Magnesium, pH and Urine volume, except for 24-hour 
urine collection within 52 weeks of Screening or during Screening for confirmation of eligibility which only includes Calcium, Creatinine, and urine volume. 
12 24-hour urine collection is performed by the subject at home within 52 weeks prior to Screening or during the Screening Period, within one week (+/- one week) of Visit 7 and within one 
week prior to Visit 10. 
13 After the investigator has confirmed the subject is eligible to move into the Blinded Treatment Period, 24-hour urine collection is performed within one week prior to Visit 1. 
 

Clinical Trial Protocol 
 
Ascendis Pharma 
TCP-304, Version 7.0 
 
Page 125 of 125 
VV-SUB-023233-12.0 
 
CONFIDENTIAL 
1 LV4-LV8 are performed only for subjects still taking active vitamin D at Visit 10 or for subjects off active vitamin D and taking TransCon PTH/placebo dose ≥ 30 μg/day at the 
end of the Blinded Treatment Period. 
2 Local lab assessment may be performed at clinic visits of V15+ or at any time at the investigator’s discretion e.g., for symptoms or to guide SoC or TransCon PTH titration. 
3 25(OH) vitamin D, 1,25(OH)2 vitamin D, TSH, chemistry panel, and hematology panel are assessed at Visit 16 and then every other visit. 
4 Anti-PTH, anti-TransCon PTH and anti- PEG antibodies are assessed at LV7, 12, 13, 16, 17, 18, 19, 20 and every other visit after. 
5 Bone turnover markers are assessed at Visit 16, and every other visit after. 
6 Serum hCG (pregnancy test) is assessed at Visit 16, 17, 18, 19, 20 and every other visit after. 
7 24-hour urine collection is performed by the subject at home within one week (+/- one week) of Visit 16, 20, 24, and within one week prior to Visit 26. 
Period 
 
Extension Period 
Visit 
LV4-
LV51   
11 
LV61 
LV71 
LV81 
12 
13 
14 
152 
16+2 
Week 
26-27 
28 
29 
30 
32 
34 
38 
42 
46 
52+ 
Laboratory 
Type 
Local  
ONLY 
Local 
Central 
Local  
ONLY 
Local 
Central 
Local 
ONLY 
Local 
Central 
Local 
Central 
Local 
ONLY 
Central 
Central 
Calcium & 
Albumin 
or Ionized 
Calcium2 
X 
X 
Included 
in Chem 
Panel 
X 
 
X 
Included 
in Chem 
Panel 
X 
X 
 
X 
Included 
in Chem 
Panel 
X 
Included 
in Chem 
Panel 
Included 
in Chem 
Panel 
25(OH) 
Vitamin D 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X3   
1,25(OH)2 
Vitamin D 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X3 
TSH 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X3 
Chemistry 
Panel3 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
X3 
Hematology 
Panel3 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
X3 
Antibodies 
against PTH, 
TransCon 
PTH & PEG4   
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X4 
Bone turnover 
markers 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X5   
Serum hCG 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X6   
24-hour Urine 
Panel 
 
 
 
 
 
 
 
 
 
 
 
 
 
X7   

   Approval Signatures
Document Name:
TCP-304 Protocol v.6
Document Number:
VV-SUB-023233
Version:
12.0
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:
25-May-2023 16:08:58 GMT+0000
 Approved
SIGNATURE INFORMATION:
30-May-2023 00:12:14 GMT+0000
 Approved
SIGNATURE INFORMATION:
30-May-2023 06:25:57 GMT+0000
PPD
PPD
PPD
PPD
PPD
PPD

   Approval Signatures
Document Name:
TCP-304 Protocol v.6
Document Number:
VV-SUB-023233
Version:
12.0
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:
25-May-2023 16:08:58 GMT+0000
 Approved
SIGNATURE INFORMATION:
30-May-2023 00:12:14 GMT+0000
 Approved
SIGNATURE INFORMATION:
30-May-2023 06:25:57 GMT+0000
PPD
PPD
PPD
PPD
PPD
PPD