PaTH Forward: A Phase 2, 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: PHASE2
Conditions: Hypoparathyroidism, Endocrine System Diseases, Parathyroid Diseases
Sponsor: Ascendis Pharma A/S

Official Title:  
PaTH Forward: A Phase 2, 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: 
 NCT04009291 
 
Document Date:   Protocol Amendment 3: 10 March 2021 

Clinical Study Protocol 
 
Ascendis Pharma 
PaTH Forward (TCP-201) 
 
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9.5.3. Extension Period 
(Visits 3-21; Weeks 4-
214) 
10.1. Trial Duration 
10.1.1 Trial Periods and 
Visits 
10.1.4. Extension Period 
(Week 4-214) 
10.1.4.5. Laboratory 
Visits 7-12 (LV7-LV12; 
Weeks 71-201; Day 
497-201 ±14 days) 
procedures 
10.1.4.6. Visits 16-21 
(Weeks 84-214; Day 
588-1498 ±14 days) 
procedures 
11.12.1.8. Visit 9-21 
(V9-21) Laboratory 
Assessments 
Appendix 4. Schedule of 
Events 
Appendix 5. Schedule of 
Laboratory Assessments 
Change Extension Period from Visits 3-
15 or Visit 3+ to Visit 3-21 
Change Extension Period from Weeks 
4-58 or Weeks 4+ to Weeks 4-214 
Update to the Study Design image to 
capture change in duration of Extension 
Period 
Addition of the following study visits: 
Visit 15A (Week 66, Day 462, ±7 days) 
Laboratory Visit 7 (Week 71, Day 497, 
±14 days) 
Visit 15B (Week 74, Day 518, ±7 days) 
Visit 16 (Week 84, Day 588, ±14 days) 
Visit 16A (Week 92, Day 644, ±7 days) 
Laboratory Visit 8 (Week 97, Day 679, 
±14 days) 
Visit 16B (Week 100, Day 700, ±7 
days) 
Visit 17 (Week 110, Day 770, ±14 
days) 
Visit 17A (Week 118, Day 826, ±7 
days) 
Laboratory Visit 9 (Week 123, Day 
861, ±14 days) 
Visit 17B (Week 126, Day 882, ±7 
days) 
Visit 18 (Week 136, Day 952, ±14 
days) 
Visit 18A (Week 144, Day 1008, ±7 
days) 
Laboratory Visit 10 (Week 149, Day 
1043, ±14 days) 
Visit 18B (Week 152, Day 1064, ±7 
days) 
Visit 19 (Week 162, Day 1134, ±14 
days) 
Visit 19A (Week 170, Day 1190, ±7 
days) 
Laboratory Visit 11 (Week 175, Day 
1225, ±14 days) 
to align with current 
standard of care practices for 
hypoparathyroid patient 
• 
Interim dispensation of 8- or 
10-week supply of study 
drug between in-person 
study visits (Visits A and B) 
to align with estimated 
maximum refrigerated 
storage capacity at subjects’ 
homes and minimize risk of 
misuse due to inappropriate 
storage, confusion between 
kits, or kit expiry  

Clinical Study Protocol 
 
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Visit 19B (Week 178, Day 1246, ±7 
days) 
Visit 20 (Week 188, Day 1407, ±14 
days) 
Visit 20A (Week 196, Day 1372, ±7 
days) 
Laboratory Visit 12 (Week 201, Day 
1316, ±14 days) 
Visit 20B (Week 204, Day 1428, ±7 
days) 
Visit 21 (Week 214, Day 1498, ±14 
days)  
Addition of the following protocol 
sections:  
10.1.4.5. Laboratory Visits 7-12 (LV7-
LV12; Weeks 71-201; Day 497-201 
±14 days) procedures 
10.1.4.6. Visits 16-21 (Weeks 84-214; 
Day 588-1498 ±14 days) procedures 
11.12.1.9. Laboratory Visits 7-12 (LV7-
LV12) Laboratory Assessments 
Synopsis: Trial Design 
 
Synopsis: Investigational 
Product 
 
9.2. Treatment 
Administered 
 
9.3. Selection of Trial 
Doses 
 
9.5.3.1. Study Drug Dose 
Adjustments during 
Extension Period 
 
10.1.4. Extension Period 
(Week 4-214) 
 
“Dose range…will be 6-30 µg/day” to 
“Dose range…is expected to be 6-30 
µg/day” 
 
Change from “a dose range of 6-30 µg/day” 
to “an expected dose range of 6-30 µg/day” 
 
Change from “an optimal dose of 6-30 µg 
PTH/day” to “an expected optimal dose of 
6-30 µg PTH/day” 
 
“with the availability of a larger dose range 
from 6 to 30 µg/day in 3 pen 
presentations…” to “with the availability of 
3 pen presentations …, allowing for an 
expanded dose range.” 
 
Clarification that the dose range 
during the Extension Period is 
expected to be 6-30mcg/day, but 
that dosing <6 mcg/day or >30 
mcg/day is allowed 
 
Synopsis: Trial Design 
 
9.5.3.1. Study Drug Dose 
Adjustments during 
Extension Period 
 
Addition of “However, dose adjustments 
should continue as needed based on sCa 
results and following Appendix 2 and 
Appendix 3” and “dose adjustments should 
continue as needed based on sCa results and 
following Appendix 2 and Appendix 3”  
Clarification that adjustments to 
TransCon PTH and SOC doses is 
allowed per protocol throughout the 
Extension Period and such 
adjustments should be based on 
Appendix 2 and Appendix 3 

Clinical Study Protocol 
 
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9.5.3.2. SOC Dose 
Adjustments during 
Extension Period, 10.1.4. 
Extension Period (Week 4-
214) 
 
10.1.4.3. Visits 9-11 
(Weeks 18-26; Day 126-
182 ±3 days) procedures  
 
10.1.4.4. Visits 12-15 
(Weeks 34-58; Day 238-
406 ±7 days) procedures 
 
10.1.4.5. Laboratory Visits 
7-12 (LV7-LV12; Weeks 
71-201; Day 497-201 ±14 
days ) procedures 
 
10.1.4.6. Visits 16-21 
(Weeks 84-214; Day 588-
1498 ±14 days) procedures 
 
Appendix 4. Schedule of 
Events 
 
Addition of “Titration of TransCon PTH 
and/or SOC dose adjustment, if needed (See 
Section 9.5.3)” to Visits 9+ procedures 
 
Synopsis: Trial Design 
9.5.3.1. Study Drug 
Dose Adjustments 
during Extension Period 
10.1.4. Extension Period 
(Week 4-214) 
Change “Due to the extended length of 
time between visits after Visit 9 (4-8 
weeks), the TransCon PTH dose may be 
adjusted to control persistent hypo- or 
hypercalcemia between clinic visits 
with prior approval of the Medical 
Monitor/Medical Expert” to “Due to the 
extended length of time between visits 
after Visit 9, the TransCon PTH dose 
may be adjusted to control persistent 
hypo- or hypercalcemia between clinic 
visits” 
Change “Due to the extended length of 
time between visits (4 and 8 weeks) 
after Visit 9, the TransCon PTH dose 
may be adjusted between clinic visits 
with the approval of the Medical 
Monitor/Medical Expert” to “Due to the 
extended length of time between visit 
after Visit 9, the TransCon PTH dose 
may be adjusted between clinic visits” 
With the additional visits added 
to the Extension Period, visits 
will occur less frequently than 
every 4-8 weeks. 
Since approval from the Medical 
Monitor/Medical Expert is not 
needed prior to adjusting 
TransCon PTH doses at visits, it 
is unnecessary requirement to 
have for dose adjustments 
between Extension Period visits 
as sCa level from local 
laboratories and symptoms will 
be guiding such adjustments in 
either situation. 
Synopsis: Trial and 
Treatment Duration 
Change from “stable dosing” to 
“individualized dosing” 
Clarification that adjustments to 
TransCon PTH and SOC doses 

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7.1 Overall Trial Design 
and Plan 
Section 10.1. Trial 
Duration 
is allowed per protocol 
throughout the Extension Period, 
though generally subjects are 
expected to remain stable on 
their individualized dosing 
Synopsis: Endpoints: 
Secondary Efficacy 
Endpoints: Other 
Secondary Efficacy 
Endpoints 
14.2.1.2.2. Other 
Secondary Efficacy 
Endpoints 
Addition of “For the analysis of these 
endpoints in the Extension Period, the 
24-hour urine calcium excretion will be 
used.” 
Clarification of analysis to be 
performed during the Extension 
Period 
Synopsis: Endpoints: 
Secondary Efficacy 
Endpoints: Other 
Secondary Efficacy 
Endpoints 
14.2.1.2.2. Other 
Secondary Efficacy 
Endpoints 
Addition of “At predefined timepoints 
over the Extension Period: 
24-hour urine calcium excretion” 
Clarification of analysis to be 
performed during the Extension 
Period 
Synopsis: Endpoints: 
Safety & Tolerability 
Endpoints 
14.2.2. Safety & 
Tolerability Endpoints 
Change from “Physical examinations 
(AE-directed), including vital signs” to 
“Physical examinations, including vital 
signs” 
Update to include physical 
examinations performed at Visits 
16-21 in addition to those 
performed in evaluation of 
potential AEs 
Synopsis: Endpoints: 
Exploratory Endpoints 
14.2.3. Exploratory 
Endpoints 
Addition of annual assessments (weeks 
110, 162, and 214) of: 
• 
BMD and TBS by DXA 
• 
Bone turnover markers (serum 
P1NP and CTx) 
• 
Clinical Outcomes Assessments 
(COAs)  
Addition of every 6-month assessments 
(weeks 84, 110, 136, 162, 188, and 214) 
of: 
• 
Albumin-adjusted sCa, magnesium, 
phosphate, and sCa x sP product 
• 
24-hour urine calcium excretion 
Addition of timepoints for 
exploratory endpoint analyses 
throughout the Extension Period 
with the addition of the 3 years 
to the Extension Period 
Synopsis: Endpoints: 
Exploratory Endpoints 
Change from “Albumin-adjusted or 
ionized sCa” to “Albumin-adjusted 
sCa” 
Correction that analysis of this 
endpoint will be performed with 
albumin-adjusted sCa only 

Clinical Study Protocol 
 
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PaTH Forward (TCP-201) 
 
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14.2.3. Exploratory 
Endpoints 
4. List of Abbreviations 
Addition of “COA” for “clinical 
outcomes assessment” 
Administrative change 
9.1.2. Accountability, 
Storage, and Dispensing 
Addition of “Study drug may be 
shipped from site or depot to subjects 
using an Ascendis-approved courier 
service. In such cases, accountability for 
study drug remains the responsibility of 
the principal investigator until subject 
has confirmed receipt of study drug. 
Documentation of study drug shipments 
must be maintained by the site and 
include, at minimum, the following: 
date of shipment from site, kit numbers 
shipped, date of receipt by subject, and 
temperature monitoring during 
shipment.” 
Clarification that shipments of 
study drug to subjects is 
acceptable per protocol 
9.6. Study Drug 
Stopping or Change to 
Administration 
Change “Stopping” to “Study Drug 
Stopping” 
Change “Dose Reductions” to “or 
Change to Administration” 
Clarification of topics covered in 
the section 
9.6.1. Required Stopping Removal of the following from 
“Required Stopping” section: “If during 
the Extension Period, albumin-adjusted 
sCa level remains >ULN while subject 
is taking TransCon PTH 6 µg/day (the 
minimum allowable TransCon dose) 
and the subject has discontinued active 
vitamin D and calcium supplements and 
notes symptoms of hypercalcemia, after 
discussion with the Sponsor Medical 
Monitor/Medical Expert, study drug 
should be permanently discontinued and 
SOC treatment resumed.” 
Correction that subjects are not 
required to stop taking the study 
drug if they need <6 µg/day of 
TransCon PTH 
9.6.2. Possible Stopping 
or Change to 
Administration 
Change “Possible Stopping/Dose 
Reduction” to “Possible Stopping or 
Change to Administration” 
Clarification of topics covered in 
the section 
9.6.2. Possible Stopping 
or Change to 
Administration 
Change of “The investigator may stop 
or reduce the dose of study drug at any 
time during the trial” to “The 
Clarification that reductions are 
not allowed during Blinded 
Period 

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investigator may stop study drug at any 
time during the trial” 
9.6.2. Possible Stopping 
or Change to 
Administration 
Change “If during the Extension Period 
sCa level remains <LLN while subject 
is taking TransCon PTH 30 µg/day (the 
maximum allowable dose), and the 
subject notes symptoms of 
hypocalcemia…active vitamin D and/or 
calcium supplements may be resumed” 
to “If during the Extension Period sCa 
level remains <LLN while subject is 
taking TransCon PTH 30 µg/day the 
TransCon PTH dose may be increased.” 
Clarification that while 
30mcg/day is the maximum 
available dose per injection, 
>30 mcg/day dosing is allowed 
Clarification that increase in 
TransCon PTH is the expected 
action if sCa level remains 
<LLN rather than resuming SOC 
9.6.2. Possible Stopping 
or Change to 
Administration 
Addition of “If during the Extension 
Period, albumin-adjusted or ionized sCa 
level remains >ULN while subject is 
taking TransCon PTH 6 µg/day and has 
discontinued active vitamin D and 
calcium supplements, after discussion 
with the Medical Monitor/Medical 
Expert, the TransCon PTH dose may be 
decreased.” 
Clarification that while 
6mcg/day in the minimum 
available dose per injection, <6 
mcg/day dosing is allowed  
10.1.2. Screening Period 
(Week -4 to -1, Day 28 
to -7) 
Change “Rescreened subjects should 
keep the same Subject Number as they 
had during their initial screening” to 
“Rescreened subjects should receive a 
new Subject Number” 
Alignment with logistical need 
to provide new Subject Numbers 
for rescreened subjects 
10.1.2. Screening Period 
(Week -4 to -1, Day -28 
to -7) 
10.1.3.1 Visit 1 (Week 
0, Day 1) procedures 
10.1.3.4 Visit 3 (Week 
4, Day 28 ±2 days) 
procedures 
10.4.1.2 Visits 4-8 
(Weeks 6-14; Days 42, 
56, 70, 84, 98 ±2 days) 
procedures 
10.4.1.3 Visits 9-11 
(Weeks 18-26; Day 126-
182 ±3 days) procedures 
Change from “PRO validation battery” 
to “HPES validation battery” 
Update to reflect that validation 
battery includes a clinician-
reported outcome measure and 
not only patient-reported 
outcome measures 

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10.4.1.4 Visits 12-15 
(Weeks 34-58; Day 238-
406 ±7 days) procedures 
10.4.1.6 Visits 16-21 
(Weeks 84-214; Day 
588-1498 ±14 days) 
procedures 
10.1.4.4. Visits 12-15 
(Weeks 34-58; Day 238-
406 ±7 days) procedures 
Change “24-hour urine collection (only 
the week prior to Visit 15)” to “24-hour 
urine collection (only within a week of 
Visit 15)” 
Change “DXA and TBS (only the week 
prior to Visit 15)” to “DXA and TBS 
(only within a week of Visit 15)” 
As Visit 15 is no longer the final 
study visit, 24-hour urine 
collection and DXA can occur 
within a week of the visit rather 
than only the week prior to the 
visit 
11.7. 
Hypoparathyroidism 
Patient Experience Scale 
Validation Battery 
Change from “Patient-Reported 
Outcome Measures” to 
“Hypoparathyroidism Patient 
Experience Scale Validation Battery” 
Update to reflect that validation 
battery includes a clinician-
reported outcome measure and 
not only patient-reported 
outcome measures 
11.7. 
Hypoparathyroidism 
Patient Experience Scale 
Validation Battery 
Change “The Hypoparathyroid 
Experience Scale” to “The 
Hypoparathyroidism Patient Experience 
Scale” 
Update to reflect finalized title 
of the patient-reported outcome 
measure 
11.7. 
Hypoparathyroidism 
Patient Experience Scale 
Validation Battery 
Change from “The data collected in this 
trial will be combined with similar data 
collected via a web-study and a clinic-
based study” to “The data collected in 
this trial will be combined with similar 
data collected via a web-study” 
Change from “A separate Statistical 
Analysis Plan based on the data 
collected from all three studies will be 
prepared” to “A separate Psychometric 
Analysis Plan based on the data 
collected from the two studies will be 
prepared” 
Change from “Data from the validation 
battery will be used to assess the 
measurement properties of the HPES” 
to “Data from the validation battery, 
and a subset thereof at various time 
Update to reflect finalized HPES 
validation study  

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points, will be used to assess the 
measurement properties of the HPES” 
11.7. 
Hypoparathyroidism 
Patient Experience Scale 
Validation Battery 
Change from “The Validation Battery 
consists of the HPES and other 
questionnaires” to “The Validation 
Battery consists of the following 
Clinical Outcome Assessments (COAs): 
the HPES, other PROs, and a clinician-
reported outcome measure 
Update to reflect that validation 
battery includes a clinician-
reported outcome measure and 
not only patient-reported 
outcome measures 
11.7. 
Hypoparathyroidism 
Patient Experience Scale 
Validation Battery 
Addition of “In addition, one of the 
PROs will also be used for resource 
utilization evaluation.” 
Clarification that one of the 
PROs will be used for resource 
utilization evaluation in addition 
to HPES validation 
11.7. 
Hypoparathyroidism 
Patient Experience Scale 
Validation Battery 
Change from “A subset of the 
Validation Battery PROs will also be 
completed later in the trial for 
exploratory purposes” to “The 
Validation Battery, or a subset, will also 
be completed later in the trial for 
exploratory purposes” 
Removal of “PRO” to reflect 
that validation battery includes a 
clinician-reported outcome 
measure and not only patient-
reported outcome measures 
Clarification that the complete 
Validation Battery or a subset 
will be used in Exploratory 
Endpoint analyses 
11.12.1.4. Visit 2 (V2) 
Laboratory Assessments 
11.12.1.5. Visit 3 (V3) 
Laboratory Assessments 
11.12.1.7. Visit 4-8 (V4-
8) Laboratory 
Assessments 
11.12.1.8. Visit 9-21 
(V9-21) Laboratory 
Assessments 
Change from “performed centrally on 
blood collected” to “performed 
centrally on blood and urine collected”  
Correction to include urine 
collection to perform urine 
laboratory assessments listed 
11.12.1.8. Visit 9-21 
(V9-21) Laboratory 
Assessments 
Change “Visit 9-15 (V9-15)” to “Visit 
9-21 (V9-V21)” 
Change “Urine calcium and creatinine 
(only at Visits 9, 11, and 15)” to “Urine 
calcium and creatinine (only at Visits 9, 
11, and 16-21) 
Change “Bone turnover markers (only 
at Visits 11, and 15)” to “Bone turnover 
Addition of timepoints for 
laboratory assessments 
throughout the Extension Period 
with the addition of the 3 years 
to the Extension Period 

Clinical Study Protocol 
 
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14.2.3. Exploratory 
Endpoints 
Change from “14.2.3. Exploratory 
Endpoints:” to “14.2.3. Exploratory 
Endpoints” 
Consistency 
Appendix 2. TransCon 
PTH Titration for 
Subjects Taking Daily 
Active Vitamin D 
(Starting at Visit 4) 
Appendix 3. TransCon 
PTH Titration for 
Subjects Not Taking 
Daily Active Vitamin D 
(Starting at Visit 3) 
Change from “TransCon PTH Dose 
Adjustment” to “Dose Adjustment”  
Clarification as both TransCon 
PTH and SOC dose adjustments 
are indicated within the table 
Appendix 2. TransCon 
PTH Titration for 
Subjects Taking Daily 
Active Vitamin D 
(Starting at Visit 4) 
Appendix 3. TransCon 
PTH Titration for 
Subjects Not Taking 
Daily Active Vitamin D 
(Starting at Visit 3) 
Change from “Increase TransCon PTH 
by 3 µg (up to max of 30 µg/day)” to 
“Increase TransCon PTH by 3 µg” 
when sCa is <LLN with or without 
symptoms 
Clarification that while 
30mcg/day is the maximum 
available dose per injection, >30 
mcg/day dosing is allowed 
Appendix 2. TransCon 
PTH Titration for 
Subjects Taking Daily 
Active Vitamin D 
(Starting at Visit 4) 
Appendix 3. TransCon 
PTH Titration for 
Subjects Not Taking 
Daily Active Vitamin D 
(Starting at Visit 3) 
Addition of SOC and TransCon PTH 
dose titration guidance for sCa WNL 
without symptoms, WNL with 
hypocalcemic symptoms, and WNL 
with hypercalcemic symptoms 
Because the trial is assessing the 
potential for TransCon PTH to 
be a hormone replacement 
therapy, the goal is for subjects 
to achieve independence from 
standing doses of calcitriol and 
alfacalcidol, and to progressively 
reduce calcium supplements to 
≤500 mg/day (a dose considered 
as “supplemental” to meeting 
recommended daily intake for 
general health, as opposed to a 
“therapeutic” dose to treat 
hypoparathyroidism). Thus, the 
guidance is updated to further 
adjust the TransCon PTH and 
SOC doses when sCa is WNL 
and subject remains on SOC. 

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Appendix 2. TransCon 
PTH Titration for 
Subjects Taking Daily 
Active Vitamin D 
(Starting at Visit 4) 
Appendix 3. TransCon 
PTH Titration for 
Subjects Not Taking 
Daily Active Vitamin D 
(Starting at Visit 3) 
Additional guidance to SOC and 
TransCon PTH dose titration for sCa 
<LLN and >ULN 
Update to provide more detailed 
instructions to safely and 
adequately adjust the TransCon 
PTH and SOC doses when sCa 
is <LLN and >ULN 
Appendix 2. TransCon 
PTH Titration for 
Subjects Taking Daily 
Active Vitamin D 
(Starting at Visit 4) 
Appendix 3. TransCon 
PTH Titration for 
Subjects Not Taking 
Daily Active Vitamin D 
(Starting at Visit 3) 
Removal of “Do not adjust TransCon 
PTH more than once every 2 weeks” 
Clarification that, for subject 
safety, adjustments to TransCon 
PTH may be required more often 
than every 2 weeks in order to 
alleviate hypercalcemic 
symptoms 
Appendix 2. TransCon 
PTH Titration for 
Subjects Taking Daily 
Active Vitamin D 
(Starting at Visit 4) 
Appendix 3. TransCon 
PTH Titration for 
Subjects Not Taking 
Daily Active Vitamin D 
(Starting at Visit 3) 
Addition of “If albumin-adjusted sCa is 
far below the normal range [≤7.3 mg/dL 
(1.82 mmol/L)] or far above the normal 
range [≥11.6 mg/dL (2.89 mmol/L)], 
additional adjustments to active vitamin 
D, calcium, or TransCon PTH may 
occur for the safety of the subject after 
discussion with the Medical Monitor” 
Clarification that, for subject 
safety, further adjustments to 
TransCon PTH and/or SOC are 
acceptable if sCa levels are 
farther out of range than is 
expected 
Appendix 2. TransCon 
PTH Titration for 
Subjects Taking Daily 
Active Vitamin D 
(Starting at Visit 4) 
Appendix 3. TransCon 
PTH Titration for 
Subjects Not Taking 
Daily Active Vitamin D 
(Starting at Visit 3) 
Addition of “If ionized sCa is far below 
the normal range (≤1.03 mmol/L) or far 
above the normal range (≥1.45 
mmol/L), additional adjustments to 
active vitamin D, calcium, or TransCon 
PTH may occur for the safety of the 
subject after discussion with the 
Medical Monitor” 
Clarification that, for subject 
safety, further adjustments to 
TransCon PTH and/or SOC are 
acceptable if sCa levels are 
farther out of range than is 
expected 
Appendix 2. TransCon 
PTH Titration for 
Replacing the following from 
throughout the appendices:  
Consistency in laboratory 
follow-up for any time SOC or 

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Subjects Taking Daily 
Active Vitamin D 
(Starting at Visit 4) 
Appendix 3. TransCon 
PTH Titration for 
Subjects Not Taking 
Daily Active Vitamin D 
(Starting at Visit 3) 
“performing an ULV approximately 9-
11 days after dose adjustment” 
“performing an ULV approximately 3 
days after every dose adjustment if 
symptoms persist, or 9-11 days after 
dose adjustment if symptoms resolved” 
With the following at the bottom of the 
appendices: 
• 
“If a TransCon PTH dose(s) is 
skipped, perform local laboratory 
testing of albumin-adjusted or 
ionized sCa 9-31 days after 
restarting TransCon PTH. These 
local laboratory assessments may 
occur at the next scheduled visit if 
one occurs within the 9-31 day 
window, otherwise an ULV should 
be performed. 
• 
If an adjustment(s) is made to 
active vitamin D, calcium, or 
TransCon PTH dose(s) without a 
TransCon PTH dose(s) skipped, 
perform local laboratory testing of 
albumin-adjusted or ionized sCa 9-
31 days after dose adjustment. 
These local laboratory assessments 
may occur at the next scheduled 
visit if one occurs within the 9-31 
day window, otherwise an ULV 
should be performed. 
• 
If symptoms persist despite an 
adjustment(s) made to active 
vitamin D, calcium, or TransCon 
PTH dose(s), perform local 
laboratory testing of albumin-
adjusted or ionized sCa 2-3 days 
after restarting of TransCon PTH or 
dose adjustment. (Because 
symptoms persist, please do NOT 
wait 9-31 days.)”  
TransCon PTH dose adjustments 
are performed 
Extend laboratory follow-up 
window from 9-11 days to 9-31 
days, allowing investigator to 
determine appropriate follow-up 
for a given subject. Increasing 
the window also allows 
appropriate follow-up to occur at 
the next study visit rather than 
requiring an additional 
laboratory visit. The extension of 
the window is not considered a 
safety concern as the protocol 
requires additional ULVs for 
persistent hypo- or 
hypercalcemic symptoms.  
Appendix 4. Schedule of 
Events 
Split of Extension Period schedule into 
two separate tables 
Readability 
Appendix 4. Schedule of 
Events 
Change in table header for Extension 
Period from “Titration: Study Drug 
Titration with SOC Optimization” and 
Clarification that adjustments to 
TransCon PTH and SOC doses 
is allowed per protocol 

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v 3.0 
Section(s) 
Change(s) 
Rationale 
“Follow-Up Study Drug & SOC Stable” 
to “Individualized Dosing” 
throughout the Extension Period, 
though generally subjects are 
expected to remain stable on 
their individualized dosing 
Appendix 4. Schedule of 
Events 
Removal of rows for PRO validation 
battery, 24-hour urine collection, and 
local DXA from first section of the 
Extension Period table 
Adjustment of footnote numbering 
Due to splitting of Extension 
Period schedule into two 
separate tables, these procedures 
do not occur during the 
timeframe that falls within the 
first section of the Extension 
Period table 
Footnotes associated with 
removed procedure rows 
required renumbering of 
footnotes within the first section 
of the Extension Period table 
Appendix 4. Schedule of 
Events 
Addition of “TransCon PTH 
dispensing” at Visit 15 
As Visit 15 is no longer the final 
study visit, subjects must be 
dispensed study drug at this visit 
Appendix 4. Schedule of 
Events 
Addition of rows for procedures 
associated with Laboratory Visit 7 
through Visit 21 to second section of 
the Extension Period table 
Adjustment of footnote numbering 
Due to addition of study visits to 
the Extension Period of the trial, 
these procedures occur during 
the timeframe that falls within 
the second section of the 
Extension Period table 
Footnotes associated with added 
procedure rows required 
renumbering of footnotes within 
the second section of the 
Extension Period table 
Appendix 5. Schedule of 
Laboratory Assessments 
Changed “Calcium & Albumin or 
Ionized Calcium” to “Corrected 
Calcium (Calcium & Albumin or 
Ionized Calcium)” 
Clarification required with the 
addition of separate serum 
Calcium to be assessed only if 
Ionized Calcium is used for 
Corrected Calcium. If Albumin-
Adjusted Calcium is used for 
Corrected Calcium, Calcium is 
already assessed as part of 
Corrected Calcium and thus a 
separate(second) serum Calcium 
is not required. 

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v 3.0 
Section(s) 
Change(s) 
Rationale 
Appendix 5. Schedule of 
Laboratory Assessments 
Change Visit “9+” to “9-15” and Weeks 
from “18+” to “18-58” 
Addition of columns for LV7-LV12 and 
V16-V21 
Addition of rows for Calcium and 
Phosphate 
Adjustment of footnote numbering 
Addition of timepoints and 
laboratory assessments 
throughout the additional 3 years 
of the Extension Period 
Footnotes associated with added 
procedure rows required 
renumbering of footnotes within 
the second section of the 
Extension Period table 
Appendix 5. Schedule of 
Laboratory Assessments 
Change from “hCG (pregnancy test) is 
assessed only at Visits 10, 12, and 14” 
to “Local urine hCG (pregnancy test) is 
assessed only at Visits 10, 12, and 14” 
Clarification that urine hCG is 
expected to be performed at 
site/local laboratory rather than 
through the Central Laboratory 
Appendix 5. Schedule of 
Laboratory Assessments 
Change “24-hour urine collection will 
be performed… within a week of Visit 
11and the week prior to Visit 15” to 
“24-hour urine collection will be 
performed… within the week prior to 
Visit 1, and within a week of Visits 11 
and 15” 
Clarification that 24-hour urine 
collection is to occur the week 
prior to Visit 1 rather than at 
Visit 1 
As Visit 15 is no longer the final 
study visit, 24-hour urine 
collection and DXA can occur 
within a week of the visit rather 
than only the week prior to the 
visit 
Appendix 6. Laboratory 
Panel Analytes 
Change from “Labataorty Panel 
Analysis” to “Laboratory Panel 
Analysis” 
Correction to spelling 
Appendix 6. Laboratory 
Panel Analytes 
Change from “Phosphorous” to 
“Phosphate” 
Correction to accurately reflect 
laboratory analyte tested 
Appendix 8. Remote 
Study Visits 
Addition of Appendix 
Allow for remote visits when a 
subject is unable to attend 
Extension Period study visits in-
person, while still ensuring 
subject safety 
 

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US ADDENDUM 1 SUMMARY 
Rationale 
This US-specific addendum to the protocol is being issued to incorporate feedback from clinical 
trial sites and patient advocacy groups for humanitarian reasons, to enable US patients on 
Natpara at the time of the Takeda recall on 5 September 2019 to be enrolled in the PaTH 
Forward Trial within the limited enrollment window.  Amending the protocol globally would not 
affect the eligibility criteria for the majority of subjects in other regions because Natpara is 
neither readily accessible in the majority of other countries where this trial is being conducted, 
nor has it been recalled outside of the US.  Furthermore, this country-specific addendum will not 
create a difference in study population between the US and other regions as hypoparathyroid 
patients in both regions may still be treated either exclusively with SOC or returned to SOC 
following treatment with PTH, if available.  
This addendum shortens the washout period from PTH-like drugs from 12 weeks to 5 weeks.  
The current washout period of 12 weeks prior to Visit 1 was established out of an abundance of 
caution.  The half-life of Natpara guarantees that, even with a shortened washout period of 
5 weeks, the drug will be out of the body prior to first dose of study drug and therefore not likely 
to be considered an acute cause of adverse events experienced during study drug treatment.  
Shortening the washout period will not affect the potential for long-term adverse events from 
previous PTH use to appear during the trial as the protocol currently allows subjects who have 
previously taken PTH to enter the trial.  
Reducing the stabilization requirement for SOC from 12 weeks prior to Screening is not of 
clinical concern as subjects will still require optimization of their SOC during screening and 
prior to first study drug dosing (Visit 1).  It should be noted however, that upon immediately 
discontinuing Natpara, patients may acutely require increased SOC doses due to “hungry bone 
syndrome” induced by the anabolic effect of intermittent Natpara.  This generally resolves within 
one week.  Thus, the protocol addendum still requires 4 weeks of stable SOC prior to Screening 
to reduce the likelihood of a meaningful difference between subjects who may enter the study 
after a decreased stabilization period after stopping Natpara due to the recall and those entering 
the study after a longer stabilization period. 
Section(s) 
Change(s) 
Rationale 
Synopsis: Eligibility 
Criteria: Inclusion 
Criteria #3 
Section 8.1.1. Inclusion 
Criteria #3 
Change “On a stable dose* for at least 
12 weeks prior to Screening” to “On a 
stable dose* for at least 12 weeks (or 
4 weeks if on Natpara as of 
September 2019) prior to Screening”  
Reduce the wait period for US 
patients previously treated with 
the only marketed PTH for 
hypoparathyroidism which is 
currently unavailable due to the 
recall. 
Synopsis: Eligibility 
Criteria: Exclusion 
Criteria #6 
Section 8.1.2. Exclusion 
Criteria #6 
Change “Use of PTH-like 
drugs…within 12 weeks prior to Visit 
1” to “Use of PTH-like drugs…within 
5 weeks prior to Visit 1” 
Reduce the wait period for US 
patients previously treated with 
the only marketed PTH for 
hypoparathyroidism which is 
currently unavailable due to the 
recall. 

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v 3.0 
CANADA ADDENDUM 1 SUMMARY 
Rationale 
This addendum to the protocol is being issued to incorporate feedback from Health Canada: 
Section(s) 
Change(s) 
Rationale 
Section 10.1.2 
Screening Period (Week 
-4 to -1, Day -28 to -7) 
Section 10.1.4.3 Visits 
9-11 (Weeks 18-26; Day 
126-182 ±3 days) 
procedures 
Section 10.1.4.4 Visits 
12-15 (Weeks 34-58; 
Day 238-406 ±7 days) 
procedures 
Addition of bulleted statement: 
“TBS scoring will not be performed 
for subjects 18 to 20 years of age” 
Remove TBS scoring for subjects 
18 to 20 years old as requested by 
Health Canada 
Section 11.5. Dual-
Energy X-Ray 
Absorptiometry (DXA) 
and Trabecular Bone 
Score (TBS) 
Addition of “TBS scoring will not be 
performed for subjects 18 to 20 years 
of age.” 
Change “If the historical DXA did 
not include TBS, TBS analysis 
should be performed” to “If the 
historical DXA did not include TBS, 
TBS analysis should be performed 
unless subject is 18 to 20 years of 
age.” 
Remove TBS scoring for subjects 
18 to 20 years old as requested by 
Health Canada 
 

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v 3.0 
Section(s) 
Change(s) 
Rationale 
Synopsis: Eligibility 
Criteria: Exclusion 
Criteria #11 
Section 8.1.2. Exclusion 
Criteria #11 
Addition of “Sexually active women 
of childbearing potential who are 
unwilling to use highly effective 
contraception are excluded from the 
trial.” 
To clarify as requested by Health 
Authorities 
Synopsis: Eligibility 
Criteria: Exclusion 
Criteria #17 
Section 8.1.2. Exclusion 
Criteria #17 
Change “Any disease or condition 
that, in the opinion of the investigator, 
may 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-year duration of the 
trial” to “Any disease or condition 
that, in the opinion of the investigator, 
may 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 1-year duration of the 
trial” 
As requested by Health 
Authorities to reduce the 
Extension Period to 1 year 
Synopsis: Trial Design 
Reduction of Extension Period from 
“at least 3 years” to “54 weeks” 
Reduction of “Extension Period 
(Visits 3+; Week 4+)” to “Extension 
Period (Visits 3-15; Weeks 4-58) 
As requested by Health 
Authorities to reduce the 
Extension Period to 1 year 
Synopsis: Blinding 
Section 7.1 Overall Trial 
Design and Plan 
Section 10.1. Trial 
Duration 
Reduction of the open-label extension 
period of “at least 158 weeks” to “54 
weeks” 
As requested by Health 
Authorities to reduce the 
Extension Period to 1 year 
Synopsis: Trial & 
Treatment Duration 
Section 7.1 Overall Trial 
Design and Plan 
Section 10.1. Trial 
Duration 
Section 10.1.4 Extension 
Period 
Reduction of the total duration of trial 
for an individual subject from “at 
least approximately 162 weeks” to 
“58 weeks” 
Reduction of “followed by 
approximately “144 weeks of stable 
dosing” in the Extension Period to 
“40 weeks of stable dosing” 
Reduction from “Extension Period 
(Week 4+)” to “Extension Period 
(Week 4-58) 
As requested by Health 
Authorities to reduce the 
Extension Period to 1 year 

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v 3.0 
Section(s) 
Change(s) 
Rationale 
Synopsis: End of Trial 
Addition of section to synopsis to 
capture definition of end of trial as 
last subject last visit 
To highlight within the synopsis 
the addition requested by Health 
Authorities 
Synopsis: Stopping 
Rules 
Section 12.2.1.3. Non-
Serious Adverse Events 
Leading to Study drug 
Discontinuation 
Section 12.2.2. 
Reporting of SAEs 
and/or SUSARs 
Change of “Medical Expert/Medical 
Monitor,” “Medical Monitor,” or 
“Medical Monitor/Expert” to 
“Medical Monitor/Medical Expert” 
For consistency throughout 
document 
Synopsis: Endpoints 
Section 14.2.1. Efficacy 
Endpoints 
Addition of “Efficacy” to Primary and 
Secondary Endpoints 
Addition of “Primary and key 
secondary endpoints measured at 
predefined timepoints over the 
Extension Period” for Other 
Secondary Endpoints 
Addition of “and at predefined 
timepoints over the Extension Period” 
for the Other Secondary Efficacy 
Endpoints 
Moved “Safety & Tolerability 
Endpoints” below “Other Secondary 
Efficacy Endpoints” 
Addition of “The following safety 
endpoints will be assessed for both 
Blinded Treatment and Extension 
Periods” for Safety & Tolerability 
Endpoints 
As requested by Health 
Authorities to align the objectives 
with the endpoints and clarify 
which endpoints include analysis 
of data from the Extension Period 
Synopsis: Endpoints 
Section 14.2.3. 
Exploratory Endpoints 
Removal of Exploratory Endpoint 
assessments after 58 weeks 
Addition of 24-hour urine calcium 
excretion at 58 weeks (in place of 74 
weeks)  
Addition of PRO measure at 58 weeks 
(in place of “every 26 weeks 
thereafter”) 
To align endpoints with the 
procedures to be performed at the 
last visit of the Extension Period 
(V15) due to the reduction of the 
Extension Period to 1 year as 
requested by Health Authorities 
Synopsis: Endpoints 
Section 14.2.3. Efficacy 
Endpoints 
Change of albumin-adjusted or 
ionized sCa, magnesium, phosphate, 
and sCa x sP product at “every clinic 
visit” to “at 8, 18, 26, 42, and 58 
weeks” 
To match Schedule of Events and 
Schedule of Laboratory 
Assessments 

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Section(s) 
Change(s) 
Rationale 
Synopsis: Statistical 
Methods 
Section 14.1. General 
Change of finalization of SAP from 
before “database lock” to before “trial 
unblinding and database lock of the 
Blinded Treatment Period”  
To clarify as requested by Health 
Authorities 
List of Abbreviations 
Addition of “Clinical Trial 
Facilitation Group” for “CTFG” 
To provide the abbreviation for 
the group referenced in the 
protocol which provides the 
guidance for highly effective 
contraception as requested by 
Health Authorities  
Section 5.3. Clinical 
Experience 
Addition of “conducted under GCP, 
IEC, and Declaration of Helsinki 
guidelines” in regard to the TransCon 
PTH Phase 1 trial 
To clarify as requested by Health 
Authorities 
Section 5.5. Summary of 
Potential Risks and 
Benefits 
Section split into 5.5.1. Potential 
Risks and 5.5.2. Potential Benefits 
To increase readability 
Section 5.5. Potential 
Risks 
Change of “Some of the potential 
risks associated with PTH(1-34) 
and/or approved PTH therapies are 
provided below” to “The following 
risks have been seen in either the 
TransCon PTH Phase 1 volunteers or 
have been reported for approved PTH 
medications, and thus considered to 
be potential risks for TransCon PTH:” 
To clarify as requested by Health 
Authorities 
Section 5.5. Potential 
Risks 
Addition of “Nausea” as a potential 
risk 
To match TransCon PTH 
Investigator Brochure 
Section 5.5. Potential 
Risks 
Addition of hypercalcemia as a risk 
during the Blinded Treatment Period 
due to the requirement of subjects to 
remain on a fixed dose of study drug 
and methods of minimization and 
management 
Addition of hypocalcemia as a risk 
during the reduction in SOC 
following initiation of study drug at 
Visit 1 (and Visit 3 for those on active 
vitamin D at Visit 3) and methods of 
minimization and management 
As requested by Health 
Authorities to address risks 
associated with protocol-required 
adjustments to therapies  
Section 7.1. Overall Trial 
Design and Plan 
Update to the Study Design image to 
capture change in duration of 
Extension Period 
As requested by Health 
Authorities to reduce the 
Extension Period to 1 year 

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v 3.0 
Section(s) 
Change(s) 
Rationale 
Section 7.1.1. Measures 
Taken to Maximize 
Study Integrity and 
Minimize Bias 
Addition of explanation that 
Appendices 1-3 act as methods of 
minimizing individual investigator 
bias by providing standardized 
guidelines based on objective 
laboratory tests and subjects’ 
experience of hypo- or hypercalcemic 
symptoms.   
Addition of explanation that the 
Medical Monitor/Medical Expert will 
perform timely review of laboratory 
results and prescribed dosing to 
confirm investigator compliance with 
Appendices 1-3. 
As requested by Health 
Authorities to revise section to 
include a discussion on the risk of 
bias associated as treatment 
allocation may be revealed based 
on evaluation of serum and 
urinary calcium levels 
Section 9.6.1. Required 
Stopping 
Section split into 9.6.1. Required 
Stopping and 9.6.2. Possible 
Stopping/Dose Reductions  
Change of wording to require 
investigators to stop study drug for 
evidence of severe hypersensitivity to 
TransCon PTH, drug-related SAE or 
drug-related severe AE (other than 
hypercalcemia), severe hypo- or 
hypercalcemia that cannot be 
corrected with protocol-allowable 
dose adjustments to SOC and/or 
TransCon PTH, neutralizing anti-PTH 
antibodies that correlate with reduced 
PD response, suspicion of 
osteosarcoma, and pregnancy 
Addition of “Suspicion of 
osteosarcoma (eg, 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) 
Addition of “See Section 8.2.1 for 
further guidance on study drug 
discontinuation” to Section 9.6.1. 
As requested by Health 
Authorities to discriminate 
between “may” and “must” 
criteria for subject discontinuation 
and to add a stopping rule for 
“suspicion of osteosarcoma” 
Section 10.1.1. Trial 
Periods and Visits 
Addition of “Visit 14 (Week 50, Day 
350, ±7 days)” and “Visit 15 (Week 
58, Day 406, ±7 days)” in place of 
“Visits every 8 weeks ±7 days until 
the end of the trial” 
As requested by Health 
Authorities to reduce the 
Extension Period to 1 year 

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Section(s) 
Change(s) 
Rationale 
Section 10.1.3.1. Visit 1 
(Week 0, Day 1) 
procedures 
Addition to vital signs of “including 
30-minute post-dose orthostatic 
measurements” 
As requested by Health 
Authorities to include orthostatic 
measurements 
Section 10.1.3.4. Visit 3 
(Week 4, Day 28 ±2 
days) procedures 
Addition of “For subjects on active 
vitamin D only: 30-minute post-dose 
orthostatic measurements” 
As requested by Health 
Authorities to include orthostatic 
measurements 
Section 10.1.4.2. Visits 
4-8 (Weeks 6-14; Days 
42, 56, 70, 84, 98 ±2 
days) procedures 
Section 11.12.1.7. Visits 
4-8 (V4-V8) Laboratory 
Assessments 
Addition of “Only for women of 
childbearing potential: Urine 
collection for local hCG (only at 
Visits 6 and 8)” 
Addition of “Only for women of child-
bearing potential: urine hCG (only at 
Visits 6 and 8)” 
As requested by Health 
Authorities to increase number of 
pregnancy testing 
Section 10.1.4.3. Visits 
9+ (Weeks 18+; Day 
126+) procedures 
Split Section 10.1.4.3. into “Section 
10.1.4.3. Visits 9-11 (Weeks 18-26; 
Day 126-182 ±3 days) procedures” 
and “Section 10.1.4.4. Visits 12-15 
(Weeks 34-58; Day 238-406; ±7 days) 
procedures” 
To group visits that have the same 
visit window for increased 
readability 
Section 10.1.4.3. Visits 
9+ (Weeks 18+; Day 
126+) procedures 
Removal of “Clinic Visits 9-11 will 
be performed every four (4) weeks ±3 
days. Clinic Visits 12-15 will be 
performed every either (8) weeks ±7 
days.” 
To remove redundancy due to 
splitting of Section 10.1.4.3. as 
these details are now provided in 
the section titles 
Section 10.1.4.3. Visits 
9-11 (Weeks 18-26; Day 
126-182 ±3 days) 
procedures 
Section 11.12.1.8. Visits 
9-15 (V9-15) Laboratory 
Assessments 
Addition of “Only for women of 
childbearing potential: Urine 
collection for local hCG (only at Visit 
10)” 
Addition of “The following laboratory 
assessments will be performed locally 
at Visits 9-15: Only for women of 
child-bearing potential: urine hCG 
(only at Visits 10, 12, and 14)” 
As requested by Health 
Authorities to increase frequency 
of pregnancy tests 
Section 10.1.4.4. Visits 
12-15 (Weeks 34-58; 
Day 238-406 ±7 days) 
procedures 
Section 11.12.1.8. Visits 
9-15 (V9-15) Laboratory 
Assessments 
Addition of “Only for women of 
childbearing potential: Urine 
collection for local hCG (only at Visit 
12 and 14)” 
Addition of “The following laboratory 
assessments will be performed locally 
at Visits 9-15: Only for women of 
child-bearing potential: urine hCG 
(only at Visits 10, 12, and 14)” 
As requested by Health 
Authorities to increase frequency 
of pregnancy tests 

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Section(s) 
Change(s) 
Rationale 
Section 10.1.4.4. Visits 
12-15 (Weeks 34-58; 
Day 238-406 ±7 days) 
procedures 
Change of “24-hour urine collection 
(only within a week of Visit 17)” to 
“Change of “24-hour urine collection 
(only the week prior to Visit 15)” 
To align procedures to the last 
visit of the Extension Period 
(V15) due to the reduction of the 
Extension Period to 1 year as 
requested by Health Authorities 
Section 10.1.7. End of 
Study (EOS) Visits 
Change of “If EOS Visits occur after 
Visit 3, the structure and assessments 
of the EOS Visit should be as similar 
as possible to Visit 11” to “If EOS 
Visits occur after Visit 3, the structure 
and assessments of the EOS Visit 
should be as similar as possible to 
Visit 15” 
To align procedures to the last 
visit of the Extension Period 
(V15) due to the reduction of the 
Extension Period to 1 year as 
requested by Health Authorities 
Section 10.1.7. End of 
Study (EOS) Visits 
Addition of “Additionally, 
correspondence (eg, phone call, 
email) with the subject 2 weeks (+7 
days) after last study drug 
administration is required to evaluate 
the subject for any further AEs during 
the 2 weeks since last study drug 
administration.  
As requested by Health 
Authorities to include follow-up 
with subject after at least five 
times the half-life of study drug 
from the date of last study drug 
administration 
Section 11.1 Vital Sign 
Measurements 
Change of order of vital sign 
measurements to list “Respiratory 
Rate” and “Body Temperature” 
before “Orthostatic Blood Pressure & 
Heart Rate”  
As requested by Health 
Authorities to include orthostatic 
measurements 
Section 11.1 Vital Sign 
Measurements 
Removal of Heart Rate and Blood 
Pressure  
Addition of “Orthostatic Blood 
Pressure & Heart Rate”  
Addition of “Blood pressure and heart 
rate are measured while subject is 
sitting. Subject is then asked to stand 
up and, within 3 minutes of doing so, 
blood pressure and heart rate are 
measured again.” 
As requested by Health 
Authorities to include orthostatic 
measurements 
Section 11.1.1. Post-
Dose Orthostatic 
Measurement 
Addition of Section 11.1.1. Post-Dose 
Orthostatic Measurement  
Addition of a 30-minute post-dose 
measurement of orthostatic blood 
pressure and heart rate at Visit 1 and 
Visit 3 (for those on active vitamin D 
at Visit 3)  
As requested by Health 
Authorities to include orthostatic 
measurements 

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Section(s) 
Change(s) 
Rationale 
Section 11.5. Dual-
Energy X-Ray 
Absorptiometry (DXA) 
and Trabecular Bone 
Score (TBS) 
Change of “To evaluate bone density, 
a DXA of the spine, hip, and forearm 
must be performed” to “To evaluate 
bone density and quality, a DXA scan 
of the spine, hip, and forearm, as well 
as TBS scoring must be performed” 
To clarify intent and analysis for 
DXA assessments 
Section 11.10. Local 
Tolerability Assessment 
Addition of “induration” as an 
injection site reaction (ISR) ordinarily 
observed in subcutaneous (SC) 
injections 
To provide further guidance to 
investigators for potential ISRs 
Section 11.10. Local 
Tolerability Assessment 
Removal of “An ISR noted during the 
local tolerability assessment is only 
reported as an AE if it meets the 
criteria for an AE as described in 
Section 11.11.1.” 
To remove reference to a section 
that has been removed as 
requested by Health Authorities 
Section 11.11.1. 
Injection Site Reactions 
(ISRs) as Adverse 
Events (AEs) 
Removal of section 
As requested by Health 
Authorities to remove restrictions 
on AE assessment by investigators 
Section 11.11.2. 
Erythema as Adverse 
Events (AEs) 
Removal of section 
As requested by Health 
Authorities to remove restrictions 
on AE assessment by investigators 
Section 11.12. 
Laboratory Assessments 
Addition of “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” 
To clarify that, while fasting is not 
required, consistency of either 
fasting or not fasting is important 
when comparing laboratory test 
results between visits  
Section 11.12.1.2. Visit 1 
(V1) Laboratory 
Assessments 
Section 11.12.1.4. Visit 2 
(V2) Laboratory 
Assessments 
Section 11.12.1.5. Visit 3 
(V3) Laboratory 
Assessments 
Section 11.12.1.7. Visit 
4-8 (V4-V8) Laboratory 
Assessments 
Section 14.3. Statistical 
Analysis: 
Pharmacokinetic analysis 
Increase of cohort size for assessment 
of Free PTH[PTH(1-34) and PTH(1-
33)] from “12 subjects” to 
“approximately 24” 
As requested by Health 
Authorities to increase the sample 
size for PK analysis 

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Section(s) 
Change(s) 
Rationale 
Section 11.12.1.3. 
Laboratory Visits 1-3 
(LV1-LV3) Laboratory 
Assessments 
Addition of “If, at selected sites where 
the Free PTH assessment will be 
performed at Visit 1, subjects return 
to the site’s own local laboratory for 
LV1-LV3, an additional assessment 
of Free PTH [PTH(1-34) and PTH(1-
33)] will be performed centrally.” 
As requested by Health 
Authorities to increase the 
sampling timepoints for PK 
analysis 
Section 11.12.1.8. Visits 
9-15 (V9-15) Laboratory 
Assessments 
Changed from “Visits 9+ (V9+) 
Laboratory Assessments” to “Visits 9-
15 (V9-V15) Laboratory 
Assessments” 
As requested by Health 
Authorities to reduce the 
Extension Period to 1 year 
Section 11.12.1.8. Visits 
9-15 (V9-15) Laboratory 
Assessments 
Addition of “The following laboratory 
assessments will be performed locally 
at Visits 9-15: Only for women of 
child-bearing potential: urine hCG 
(only at Visits 10, 12, and 14)” 
As requested by Health 
Authorities to increase frequency 
of pregnancy tests 
Section 11.12.1.8. Visits 
9-15 (V9-15) Laboratory 
Assessments 
Removal of laboratory assessments 
after 58 weeks 
As requested by Health 
Authorities to reduce the 
Extension Period to 1 year 
Section 11.12.1.8. Visits 
9-15 (V9-15) Laboratory 
Assessments 
Change of “Only for female subjects” 
to “Only for women” 
For consistency throughout 
document 
Section 11.12.1.8. Visits 
9-15 (V9-15) Laboratory 
Assessments 
Change of 24-hour urine collection 
being performed “within a week of 
Visits 11 and 17” to “within a week of 
Visit 11 and within the week prior to 
Visit 15” 
To align procedures to the last 
visit of the Extension Period 
(V15) due to the reduction of the 
Extension Period to 1 year as 
requested by Health Authorities 
Section 11.13.2 Exercise 
Modification  
Addition of section on avoiding 
exercise prior to visits which include 
blood collection 
As requested by Health 
Authorities to align instructions 
given to subjects between Section 
11.12. Laboratory Assessments 
and Section 11.13 
Section 11.13.3.1. 
Blinded Treatment 
Period Administration 
Section 11.13.3.2. 
Extension Period 
Administration 
Addition of orthostatic hypotension to 
adverse reactions which may be 
observed within the 30 minutes after 
study drug administration at the study 
visit 
As requested by Health 
Authorities to include orthostatic 
measurements 
Section 12.1.3. 
Reporting Procedures for 
All Adverse Events 
Addition of “from the time of signed 
consent to 2 weeks after the last study 
drug administration” for reporting of 
AEs 
As requested by Health 
Authorities to collect AEs until at 
least five times the half-life after 
the last study drug administration 

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Section(s) 
Change(s) 
Rationale 
Section 12.2.2. 
Reporting of SAEs 
and/or SUSARs 
Change of “within the time frames 
required by applicable regulations” to 
“in accordance with Directive 
2001/20/EC or as per national 
regulatory requirements in 
participating countries” 
As requested by Health 
Authorities 
Section 14.2.1.Efficacy 
Endpoints 
Split Section 14.2.1. Efficacy 
Endpoints into “Section 14.2.1.1. 
Primary Efficacy Endpoint,” and 
“14.2.1.2. Secondary Efficacy 
Endpoints” 
As requested by Health 
Authorities to align the objectives 
with the endpoints  
Section 14.2.2. Safety & 
Tolerability Endpoints 
Addition of section 
Moved Safety & Tolerability 
Endpoints into new section from 
Section 14.2.1 Efficacy Endpoints 
As requested by Health 
Authorities to align the objectives 
with the endpoints 
Section 14.2.3. 
Exploratory Endpoints 
Addition of section 
Moved Exploratory Endpoints into 
new section from Section 14.2.1 
Efficacy Endpoints 
As requested by Health 
Authorities to align the objectives 
with the endpoints 
Section 14.8. Unblinding 
Procedures 
Addition of section 
As requested by Health 
Authorities to include unblinding 
procedures 
Section 15.6. Trial 
Termination or 
Completion 
Addition of “End of trial is defined as 
last subject last visit” 
As requested by Health 
Authorities to include definition 
of end of trial 
Section 15.6. Trial 
Termination or 
Completion 
Addition of “including insufficient 
efficacy and unanticipated safety 
concerns” to “reason for Sponsor to 
terminate the trial at any time” 
As requested by Health 
Authorities 
Section 17. References 
Addition of Clinical Trial Facilitation 
Group reference 
Reference for guidance on highly 
effective contraception as 
requested by Health Authorities 
Appendix 1 
Addition of guidance if, at Visit 2, 
subject is on calcium >500 mg/day 
and has sCa within normal range 
To give further guidance to 
investigators on SOC dose 
adjustment 
Appendix 2 
Appendix 3 
Change of “skip one dose” for 
subjects with sCa >ULN and 
symptoms to “skip at least one dose” 
To clarify guidance to 
investigators on TransCon PTH 
titration as skipping a single dose 
may not reduce sCA levels 
enough to adequately alleviate 
symptoms 

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Section(s) 
Change(s) 
Rationale 
Appendix 4 
Addition of footnote for vital sign 
measurements to perform orthostatic 
blood pressure and heart rate should 
also be performed 30 minutes after 
study drug administration at Visit 1 
As requested by Health 
Authorities to include orthostatic 
measurements 
Appendix 4 
Addition of footnote for vital sign 
measurements to perform orthostatic 
blood pressure and heart rate should 
also be performed 30 minutes after 
study drug administration at Visit 3 
only for subjects taking active vitamin 
D at Visit 3 
As requested by Health 
Authorities to include orthostatic 
measurements 
Appendix 4 
Addition of Blood & urine collection 
for central lab assessments at LV1-
LV3 
Addition of footnote for LVI-LV3 for 
Blood & urine collection for central 
lab assessments to clarify that this is 
to only be performed only for subjects 
who, at selected sites where the Free 
PTH assessment will be performed at 
Visit 1, return to the site’s own local 
laboratory for LV1-LV3, to have an 
additional assessment of Free PTH 
[PTH(1-34) and PTH(1-33)] 
As requested by Health 
Authorities to increase the 
sampling timepoints for PK 
analysis 
Appendix 4 
Change of vital sign footnotes from 
“heart rate, blood pressure, respiratory 
rate and temperature” to “respiratory 
rate, temperature, and orthostatic 
blood pressure and heart rate” 
As requested by Health 
Authorities to include orthostatic 
measurements 
Appendix 4 
Separated out Visits 12-15 into 
separate columns from a single 
column labelled Visit 12-28+  
Update to footnotes accordingly 
To increase readability 
Appendix 4 
Addition of Urine collection for local 
lab assessments for local urine hCG 
tests 
Addition of footnote “Urine collection 
only for female subjects of 
childbearing potential” for Urine 
collection for local lab assessments 
As requested by Health 
Authorities to increase number of 
pregnancy testing 
Appendix 4 
Change of footnotes to capture 
removal of assessments after 58 
weeks 
As requested by Health 
Authorities to reduce the 
Extension Period to 1 year 

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Section(s) 
Change(s) 
Rationale 
Appendix 4 
Change of footnotes to capture 
addition of 24-hour urine calcium 
excretion “within the week prior to 
Visit 15” (in place of “within a week 
of Visit 17”) 
To align procedures to the last 
visit of the Extension Period 
(V15) due to the reduction of the 
Extension Period to 1 year as 
requested by Health Authorities 
Appendix 4 
Addition of footnote to capture 
addition of “Correspondence with 
subject (eg, phone call, email) should 
be made 2 weeks (+7 days) after last 
study drug administration to evaluate 
for AEs during the 2 weeks after last 
study drug administration for Adverse 
event review at Visit 15  
As requested by Health 
Authorities to include follow-up 
with subject after at least five 
times the half-life of study drug 
from the date of last study drug 
administration 
Appendix 4 
Addition of footnote referring to 
Appendix 6 
To provide reference to a 
complete list of analytes for 
Chemistry, Hematology, and 24-
hour Urine Panels as requested by 
Health Authorities 
Appendix 6 
Addition of Appendix 6 Laboratory 
Panel Analytes 
As requested by Health 
Authorities to include a complete 
list of analytes for Chemistry, 
Hematology, and 24-hour Urine 
Panels 
Appendix 7 
Addition of Appendix 7 
Contraception 
As requested by Health 
Authorities to include guidance on 
highly effective contraception 
methods 
 

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STATEMENT OF COMPLIANCE 
This trial will be conducted in accordance with the following:  
• Protocol-related and trial-related documents 
• Declaration of Helsinki 
• Good Clinical Practice (GCP) as outlined by the International Conference on Harmonisation 
(ICH) E6 (R2) and regional regulations 
• Regional subject data protection laws and regulations 
• Other applicable regional and local regulations 
• US Federal Regulations, as applicable 

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2. 
SYNOPSIS 
PRODUCT 
NUMBER/NAME 
TransCon PTH 
PROTOCOL NUMBER 
TransCon PTH TCP-201 
IND NUMBER 
133469 
EUDRACT NUMBER 
2018-004815-33 
DEVELOPMENT PHASE 
2 
PROTOCOL TITLE 
PaTH Forward: A Phase 2, 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  
INDICATION 
Hypoparathyroidism (HP) in Adults 
OBJECTIVES 
Primary: 
• 
To assess the effectiveness of daily TransCon PTH on serum and 
urine calcium levels (FECa) and active vitamin D and calcium doses 
at 4 weeks of treatment  
Secondary: 
• 
To assess the safety and tolerability of daily TransCon PTH  
• 
To assess the effectiveness of daily TransCon PTH on serum and 
urine calcium levels (FECa) and active vitamin D and calcium 
doses during the Extension Period 
• 
To assess the treatment effect of daily TransCon PTH on daily pill 
burden (vitamin D and calcium) 
• 
To assess the treatment effect of daily TransCon PTH on serum 
phosphate, serum magnesium, and calcium x phosphate product 
(sCa x sP product) 
• 
To assess the treatment effect of daily TransCon PTH on 
hypocalcemia and hypercalcemia symptoms, emergency room (ER) 
visits, and hospitalizations  
• 
To assess anti-PTH and anti-PEG antibody responses 
Exploratory: 
• 
To assess the treatment effect of daily TransCon PTH on:  
− 
Bone Mineral Density (BMD) and Trabecular Bone Score 
(TBS) by DXA 
− 
24-hour urine calcium excretion  
− 
Clinical Outcomes Assessments (COAs) 
− 
Bone turnover markers (serum P1NP and CTx) 
− 
Vascular calcifications, nephrocalcinosis, and nephrolithiasis 
• 
To assess the usability of the pre-filled injection pen 

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PLANNED TRIAL SITES 
Up to 40 sites worldwide 
PLANNED NUMBER OF 
SUBJECTS 
Approximately 40 
TRIAL POPULATION 
Male and female adults with either postsurgical HP or autoimmune, 
genetic, or idiopathic HP for at least 26 weeks, 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 
ELIGIBILITY CRITERIA Inclusion Criteria 
1. 
Males and females aged ≥18 years  
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 hypocalcemia in the setting of inappropriately low serum 
parathyroid hormone (PTH) levels. 
3. 
On a stable dose* for at least 12 weeks (US only: or 4 weeks if on 
Natpara as of September 2019) prior to Screening of: 
• 
≥0.25 µg BID of calcitriol (active vitamin D) or ≥0.5 µg BID or 
≥1.0 µg daily of alfacalcidol (active vitamin D) and 
• 
≥400 mg BID calcium citrate or carbonate 
If subject has a history of hypercalcemia on such doses, subject 
may be taking <0.25 µg BID of calcitriol, <0.5 µg BID or <1.0 µg 
daily of alfacalcidol, or <400 mg BID of calcium citrate or 
carbonate, with approval of Medical Monitor/Medical Expert 
*Does not preclude occasional (<3/week) rescue doses of active 
vitamin D and/or calcium for symptomatic hypocalcemia 
4. 
Optimization of supplements prior to randomization to achieve the 
target levels of: 
− 25(OH) vitamin D levels of 30-70 ng/mL (75-175 pmol/mL) 
and  
− Magnesium level within the normal range* and 
− Albumin-adjusted or ionized serum calcium (sCa) level in the 
lower half of the normal range  
* If subject has a history of inability to be successfully managed 
within the normal range for magnesium level, a level slightly 
below the normal range is acceptable with approval of the Medical 
Monitor/Medical Expert 
5. 
BMI 17-40 kg/m2 at Visit 1 
6. 
If ≤25 years of age, radiological evidence of epiphyseal closure 
based on x-ray of non-dominant wrist and hand 
7. 
eGFR >30 mL/min/1.73m2 during Screening 
8. 
Thyroid-stimulating hormone (TSH) within normal laboratory 
limits within the 12 weeks prior to Visit 1; if on suppressive 
therapy for thyroid cancer, TSH level must be ≥0.2 µIU/mL 
9. 
If treated with thyroid hormone replacement therapy, the dose 
must be stable for at least 12 weeks prior to Visit 1 

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10. Able to perform daily subcutaneous self-injections of study drug 
(or have a designee perform injection) via a pre-filled injection 
pen 
11. Written, signed, informed consent of the subject 
Exclusion Criteria 
1. Known activating mutation in the calcium-sensing receptor (CaSR) 
gene  
2. Impaired responsiveness to PTH (pseudohypoparathyroidism) 
which is characterized as PTH-resistance, with elevated PTH levels 
in the setting of hypocalcemia 
3. Any disease that might affect calcium metabolism or 
calcium-phosphate homeostasis or PTH levels other than HP, such 
as active hyperthyroidism; Paget’s disease; hypomagnesemia; type 
1 diabetes mellitus or poorly controlled type 2 diabetes mellitus; 
severe and chronic cardiac, liver, or renal disease; Cushing 
syndrome; rheumatoid arthritis; multiple myeloma; active 
pancreatitis; malnutrition; rickets; recent prolonged immobility; 
active malignancy (other than low-risk well differentiated thyroid 
cancer or basal cell skin cancer); parathyroid carcinoma within 
5 years prior to Screening; acromegaly; multiple endocrine 
neoplasia types 1 and 2 
4. Use of loop diuretics, phosphate binders (other than calcium 
carbonate/calcium citrate), digoxin, lithium, methotrexate, or 
systemic corticosteroids (other than replacement therapy)  
5. Use of thiazide diuretic within 4 weeks prior to the Screening 
24-hour urine collection or the first dose adjustment of SOC during 
Screening  
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 12 weeks (US only: 5 weeks) prior to 
Visit 1  
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 
Visit 1 
8. Use of bisphosphonates (oral or IV) or denosumab within 2 years 
prior to Visit 1 
9. Non-hypocalcemic seizure disorder with a history of a seizure 
within 26 weeks prior to Visit 1  
NOTE: History of seizures that occur in the setting of 
hypocalcemia is not exclusionary 

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10. Increased risk for osteosarcoma, such as those with Paget’s disease 
of bone or unexplained elevations of alkaline phosphatase, open 
epiphyses, 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: Highly effective contraception (see Appendix 7) 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 highly effective contraception are excluded 
from the trial. 
12. Diagnosis of drug or alcohol dependence within 3 years prior to 
Visit 1 
13. Disease processes that may adversely affect gastrointestinal 
absorption including but not limited to short bowel syndrome, 
bowel resection, gastric bypass, tropical sprue, active celiac 
disease, active ulcerative colitis, gastroparesis, AIRE gene 
mutations with malabsorption, and active Crohn’s disease 
14. Chronic or severe cardiac disease within 26 weeks prior to Visit 1 
including but not limited to congestive heart failure, myocardial 
infarction, QTcF >430 msec (males) or >450 msec (females), 
severe or uncontrolled arrhythmias, bradycardia (resting heart rate 
<50 beats/minute), symptomatic hypotension, systolic BP <80 mm 
Hg or diastolic <40 mm Hg, or poorly controlled hypertension 
(systolic BP >150 mm Hg or diastolic >95 mm Hg)  
15. Cerebrovascular accident within 5 years prior to Visit 1 
16. History of renal colic or acute gout within 52 weeks prior to Visit 1 
17. Any disease or condition that, in the opinion of the investigator, 
may 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 1-year duration of the trial 
18. Known allergy or sensitivity to PTH or any of the excipients 
[metacresol, mannitol, succinic acid, NaOH/(HCl)] 
19. Participation in another clinical trial in which receipt of 
investigational drug or device occurred within 8 weeks (or at least 
5.5 times the half-life of the investigational drug) prior to Visit 1  
20. Likely to be non-compliant with respect to trial conduct  
21. Any other reason that in the opinion of the investigator would 
prevent the subject from completing participation or following the 
trial schedule 

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TRIAL DESIGN 
This is a phase 2, multicenter, randomized, double-blind, 
placebo-controlled, parallel group, 4-week trial with an open-label 
extension of 210 weeks of daily TransCon PTH in male and female 
adults with either postsurgical HP or autoimmune, genetic, or 
idiopathic HP for at least 26 weeks, treated with a stable dose of 
≥0.25 µg BID active vitamin D (or ≥1.0 µg/day alfacalcidol) and ≥400 
mg BID calcium for at least 12 weeks prior to Screening. 
NOTE: If during the Blinded Treatment Period clinical symptoms 
of hypo- or hypercalcemia occur, an Unscheduled Laboratory Visit 
(ULV) should be scheduled to assess albumin-adjusted or ionized 
sCa levels to guide calcium and/or active vitamin D dose 
adjustments.  During either the Blinded Treatment Period or 
Extension Period, rescue doses of active vitamin D and/or calcium 
are allowable, even prior to the ULV.  However, unlike in the 
Blinded Treatment Period when study drug dose must remain 
stable, if symptoms of hypo- or hypercalcemia are persistent during 
the Extension Period, the TransCon PTH dose should be adjusted 
at the following clinic visit.  Due to the extended length of time 
between visits after Visit 9, the TransCon PTH dose may be 
adjusted to control persistent hypo- or hypercalcemia between 
clinic visits.  
Screening Period (Week -4 to Week -1): 
The Screening Period consists of determining eligibility, documenting 
baseline status, and optimizing vitamin D and magnesium levels, and 
doses of standard of care (SOC; active vitamin D and calcium) prior to 
study drug dosing to achieve the following target levels: 
• 
25(OH) vitamin D: 30-70 ng/mL 
• 
Magnesium: within the normal range* 
• 
Albumin-adjusted or ionized sCa: within the lower half of the 
normal range 
SOC doses are adjusted only after initial Screening laboratory results 
are received.  Follow-up laboratory assessment of the above values, 
with exception of vitamin D level, are performed approximately 3 days 
after SOC dose adjustment.  If required, additional SOC 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* with 
at least one confirmation laboratory result, and all other entry criteria 
including the Screening 24-hour urine collection are met, the subject is 
eligible to move to the Blinded Treatment Period and be randomized 
following Medical Monitor/Medical Expert or designee confirmation.  
*If subject has a history of inability to be successfully managed within 
the normal range for magnesium level, a level slightly below the 
normal range is acceptable with approval of Medical Monitor/ Medical 
Expert. 

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Blinded Treatment Period (Visits 1-3; Weeks 0-4): 
At Visit 1, subjects are randomized into one of 4 treatment groups 
(1:1:1:1):  
• 
TransCon PTH 15 µg/day* 
• 
TransCon PTH 18 µg/day 
• 
TransCon PTH 21 µg/day  
• 
Placebo for TransCon PTH (excipient solution) 
*Dose of TransCon PTH refers to dose of PTH(1-34) administered 
To maintain blinding, the placebo group will be sub-randomized into 3 
groups (1:1:1) to mimic doses of 15, 18, and 21 µg/day. 
Subjects are to remain on the same dose of study drug throughout the 4-
week Blinded Treatment Period; however, SOC doses will be 
optimized as follows assuming sCa remains ≥LLN but ≤ULN: 
Visit 1: Decrease active vitamin D dose by 33-50% (eg, skip 2nd dose 
of the day if taking BID, skip last dose of the day if taking TID, or 
reduce once daily dose of alfacalcidol ≥1.0 µg by ≥0.5 µg) 
Day 3-4: Discontinue active vitamin D  
Day 6-7: Decrease calcium by ≥50% (≥400 mg/day) if taking ≤2000 
mg/day or decrease calcium by ≥800 mg/day if taking >2000 mg/day  
Day 9-10: Discontinue or decrease calcium to ≤500 mg/day if taking 
≤2000 mg/day or decrease calcium by ≥800 mg/day if taking >2000 
mg/day  
Complete guidance on SOC optimization is provided in Section 9.5.2.2 
and Appendix 1.  
NOTE: If during the Blinded Treatment Period clinical symptoms 
of hypo- or hypercalcemia occur, an Unscheduled Laboratory Visit 
(ULV) should be scheduled to assess albumin-adjusted or ionized 
sCa levels to guide calcium and/or active vitamin D dose 
adjustments.  Rescue doses of active vitamin D and/or calcium are 
allowable, even prior to the ULV. 
Extension Period (Visits 3-21; Weeks 4-214): 
At Visit 3, subjects will be assigned to open-label treatment as follows: 
• 
If taking active vitamin D: Start TransCon PTH at a dose of 
15 µg/day, and undergo titration of SOC as performed during the 
4-week Blinded Treatment Period 
• 
If not taking active vitamin D: Start TransCon PTH at the same 
dose of study drug taken during the Blinded Treatment Period.  
Exception should be made if hypo- or hypercalcemic symptoms are 
present at Visit 3, in which case TransCon PTH dose may be 
adjusted by 3 µg/day. 
Subsequently, at every clinic visit (every 2 weeks) up to and including 
Visit 8, the TransCon PTH dose is increased by 3µg/day if the 
albumin-adjusted or ionized sCa level is <LLN or subject is 
experiencing persistent hypocalcemic symptoms.  Conversely, if a 
subject not taking SOC experiences persistent hypercalcemic symptoms 

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in the setting of an elevated adjusted or ionized sCa value, the 
TransCon PTH dose is decreased by 3µg/day. 
Dose range for the Extension Period is expected to be 6-60 
µg/day in 3 pen presentations (6, 9, and 12 µg/day; 15, 18, and 21 
µg/day; and 24, 27 and 30 µg/day, respectively).  Starting at Visit 
9, TransCon PTH, active vitamin D, and calcium doses are 
expected to remain stable. However, dose adjustments should 
continue as needed based on sCa results and following 
Appendix 2 and Appendix 3. 
NOTE: Rescue doses of active vitamin D and/or calcium are 
allowable throughout the Extension Period.  However, if symptoms 
of hypo- or hypercalcemia are persistent, the TransCon PTH dose 
should be adjusted at the following clinic visit.  Due to the extended 
length of time between visits after Visit 9, the TransCon PTH dose 
may be adjusted to control persistent symptomatic hypo- or 
hypercalcemia between clinic visits.  Due to the long half-life of 
TransCon PTH, the full effect of a dose change cannot be 
determined until 8 to 10 days after the dose change. 
INVESTIGATIONAL 
PRODUCT 
Name: TransCon PTH 
TransCon PTH drug product is supplied as a clear solution containing 
TransCon PTH with a nominal PTH(1-34) content of 0.3 mg/mL in a 
pre-filled 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 pre-filled injection pen.  The 
cartridge contains a liquid formulation of TransCon PTH with a fill 
volume sufficient for 14 doses.  Three pre-filled pen presentations are 
available.  For the Blinded Treatment Period, the mid-dose pen will be 
used, which allows for a dose range of 15-21 µg/day (15, 18, and 
21 µg/day).  For the Extension Period, all three pen presentations will 
be available, which allows for an expected dose range of 6-60 µg/day 
(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. 
REFERENCE 
PRODUCT(S) 
Placebo for TransCon PTH (excipient solution in the mid-dose pen) to 
mimic doses of 15, 18, and 21 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 Uno Pen Fix 
using 31G, 5 mm needles to deliver doses of 15, 18, or 21 µg/day in 
volumes of 50, 60, and 70 µL, respectively, to either abdomen or 
anterior thigh, rotating injections sites.  All treatment groups should 
continue to take stable doses of magnesium and vitamin D3 to maintain 
the defined ranges, as well as active vitamin D and/or calcium 
supplements with dose adjustments as required. 

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BLINDING 
This trial consists of a 4-week randomized, double-blind, 
placebo-controlled treatment period followed by an open-label 
extension period of 210weeks. 
To maintain the double-blind during the Blinded Treatment Period, the 
placebo group will be sub-randomized into 3 groups (1:1:1) to mimic 
doses of 15, 18, and 21 µg/day delivered by the mid-dose pen. 
TRIAL AND 
TREATMENT 
DURATION 
The total duration of the trial for an individual subject is 214 weeks 
plus a screening period of up to approximately 4 weeks. 
• 
Blinded Treatment Period (study drug stable with SOC 
optimization): 4 weeks 
• 
Extension Period (open-label TransCon PTH treatment): 
210 weeks, with up to an initial 14 weeks of TransCon PTH 
titration and SOC optimization, followed by approximately 
196 weeks of individualized dosing 
Only subjects who successfully complete the Blinded Treatment Period 
on blinded study drug (TransCon PTH or placebo for TransCon PTH) 
may enter the open-label Extension Period (TransCon PTH only). 
END OF TRIAL 
The end of trial is defined as the last subject last visit 
STOPPING RULES 
Study drug may be temporarily held for symptomatic hypercalcemia or 
permanently discontinued for a drug-related AE at investigator 
discretion, with notification of the sponsor Medical Monitor/Medical 
Expert.  If study drug is permanently discontinued prior to Visit 3, 
subjects are expected to continue within the trial off study drug until 
Visit 3.  If study drug is permanently discontinued after Visit 3, 
subjects are withdrawn following an Early Termination Visit. 
ENDPOINTS 
Primary Efficacy Endpoint: 
At 4 weeks of treatment, the proportion of subjects with: 
• 
Albumin-adjusted or ionized sCa within the normal range and 
• 
Spot morning fractional excretion of calcium (spot AM FECa) 
within normal range (≤2%) or a reduction by at least 50% from 
baseline and 
• 
Not taking active vitamin D supplements and 
• 
Taking ≤1000 mg/day of calcium supplements 
Secondary Efficacy Endpoints: 
Key Secondary Efficacy Endpoint:  
At 4 weeks of treatment, the proportion of subjects with: 
• 
Albumin-adjusted or ionized sCa within the normal range and  
• 
FECa within the normal range or a reduction by at least 50% from 
baseline and 
• 
Not taking active vitamin D supplements and  
• 
Taking ≤500 mg/day of calcium supplements 
Other Secondary Efficacy Endpoints: 

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• 
Primary and key secondary endpoints measured at predefined 
timepoints over the Extension Period. For the analysis of these 
endpoints in the Extension Period, the 24-hour urine calcium 
excretion will be used. 
At 4 weeks of treatment and at predefined timepoints over the 
Extension Period: 
• 
Calcium and vitamin D doses 
• 
Number of SOC supplements (pill burden) 
• 
Spot AM FECa 
• 
Serum phosphate 
• 
Serum magnesium 
• 
sCa x sP product, including proportion of subjects with sCa x sP 
product ≤55 mg2/dL2, ≤52 mg2/dL2, and ≤44 mg2/dL2 
• 
Albumin-adjusted or ionized sCa 
At predefined timepoints over the Extension Period: 
• 
24-hour urine calcium excretion 
Safety & Tolerability Endpoints: 
The following safety endpoints will be assessed for both Blinded 
Treatment and Extension Periods:  
• 
Serum chemistry, hematology, and spot urine parameters 
• 
Incidence of AEs, adverse event of special interest (AESI), and 
serious adverse events (SAEs) 
• 
Clinical events of hypo- or hypercalcemia (emergency/urgent care 
visits and hospitalizations) and progression of vascular 
calcifications, nephrocalcinosis, and nephrolithiasis  
• 
Injection site tolerability (based on Local Tolerability Scale and 
AEs) 
• 
Evaluation of anti-PTH and anti-PEG antibody response 
• 
Physical examinations, including vital signs 
Exploratory Endpoints 
At 4 weeks of treatment, assessment of the following: 
• 
Patient-Reported Outcome (PRO) measures  
• 
Bone turnover markers (serum P1NP and CTx) 
• 
Device usability questionnaire 
Throughout the Extension Period, assessment of the following: 
• 
BMD and TBS by DXA at 26, 58, 110, 162, and 214 weeks  
• 
24-hour urine calcium excretion at 26,58, 84, 110, 136, 162, 188, 
and 214 weeks  
• 
Clinical Outcome Assessments (COAs) at 6, 8, 12, 26, 58, 110, 
162, and 214 weeks  

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• 
Bone turnover markers (serum P1NP and CTx) at 8, 12, 26, 58, 
110, 162, and 214 weeks  
• 
Albumin-adjusted sCa, magnesium, phosphate, and sCa x sP 
product at 8, 18, 26, 42, 58, 84, 110, 136, 162, 188, and 214 weeks 
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. 
SAMPLE SIZE 
DETERMINATION 
Based on clinical experience, the proportion of subjects on SOC 
meeting the primary endpoint will be rare and close to 0.  According to 
simulation data from the FDA, 66% of subjects with continuous 
infusion of PTH will have normal sCa.  The phase 1 study data predict 
that a large proportion of HP subjects, around 90%, on TransCon PTH 
will have normal FECa.  Assuming that TransCon PTH has the same 
profile as PTH by continuous infusion, the proportion of subjects able 
to discontinue active vitamin D and require less than 1000 mg/day of 
supplemental calcium is estimated to be at least 70%.  This translates to 
an estimate of the proportion of TransCon PTH-treated subjects 
meeting the primary endpoint at more than 40%.  With 10 subjects per 
arm, the statistical power to detect a significant treatment difference is 
calculated in the following table. 
Power calculation for 10 subjects per arm with alpha level at 0.05 and 
0.10 (two-sided) 
Proportion for 
TransCon 
PTH 
Proportion for 
Placebo 
Power 
α=0.05 (2-sided) 
α=0.10 (2-sided) 
40% 
1% 
40.7% 
53.2% 
50% 
1% 
58.8% 
70.4% 
60% 
1% 
74.8% 
83.8% 
80% 
1% 
94.7% 
97.3% 
 

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3. 
TABLE OF CONTENTS 
AMENDMENT 3 SUMMARY .......................................................................................................2 
AMENDMENT 2 SUMMARY .......................................................................................................3 
US ADDENDUM 1 SUMMARY .................................................................................................18 
CANADA ADDENDUM 1 SUMMARY .....................................................................................19 
AMENDMENT 1 SUMMARY .....................................................................................................20 
STATEMENT OF COMPLIANCE ...............................................................................................32 
1. 
APPROVAL SIGNATURES .....................................................................................33 
1.1. 
Sponsor .......................................................................................................................33 
2. 
SYNOPSIS .................................................................................................................34 
3. 
TABLE OF CONTENTS ...........................................................................................44 
4. 
LIST OF ABBREVIATIONS.....................................................................................51 
5. 
INTRODUCTION ......................................................................................................53 
5.1. 
Background and Rationale ..........................................................................................53 
5.1.1. 
Parathyroid Hormone ..................................................................................................53 
5.1.2. 
Hypoparathyroidism ...................................................................................................53 
5.1.3. 
Current Standard Therapy for Hypoparathyroidism ...................................................54 
5.2. 
Relevant Findings from Nonclinical Studies ..............................................................56 
5.3. 
Clinical Experience .....................................................................................................57 
5.4. 
Trial Rationale ............................................................................................................61 
5.5. 
Summary of Potential Risks and Benefits ..................................................................62 
5.5.1. 
Potential Risks ............................................................................................................62 
5.5.2. 
Potential Benefits ........................................................................................................63 
6. 
OBJECTIVES .............................................................................................................63 
6.1. 
Primary Objective .......................................................................................................63 
6.2. 
Secondary Objectives .................................................................................................63 
6.3. 
Exploratory Objectives ...............................................................................................64 
7. 
TRIAL DESIGN .........................................................................................................64 
7.1. 
Overall Trial Design and Plan ....................................................................................64 
7.1.1. 
Measures Taken to Maximize Study Integrity and Minimize Bias ............................65 
7.2. 
Trial Sites ....................................................................................................................65 
8. 
SUBJECT POPULATION .........................................................................................66 
8.1. 
Trial Entry Criteria .....................................................................................................66 

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8.1.1. 
Inclusion Criteria ........................................................................................................66 
8.1.2. 
Exclusion Criteria .......................................................................................................67 
8.2. 
Premature Subject Withdrawal ...................................................................................68 
8.2.1. 
Study Drug Discontinuation and Subject Withdrawal ................................................69 
8.2.1.1. 
Study Drug Discontinuation During Blinded Treatment Period ................................69 
8.2.1.2. 
Study Drug Discontinuation During Extension Period ..............................................69 
8.3. 
Subject Replacement Criteria .....................................................................................69 
9. 
TREATMENTS ..........................................................................................................69 
9.1. 
Investigational Product ...............................................................................................69 
9.1.1. 
Labeling ......................................................................................................................69 
9.1.2. 
Accountability, Storage, and Dispensing ....................................................................69 
9.2. 
Treatment Administered .............................................................................................70 
9.3. 
Selection of Trial Doses ..............................................................................................71 
9.4. 
Treatment Assignment ................................................................................................71 
9.4.1. 
Treatment Assignment During Blinded Treatment Period .........................................71 
9.4.2. 
Treatment Assignment During Extension Period .......................................................71 
9.5. 
Dose Adjustments .......................................................................................................72 
9.5.1. 
Screening Period Supplement Dose Adjustments ......................................................72 
9.5.2. 
Blinded Treatment Period (Visits 1-3; Weeks 0-4) Dose Adjustments ......................72 
9.5.2.1. 
Study Drug Dose Adjustments During Blinded Treatment Period ............................72 
9.5.2.2. 
SOC Dose Adjustments During Blinded Treatment Period .......................................72 
9.5.3. 
Extension Period (Visits 3-21; Weeks 4-214) Dose Adjustments ..............................73 
9.5.3.1. 
Study Drug Dose Adjustments During Extension Period ...........................................73 
9.5.3.2. 
SOC Dose Adjustments During Extension Period .....................................................73 
9.6. 
Study Drug Stopping or Change to Administration ...................................................73 
9.6.1. 
Required Stopping ......................................................................................................73 
9.6.2. 
Possible Stopping or Change to Administration .........................................................74 
9.7. 
Treatment Compliance ................................................................................................75 
9.8. 
Prior and Concomitant Therapies ...............................................................................75 
9.8.1. 
Required HP Therapies ...............................................................................................75 
9.8.2. 
Prohibited Therapies ...................................................................................................76 
10. 
TRIAL PROCEDURES..............................................................................................76 
10.1. 
Trial Duration .............................................................................................................76 

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10.1.1. 
Trial Periods and Visits ..............................................................................................77 
10.1.2. 
Screening Period (Week -4 to -1, Day -28 to -7) ........................................................78 
10.1.3. 
Blinded Treatment Period (Week 0 to Week 4) .........................................................80 
10.1.3.1. 
Visit 1 (Week 0, Day 1) Procedures ...........................................................................81 
10.1.3.2. 
Laboratory Visits 1-3 (LV1-LV3; Weeks 0-1, Days 3, 6, 9 +1 day) 
Procedures ...................................................................................................................81 
10.1.3.3. 
Visit 2 (Week 2, Day 14 ±2 days) Procedures ............................................................82 
10.1.3.4. 
Visit 3 (Week 4, Day 28 ±2 days) Procedures ............................................................82 
10.1.4. 
Extension Period (Week 4 – 214) ...............................................................................83 
10.1.4.1. 
Laboratory Visits* 4-6 (LV4-LV6) Procedures .........................................................83 
10.1.4.2. 
Visits 4-8 (Weeks 6-14; Days 42, 56, 70, 84, 98 ±2 days) Procedures ......................84 
10.1.4.3. 
Visits 9-11 (Weeks 18-26; Day 126-182 ±3 days) Procedures ..................................84 
10.1.4.4. 
Visits 12-15 (Weeks 34-58; Day 238-406 ±7 days) Procedures ................................85 
10.1.4.5. 
Laboratory Visits 7-12 (LV7-LV12; Weeks 71-201; Day 497-201 ±14 days ) 
Procedures ...................................................................................................................85 
10.1.4.6. 
Visits 16-21 (Weeks 84-214; Day 588-1498 ±14 days) Procedures ..........................86 
10.1.5. 
Unscheduled Visits (UV) ............................................................................................86 
10.1.6. 
Unscheduled Laboratory Visits (ULV) ......................................................................87 
10.1.7. 
End of Study (EOS) Visits ..........................................................................................87 
11. 
ASSESSMENTS.........................................................................................................87 
11.1. 
Vital Sign Measurements ............................................................................................87 
11.1.1. 
Post-Dose Orthostatic Measurements .........................................................................87 
11.2. 
Prior and Concomitant Medication Review ...............................................................88 
11.3. 
Electrocardiogram (ECG) ...........................................................................................88 
11.4. 
X-Ray of Non-Dominant Wrist and Hand ..................................................................88 
11.5. 
Dual-Energy X-Ray Absorptiometry (DXA) and Trabecular Bone Score 
(TBS) ..........................................................................................................................88 
11.6. 
Dietary Calcium Questionnaire ..................................................................................88 
11.7. 
Hypoparathyroidism Patient Experience Scale Validation Battery ............................89 
11.8. 
Device Usability Questionnaire ..................................................................................89 
11.9. 
Daily Diary .................................................................................................................89 
11.10. 
Local Tolerability Assessment ...................................................................................90 
11.11. 
Adverse Event Review ...............................................................................................90 

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11.12. 
Laboratory Assessments .............................................................................................90 
11.12.1. 
Laboratory Assessments by Visit ...............................................................................91 
11.12.1.1. Screening Period Laboratory Assessments .................................................................91 
11.12.1.2. Visit 1 (V1) Laboratory Assessments .........................................................................92 
11.12.1.3. Laboratory Visits 1-3 (LV1-LV3) Laboratory Assessments ......................................92 
11.12.1.4. Visit 2 (V2) Laboratory Assessments .........................................................................93 
11.12.1.5. Visit 3 (V3) Laboratory Assessments .........................................................................93 
11.12.1.6. Laboratory Visits 4-6 (LV4-LV6) Laboratory Assessments ......................................94 
11.12.1.7. Visits 4-8 (V4-V8) Laboratory Assessments ..............................................................94 
11.12.1.8. Visit 9-21 (V9-V21) Laboratory Assessments ...........................................................94 
11.12.1.9. Laboratory Visits 7-12 (LV7-LV12) Laboratory Assessments ..................................95 
11.13. 
Lifestyle Modification ................................................................................................95 
11.13.1. 
Dietary Modifications .................................................................................................95 
11.13.2. 
Exercise Modifications ...............................................................................................95 
11.13.3. 
Contraception ..............................................................................................................96 
11.13.4. 
Study Drug Administration.........................................................................................96 
11.13.4.1. Blinded Treatment Period Administration..................................................................96 
11.13.4.2. Extension Period Administration ................................................................................96 
11.13.5. 
Hypo- or Hypercalcemia Symptom Management ......................................................96 
11.13.6. 
Daily Diary .................................................................................................................97 
12. 
ADVERSE EVENT ASSESSMENT AND REPORTING ........................................97 
12.1. 
Definition ....................................................................................................................97 
12.1.1. 
Adverse Event .............................................................................................................97 
12.1.2. 
Serious Adverse Events ..............................................................................................97 
12.1.3. 
Adverse Events of Special Interest (AESIs) ...............................................................98 
12.1.4. 
TransCon PTH Adverse Events of Special Interest ....................................................98 
12.1.5. 
Special Situation .........................................................................................................98 
12.2. 
Methods and Timing for Assessing and Recording Safety Variables ........................99 
12.3. 
Adverse Event Reporting Period ................................................................................99 
12.3.1. 
Assessment of Severity of Adverse Events ................................................................99 
12.3.1.1. 
Causality Rating ........................................................................................................100 
12.3.1.2. 
Outcome Assessment ................................................................................................100 
12.4. 
Procedures for Eliciting, Recording and Reporting Adverse Events .......................101 

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12.4.1. 
Eliciting Adverse Events ..........................................................................................101 
12.4.2. 
Recording Procedures for All Adverse Events .........................................................101 
12.4.3. 
Specific Instructions for Recording Adverse Events ................................................102 
12.4.3.1. 
Abnormal Laboratory Values ...................................................................................102 
12.4.3.2. 
Abnormal Vital Sign Values .....................................................................................102 
12.4.3.3. 
Diagnosis vs. Signs and Symptoms ..........................................................................103 
12.4.3.4. 
Injection Related Reaction ........................................................................................103 
12.4.3.5. 
Deaths .......................................................................................................................103 
12.4.3.6. 
Hospitalizations for Medical or Surgical Procedures ...............................................103 
12.4.3.7. 
Preexisting Medical Conditions ................................................................................104 
12.4.3.8. 
Pregnancy .................................................................................................................104 
12.4.3.9. 
Product Complaints ..................................................................................................104 
12.5. 
Serious Adverse Events (SAE) and Suspected Unexpected Serious Adverse 
Reactions (SUSAR) ..................................................................................................104 
12.5.1. 
Non-Serious Adverse Events Leading to Discontinuation .......................................104 
12.5.2. 
Reporting ..................................................................................................................105 
13. 
SAFETY MONITORING ........................................................................................105 
14. 
STATISTICS ............................................................................................................106 
14.1. 
General ......................................................................................................................106 
14.2. 
Endpoints ..................................................................................................................106 
14.2.1. 
Efficacy Endpoints ....................................................................................................106 
14.2.1.1. 
Primary Efficacy Endpoint .......................................................................................106 
14.2.1.2. 
Secondary Efficacy Endpoints ..................................................................................106 
14.2.2. 
Safety & Tolerability Endpoints ...............................................................................107 
14.2.3. 
Exploratory Endpoints ..............................................................................................107 
14.3. 
Statistical Analysis ....................................................................................................108 
14.3.1. 
Baseline Characteristics and Analysis Population ....................................................108 
14.3.2. 
Efficacy Analysis ......................................................................................................108 
14.3.3. 
Pharmacokinetic Analysis ........................................................................................108 
14.3.4. 
Safety Analysis .........................................................................................................109 
14.3.5. 
Interim Analysis ........................................................................................................109 
14.4. 
Power Calculation .....................................................................................................109 
14.5. 
Significance ..............................................................................................................109 

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LIST OF TABLES 
Table 1: 
Normal Urine Calcium Values ...................................................................................54 
Table 2: 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
WHO Toxicity Grading Scale ....................................................................................99 
Table 3: 
Power Calculation for 10 Subjects Per Arm with Alpha Level at 0.05 and 
0.10 (two-sided) ........................................................................................................109 
 
LIST OF FIGURES 
Figure 1: 
Structure of TransCon PTH Drug Substance ..............................................................55 
Figure 2: 
Schematic of TransCon PTH and the Release of PTH ...............................................56 
Figure 3: 
Arithmetic Mean Plasma Concentrations of Free PTH on Day 10 ............................58 
Figure 4: 
Albumin-Adjusted Serum Calcium: MAD Cohorts ...................................................58 
Figure 5: 
Spot Fractional Excretion of Calcium: MAD Cohorts ...............................................59 
Figure 6: 
Absolute Intact PTH(1-84): MAD Cohorts ................................................................60 
 

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4. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AC 
arterial calcification 
AE 
adverse events 
AESI 
adverse event of special interest 
BID 
twice daily 
BMD 
bone mineral density 
BMI 
body mass index 
CaSR 
calcium-sensing receptor 
COA 
clinical outcomes assessment 
CRO 
contract research organization 
CTFG 
Clinical Trial Facilitation Group 
CTx 
c-telopeptide of type 1 collagen 
CxP 
calcium-phosphate 
DLT 
dose-limiting toxicity 
DXA 
dual-energy x-ray absorptiometry 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
eGFR  
estimated glomerular filtration rate 
ER  
emergency room 
FECa 
fractional excretion of calcium  
HP 
Hypoparathyroidism 
HPES 
hypoparathyroid experience scale 
ISR 
injection site reaction 
LLN 
lower level of normal 
MAD 
multiple ascending dose 
mPEG 
methoxypolyethylene glycol 
MTD 
maximal tolerated dose 
NOAEL 
no-observed-adverse-effect level 
P1NP 
procollagen type 1 amino-terminal propeptide 
PD 
Pharmacodynamics 
PI 
principal investigator 
PK 
Pharmacokinetics 

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Abbreviation 
Definition 
pQCT 
peripheral quantitative computed tomography 
PTH 
parathyroid hormone 
PRO 
patient-reported outcome 
qHS 
every night at bedtime 
SAD 
single ascending dose  
SAE 
serious adverse events 
SAP 
statistical analysis plan 
SC 
Subcutaneous 
sCa 
serum calcium 
sMg 
serum magnesium 
SOC 
standard of care (active vitamin D plus calcium) 
SOP 
standard operating procedure 
sP 
serum phosphate 
TBS 
trabecular bone score 
TID 
three times daily 
TPTx 
Thyroparathyroidectomized 
TSH 
thyroid-stimulating hormone 
uCa 
urine calcium 
ULN 
upper level of normal 

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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, ie, 
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 
[1,25(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, ie, 
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, and calcium-
phosphate homeostasis is disrupted.  The kidneys decrease calcium reabsorption, phosphate 
excretion, and conversion of 25D to active 1,25D.  Given decreased 1,25D 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 BMD.  Despite decreased GI absorption of phosphate from 
decreased 1,25D production, patients with HP typically show either elevated or high-normal 
levels of serum phosphate due to decreased renal phosphate excretion. 

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5.1.3. 
Current Standard Therapy for Hypoparathyroidism  
Current standard of care (SOC) for HP – specifically active vitamin D and calcium (calcium 
carbonate or calcium citrate) 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 serum phosphate/decreased phosphate excretion 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, ie, a low 
bone turnover – high bone mass state.  Finally, as SOC increases both sCa (which is low in HP) 
and serum phosphate (sP) (which is elevated in HP), SOC can also result in an increased 
calcium-phosphate (CxP) product, 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 product below 55 mg2/dL2 (4.4 mmol2/L2); 4) avoid 
hypercalciuria (see Table 1); 5) avoid hypercalcemia; and 6) avoid renal 
(nephrocalcinosis/nephrolithiasis) and other extra-skeletal calcifications (Bilezikian 2016, 
Brandi 2016). 
Table 1: 
Normal Urine Calcium Values 
 
24 Hour Urine 
FECa 
Urine Calcium/Creatinine Ratio 
Females 
≤250 mg 
≤2% 
0.05 to 0.20 
Males 
≤300 mg 
≤2% 
0.05 to 0.20 
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 has been a challenge, 
especially in patients with moderately severe to severe deficiency of PTH.  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 administration has been shown to achieve better calcemic 
control than daily, and continuous infusion has been shown to achieve better control than twice 
daily (Winer 1998, Winer 2008, Winer 2012).  In addition to normalizing 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 twice daily 
PTH(1-34) administration, despite a 65% lower dose of infused vs twice daily (BID) PTH(1-34) 
(Winer 2012).  While intermittent PTH administration results in high hormone fluctuations, with 
an initial supraphysiological PTH level (high Cmax) followed by a rapid decline to subtherapeutic 
levels, continuous infusion maintains PTH levels in the physiological range throughout the day.  

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The nonclinical data are provided in further detail in the Investigator’s Brochure. 
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, and 
pharmacokinetics of TransCon PTH in healthy adult subjects] conducted under GCP, IEC, and 
Declaration of Helsinki guidelines has been completed.  
A total of 132 male and female normal healthy subjects were randomized and received study 
treatment; 69 subjects in SAD cohorts (56 received TransCon PTH and 13 placebo) and 
63 subjects in MAD cohorts (50 received TransCon PTH and 13 placebo).  
Cohorts of 10 subjects each (8 on TransCon PTH and 2 on placebo) were sequentially 
randomized to receive an ascending single dose of TransCon PTH in 7 SAD cohorts [3.5, 12, 32, 
48, 72, 100, and 124 µg/day PTH] or an ascending daily dose of TransCon PTH for 10 days in 
6 MAD cohorts [3.5, 7.0, 12, 16, 20, and 24 µg/day PTH].   
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 serum calcium and suppression of intact PTH(1-84) at all single 
doses of ≥32 µg.  Despite moderate hypercalcemia over 3 days in the cohorts receiving single 
doses of TransCon ≥100 µg PTH, at the time of greatest serum calcium (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 
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.  The data from the MAD 
cohorts is summarized below. 
Figure 3 shows a dose-dependent increase in Free PTH corresponding to the sum of active Free 
PTH [intact Free PTH(1-34)] and the main metabolite Free PTH(1-33) ; with a half-life of 
∼60 hours, resulting in an infusion-like profile 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.  The 1st MAD dose to 
significantly increase albumin-adjusted serum calcium (12 µg/day) resulted in a sustained, 
infusion-like Free PTH level at the low end of the calculated normal range.  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. 

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In the MAD cohorts, no increase in P1NP or BSAP (bone formation markers) was observed, 
suggesting that by producing a flat-infusion-like profile of TransCon PTH within the calculated 
normal range the study drug is not anabolic.  TransCon PTH modestly increased CTx but less 
than that seen in published data with short-acting PTH (Rubin 2016) and did not show a 
meaningful increase in NTx (bone resorption markers).  These data are similar to published 
literature illustrating the effects of continuous PTH administration (Horwitz 2011, Winer 2012, 
Winer 2014). 
In summary, TransCon PTH demonstrated a potent serum calcemic and renal calcium 
reabsorption effect in normal subjects, predicting control of both serum calcium (sCA) and urine 
calcium (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. 
Phase 1 data support the target product profile of TransCon PTH as a replacement therapy for HP 
patients, providing physiological levels of PTH 24 hours per day, and supports further 
advancement of TransCon PTH into Phase 2 clinical development.  
5.4. 
TRIAL RATIONALE 
A NIH study 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 study 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 study demonstrated that long-term twice daily PTH administration maintained 
mean sCa within or just below the normal range over a 3-year period with concurrent 
normalization of mean uCa excretion (Winer 2003).  Subsequently, a study of continuous 
PTH(1-34) delivery, by insulin pump, compared with twice daily SC injection in adult HP 
patients, showed that continuous exposure to PTH was superior in maintaining normal levels of 
sCa, sP and serum magnesium (sMg), normalizing uCa excretion, and 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 study also hypothesized that pump 
delivery of PTH(1-34) would provide more physiological control of serum and urine calcium 
(compared with conventional treatment or intermittent PTH delivery), would reduce symptoms 
of hypoparathyroidism, improve quality of life, and lower the long-term risk of renal damage, 
without adverse effect on bone (Winer 2012).  Similar benefits of continuous infusion of 
PTH(1-34) vs. twice-daily injections was demonstrated in children with HP (Winer 2014). 
Recombinant PTH(1-84) (Natpara) was approved as an adjunct to active vitamin D and calcium 
by the Food and Drug Administration (FDA) in 2015 and by the Committee for Medicinal 
Products for Human Use (CHMP) in 2017 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 2018).  Similar comments were made by CHMP (CHMP 2017). 

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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 the non-IND Phase 1 clinical trial (TransCon PTH CT-103), as well as a lack 
of the anabolic effect seen with short-lived PTH molecules.  Due to the well characterized 
correlation between PK and PD of PTH(1-34) established in subjects with and without intact 
parathyroid function, and the similarity of response in both groups, the Phase 1 clinical trial is 
considered adequate to start Phase 2 clinical trial. 
5.5. 
SUMMARY OF POTENTIAL RISKS AND BENEFITS 
5.5.1. 
Potential Risks  
There were no significant risks identified in the Phase 1 clinical trial besides vasodilatory 
symptoms (such as headache, tachycardia/palpitations, dizziness, and syncope) seen in the top 
MAD cohort (24 µg PTH/day) in both active and placebo-treated subjects, which has also been 
seen with approved PTH compounds.  Asymptomatic transient erythema at injection sites, 
especially at higher doses, was also observed.  These symptoms/signs are known to be associated 
with all PTH therapies where they are usually transient in nature and tend to resolve with 
continued dosing.  The vasodilatory effects can be managed by dosing at bedtime, while 
reclining.   
The following risks have been seen in either the TransCon PTH Phase 1 volunteers 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 
• Fatigue 
• Nausea 
• Osteosarcoma 
Please refer to the current version of the TransCon PTH Investigator’s Brochure for further 
details.  
During the Blinded Treatment Period, there is an increased risk of hypercalcemia due to the 
requirement of subjects to remain on a fixed dose of study drug.  This increased risk is limited to 
the brief period of time between achieving steady-state (9-11 days after Visit 1) and Visit 3, 
when TransCon PTH dose reduction can occur.  Additionally, this risk can be managed in most 
situations by reducing or stopping SOC. 

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During the reduction in SOC following initiation of study drug at Visit 1 (and Visit 3 for those 
on active vitamin D at Visit 3), there is a 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, as per Appendix 1 
• Returning subjects with symptomatic hypocalcemia to their previous SOC dose, as per 
Appendix 1 
• Allowing subjects who experience hypocalcemic symptoms during this period (and 
throughout the trial) to use rescue doses of SOC  
5.5.2. 
Potential Benefits 
In healthy volunteers, an infusion-like profile of Free PTH PK translated into a predicted, 
sustained dose-dependent PD response, suggesting the ability to titrate patients with HP into the 
normal calcemic range, consistent with preclinical data.  TransCon PTH demonstrated a potent 
serum calcemic and renal calcium reabsorption effect, predicting control of both serum calcium 
(sCA) and urine calcium (uCa) in normal healthy subjects.  
6. 
OBJECTIVES 
6.1. 
PRIMARY OBJECTIVE 
• To assess the effectiveness of daily TransCon PTH on serum and urine calcium levels 
(FECa) and active vitamin D and calcium doses at 4 weeks of treatment 
6.2. 
SECONDARY OBJECTIVES 
• To assess the safety and tolerability of daily TransCon PTH  
• To assess the effectiveness of daily TransCon PTH on serum and urine calcium levels 
(FECa) and active vitamin D and calcium doses during the Extension Period 
• To assess the treatment effect of daily TransCon PTH on daily pill burden (vitamin D and 
calcium) 
• To assess the treatment effect of daily TransCon PTH on serum phosphate, serum 
magnesium, and calcium x phosphate product (sCa x sP product) 
• To assess the treatment effect of daily TransCon PTH on hypocalcemia and hypercalcemia 
symptoms, emergency room (ER) visits, and hospitalizations  
• To assess anti-PTH and anti-PEG antibody responses 

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6.3. 
EXPLORATORY OBJECTIVES 
• To assess the treatment effect of daily TransCon PTH on:  
− Bone Mineral Density (BMD) and Trabecular Bone Score (TBS) by DXA 
− 24-hour urine calcium excretion  
− Patient-Reported Outcomes 
− Bone turnover markers (serum P1NP and CTx) 
− Vascular calcifications, nephrocalcinosis, and nephrolithiasis 
• To assess the usability of the pre-filled injection pen 
7. 
TRIAL DESIGN 
7.1. 
OVERALL TRIAL DESIGN AND PLAN 
The double-blind, placebo-controlled, parallel group treatment period of this trial is expected to 
enroll approximately 40 subjects from up to approximately 40 sites worldwide.  
Subjects are randomized into 4 treatment groups (1:1:1:1):  
• TransCon PTH 15 µg/day* 
• TransCon PTH 18 µg/day 
• TransCon PTH 21 µg/day  
• Placebo for TransCon PTH (excipients solution) 
*Dose of TransCon PTH refers to dose of PTH(1-34) administered 
To maintain blinding, the placebo group will be sub-randomized into 3 groups (1:1:1) to mimic 
doses of 15, 18, and 21 µg/day. 
Subjects are to remain on the same dose of study drug throughout the 4-week Blinded Treatment 
Period.  Following successful completion of the Blinded Treatment Period, subjects enter the 
open-label Extension Period at which time all subjects will receive TransCon PTH. 
Each subject’s participation is expected to last up to 214weeks plus a screening period of up to 
approximately 4 weeks. 
• Screening Period (supplement optimization): Up to approximately 4 weeks  
• Blinded Treatment Period (study drug stable with SOC optimization): 4 weeks 
• Extension Period (open-label TransCon PTH treatment): 210 weeks, with up to an initial 
14 weeks of TransCon PTH titration and SOC optimization, followed by approximately 
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Study Design 
 
7.1.1. 
Measures Taken to Maximize Study Integrity and Minimize Bias 
Subject visits should be performed in the morning at approximately the same time of day.  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 Blinded Treatment 
Period 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 transportation to the clinic 
• All study visits have visit windows to allow flexibility for clinic attendance (see Schedule of 
Events, Appendix 4) 
• Every effort will be made to maintain contact with subjects or other family members  
• The key components of the primary endpoint, sCa and urine calcium levels, are based on 
objective laboratory tests 
• To minimize individual investigator bias, Appendices 1-3 provide standardized guidelines for 
withdrawal of SOC and titration of TransCon PTH based on objective laboratory tests and 
subjects’ experience of hypo- or hypercalcemic symptoms.  Additionally, the Medical 
Monitor/Medical Expert will perform timely review of albumin-adjusted serum calcium 
and/or ionized serum calcium results and prescribed dosing to confirm investigator 
compliance with Appendices 1-3. 
7.2. 
TRIAL SITES 
The trial will be conducted at up to approximately 40 sites worldwide.  All sites are specialized 
treatment centers in the management of adult HP. 

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8. 
SUBJECT POPULATION 
Approximately forty (40) male and female adults with either postsurgical HP or autoimmune, 
genetic, or idiopathic HP for at least 26 weeks, treated with a stable dose (requiring <3 rescue 
doses of active D/calcium per week) 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 may enter the 
Screening Period. 
8.1. 
TRIAL ENTRY CRITERIA 
8.1.1. 
Inclusion Criteria 
1. Males and females aged ≥18 years  
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 hypocalcemia in the setting of 
inappropriately low serum parathyroid hormone (PTH) levels. 
3. On a stable dose* for at least 12 weeks (US only: or 4 weeks if on Natpara as of September 
2019) prior to Screening of: 
− ≥0.25 µg BID of calcitriol (active vitamin D) or ≥0.5 µg BID or ≥1.0 µg daily of 
alfacalcidol (active vitamin D) and 
− ≥400 mg BID calcium citrate or carbonate 
− If subject has a history of hypercalcemia on such doses, subject may be taking <0.25 µg 
BID of calcitriol, <0.5 µg BID or < 1.0 µg daily of alfacalcidol, or <400 mg BID of 
calcium citrate or carbonate, with approval of Medical Monitor/Medical Expert 
*Does not preclude occasional (<3/week) rescue doses of active vitamin D and/or 
calcium for symptomatic hypocalcemia 
4. Optimization of supplements prior to randomization to achieve the target levels of: 
− 25(OH) vitamin D levels of 30-70 ng/mL (75-175 pmol/mL) and  
− Magnesium level within the normal range* and 
− Albumin-adjusted or ionized serum calcium (sCa) level in the lower half of the normal 
range  
*If subject has a history of inability to be successfully managed within the normal range 
for magnesium level, a level slightly below the normal range is acceptable with approval 
of the Medical Monitor/Medical Expert 
5. BMI 17-40 kg/m2 at Visit 1 
6. If ≤25 years of age, radiological evidence of epiphyseal closure based on x-ray of 
non-dominant wrist and hand 
7. eGFR >30 mL/min/1.73m2 during Screening 
8. Thyroid-stimulating hormone (TSH) within normal laboratory limits within the 12 weeks 
prior to Visit 1; if on suppressive therapy for thyroid cancer, TSH level must be ≥0.2 µIU/mL 

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9. If treated with thyroid hormone replacement therapy, the dose must be stable for at least 
12 weeks prior to Visit 1 
10. Able to perform daily subcutaneous self-injections of study drug (or have a designee perform 
injection) via a pre-filled injection pen 
11. Written, signed, informed consent of the subject 
8.1.2. 
Exclusion Criteria 
1. Known activating mutation in the calcium-sensing receptor (CaSR) gene  
2. Impaired responsiveness to PTH (pseudohypoparathyroidism) which is characterized as 
PTH-resistance, with elevated PTH levels in the setting of hypocalcemia 
3. Any disease that might affect calcium metabolism or calcium-phosphate homeostasis or PTH 
levels other than HP, such as active hyperthyroidism; Paget’s disease; hypomagnesemia; type 
1 diabetes mellitus or poorly controlled type 2 diabetes mellitus; severe and chronic cardiac, 
liver, or renal disease; Cushing syndrome; rheumatoid arthritis; multiple myeloma; active 
pancreatitis; malnutrition; rickets; recent prolonged immobility; active malignancy (other 
than low-risk well differentiated thyroid cancer or basal cell skin cancer); parathyroid 
carcinoma within 5 years prior to Screening; acromegaly; multiple endocrine neoplasia types 
1 and 2 
4. Use of loop diuretics, phosphate binders (other than calcium carbonate/calcium citrate), 
digoxin, lithium, methotrexate, or systemic corticosteroids (other than replacement therapy)  
5. Use of thiazide diuretic within 4 weeks prior to the Screening 24-hour urine collection or the 
first dose adjustment of SOC during Screening 
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 12 weeks (US only: 5 weeks) prior to Visit 1  
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 Visit 1 
8. Use of bisphosphonates (oral or IV) or denosumab within 2 years prior to Visit 1 
9. Non-hypocalcemic seizure disorder with a history of a seizure within 26 weeks prior to 
Visit 1  
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, open epiphyses, hereditary disorders predisposing to 
osteosarcoma, or with a prior history of substantial external beam or implant radiation 
therapy involving the skeleton 

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11. Pregnant or lactating women.   
NOTE: Highly effective contraception (see Appendix 7) 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 highly effective 
contraception are excluded from the trial.  
12. Diagnosis of drug or alcohol dependence within 3 years prior to Visit 1 
13. Disease processes that may adversely affect gastrointestinal absorption including but not 
limited to short bowel syndrome, bowel resection, gastric bypass, tropical sprue, active celiac 
disease, active ulcerative colitis, gastroparesis, AIRE gene mutations with malabsorption, and 
active Crohn’s disease 
14. Chronic or severe cardiac disease within 26 weeks prior to Visit 1 including but not limited 
to congestive heart failure, myocardial infarction, QTcF >430 msec (males) or >450 msec 
(females), severe or uncontrolled arrhythmias, bradycardia (resting heart rate <50 
beats/minute), symptomatic hypotension, systolic BP <80 mm Hg or diastolic <40 mm Hg, 
or poorly controlled hypertension (systolic BP >150 mm Hg or diastolic >95 mm Hg)  
15. Cerebrovascular accident within 5 years prior to Visit 1 
16. History of renal colic or acute gout within 52 weeks prior to Visit 1 
17. Any disease or condition that, in the opinion of the investigator, may 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 1-year duration of the trial 
18. Known allergy or sensitivity to PTH or any of the excipients [metacresol, mannitol, succinic 
acid, NaOH/(HCl)] 
19. Participation in another clinical trial in which receipt of investigational drug or device 
occurred within 8 weeks (or at least 5.5 times the half-life of the investigational drug) prior to 
Visit 1  
20. Likely to be non-compliant with respect to trial conduct  
21. Any other reason that in the opinion of the investigator would prevent the subject from 
completing participation or following the trial schedule 
8.2. 
PREMATURE SUBJECT WITHDRAWAL 
Premature subject withdrawal occurs when an enrolled subject ceases participation in the trial, 
regardless of the circumstances, prior to the expected completion of the trial.   
In the case of premature subject withdrawal, the investigator should schedule an End of Study 
(EOS) 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 10.1.7. 
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. 

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8.2.1. 
Study Drug Discontinuation and Subject Withdrawal 
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 EOS Visit in place of Visit 3  
• Not continue into the Extension Period   
* 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 EOS Visit should be 
scheduled.  
See Section 10.1.7 for details on End of Study 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 EOS Visit should be scheduled immediately. 
See Section 10.1.7 for details on End of Study Visit.  
8.3. 
SUBJECT REPLACEMENT CRITERIA 
Subjects who terminate early are not expected to be replaced.  
9. 
TREATMENTS 
9.1. 
INVESTIGATIONAL PRODUCT 
TransCon PTH drug product is supplied as a clear solution containing TransCon PTH with a 
nominal PTH(1-34) content of 0.3 mg/mL in a pre-filled pen intended for SC injection.  
Excipients include metacresol, mannitol, succinic acid, and NaOH/(HCl).  The pens are stored in 
the refrigerator until first use; the pens are stable at room temperature for 14 days.  Refer to the 
Investigator’s Brochure for details on the composition and characteristics of TransCon PTH and 
the Pharmacy Manual for complete details on storage and handling.   
9.1.1. 
Labeling 
All study drug will be labeled according to Good Manufacturing Practice and local regulatory 
requirements.  The labels are trial-specific and carry unique identification pack numbers. 
Subjects will be provided with dosing and storage instructions.  
9.1.2. 
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.  

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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 Ascendis Pharma 
immediately if study drug has been stored outside the specified conditions on the label. 
The trial will use an internet-based interactive web response system (IWRS) as source to capture 
drug inventory and accountability data, including receipt of drug inventory and supplies by the 
site, treatment assignment for each subject, distribution to subjects, return to the site from 
subjects, and return to the Sponsor (or destruction with the Sponsor’s approval).  The IWRS 
system complies with all applicable regulatory requirements for record keeping and record 
retention in clinical trials [21 CFR Part 11 and ICH E6 (R2) GCP].   
Investigator or delegated site staff will be responsible for accountability and reconciliation of 
study drug. 
Study drug may be shipped from site or depot to subjects using an Ascendis-approved courier 
service. In such cases, accountability for study drug remains the responsibility of the principal 
investigator until subject has confirmed receipt of study drug. Documentation of study drug 
shipments must be maintained by the site and include, at minimum, the following: date of 
shipment from site, kit numbers shipped, date of receipt by subject, and temperature monitoring 
during shipment. 
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 Instructions for Use (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. 
9.2. 
TREATMENT ADMINISTERED 
The TransCon PTH delivery system consists of a multi-use cartridge integrated into a modified 
Ypsomed Uno Pen Fix using 31G, 5 mm needles.  The cartridge contains a liquid formulation 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 and is to be self-administered (following 
training by study staff) to the upper or lower abdomen or anterior thigh.  There are a total of 
4 possible injection areas: right abdomen, left abdomen, right anterior thigh, and left anterior 
thigh.  Subjects should be instructed to rotate injection sites.  Refer to the IFU for complete 
instructions on administration.  
In the Blinded Treatment Period, both TransCon PTH and placebo for TransCon PTH are 
provided in the mid-dose pen allowing for doses of 15, 18, and 21 µg/day.  
In the Extension Period, three pen presentations are available for the open-label TransCon PTH 
allowing for an expected dose range of 6-60 µg (6, 9, and 12 µg; 15, 18, and 21 µg; and 24, 27 
and 30 µg, respectively). 

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In addition to the study drug, subjects should continue to take their stable dose of magnesium 
and vitamin D3, as well as active vitamin D and/or calcium supplements with dose adjustments 
as per Section 9.7. 
9.3. 
SELECTION OF TRIAL DOSES 
TransCon PTH is an inactive prodrug.  The Phase 1 clinical trial with TransCon PTH 
demonstrated that a dose range of 12-20 µg/day was identified as both active and well-tolerated 
with 20 µg identified as the MTD in healthy volunteers.  Although 12 µg daily was the first dose 
to significantly increase albumin-adjusted calcium in NHVs, as they must first suppress their 
endogenous PTH, it is possible that somewhat lower doses might be optimal for some patients 
with HP, explaining the lower doses of 9 and 6 µg in the low-dose pen.  Although doses >20 µg 
daily were not optimally tolerated in healthy adult women with normal calcium levels, it is 
possible that doses >20 µg daily may be both tolerated and required for some subjects with HP, 
therefore the dose range for the Blinded Treatment Period will be 15, 18, and 21 µg/day, while 
during the Extension Period subjects will be individually titrated to an expected optimal dose of 
6-60 µg PTH/day in 3 pen presentations (6, 9, and 12 µg/day; 15, 18, and 21 µg/day; and 24, 27 
and 30 µg/day, respectively).  
9.4. 
TREATMENT ASSIGNMENT 
9.4.1. 
Treatment Assignment During Blinded Treatment Period 
At Visit 1, subjects will be randomized (1:1:1:1) to one of the following: 
• TransCon PTH 15 µg/day 
• TransCon PTH 18 µg/day 
• TransCon PTH 21 µg/day 
• Placebo for TransCon PTH (sub-randomized 1:1:1) 
− Mimicking dose of 15 µg/day 
− Mimicking dose of 18 µg/day 
− Mimicking dose of 21 µg/day 
9.4.2. 
Treatment Assignment During Extension Period 
At Visit 3, subjects will be assigned to open-label treatment as follows: 
• If taking active vitamin D: Start TransCon PTH at a dose of 15 µg/day and undergo 
titration of SOC as performed during the 4-week Blinded Treatment Period. 
• If not taking active vitamin D: Start TransCon PTH at the same dose of study drug taken 
during the Blinded Treatment Period.  Exception should be made if hypo- or hypercalcemic 
symptoms are present at Visit 3, in which case TransCon PTH dose may be adjusted by 
3 µg/day. 

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9.5. 
DOSE ADJUSTMENTS  
9.5.1. 
Screening Period Supplement Dose Adjustments 
During the Screening Period, adjustments to doses of HP-related supplements (SOC, magnesium, 
vitamin D) will be made to achieve the following laboratory levels: 
• 25(OH) vitamin D: 30-70 ng/mL 
• Magnesium: within the normal range 
− If a subject has a history of inability to be successfully managed within the normal range 
for magnesium level, a level slightly below the normal range is acceptable with approval 
of Medical Monitor/ Medical Expert. 
• Albumin-adjusted or ionized sCa: within the lower half of the normal range 
Supplement doses are adjusted only after initial Screening laboratory results are received. 
Follow-up laboratory assessment of the above values, with exception of vitamin D level, are 
performed approximately 3 days after every supplement dose adjustment during the Screening 
Period.  If required, additional supplement dose adjustments, with follow-up laboratory 
assessments approximately 3 days later, may be performed.  
If subjects fail to optimize to the target laboratory ranges within the Screening window, 
investigators may, with Medical Monitor/Medical Expert approval, extend the Screening Period. 
Subjects who appear to already be optimized to the target laboratory ranges based on historical 
laboratory results within 4 weeks prior to Screening require only a single confirmatory 
laboratory assessment during the Screening Period.   
When laboratory results are within the above optimization ranges, with at least one confirmation 
laboratory result, and all other entry criteria including the Screening 24-hour urine collection are 
met, the subject is eligible to move to the Blinded Treatment Period and be randomized 
following Medical Monitor/Medical Expert or designee confirmation.  
9.5.2. 
Blinded Treatment Period (Visits 1-3; Weeks 0-4) Dose Adjustments 
9.5.2.1. 
Study Drug Dose Adjustments During Blinded Treatment Period 
Subjects remain on the same dose of study drug throughout the Blinded Treatment Period.   
9.5.2.2. 
SOC Dose Adjustments During Blinded Treatment Period 
Active vitamin D and/or calcium doses will be optimized as per Appendix 1.  The investigator 
may adjust SOC in a different manner than as outlined in Appendix 1with prior Medical 
Monitor/Medical Expert approval. 
SOC adjustments should be made within 48 hours of blood collection at Laboratory Visits.  If at 
Visit 2 SOC dose adjustments are performed, follow-up laboratory assessment approximately 
3 days later should be performed via an Unscheduled Laboratory Visit (ULV).  

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NOTE: If during the Blinded Treatment Period clinical symptoms of hypo- or 
hypercalcemia occur, an ULV should be scheduled to assess albumin-adjusted or ionized 
sCa levels to guide calcium and/or active vitamin D dose adjustments.  During the Blinded 
Treatment Period, rescue doses of active vitamin D and/or calcium are allowable, even 
prior to the ULV.  
9.5.3. 
Extension Period (Visits 3-21; Weeks 4-214) Dose Adjustments 
9.5.3.1. 
Study Drug Dose Adjustments During Extension Period 
For subjects taking active vitamin D at Visit 3, the TransCon PTH dose is titrated starting at Visit 
4 as shown in Appendix 2. 
For subjects not taking active vitamin D at Visit 3, the TransCon PTH dose is titrated starting at 
Visit 3 as shown in Appendix 3. 
Starting at Visit 9, all subjects are expected to remain on a stable dose of TransCon PTH. 
However, dose adjustments should continue as needed based on sCa results and following 
Appendix 2 and Appendix 3.Dose range for the Extension Period is expected to be 6-360 µg/day 
in 3 pen presentations (6, 9, and 12 µg/day; 15, 18, and 21 µg/day; and 24, 27 and 30 µg/day, 
respectively). 
NOTE:  Rescue doses of active vitamin D and/or calcium are allowable throughout the 
Extension Period.  However, if symptoms of hypo- or hypercalcemia are persistent, the 
TransCon PTH dose should be adjusted at the following clinic visit (except if prior to Visit 
4 for subjects taking active vitamin D at Visit 3).  Due to the extended length of time 
between visits after Visit 9, the TransCon PTH dose may be adjusted between clinic visits.  
Due to the long half-life of TransCon PTH, the full effect of a dose change cannot be 
determined until 8 to 10 days after the dose change. 
9.5.3.2. 
SOC Dose Adjustments During Extension Period 
For subjects taking active vitamin D at Visit 3, active vitamin D and/or calcium doses will be 
optimized in the same manner as performed during the Blinded Treatment Period (see 
Appendix 1) PRIOR to adjustment of TransCon PTH dosing at Visit 4 (see Appendix 2). 
Dose adjustments should continue as needed based on sCa results and following Appendix 2 and 
Appendix 3. 
9.6. 
STUDY DRUG STOPPING OR CHANGE TO ADMINISTRATION 
9.6.1. 
Required Stopping 
The investigator, with Sponsor Medical Monitor/Medical Expert notification, must stop 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 

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• Suspicion of osteosarcoma (eg, 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 
See Section 8.2.1 for further guidance on study drug discontinuation. 
9.6.2. 
Possible Stopping or Change to Administration 
The investigator may change the dose, and/or temporarily hold the study drug for an individual 
subject as per the dose titration appendices (Appendix 2 and Appendix 3). 
A discussion between the investigator and medical monitor will occur to 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 
− study drug dose ≥30 μg/day 
• 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 

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− 
Thresholds for albumin-corrected serum calcium: <8.3 mg/dL (<2.07 mmol/L), or 
ionized calcium: <1.16 mmol/L 
− Thresholds for albumin-corrected serum calcium: <7.0 mg/dL (>1.75 mmol/L), or 
ionized calcium: <0.95 mmol/L 
− Thresholds for albumin-corrected serum calcium: >10.6 mg/dL (>2.64 mmol/L), or 
ionized calcium: >1.32 mmol/L 
− Thresholds for albumin-corrected serum calcium: >12.0 mg/dL (>3.00 mmol/L), or 
ionized calcium: >1.50 mmol/L 
• “Non-responders” to TransCon PTH may be evaluated for discontinuation of TransCon PTH 
therapy. 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).  
Persistent severe hypocalcemia and persistent severe hypercalcemia (as defined above) will be 
reported to the regulatory authorities, based on local requirements (Section 12). 
If study drug is permanently discontinued, see Section 8.2.1. 
NOTE: Reinstitution of TransCon PTH treatment following any of the above events 
requires prior approval by the Sponsor Medical Monitor/Medical Expert. 
9.7. 
TREATMENT COMPLIANCE 
Compliance of both study drug and HP-related supplements (SOC, magnesium, vitamin D) will 
be assessed based on review of the daily diary and returned pens at every clinic visit.   
9.8. 
PRIOR AND CONCOMITANT THERAPIES 
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.   
9.8.1. 
Required HP Therapies 
Prior to Screening, subjects must be taking stable doses of the following SOC HP treatments for 
at least 12 weeks: 
• ≥0.25 µg BID of calcitriol (active vitamin D) or ≥0.5 µg BID or ≥1.0 µg daily of alfacalcidol 
(active vitamin D) and 
• ≥400 mg BID calcium citrate or carbonate  

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With approval of the Medical Monitor/Medical Expert, subjects may be on doses less than those 
above if there is a history of hypercalcemia on such doses.  
Subjects may also be on cholecalciferol (vitamin D3) and magnesium supplements as part of 
their HP treatment, as long as doses are expected to remain stable throughout the trial.  Subjects 
are to be instructed to take their HP-related supplements at approximately the same times every 
day throughout the trial.  Subjects taking a thiazide diuretic should discontinue at least 4 weeks 
prior to Screening activities, including supplement dose optimization and Screening 24-hour 
urine collection.   
9.8.2. 
Prohibited Therapies  
The following therapies are prohibited throughout the trial: 
• PTH therapies other than TransCon PTH 
• Thiazide or loop diuretics  
• Phosphate binders (other than calcium carbonate/calcium citrate) 
• Digoxin, lithium, methotrexate 
• Systemic corticosteroids (other than as replacement therapy) 
• Bisphosphonates  
• Denosumab 
In case of any questions regarding current medication or prior therapy(ies), Sponsor Medical 
Monitor/Medical Expert should be contacted. 
If the administration of a prohibited concomitant medication becomes necessary, participation in 
the trial may be discontinued prematurely for that subject, based on a decision made jointly by 
the Investigator and Sponsor Medical Monitor/Medical Expert. 
See Section 8.1.2 Exclusion Criteria for prohibited prior therapies.  
10. TRIAL PROCEDURES 
10.1. TRIAL DURATION 
Each subject’s participation is expected to last up to 214 weeks plus a screening period of up to 
approximately 4 weeks. 
• Screening Period (supplement optimization): Up to approximately 4 weeks  
• Blinded Treatment Period (study drug stable with SOC optimization): 4 weeks 
• Extension Period (open-label TransCon PTH treatment): 210 weeks, with up to an initial 
14 weeks of TransCon PTH titration and SOC optimization, followed by 196 weeks of 
individualized dosing  

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10.1.1. Trial Periods and Visits  
See Appendix 4 for Schedule of Events.  
Following the Screening Period, each subject attends: 
• Blinded Treatment Period  
− Visit 1 (Week 0, Day 1) 
− Laboratory Visit 1 (Week 0, Day 3, +1 day) 
− Laboratory Visit 2 (Week 0, Day 6, +1 day) 
− Laboratory Visit 3 (Week 1, Day 9, +1 day) 
− Visit 2 (Week 2, Day 14, ±2 days) 
− Visit 3 (Week 4, Day 28, ±2 days) 
• Extension Period  
− Laboratory Visit 4 (Week 4, 3 Days Post-Visit 3, +1 day)* 
− Laboratory Visit 5 (Week 4, 6 Days Post-Visit 3, +1 day)* 
− Laboratory Visit 6 (Week 5, 9 Days Post-Visit 3, +1 day)* 
− Visit 4 (Week 6, Day 42, ±2 days) 
− Visit 5 (Week 8, Day 56, ±2 days) 
− Visit 6 (Week 10, Day 70, ±2 days) 
− Visit 7 (Week 12, Day 84, ±2 days) 
− Visit 8 (Week 14, Day 98, ±2 days) 
− Visit 9 (Week 18, Day 126, ±3 days) 
− Visit 10 (Week 22, Day 154, ±3 days) 
− Visit 11 (Week 26, Day 182, ±3 days) 
− Visit 12 (Week 34, Day 238, ±7 days) 
− Visit 13 (Week 42, Day 294, ±7 days) 
− Visit 14 (Week 50, Day 350, ±7 days) 
− Visit 15 (Week 58, Day 406, ±7 days) 
− Visit 15A (Week 66, Day 462, ±7 days) 
− Laboratory Visit 7 (Week 71, Day 497, ±14 days) 
− Visit 15B (Week 74, Day 518, ±7 days) 
− Visit 16 (Week 84, Day 588, ±14 days) 
− Visit 16A (Week 92, Day 644, ±7 days) 

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− Laboratory Visit 8 (Week 97, Day 679, ±14 days) 
− Visit 16B (Week 100, Day 700, ±7 days) 
− Visit 17 (Week 110, Day 770, ±14 days) 
− Visit 17A (Week 118, Day 826, ±7 days) 
− Laboratory Visit 9 (Week 123, Day 861, ±14 days) 
− Visit 17B (Week 126, Day 882, ±7 days) 
− Visit 18 (Week 136, Day 952, ±14 days) 
− Visit 18A (Week 144, Day 1008, ±7 days) 
− Laboratory Visit 10 (Week 149, Day 1043, ±14 days) 
− Visit 18B (Week 152, Day 1064, ±7 days) 
− Visit 19 (Week 162, Day 1134, ±14 days) 
− Visit 19A (Week 170, Day 1190, ±7 days) 
− Laboratory Visit 11 (Week 175, Day 1225, ±14 days) 
− Visit 19B (Week 178, Day 1246, ±7 days) 
− Visit 20 (Week 188, Day 1316, ±14 days) 
− Visit 20A (Week 196, Day 1372, ±7 days) 
− Laboratory Visit 12 (Week 201, Day 1407, ±14 days) 
− Visit 20B (Week 204, Day 1428, ±7 days) 
− Visit 21 (Week 214, Day 1498, ±14 days)  
* Only for subjects taking active vitamin D at Visit 3 
10.1.2. Screening Period (Week -4 to -1, Day -28 to -7) 
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/independent ethics committee/human research ethics 
committee (IRB/ERC) prior to implementation.   

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The following must be performed during the Screening period prior to 
enrollment/randomization: 
1. HPES validation battery 
2. Demographics review 
3. Height and weight measurements 
4. Vital sign measurements 
5. Medical history review 
6. Prior and concomitant medication review 
7. Physical examination 
8. 12-lead electrocardiogram (ECG) 
9. Dual-energy X-ray absorptiometry (DXA) and trabecular bone score (TBS)  
• Canada Only: TBS scoring will not be performed for subjects 18 to 20 years of age 
10. Only for subjects ≤25 years old as of Visit 1: X-ray of non-dominant wrist and hand with 
evidence of epiphyseal closure 
11. Only for females of childbearing potential: Urine collection for local hCG  
12. Blood collection for local laboratory assessments 
13. Blood and urine collection for central laboratory assessments 
14. Dietary calcium questionnaire and counseling based on results 
15. Dispensing and training on daily diary 
16. Optimization of vitamin D3, magnesium, active vitamin D, and/or calcium to establish target 
laboratory values prior to randomization (See Section 9.5.1): 
a. 25(OH) vitamin D: 30-70 ng/mL (75-175 nmol/L)  
b. Magnesium: within the normal range 
− If a subject has a history of inability to be successfully managed within the normal 
range for magnesium level, a level slightly below the normal range is acceptable with 
approval of Medical Monitor/ Medical Expert 
c. Albumin-adjusted or ionized sCa: within the lower half of the normal range*  
* For the purpose of this trial, the normal range for albumin-adjusted sCa is 
8.3-10.6 mg/dL (2.07-2.64 mmol/L) and the normal range for ionized sCa is 
1.16-1.32 mmol/L 
17. 24-hour urine collection (within the week prior to Visit 1 following investigator confirmation 
of eligibility) 

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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 lower half of the 
normal range, as well as normalize the serum magnesium and vitamin D level.  Once the 
laboratory results are within the above optimization ranges, a set of confirmation laboratory 
results should be obtained 2-7 days following previous laboratory assessment. 
When confirmation laboratory results are obtained, and all other entry criteria are met, the 
subject is eligible to move to the Blinded Treatment Period and be randomized following 
Medical Monitor/Medical Expert or designee confirmation.  
Subjects who fail to optimize to the target laboratory ranges within the Screening window, may, 
with Medical Monitor/Medical Expert approval, extend the Screening Period. 
Subjects who appear to already be optimized to the target laboratory ranges based on historical 
laboratory results within 4 weeks prior to Screening require only a single confirmatory 
laboratory assessment and a 24-hour urine collection during the Screening Period.   
See Section 11 for further details on procedures listed above.  
See Appendix 5 for further details on laboratory assessments to be performed.  
Subjects who sign the informed consent form but do not meet one or more eligibility criteria 
(including withdrawing of consent) prior to first study drug dosing will be considered screen 
failures.  A minimal set of screen failure information is required to ensure transparent reporting 
of screen failure participants.  Minimal information includes demography and screen failure 
details (eligibility criteria). 
The decision to rescreen will be made on a case by case basis after discussion with Sponsor 
Medical Monitor/Medical Expert, including which screening procedures may not need repeating.  
Rescreened subjects should receive a new Subject Number.  Documentation for rescreening must 
include date and reason for initial exclusion. 
10.1.3. Blinded Treatment Period (Week 0 to Week 4) 
During the Blinded Treatment Period, subjects are randomized into 4 treatment groups (1:1:1:1):  
• TransCon PTH 15 µg/day* 
• TransCon PTH 18 µg/day 
• TransCon PTH 21 µg/day  
• Placebo for TransCon PTH (excipients solution) 
* Dose of TransCon PTH refers to dose of PTH(1-34) administered 
To maintain blinding, the placebo group will be sub-randomized into 3 groups (1:1:1) to mimic 
doses of 15, 18, and 21 µg/day. 
NOTE: Subjects remain on the same dose of study drug throughout the Blinded Treatment 
Period, however active vitamin D and/or calcium doses will be optimized (See 
Section 9.5.2).  
Vitamin D3 and magnesium dosing are expected to remain stable throughout the remainder of 
the trial.  

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10.1.3.1. Visit 1 (Week 0, Day 1) Procedures 
The following procedures are performed at this morning visit: 
1. Subset of HPES validation battery 
2. Vital sign measurements, including 30-minute post-dose orthostatic measurements 
3. Daily diary review 
4. Concomitant medication review, including SOC  
5. Adverse event review 
6. Only for women of childbearing potential: Urine collection for local hCG (results must 
confirm subject is not pregnant prior to first study drug dose administration) 
7. Blood and urine collection for central laboratory assessments  
8. Dietary calcium questionnaire and counseling based on results 
9. Blinded treatment assignment 
10. Daily diary dispensing 
11. Study drug dispensing and training via Instructions For Use (IFU)  
− Reminder to dose every morning up to (but NOT including) the day of Visit 2 
12. Study drug administration by subject 
13. Local tolerability assessment by site staff 
14. SOC dose adjustment (See Section 9.5.2.2) 
15. Device usability questionnaire 
See Section 11 for further details on procedures listed above.  
See Appendix 5 for further details on laboratory assessments to be performed.  
10.1.3.2. Laboratory Visits 1-3 (LV1-LV3; Weeks 0-1, Days 3, 6, 9 +1 day) Procedures 
The following is performed at these morning visits: 
1. Blood collection for local laboratory assessments 
2. SOC dose adjustment (See Section 9.5.2.2) 
See Section 11 for further details on procedures listed above. 
See Appendix 5 for further details on laboratory assessments to be performed.  

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10.1.3.3. Visit 2 (Week 2, Day 14 ±2 days) Procedures 
The following will be performed at this morning visit: 
1. Blood collection for local laboratory assessments  
2. Blood and urine collection for central laboratory assessments  
3. Vital sign measurements 
4. Daily diary review 
5. Study drug receipt and compliance review 
6. Concomitant medication review, including SOC 
7. Adverse event review 
8. Dietary calcium questionnaire and counseling based on results 
9. Device usability questionnaire 
10. SOC dose adjustment (See Section 9.5.2.2) 
11. Daily diary dispensing 
12. Study drug dispensing 
− Reminder to begin to evening dosing [ideally every night at bedtime (qHS) in bed]  
Multiple local laboratory assessments between Visits 2 and 3 may be necessary to guide SOC 
dose adjustment. 
See Section 11 for further details on procedures listed above.  
See Appendix 5 for further details on laboratory assessments to be performed.  
10.1.3.4. Visit 3 (Week 4, Day 28 ±2 days) Procedures 
The following will be performed at this morning visit: 
1. Subset of HPES validation battery 
2. Device usability questionnaire 
3. Blood collection for local laboratory assessments  
4. Blood and urine collection for central laboratory assessments  
5. Vital sign measurements 
6. Daily diary review 
7. Study drug receipt and compliance review 
8. Concomitant medication review, including SOC 
9. Adverse event review 
10. Dietary calcium questionnaire and counseling based on results 
11. Daily diary dispensing 

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12. Open-label treatment assignment 
13. Titration of TransCon PTH and/or SOC dose adjustment (See Section 9.5.3) 
14. Study drug dispensing 
− For subjects on active vitamin D only: Reminder to dose every morning up to (but NOT 
including) the day of Visit 4 
− For subjects on active vitamin D only: Study drug administration by subject 
− For subjects on active vitamin D only: Local tolerability assessment by site staff 
− For subjects on active vitamin D only: 30-minute post-dose orthostatic measurements 
See Section 11 for further details on procedures listed above. 
See Appendix 5 for further details on laboratory assessments to be performed.  
10.1.4. Extension Period (Week 4 – 214) 
During the Extension Period, all subjects begin treatment with open-label TransCon PTH with 
the availability of 3 pen presentations (6, 9, and 12 µg/day; 15, 18, and 21 µg/day; and 24, 27 
and 30 µg/day, respectively), allowing for an expanded dose range. 
For subjects taking active vitamin D at Visit 3, the TransCon PTH dose is titrated starting at Visit 
4 as shown in Appendix 2. 
For subjects not taking active vitamin D at Visit 3, the TransCon PTH dose is titrated starting at 
Visit 3 as shown in Appendix 3.  
Starting at Visit 9, all subjects are expected to remain on a stable dose of TransCon PTH. 
However, dose adjustments should continue as needed based on sCa results and following 
Appendix 2 and Appendix 3. 
NOTE: Rescue doses of active vitamin D and/or calcium are allowable throughout the 
Extension Period.  However, if symptoms of hypo- or hypercalcemia are persistent, the 
TransCon PTH dose should be adjusted at the following clinic visit (except if prior to Visit 
4 for subjects taking active vitamin D at Visit 3).  Due to the extended length of time 
between visits after Visit 9, the TransCon PTH dose may be adjusted between clinic visits. 
10.1.4.1. Laboratory Visits* 4-6 (LV4-LV6) Procedures 
If Visit 3 occurs on Day 26: LV4-LV6 occur on Day 29, 32, 35 +1 day 
If Visit 3 occurs on Day 27: LV4-LV6 occur on Day 30, 33, 36 +1 day 
If Visit 3 occurs on Day 28: LV4-LV6 occur on Day 31, 34, 37 +1 day 
If Visit 3 occurs on Day 29: LV4-LV6 occur on Day 32, 35, 38 +1 day 
If Visit 3 occurs on Day 30: LV4-LV6 occur on Day 33, 36, 39 +1 day 
*Only for subjects who are still taking active vitamin D at Visit 3  
The following will be performed at these morning visits: 
1. Blood collection for local laboratory assessments  

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2. SOC dose adjustment (See Section 9.5.3.2) 
See Section 11 for further details of procedures listed above.  
See Appendix 5 for further details on laboratory assessments to be performed.  
10.1.4.2. Visits 4-8 (Weeks 6-14; Days 42, 56, 70, 84, 98 ±2 days) Procedures 
The following will be performed at these morning visits: 
1. Subset of HPES validation battery (only Visits 4, 5, and 7) 
2. Only for women of childbearing potential: Urine collection for local hCG (only at 
Visits 6 and 8) 
3. Blood collection for local laboratory assessments  
4. Blood collection for central laboratory assessments (only Visits 4, 5, and 7) 
5. Urine collection for central laboratory assessments (only Visit 5) 
6. Vital sign measurements 
7. Daily diary review  
8. TransCon PTH receipt and compliance review 
9. Concomitant medication review, including active vitamin D and calcium 
10. Adverse event review 
11. Daily diary dispensing (only Visits 4-7) 
12. Titration of TransCon PTH and/or SOC dose adjustment (See Section 9.5.3)  
13. TransCon PTH dispensing 
− Only for subjects on active vitamin D at Visit 3: Reminder to begin evening dosing 
(ideally qHS in bed) (only Visit 4) 
See Section 11 for further details of procedures listed above.  
See Appendix 5 for further details on laboratory assessments to be performed.  
10.1.4.3. Visits 9-11 (Weeks 18-26; Day 126-182 ±3 days) Procedures 
The following will be performed at these morning visits: 
1. HPES validation battery (only at Visit 11) 
2. Only for women of childbearing potential: Urine collection for local hCG (only at Visit 10) 
3. Blood collection for central laboratory assessments (only at Visits 9 and 11) 
4. Urine collection for central laboratory assessments (only at Visits 9 and 11) 
5. 24-hour urine collection (only within a week of Visit 11) 
6. Vital sign measurements 
7. TransCon PTH receipt and compliance review 

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8. Concomitant medication review, including rescue doses of SOC 
9. Adverse event review 
10. DXA and TBS (only within a week of Visit 11) 
a. Canada Only: TBS scoring will not be performed for subjects 18 to 20 years of age 
11. Titration of TransCon PTH and/or SOC dose adjustment, if needed (See Section 9.5.3) 
12. TransCon PTH dispensing 
See Section 11 for further details of procedures listed above.  
See Appendix 5  for further details on laboratory assessments to be performed.  
10.1.4.4. Visits 12-15 (Weeks 34-58; Day 238-406 ±7 days) Procedures 
The following will be performed at these morning visits: 
1. HPES validation battery (only at Visit 15) 
2. Only for women of childbearing potential: Urine collection for local hCG (only at 
Visits 12 and 14) 
3. Blood collection for central laboratory assessments (only at Visits 13 and 15) 
4. Urine collection for central laboratory assessments (only at Visit 15) 
5. 24-hour urine collection (only within a week of Visit 15) 
6. Vital sign measurements 
7. TransCon PTH receipt and compliance review 
8. Concomitant medication review, including rescue doses of SOC 
9. Adverse event review 
10. DXA and TBS (only within a week of Visit 15) 
a. Canada Only: TBS scoring will not be performed for subjects 18 to 20 years of age 
11. TransCon PTH dispensing 
See Section 11 for further details of procedures listed above.  
See Appendix 5  for further details on laboratory assessments to be performed.  
10.1.4.5. Laboratory Visits 7-12 (LV7-LV12; Weeks 71-201; Day 497-201 ±14 days ) 
Procedures 
The following will be performed at these morning visits: 
1. Blood collection for local laboratory assessments  
2. Only for women of childbearing potential: Urine collection for local hCG  
Correspondence (eg, phone call, email) with the subject within 3 days following receipt of 
abnormal sCa result or within 5 days following receipt of normal sCa result is required to 
perform the following: 

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1. Concomitant medication review, including rescue doses of SOC 
2. Adverse event review 
See Section 11 for further details of procedures listed above.  
See Appendix 5 for further details on laboratory assessments to be performed.  
10.1.4.6. Visits 16-21 (Weeks 84-214; Day 588-1498 ±14 days) Procedures 
The following will be performed at these morning visits: 
1. Subset of HPES validation battery (only Visits 17, 19, and 21) 
2. Only for women of childbearing potential: Urine collection for local hCG  
3. Blood and urine collection for central laboratory assessments 
4. 24-hour urine collection (within a week of Visits 16-20, and within the week prior to 
Visit 21) 
5. Vital sign measurements 
6. TransCon PTH receipt and compliance review 
7. Concomitant medication review, including rescue doses of SOC 
8. Physical exam 
9. Adverse event review 
10. DXA and TBS (only within a week of Visits 17 and 19, and within the week prior to Visit 21 
a. Canada Only: TBS scoring will not be performed for subjects 18 to 20 years of age 
11. TransCon PTH dispensing (except for Visit 21) 
Additional TransCon PTH dispensing will occur 8 and 16 weeks (±7 days) after Visits 15-20. 
These Visits will be labelled as Visits A and B (e.g. Visit 15A is 8 weeks after Visit 15 and 
Visit 15B is 16 weeks after Visit 15).  
Correspondence (eg, phone call, email) with the subject 2 weeks (+7 days) after Visit 21 is 
required to evaluate the subject for any further AEs during the 2 weeks since last study drug 
administration.  
See Section 11 for further details of procedures listed above.  
See Appendix 5 for further details on laboratory assessments to be performed.  
10.1.5. Unscheduled Visits (UV) 
Unscheduled Visits 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. 

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10.1.6. Unscheduled Laboratory Visits (ULV) 
Unscheduled Laboratory Visits 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 inludes 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. End of Study (EOS) Visits 
End of Study (EOS) Visits are performed for any withdrawal of a subject from this clinical trial.   
If EOS Visits occur prior to Visit 3, the structure and assessments of the EOS Visit should be 
as similar as possible to Visit 3.  
If EOS Visits occur after Visit 3, the structure and assessments of the EOS Visit should be as 
similar as possible to Visit 15.  If prior to Visit 8, diary review should also be included in the 
EOS Visit. 
Additionally, correspondence (eg, phone call, email) with the subject 2 weeks (+7 days) after last 
study drug administration is required to evaluate the subject for any further AEs during the 
2 weeks since last study drug administration.  
See Section 8.2 for details on Premature Subject Withdrawal. 
11. ASSESSMENTS 
11.1. 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 & Heart Rate 
Blood pressure and heart rate are measured while subject is sitting.  Subject is then asked to 
stand up and, within 3 minutes of doing so, blood pressure and heart rate are measured again. 
11.1.1. Post-Dose Orthostatic Measurements 
At Visit 1, a set of orthostatic blood pressure and heart rate should be taken 30 minutes after 
study drug administration. 
At Visit 3, a set of orthostatic blood pressure and heart rate should be taken 30 minutes after 
study drug administration for subjects on active vitamin D at Visit 3.  

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11.2. PRIOR AND CONCOMITANT MEDICATION REVIEW 
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.   
11.3. ELECTROCARDIOGRAM (ECG) 
An ECG must be performed and read locally prior to Visit 1.  Standard 12-lead ECG 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 12 weeks prior to Visit 1 is acceptable if the report 
includes QT interval (or QTcF) and Heart Rate. 
11.4. 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 Visit 1).  A historical 
x-ray showing epiphyseal closure is acceptable.  
11.5. DUAL-ENERGY X-RAY ABSORPTIOMETRY (DXA) AND TRABECULAR 
BONE SCORE (TBS) 
To evaluate bone density and quality, a DXA scan of the spine, hip, and forearm, as well as TBS 
scoring must be performed Canada Only. TBS scoring will not be performed for subjects 18 to 
20 years of age. 
See the DXA Manual for complete details.  The same DXA machine should be used throughout 
the trial. The sponsor must be notified if a change in scanner occurs. 
A historical DXA performed within the 12 weeks prior to Visit 1 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 (Canada Only: unless subject is 18 to 20 years of age). 
11.6. 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 (http://www.iofbonehealth.org/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, as well as avoiding unhealthy intake of sodium that can contribute to hypercalciuria.  

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11.7. HYPOPARATHYROIDISM PATIENT EXPERIENCE SCALE VALIDATION 
BATTERY 
The Hypoparathyroidism Patient Experience Scale (HPES) is the disease-specific 
subject-completed Patient-Reported Outcome (PRO) measure being developed by the Sponsor to 
assess relevant patient-reported symptom and disease impacts.  The HPES takes approximately 
5 minutes to complete.  The measure assesses both the key HP-related symptoms from the 
patient perspective and the key impacts of these symptoms on patient functioning and well-
being.   
The concept elicitation phase of the measure development has been completed based on 
semi-structured interviews with 43 patients and 5 clinical experts.  To continue the measure 
development process and validate these measures, data will be collected in this trial for use in the 
psychometric analyses necessary to finalize the measures.  The data collected in the trial will be 
combined with similar data collected via a web-study conducted independently of this study.  A 
separate Psychometric Analysis Plan based on the data collected from the two studies will be 
prepared independently of the SAP for this trial. 
The Validation Battery consists of the following Clinical Outcome Assessments (COAs): the 
HPES, other PROs, and a clinician-reported outcome measure needed for the psychometric 
testing.  It is expected that completion of the Validation Battery takes approximately 
30-45 minutes.  Data from the validation battery, and a subset thereof at various time points, will 
be used to assess the measurement properties of the HPES such as the factor structure and 
scoring algorithm.  The Validation Battery, or a subset, will also be completed later in the trial 
for exploratory purposes. In addition, one of the PROs will also be used for resource utilization 
evaluation. 
If suicidal ideation is spontaneously reported during PRO assessments or at any other time 
during the trial, study staff should follow their site-specific suicide safety plan.  
NOTE: All PROs must be completed by the subject without assistance and prior to 
conducting any clinical assessments.   
11.8. DEVICE USABILITY QUESTIONNAIRE  
The Device Usability Questionaire will be used to assess the usability of the pre-filled injection 
pen, including any malfunction.  
NOTE: This questionnaire should be completed by the subject without assistance. 
11.9. DAILY DIARY 
Subjects are trained on the daily diary during Screening and instructed to return the diary at 
every visit for site staff review as part of concomitant medication review, AE review and study 
drug compliance.  
Diary completion during the Screening Period assists in tracking HP-related supplement 
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 daily diary prior to enrollment/randomization.   

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11.10. LOCAL TOLERABILITY ASSESSMENT 
Local Tolerability is assessed based on presence of injection site reactions (ISRs).  An ISR is 
defined as a reaction at the site of administration that is deemed abnormal from those ordinarily 
observed in subcutaneous (SC) injections (including pain intensity, pruritus, swelling, induration, 
ulceration, lipoatrophy, lipodystrophy, and infection).  Asymptomatic erythema is not considered 
an ISR. 
At Visit 1, assessment of local tolerability is performed by trial staff using the Local Tolerability 
Scale at the time of the first study drug injection and at least 15 minutes post-dose.  
At Visit 3, the first dose of open-label study drug is administered on-site only for subjects 
currently taking active vitamin D.  An assessment of local tolerability is performed by trial staff 
using the Local Tolerability Scale at the time of the study drug injection and at least 15 minutes 
post-dose.   
11.11. ADVERSE EVENT REVIEW 
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 
• Emergency/urgent care visits or hospitalizations since the previous visit 
At applicable visits, site staff will review daily diary with the subject and any data related to 
changes in health or medications should be further assessed for potential AEs.   
Additionally, 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 study visit or if an UV or ULV must be scheduled.   
See Section 12 for details on reporting AEs. 
11.12. LABORATORY ASSESSMENTS 
Samples will be obtained at a minimum for both central and local laboratory tests to be 
performed as outlined in Section 11.12.1 and Appendix 5. 
NOTE:  
• Blood and urine 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 
• Blood and urine collection for central laboratory testing should occur within 1 hour of 
each other  

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Investigators must be able to receive local laboratory results within a time frame sufficent to 
allow instructions to subjects on dose adjustments within 48 hours of blood collection.  All local 
laboratory results will be entered into the EDC system by the site staff. 
11.12.1. Laboratory Assessments by Visit 
See Appendix 5 for the Schedule of Laboratory Assessments.  
11.12.1.1. Screening Period Laboratory Assessments  
The following laboratory assessments are performed locally during the Screening Period to guide 
optimization of HP-related supplements (vitamin D3, active vitamin D, calcium, and/or 
magnesium) prior to dosing (See Section 9.5.1).  Multiple laboratory assessments may be 
performed as needed, including at least one set of confirmation laboratory assessments once 
the laboratory results are within the optimization ranges. 
1. 25(OH) vitamin D 
2. Calcium and albumin (or ionized calcium) 
3. Magnesium 
The following laboratory assessments are performed locally once during the Screening Period to 
ensure eligibility prior to Visit 1: 
1. Urine Human chorionic gonadotropin (hCG; pregnancy test)  
Only for females of childbearing potential defined as NOT surgically sterile or 
postmenopausal (≥45 years old as of Screening, without menses for at least 52 weeks prior to 
Screening without an alternative medical cause, and FSH > 20 IU/L) 
2. Serum Follicle Stimulating Hormone (FSH)  
Only for females ≥45 years old as of Screening, without menses for at least 52 weeks prior to 
Screening without an alternative medical cause (eg, surgically sterile) to determine if 
postmenopausal status 
The following laboratory assessments will be performed centrally on blood and urine collected 
once during the Screening period to ensure eligibility or to provide another baseline prior to 
Visit 1: 
1. 25(OH) vitamin D 
2. 1,25(OH)2 vitamin D 
3. PTH(1-84) 
4. Chemistry panel including serum calcium, albumin, and creatinine  
5. Hematology panel 
6. Urine calcium and creatinine  
7. Bone turnover markers 
8. TSH 

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After the investigator confirms the subject is eligible to move into the Blinded Treatment 
Period, a 24-hour urine collection will be performed by the subject at home within the week 
prior to Visit 1 to provide baseline values.  The laboratory assessments associated with the 
24-hour urine collection will be performed centrally. 
11.12.1.2. Visit 1 (V1) Laboratory Assessments  
The following laboratory assessment is performed locally at Visit 1 to ensure eligibility prior to 
study drug dosing: 
1. Urine Human chorionic gonadotropin (hCG; pregnancy test)  
Only for females of childbearing potential defined as NOT surgically sterile or 
postmenopausal (≥45 years old as of Screening, without menses for at least 52 weeks prior to 
Screening without an alternative medical cause, and FSH > 20 IU/L) 
The following laboratory assessments will be performed centrally on blood and urine collected at 
Visit 1 to provide a baseline for each subject: 
1. 25(OH) vitamin D 
2. 1,25(OH)2 vitamin D 
3. Total PTH (corresponding to TransCon PTH) and mPEG 
4. Antibodies against PTH and PEG 
a. These data will be used to support evaluation of post-dose antibody detection 
b. Banked blood samples may be used for additional exploratory characterization of 
anti-drug antibody responses 
5. Chemistry panel including serum calcium, albumin, and creatinine 
6. Hematology panel 
7. Urine calcium and creatinine  
8. Bone turnover markers 
9. Only for female subjects of child-bearing potential: serum hCG 
For a cohort of approximately 24 subjects at selected sites, an additional assessment of Free PTH 
[PTH(1-34) and PTH(1-33)] will be performed centrally.  
11.12.1.3. Laboratory Visits 1-3 (LV1-LV3) Laboratory Assessments  
The following laboratory assessments will be performed locally at Laboratory Visits 1-3 to guide 
SOC dose adjustment between Visits 1 & 2 (see Section 9.5.2.2):  
1. Calcium and albumin (or ionized calcium) 
If, at selected sites where the Free PTH assessment will be performed at Visit 1, subjects return 
to the site’s own local laboratory for LV1-LV3, an additional assessment of Free PTH 
[PTH(1-34) and PTH(1-33)] will be performed centrally. 

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11.12.1.4. Visit 2 (V2) Laboratory Assessments  
The following laboratory assessments will be performed locally at Visit 2 to guide SOC dose 
adjustments while the subject is still in the clinic (see Section 9.5.2.2): 
1. Calcium and albumin (or ionized calcium) 
The following laboratory assessments will be performed centrally on blood and urine collected at 
Visit 2: 
1. 1,25(OH)2 vitamin D 
2. Total PTH (corresponding to TransCon PTH) and mPEG 
3. Antibodies against PTH and PEG 
a. Banked blood samples may be used for additional exploratory characterization of 
anti-drug antibody responses 
4. Chemistry panel including serum calcium, albumin, and creatinine  
5. Urine calcium and creatinine 
6. Bone turnover markers 
7. Only for female subjects of child-bearing potential: serum hCG 
For a cohort of approximately 24 subjects at selected sites, an additional assessment of Free PTH 
[PTH(1-34) and PTH(1-33)] will be performed centrally. 
11.12.1.5. Visit 3 (V3) Laboratory Assessments  
The following laboratory assessments will be performed locally at Visit 3 to guide TransCon 
PTH and/or SOC dose adjustment while the subject is still in the clinic (see Section 9.5.3): 
1. Calcium and albumin (or ionized calcium) 
The following laboratory assessments will be performed centrally on blood and urine collected at 
Visit 3: 
1. 25(OH) vitamin D 
2. 1,25(OH)2 vitamin D 
3. Total PTH (corresponding to TransCon PTH) and mPEG  
4. Antibodies against PTH and PEG 
a. Banked blood samples may be used for additional exploratory characterization of 
anti-drug antibody responses 
5. Chemistry panel including serum calcium, albumin, and creatinine  
6. Hematology panel 
7. Urine calcium and creatinine  
8. Bone turnover markers 
9. Only for female subjects of child-bearing potential: serum hCG 
For a cohort of approximately 24 subjects at selected sites, an additional assessment of Free PTH 
[PTH(1-34) and PTH(1-33)] will be performed centrally. 

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11.12.1.6. Laboratory Visits 4-6 (LV4-LV6) Laboratory Assessments  
The following laboratory assessments will be performed locally at Laboratory Visits 4-6 to guide 
SOC dose adjustments only for subjects taking active vitamin D at Visit 3 between Visits 3 & 
4 (see Section 9.5.3.2):  
1. Calcium and albumin (or ionized calcium) 
11.12.1.7. Visits 4-8 (V4-V8) Laboratory Assessments  
The following laboratory assessments will be performed locally at Visits 4-8 to guide SOC 
and/or TransCon PTH dose adjustments while the subject is still in the clinic (see Section 9.5.3):  
1. Calcium and albumin (or ionized calcium) 
2. Only for women of child-bearing potential: urine hCG (only at Visits 6 and 8) 
The following laboratory assessments will be performed centrally on blood and urine collected at 
Visits 4-8 (Visits 6 and 8 do not have central laboratory assessments): 
1. 25(OH) vitamin D (only at Visit 5) 
2. 1,25(OH)2 vitamin D (only at Visit 5) 
3. Total PTH, corresponding to TransCon PTH and mPEG (only at Visits 4, 5 and 7) 
4. Antibodies against PTH and PEG (only at Visits 4, 5 and 7) 
a. Banked blood samples may be used for additional exploratory characterization of 
anti-drug antibody responses 
5. Chemistry panel including serum calcium, albumin, and creatinine (only at Visit 5) 
6. Hematology panel (only at Visit 5) 
7. Urine calcium and creatinine (only at Visit 5) 
8. Bone turnover markers (only at Visits 5 and 7) 
9. For female subjects of child-bearing potential only: serum hCG (only at Visits 4, 5 and 7) 
For a cohort of approximately 24 subjects at selected sites, an additional assessment of Free PTH 
[PTH(1-34) and PTH(1-33)] will be performed centrally only at Visits 4, 5, and 7. 
11.12.1.8. Visit 9-21 (V9-V21) Laboratory Assessments  
The following laboratory assessments will be performed locally on urine collected at Visits 10, 
12, and 14:  
1. Only for women of child-bearing potential: urine hCG  
The following laboratory assessments will be performed centrally on blood and urine collected at 
Visits 9, 11, 13, 15, and 16-21-: 
1. 25(OH) Vitamin D  
2. 1,25(OH)2 vitamin D  
3. Total PTH (corresponding to TransCon PTH) and mPEG  

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4. Antibodies against PTH and PEG  
a. Banked blood samples may be used for additional exploratory characterization of 
anti-drug antibody responses 
5. Chemistry panel including serum calcium, albumin, and creatinine  
6. Hematology panel  
7. Urine calcium and creatinine (only at Visits 9, 11, 15, and 16-21) 
8. Bone turnover markers (only at Visits 11,15, 17, 19, and 21) 
9. Only for women of child-bearing potential: serum hCG  
Additionally, a 24-hour urine collection will be performed by the subject at home within a week 
of Visits 11, 15, 16-20, and within the week prior to Visit 21.  The laboratory assessments 
associated with the 24-hour urine collection will be performed centrally. 
For Selected Countries:  
A PD-PK sub-set study will be performed in approximately 8 subjects on any day from 
Week 58 (visit 15) and prior to 31 Aug 2021. The PD-PK sub-set study requires 24-hour 
admission in a research unit and frequent lab draws to assess the serum calcium and Free PTH. 
Please refer to Appendix 9 for further details. 
11.12.1.9. Laboratory Visits 7-12 (LV7-LV12) Laboratory Assessments  
The following laboratory assessments will be performed locally at all Laboratory Visits starting 
at Laboratory Visit 7:  
1. Calcium and albumin (or ionized calcium) 
2. Serum calcium (only if ionized calcium is collected) 
3. Serum phosphate 
4. Only for women of child-bearing potential: urine hCG 
11.13. LIFESTYLE MODIFICATION 
11.13.1. 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. 
11.13.2. Exercise Modifications 
Subjects should be advised to avoid exercise prior to visits which include blood collection. 

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11.13.3. Contraception 
Male and female fertility and embryofetal developmental studies have been conducted in rats.  
TransCon PTH did not induce adverse effects on fertility or on embryofetal development in 
pregnant rats when administered through gestation day 17.  The highest dose tested had an 
approximate 20-fold exposure margin to the Phase 1 SAD dose of 20 µg PTH(1-34)/day.  
Irrespectively, 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 7 for further guidance on highly effective contraception. 
See Appendix 5 for further details on pregnancy testing schedule.  
11.13.4. Study Drug Administration 
11.13.4.1. 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 light-headedness.  Subjects will inject subsequent doses of 
study drug daily at home. 
During the first two weeks of the Blinded Treatment Period, dosing remains in the morning. 
Subjects should continue to be careful of orthostatic changes/light-headedness.   
Starting at Visit 2, study drug dosing changes to evening dosing (ideally qHS in bed), with the 
last morning dose taken the day BEFORE Visit 2. 
11.13.4.2. Extension Period Administration 
For subjects on active vitamin D at Visit 3, 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 
light-headedness.  During the first two weeks of the Extension Period, dosing for these subjects 
remains in the morning.  Starting at Visit 4, dosing changes to evening dosing (ideally qHS in 
bed), with the last morning dose taken the day before Visit 4. 
For subjects not on active vitamin D at Visit 3, the first dose of open-label TransCon PTH is 
administered at home in the evening (ideally qHS in bed) following the clinic visit, with all 
subsequent administrations also in the evening. 
11.13.5. 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 develops any time in-between study visits, subjects should 
contact the site and visit the local laboratory (ie, ULV) to assess albumin-adjusted or ionized 
sCa.  

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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 rescue 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 serum calcium and albumin, or 
ionized calcium, levels for symptoms of hypercalcemia.  
11.13.6. Daily Diary 
Subjects will be required to complete a daily diary to capture the following:  
• HP-related supplements (name, dose, and administration date and time), including rescue 
doses 
• Study drug, starting at Visit 1 (dose, administration date and time) 
• Changes to health and concomitant medications  
See Section 11.9 for details regarding training and site review of the daily diary. 
12. ADVERSE EVENT ASSESSMENT AND REPORTING 
12.1. DEFINITION 
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: 
• 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.  
• 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 AE should be classified as an SAE if any of the following criteria are met: 
• It results in death (i.e., the AE cause or leads to death).  
• It is life threatening (i.e., the AE, in the view of the investigator, places the 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).  

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• 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, 
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 9.6.2) 
• Persistent severe hypercalcemia (as defined in Section 9.6.2) 
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 

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• 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.  
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. 
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). 

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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 Brochure 
(IB) 
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 IB.  
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: 
• 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. 

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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 
• 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. 

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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). 
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)  
• 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. 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the Adverse Event eCRF. 
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. 

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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 hypercalcemia rather than abdominal pain, nausea, polyuria, and 
high serum calcium). 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 Related Reaction  
Each sign or symptoms will be recorded as a separate AE on the AE eCRF. 
Local reaction at the site of injection administration should be captured as unified diagnosis 
rather than as individual signs and symptoms on the Adverse Event eCRF (e.g.  adverse event 
reporting as an injection site reaction rather than capturing injection site bleeding or injection site 
induration as separate adverse events ). 
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  

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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, 
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 
follow the guidance in the Pharmacy Manual for reporting product complaints and forward the 
information to the Sponsor immediately.  If the medical device results in an adverse event to the 
study patient, the event must be reported on the Adverse Event eCRF and submitted through the 
EDC system.  If the event is serious, the Adverse Event 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. SERIOUS ADVERSE EVENTS (SAE) AND SUSPECTED UNEXPECTED 
SERIOUS ADVERSE REACTIONS (SUSAR) 
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. 

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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 to: 
 
OR 
 
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: 
• 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 or Reference Safety Information. 

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• 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. STATISTICS 
14.1. 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. 
Data from clinical assessments will be summarized using descriptive statistics.  Numerical 
variables will be summarized by mean, median, standard deviation, standard error, minimum, 
and maximum while categorical variables will be summarized by counts and proportions.  In 
general subjects on placebo for TransCon PTH at different doses will be pooled as a control 
group to compare with each of the active dose groups. 
14.2. ENDPOINTS 
14.2.1. Efficacy Endpoints 
14.2.1.1. Primary Efficacy Endpoint 
At 4 weeks of treatment, the proportion of subjects with: 
• Albumin-adjusted or ionized sCa within the normal range, and 
• Spot AM FECa within normal range (≤2%) or a reduction by at least 50% from baseline, and 
• Not taking active vitamin D supplements, and 
• Taking ≤1000 mg/day of calcium supplements 
14.2.1.2. Secondary Efficacy Endpoints 
14.2.1.2.1. Key Secondary Efficacy Endpoint 
At 4 weeks of treatment, the proportion of subjects with: 
• Albumin-adjusted or ionized sCa within the normal range and  
• FECa within the normal range or a reduction by at least 50% from baseline and 
• Not taking active vitamin D supplements and  
• Taking ≤500 mg/day of calcium supplements 

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14.2.1.2.2. Other Secondary Efficacy Endpoints 
Primary and key secondary efficacy endpoints measured at predefined timepoints over the 
Extension Period. For the analysis of these endpoints in the Extension Period, the 24-hour urine 
calcium excretion will be used. 
At 4 weeks of treatment and at predefined timepoints over the Extension Period: 
• Calcium and vitamin D doses 
• Number of SOC supplements (pill burden) 
• Spot AM FECa 
• Serum phosphate 
• Serum magnesium 
• sCa x sP product, including proportion of subjects with sCa x sP product ≤55 mg2/dL2, 
≤52 mg2/dL2, and ≤44 mg2/dL2  
• Albumin-adjusted or ionized sCa 
At predefined timepoints over the Extension Period: 
• 24-hour urine calcium excretion 
14.2.2. Safety & Tolerability Endpoints 
The following safety endpoints will be assessed for both Blinded Treatment and Extension 
Periods: 
• Serum chemistry, hematology, and spot urine parameters 
• Incidence of AEs, AESI, and serious adverse events (SAEs) 
• Clinical events of hypo- or hypercalcemia (emergency/urgent care visits and hospitalizations) 
and progression of vascular calcifications, nephrocalcinosis, and nephrolithiasis  
• Injection site tolerability (based on Local Tolerability Scale and AEs) 
• Evaluation of anti-PTH and anti-PEG antibody response  
• Physical examinations, including vital signs 
14.2.3. Exploratory Endpoints 
At 4 weeks of treatment, assessment of the following: 
• Clinical Outcome Assessments (COAs)   
• Bone turnover markers (serum P1NP and CTx) 
• Device usability questionnaire 

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Throughout the Extension Period, assessment of the following: 
• BMD and TBS by DXA at 26, 58, 110, 162, and 214 weeks 
• 24-hour urine calcium excretion at 26,58, 84, 110, 136, 162, 188, and 214 weeks 
• COAs at 6, 8, 12, and 26, 58, 110, 162, and 214 weeks  
• Bone turnover markers (serum P1NP and CTx) at 8, 12, 26, 58, 110, 162, and 214 weeks  
• Albumin-adjusted sCa, magnesium, phosphate, and sCA x sP product at 8, 18, 26, 42, 58, 84, 
110, 136, 162, 188, and 214 weeks 
14.3. STATISTICAL ANALYSIS 
14.3.1. Baseline Characteristics and Analysis Population 
Safety data will be analyzed on all randomized subjects who receive at least one dose of study 
drug.  Efficacy data will be analyzed on all randomized subjects who receive at least one dose of 
study drug and have any follow-up data that comprises the primary endpoint 
Baseline and demographic data will be summarized to characterize the trial population. 
Subgroups of interest, such as prior exposure to PTH and age categories will be determined and 
corresponding subgroup analyses for safety and efficacy will be performed as appropriate. 
14.3.2. Efficacy Analysis 
Pairwise comparison between each of the active TransCon PTH dose groups and the pooled 
placebo group will be conducted for the primary endpoint and key secondary endpoints using the 
Fisher’s exact test based on all intent-to-treat (ITT) subjects.  A significant treatment effect is 
defined as adjusted P <0.05 (2-sided).   
14.3.3. Pharmacokinetic Analysis 
All subjects who will receive the study drug and for whom the primary PK data are considered 
sufficient and interpretable will be analyzed in the PK analysis.  The primary PK analysis of 
interest is the Free PTH [PTH(1-34) and PTH(1-33)], which represents the unmodified PTH 
released from the prodrug and which showed the strongest correlation with PD in the 
Phase 1 study.  Free PTH will be assessed in a cohort of approximately 24 subjects only due the 
burden on sites to acidify and freeze the sample quickly to stop the release of Free PTH by the 
TransCon pro-drug in the sample.  The PK parameters and their statistical evaluation will be 
included in the Clinical Study Report or as an appendix.  Based on the well-understood PK/PD 
relationship of PTH in general, and PTH(1-34) in particular, and data showing that continuous 
SC infusion of PTH(1-34) provides optimal treatment of both adults and children with HP, the 
PK data will primarily be used to describe the time to steady-state and the presence or lack of 
accumulation once steady-state is achieved.  Potential impact of any anti-PTH and anti-PEG 
antibodies detected will be included in the evaluation. 

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14.3.4. Safety Analysis 
The reporting of the safety data is descriptive and will include all subjects receiving at least one 
dose of study drug.  Descriptive analysis will include the incidence and type of adverse events, 
and changes in laboratory and vital signs parameters and treatment-emergent anti-PTH and 
anti-PEG antibodies from pre-dosing to listed post-dose time points.  Listings of abnormal 
laboratory data by treatment group will be presented.  Incidence of abnormal vital signs over 
time will be summarized by treatment/dose group.  All AEs will be coded using Medical 
Dictionary for Regulatory Authorities (MedDRA) and tabulated by system, organ, and class.  
Individual events within each system will be presented in descending frequency.  AEs will also 
be tabulated by severity and relationship to the trial drug and will be presented by dosage.  SAEs 
will be summarized separately.  
14.3.5. 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 prior to database lock of the Blinded Treatment Period is planned.  
14.4. POWER CALCULATION 
Based on clinical experience, the proportion of subjects on standard care meeting the primary 
endpoint will be rare and close to 0.  According to the simulation data from the FDA, 66% of 
subjects with continuous infusion of PTH will have normal sCa.  The phase 1 study data predict 
that a large proportion of HP subjects (∼ 90%) on TransCon PTH will have a normal FECa.  
Assuming that TransCon PTH has the same profile as PTH by continuous infusion, the 
proportion of subjects able to discontinue active vitamin D and require less than 1000 mg/day of 
supplemental calcium is estimated to be at least 70%.  This translates to an estimate of the 
proportion of TransCon PTH-treated subjects meeting the primary endpoint at more than 40%.  
With 10 subjects per arm, the statistical power to detect a significant treatment difference is 
calculated in Table 3. 
Table 3: 
Power Calculation for 10 Subjects Per Arm with Alpha Level at 0.05 and 
0.10 (two-sided) 
Proportion for TransCon 
PTH 
Proportion for Placebo 
Power 
α=0.05 (2-sided) 
α=0.10 (2-sided) 
40% 
1% 
40.7% 
53.2% 
50% 
1% 
58.8% 
70.4% 
60% 
1% 
74.8% 
83.8% 
80% 
1% 
94.7% 
97.3% 
14.5. SIGNIFICANCE 
Statistical significance is defined as P <0.05 (2-sided). 

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14.6. ACCOUNTABILITY 
Subjects with missing data, including missed assessments and early discontinuation will be 
summarized. 
14.7. DEVIATION REPORTING 
Major protocol deviations will be summarized. 
14.8. UNBLINDING PROCEDURES 
The Investigator and site personnel will remain blinded to the randomization code during the 
study.  Treatment assignment for an individual subject should be unblinded by the Investigator 
only in an emergency (eg, 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/Medical Expert 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 IWRS.  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 IWRS, which will be available 
24 hours a day, 7 days a week. 
15. TRIAL CONDUCT 
15.1. SITE INITIATION 
Prior to participation, investigational sites and investigators will be evaluated for appropriate 
qualifications and ability to execute the trial.  Each investigational site must undergo appropriate 
training on the trial protocol and ancillary trial procedures and documents through participation 
in a Site Initiation Visit (SIV) or Investigator Meeting (IM).  Protocol and GCP training must 
take place before any 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. 
15.2. DATA HANDLING AND RECORD KEEPING 
15.2.1. Collection of Data 
Data will be collected in the eCRF.  The eCRF is an integral part of the trial and subsequent 
reports. It must be used to capture trial-specific data collected and must be kept current to reflect 
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 identifier(s). 

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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 documents, including query resolution 
correspondence.  The system is designed so that changes to any record do not obscure the 
original information.  The audit record clearly indicates that a change was made and clearly 
provides a means to locate and read the prior information.  All changes to the data have an 
electronic audit trail, in accordance with 21 CFR 11.10(e).  Electronic signatures will be used in 
conformance with 21 CFR Part 11. 
15.2.2. Coding Dictionaries 
Prior and concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Coexistent diseases and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).   
15.2.3. Data Handling 
eCRFs should be completed in a timely manner to enable the sponsor or designee to perform 
central monitoring of safety data.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system.  Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock, the investigator will use 
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 (eg, 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 15.2.1. 
15.2.4. Direct Access to Source Data/Documents 
The investigator/trial site is to provide direct access to source data/documents for trial-related 
monitoring, audits, IRB/ERC review, and regulatory inspection. 

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15.2.5. Record Keeping 
The investigator is responsible for maintaining adequate records to fully document the conduct 
of the trial consistent with that noted in ICH E6 (R2), including but not limited to the following: 
• All versions of the Investigator’s Brochure 
• Signed Protocol and Amendments in effect during the conduct of the trial 
• Signed ICFs 
• Source documents, including adequate case histories, questionnaires, and subject diaries 
• Signed, dated, and completed eCRFs and documentation of data corrections 
• Notification of SAEs and related reports 
• Dated and documented IRB/ERC approvals and approval by regulatory authorities, as 
required 
• Normal laboratory values  
• Laboratory certifications 
• Curricula Vitae of all clinical investigators 
• Completed Forms FDA 1572, as applicable 
• SIV documentation 
• Delegation of Authority Log 
• Subject Screening & Enrollment Log(s) 
• Subject Identification Code List 
• Study drug accountability documentation 
• Signed agreements between involved parties 
• Relevant communication, including that related to monitor site visits (eg, letters, meeting 
notes, notes from telephone calls) 
• Interim, annual, or final reports to IRBs/ERCs and regulatory authorities, as required 
• Audit certificate(s), if applicable 
15.3. DATA QUALITY CONTROL 
15.3.1. Monitoring Procedures 
The Sponsor and/or its representative may make periodic visits to the investigational site to 
assess compliance with trial procedures and regulatory requirements; to ensure that the safety, 
welfare, and privacy of 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. 

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The Sponsor and/or its representative will periodically review the trial data to ensure that data 
are being appropriately collected and reported.  Queries and corrections will be made as needed. 
15.3.2. Data Management 
Sponsor or designee will be responsible for activities associated with the data management of 
this trial.  The standard procedures for handling and processing records will be followed per GCP 
and CRO’s standard operating procedures (SOPs).  A comprehensive data management plan will 
be developed including a data management overview, database development, validation and 
maintenance, data entry and processing, external data transfer, data validation and archive, and 
medical coding processes.  Trial site personnel will be responsible for providing resolutions to all 
data queries.  The investigator will be required to document electronic data review to ensure the 
accuracy of the corrected and/or clarified data.   
15.4. 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 
as strictly confidential to the extent that applicable law permits and to which it is not publicly 
available.  The purpose of audits and inspections is to evaluate compliance with the principles of 
GCP, international and local regulatory requirements, and the trial protocol.  The audit or 
inspection may include, for example, a review of all source documents, drug records, original 
clinic medical notes, and some or all of the facilities used in the trial. 
The audits may be conducted by the Sponsor or Sponsor’s selected agent in accordance with 
Sponsor’s SOP or SOPs of the selected and properly authorized agent.  A competent authority 
may also wish to conduct an inspection during the trial or after its completion.  If an inspection is 
requested by a competent authority, the investigator must inform the Sponsor immediately that 
this request has been made.  The investigator and his/her institution will permit all monitoring, 
audits, and regulatory inspections, providing direct access to source data. 
15.5. LABORATORY QUALITY STANDARDS 
Laboratory tests or evaluations 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 must provide a list of reference ranges for applicable analyses.  The methods 
employed for each assay should be available on request.  Any change in the laboratory 
procedures, reference values, etc., during the trial must promptly be communicated to the 
Sponsor.  The laboratories may also be audited by the Sponsor or by competent authorities. 
15.6. TRIAL TERMINATION OR COMPLETION 
The investigator should notify the IRB/ERC in writing of the completion or early termination of 
the trial.  End of trial is defined as last subject last visit. 

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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. 
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 electronic case report form (eCRF) 
• Inadequate cooperation with the investigator 
• Non-compliance with GCP and/or regulatory requirements 
• The investigator requests discontinuation 
15.7. CHANGES TO THE PROTOCOL 
Changes in any portion of this protocol must be documented in the form of an amendment from 
the Sponsor and must be approved by the investigational site’s IRB/ERC 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 to eliminate the 
hazard.  In this case, the deviation and the reason for it must be promptly reported as required by 
regional regulations to the applicable IRB/ERC 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/ERC, as required.  The investigator must send a copy of the 
documented approval to the Sponsor and/or its representative. 
15.8. OTHER CHANGES IN TRIAL CONDUCT 
Changes in trial conduct are not permitted.  Any unforeseen changes in trial conduct will be 
recorded in the clinical study report. 
15.9. USE OF INFORMATION AND PUBLICATION 
The data and information generated in this trial are the exclusive property of the Sponsor and are 
confidential.  Written approval from the Sponsor is required prior to disclosing any information 
related to this trial.  Publication of the results will be based on appropriate analyses and review of 
the complete data.  Authorship will be determined based on 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. 
16. 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 
• Declaration of Helsinki 

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• Regional required subject data protection laws and regulations 
• Applicable regional regulations 
• US Federal Regulations, as applicable 
16.1. DATA MONITORING SAFETY BOARD/INDEPENDENT SAFETY 
COMMITTEE 
Independent oversight of this trial may be provided by a DSMB/ISC, if deemed appropriate 
despite the relatively short duration of the pivotal trial.   
16.2. INFORMED CONSENT 
The draft ICF must be reviewed by the Sponsor and/or its representative prior to submission to a 
regional IRB/ERC 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. 
16.3. IRB/ERC APPROVALS 
The Principal Investigator at each site is responsible for obtaining approval from the appropriate 
regional IRB/ERC 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 IRB/ERC 
must comply with all applicable US FDA regulations, as applicable. 
The Principal Investigator is also responsible for the following interactions with the regional 
IRB/ERC: 
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 continuing review and approval of the trial as needed and providing copies of all 
review board re-approvals and relevant communication to the Sponsor and/or its 
representative 
4. Notifying the review board of all serious and unexpected AEs related to the study drug 
reported by the Sponsor and/or its representative, as required 
5. Notifying the review board of the end of trial participation, in accordance with regional 
guidelines and regulations 

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17. REFERENCES 
Abate EG, Clarke BL. Review of hypoparathyroidism. Front Endocrinol (Lausanne). 
2017;7:172. 
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. 2014. 
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. 
http://www.iofbonehealth.org/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. Clinical 
Pharmacology & Ther. 2018. 
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. 
Rambausek M, Ritz E, Rascher W, et al. Vascular effects of parathyroid hormone (PTH). Adv 
Exp Med Biol. 1982;151:619-632. 

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Rubin MR, Cusano NE, Fan WW, et al. Therapy of hypoparathyroidism with PTH(1-84): a 
prospective six year investigation of efficacy and safety. J Clin Endocrinol Metab. 
2016;101(7):2742-2750. 
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. 
Wu KM, Farrelly JG. Regulatory perspectives of Type II prodrug development and time-
dependent toxicity management: nonclinical Pharm/Tox analysis and the role of comparative 
toxicology. Toxicology. 2007;236(1-2):1-6. 

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

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SIGNATURE OF AGREEMENT 
I have read and understand the information in this clinical trial protocol, including the potential 
risks and side effects of the study drug, and agree to personally conduct or supervise the 
described investigation(s) in accordance with the relevant, current protocol(s) and will not 
deviate from the protocol, except when necessary to protect the safety, rights, or welfare of 
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/ERC approval, except where 
necessary to eliminate apparent immediate hazards to human subjects. 
3. I agree to maintain all information in this document and regarding the stud(ies) as 
confidential and to use it only for the purpose of conducting the stud(ies).  I agree not to 
forward this document to any other party without the prior written authorization of the 
Sponsor. 
Investigator: 
 
Printed Name and Title: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
 

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