Clinical trial NCT05239221
Conditions: Chronic Hypoparathyroidism
Sponsor: Amolyt Pharma
Start date: 2020-09-07; Completion date: 2022-08-23
Enrollment: 132 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is investigating the safety, tolerability, pharmacodynamics and pharmacokinetics of AZP-3601 following single and repeated administration in both healthy volunteers and patients with chronic hypoparathyroidism (cHP)

The protocol includes 3 parts:

* Part A: first-in-human single ascending dose (SAD) study in healthy volunteers
* Part B: multiple ascending dose (MAD) study with 2 weeks of treatment in healthy volunteers
* Part C: open-label MAD study with a total treatment duration of 3 months in patients with cHP.

Detailed description:

Arms: arm 1: subcutaneous (sc) administration once daily arm 2: subcutaneous (sc) administration once daily
Interventions: intervention 1: AZP-3601 intervention 2: Placebo
Intervention descriptions: intervention 1: Lyophilized powder of AZP-3601 to be reconstituted with water for injection before injection intervention 2: Saline solution visually matching active medication

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
VERSION 7.0_FR,  08 APR 2022 
(France) 
A SINGLE AND MULTIPLE ASCENDING DOSE STUDY TO INVESTIGATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF 
AZP-3601, A SYNTHETIC PARATHYROID HORMONE ANALOG, IN HEALTHY 
SUBJECTS AND IN SUBJECTS WITH HYPOPARATHYROIDISM  
Sponsor code: AZP-3601-CLI-001 
PRA code: AZP20005-20005X 
EudraCT number: 2020-003295-41 
AZP-3601 SAD and MAD study 
Investigational product: 
AZP-3601 
Clinical phase: 
Phase 1 
Indication to be studied: 
Hypoparathyroidism 
Sponsor: 
Amolyt Pharma 
15, chemin du Saquin 
Espace Européen, Building G 
69130 Écully 
France 
Contract Research 
PRA Health Sciences (PRA) – Early Development Services (EDS) 
Organization: 
Van Swietenlaan 6 
9728 NZ Groningen 
The Netherlands 
 
 
 
 
 
 
 
 
Clinical Sites (Subjects with 
Approximately 10 to 12 clinical sites in Europe
hypoparathyroidism - Part C): 
This study will be performed in compliance with the principles of Good Clinical Practice. 
CONFIDENTIALITY STATEMENT 
All the information included in this CLINICAL STUDY PROTOCOL (collectively, the “Confidential 
Information”) is property of Amolyt Pharma. In consideration of the above disclosures, any recipient of this 
Confidential Information agrees not to disclose the Confidential Information to any third party (unless with 
the written approval of Amolyt Pharma) and to use Confidential Information only for the execution and 
organization of the trial. This confidential and non-use obligation shall be respected by any recipient for 
the duration of the trial and five (5) years thereafter.  
The recipient may disclose the Confidential Information, on a need to know basis, only to its officers, 
directors, employees, or counsels who are involved in the trial, and who are bound by confidentiality and 
non-use provisions no less restrictive than those of this statement. 


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SYNOPSIS 
Study Title 
A SINGLE AND MULTIPLE ASCENDING DOSE STUDY TO INVESTIGATE THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF AZP-3601, A SYNTHETIC 
PARATHYROID HORMONE ANALOG, IN HEALTHY SUBJECTS AND IN SUBJECTS WITH 
HYPOPARATHYROIDISM 
Short Study Title 
AZP-3601 SAD and MAD study 
Study Codes 
Sponsor code 
: AZP-3601-CLI-001 
PRA code 
: AZP20005-20005X 
EudraCT number 
: 2020-003295-41 
Clinical Phase 
Phase 1 
Indication to be Studied 
Hypoparathyroidism (HP)  
Sponsor 
Amolyt Pharma 
Contract Research Organization 
PRA-EDS 
 
Clinical Sites for Part C in Patients with HP 
Approximately 10 to 12 clinical sites in Europe 
Objectives 
Primary 
•
•
To assess the safety and tolerability of AZP-3601 following single and 4-week multiple ascending doses
administered by sc injection to patients with HP (Part C, Main Treatment Period)
•
To assess the safety and tolerability of AZP-3601 during a 2-month treatment extension period (Part C,
Extension Phase) in patients with HP
Secondary 
•
•
To assess the PD response of AZP-3601 on maintenance of serum calcium and phosphate levels within
a target range while oral calcium and active vitamin D are progressively reduced, following multiple
ascending doses administered by sc injection to patients with HP (Part C, Main Treatment Period)


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•
To assess the PK of AZP-3601 following single and multiple ascending doses administered by sc
injection to patients with HP (Part C)
•
To assess the feasibility of individual titration of AZP3601 during a 2-month treatment extension period
(Part C, Extension Phase) in patients with HP (ie if individual dosing across a dose range can be
implemented in a safe and effective manner and can be maintained throughout the treatment period)
Exploratory 
•
•
To assess the effect of AZP-3601 on urinary excretion of calcium and phosphate as well as on bone
turnover biomarkers following multiple ascending doses administered by sc injection to patients with HP
(Part C, Main Treatment period)
•
To assess the effect of AZP-3601 on urinary excretion of calcium and phosphate as well as on bone
biomarker and Bone Mineral Density (BMD) as assessed by Dual-Energy X-Ray absorptiometry (DXA)
during a 2-month treatment extension period (Part C, Extension Phase)
Design and Treatments 
This is a first-in-human (FIH) study in healthy subjects followed by a study in patients with HP combined in a 
single protocol. 
 
  
Part B will be followed by a MAD part in patients with HP who will receive AZP3601 for 4 weeks (Part C, Main 
Treatment period).  
Patient completing the 4 weeks Main Treatment Period of Part C, will be offered to enter a 2-month open label 
treatment extension phase. Together with the initial 4-weeks treatment period, this extension phase will allow 
the collection of safety and PD data over a total of 3 months of treatment. 
In all study parts, safety, tolerability, PK (Part 
 C), and PD of sc doses of AZP­3601 will be assessed. 
The overall study schematic is presented in the figure below: 
 
 
 
  
 
 
 
 
 
  


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. 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 


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Part C (MAD part in patients with HP) 
Part C will be an open-label MAD study in male or female subjects with HP who are on treatment with oral 
calcium and active vitamin D to evaluate the safety and tolerability, PK , and PD of AZP-3601. Up to 2 
cohorts of approximately 12 patients each are planned for this part of the study. 
Part C, Main Treatment Period 
The overall study schematic for the Main Treatment Period of Part C, is presented hereafter (for more details, 
please refer to the Schedule of Assessments – Part C in Table 3): 
Prior to the treatment period, there will be an optimization period of up to 8 weeks during which doses of oral 
calcium and active vitamin D will be adjusted to achieve a baseline target range of albumin-corrected serum 
calcium (7.8 to 9.0 mg/dL, ie, 1.95 to 2.25 mmol/L) and therefore ensuring a close baseline for all patients.  
During this optimization period, any serum 25­hydroxy vitamin D (native vitamin D) and/or magnesium 
deficiencies will be corrected. 
During the treatment period, patients in Part C will receive AZP-3601 for 28 days as daily sc abdominal 
injections (with rotation of injection sites every dosing day).  


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Doses of oral calcium and active vitamin D supplements will be carefully reduced during the initial 14 days 
of treatment while maintaining albumin-corrected serum calcium in the target range (7.8 to 9.0 mg/dL, ie, 
1.95 to 2.25 mmol/L). Reductions of both oral calcium and active vitamin D supplements will be performed 
using a staged approach until the active vitamin D dose can be eliminated and the oral calcium dose can be 
reduced to or below 500 mg/day (please note that throughout this protocol doses of oral calcium refer to 
doses of elemental calcium). Based on animal data, serum calcium is expected to increase progressively 
following repeated administration of AZP-3601 and PD steady state is expected to be observed within the 
first 5 days of dosing. Staggered reductions of doses of oral calcium and active vitamin D supplements will 
therefore be performed at near-steady state based on the predose albumin-corrected serum calcium value. 
It is anticipated to perform reduction of supplements on Day 5, 8, and 11 (Cohort C1). The days of dose 
reduction of supplements for Cohort C2 have been changed to Days 3, 5 and 8 based on data from Part B 
and from Part C Cohort C1.  
If independence from active vitamin D and reduction of oral calcium is not achieved on Day 14 (ie, elimination 
of active vitamine D and reduction of oral calcium to or below 500 mg/day), the AZP-3601 dose will be 
increased and patients will be treated at this dose for the remaining duration of the treatment period (up to 
Day 28). In addition, staggered reductions of doses of oral calcium and active vitamin D supplements will 
therefore be performed and/or continued during the second 14 days of the Main Treatment Period according 
to the same principles as the first 14 days of the Main Treatment Period. 
Patients achieving independence from active vitamin D and reduction of oral calcium on Day 14 will remain 
at the same dose level. The last remaining daily dose of oral calcium, if any, may be removed on Day 17 
based on the predose albumin-corrected value of serum calcium.  
Patients will undergo frequent testing for albumin-corrected serum calcium and phosphate during the initial 
14-day treatment period and again following increase of the dose. In addition, there may be additional and
unscheduled checks for albumin-corrected serum calcium and phosphate at the discretion of the
Investigator.
At any time during the study, hypercalcemia and hypocalcemia will be managed by adjustment in active 
vitamin D and/or oral calcium supplementation. Adjustments will be based on laboratory values including 
albumin-corrected serum calcium and serum phosphate as well as on symptoms and will be performed at 
the Investigator’s judgment. As a general guidance, adjustments should be performed when calcium values 
are outside the target range of 7.8 to 9.0 mg/dL, ie, 1.95 to 2.25 mmol/L.  
The following treatments are administered in Part C in an open-label fashion: 
Cohort C1: 
multiple sc doses of 20 µg AZP-3601 (n=12) qd from Day 1 to Day 28 (dose increase of AZP-
3601 to 40 µg was allowed from Day 14 onwards) 
Cohort C2b: multiple sc doses of a fixed dose of 10a µg AZP-3601 (n=12) qd from Day 1 to Day 28 (dose 
of AZP-3601 may be increased at a fixed dose of 20a µg from Day 14 onwards) 
During the extension phase, patients may have their AZP-3601 dose increased in increments of 10a µg to a 
maximum dose of 60a µg (Cohort 1) and of 80a µg (Cohort 2) 
a The planned dose levels (including the dose levels allowed to increase the dose in the same cohort) may 
be changed following review of data from Parts A and B, and the emerging data from Part C. However, 
for each of the cohorts the doses will not exceed the doses previously tested in Part A and Part B. In 
addition, the increase from one dose level to the next dose level within the same cohort or between 
cohorts will not be more than 3­fold. 
b Doses have now been selected as per protocol based on data from all patients of Cohort C1 who have 
completed the Main Treatment Period (n=12). 


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Part C may commence after the first 3 cohorts of Part B have been completed, providing there is sufficient 
appropriate data available (safety and tolerability, PK, and PD) to enable determination of dose levels.  
The following table provides an overview of the doses (µg) planned to be adminstered in Part C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 
C 
Cohort 
C1b 
20 (dose 1) 
40 (dose 2) 
C2b 
fixed dose of 10 (dose 1) 
fixed dose of 20 (dose 2) 
 
 
b Part C may commence after completion of the first 3 cohorts of Part B. 
The follow­up visit will take place on Day 37 (±2 days) only for patients not entering the extension period. 
The Sponsor is prolonging the treatment period of each of the Part C cohorts (patients with HP) with an open 
label extension of 2 months. Eligible patients will therefore remain treated with AZP-3601 and will not perform 
the follow-up visit. This extension period will allow collection of efficacy and safety data over a longer-term 
period (3 months) and treatment protocol  is adressed in the current protocol amendment.  
Before proceeding to the second cohort, the SRC will review the data of the first cohort. Review will be 
performed on safety and tolerability data, available PD data (with at least serum and urinary calcium, serum 
phosphate, and number of patients achieving reduction/elimination in calcium and active vitamin D 
supplements), and available PK data. In addition, the safety data of each of the cohorts will be reviewed on 
a regular basis during the treatment period.  
Although this is an ascending dose study, a lower dose may be administered in the second cohort based on 
the safety, tolerability, or available PD and plasma PK results of the first cohort. Also, the same dose may 
be tested or an intermediate dose may be tested to gain more information on safety, tolerability, PD, and/or 
PK.  
There will be an interval of at least 7 days between the last dose in the first cohort and the first dose in the 
second cohort. Subjects included in the first cohort cannot participate in the second cohort. 
Part C, Extension Phase 
Patients completing the 4 weeks Main Treatment Period of Part C, will be offered to enter a 2-months open 
label treatment extension phase. For patients willing to enter the extension phase, an ICF should be signed 
on Day 28 at the latest. 
Patients will have to complete study assessments up to Day 28, as described in Table 3 and from Day 29 
onwards, as described in Table 4. 
Patients who will not participate to the Extension phase will have to complete study assessments as 
described in Table 3. 
The overall study schematic for the Extension Phase of Part C, is presented hereafter (for more details, 
please refer to the Schedule of Assessments – Part C, Extension Phase in Table 4 


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The 2 month open label treatment extension phase will start immediately following Day 28 visit of the Main 
treatment period. Patients will receive AZP-3601 for 56 days (2 months) as daily sc injections from Day 29 
onwards (with rotation of injection sites each day of administration). 
The goal is to optimize AZP-3601 dosing across a dose range while doses of oral calcium and active vitamin 
D are as low as safely possible and albumin-corrected serum calcium is maintained within the target range of 
7.8 to 9.0 mg/dL (1.95 to 2.25 mmol/L) together with an optimal control of the symptoms of hypoparathyroidism. 
For patients who are taking minimal or no supplemental calcium (≤500 mg/day) and no vitamin D on Day 28, 
the AZP-3601 dose from the previous 14 days of treatment (Part C, Main Treatment Period) can be maintained 
and adjusted when needed during the Extension Phase.  
For patients who are still taking active vitamin D and/or more than 500 mg/day of oral calcium on Day 28, a 
progressive reduction of supplements will be carried out while increasing the dose of AZP-3601. 
On Day 29 onwards, patients will continue on the same dose of AZP-3601 as on Day 28, then individual 
titration of AZP-3601 may start as early as Day 30 and patients may have their dose of AZP-3601 adjusted at 
any time during the Extension Phase.  
Patients may have their AZP-3601 dose increased, as previously defined, with the goal of achieving or 
maintaining albumin-corrected serum calcium in the target range of 7.8 to 9.0 mg/dL (1.95 to 2.25 mmol/L). 
The AZP-3601 dose may be adjusted downward at anytime as needed to maintain albumin-corrected serum 
calcium within the target range or for any safety concerns. 
Once patients achieve  a stable albumin-corrected serum calcium with the minimum doses of supplements, 
they will be maintained at that dose of  AZP-3601. 
Patients will have their serum calcium/Albumin levels measured within 5 days after any adjustment of AZP-
3601 and any other time at the discretion of the investigator. The investigator will be free to perform any other 
serum or urine test if needed. 
In addition, there may be additional and unscheduled checks for serum calcium and phosphate at the 
discretion of the investigator. 


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At any time during the study, hypercalcemia and hypocalcemia will be managed by adjustment in active 
vitamin D and/or oral calcium supplementation. Adjustments will be based on laboratory values including 
albumin-corrected serum calcium and serum phosphate as well as on symptoms and will be performed at 
the Investigator’s judgment. As a general guidance, adjustments should be performed when calcium values 
are outside the target range of 7.8 to 9.0 mg/dL, ie, 1.95 to 2.25 mmol/L.  
A separate titration guideline to help the investigator and to facilitate a standardized approach to dose 
adjustment, will be provided to the clinical site (refer to Appendix 8.3). 
Study Schedule* 
 
 
Screening/Optimization 
: Part C: between Day -56 (±2 days) and Day -1. During the optimization period, 
doses of oral calcium and active vitamin D will be adjusted to ensure a close 
albumin-corrected serum calcium baseline for all subjects. In addition, any 
serum 25­hydroxy vitamin D (native vitamin D) and/or magnesium deficiencies 
will also be corrected during this optimization period. 
On Day -1, at the end of the optimization period, subjects will visit the clinical 
site and will be evaluated for selected baseline measurements. 
Treatment period 
 
 
 
 
 
 
Part C:  
Main Treatment Period 
On Day 1, the subjects will complete the baseline measurements and receive 
the first dose of AZP­3601 at the clinical site. Subjects will leave the clinical site 
following completion of all study assessments.  
  Subjects will return to the clinical site for additional visits on Day 14, Day 15, 
Day 16, Day 28/Early Termination (ET), and Day 29.  
Serum calcium and phosphate blood samples will also be taken on Day 3 (±1 
day), Day 5 (±1 day), Day 8 (±1 day), Day 11 (±1 day), Day 21 (±1 day), and 
Day 30. In addition, there may be additional and unscheduled checks for serum 
calcium and phosphate at the discretion of the Investigator. After the last study 
drug administration, if subjects are not entering the extension period, they will 
be instructed to resume their prestudy calcium and active vitamin D treatment 
regimen and doses based on assessments performed on Day 28/ET to Day 30. 
Extension Phase  
Extension phase will start immediately following Day 28 visit. On Days 29 
onwards, patients will continue on the same dose of AZP-3601 as on Day 28, 
then individual titration of AZP-3601 may start as early as Day 30.  
Patients will return to the clinical site for additional visits on Day 56 (±4 day), 
Day 84/ET (±4 day), and Day 85 (Day 84 + 1 day).  
Serum calcium and phosphate blood samples will also be taken on Day 42 (±4 
day), Day 70 (±4 day), and Day 86 (Day 84 + 2 days). In addition, there may be 
additional and unscheduled checks for serum calcium and phosphate at the 
discretion of the Investigator. 


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Patients will have their serum calcium/albumin levels measured within 5 days 
after any adjustment of AZP-3601 or any other time at the discretion of the 
investigator. The investigator will be free to perform any serum or urine test if 
needed. 
After the last study drug administration, the patients will be instructed to resume 
their prestudy calcium and active vitamin D treatment regimen and doses based 
on assessments performed on Day 84 (±4 day) to Day 86 (Day 84 + 2 days). 
Follow-up 
 
  
 
  
Part C: For patients not entering the extension phase, the follow­up visit will be 
on Day 37 (±2 days). For patients entering the extension phase,   
the 
follow­up visit will be on Day 98 (±4 days)  
* For each study part, the planned treatment period, day of discharge, and follow-up period may be adapted
depending on emerging study results. 
Subjects/Patients 
 
 
 
 
Part C 
: Approximately 24 male or female subjects with HP who are on treatment with 
oral calcium and active vitamin D 
Diagnosis and Main Criteria for Inclusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part C 
Status 
: - 
History of HP for ≥12 months at the time of screening with documentation of 
two concomitant measurements of albumin-corrected serum calcium and 
parathyroid hormone (PTH), including:  
1) A historical (≥12 months) laboratory analysis showing:
- low serum PTH (<20 pg/mL), and,
- low albumin-corrected serum calcium or low ionized serum calcium
(below the lower limit of normal value of the laboratory).
2) A recent (<12 months) laboratory analysis showing :
- low PTH (< 20pg/mL), and,
- albumin-corrected serum calcium either:
- below the lower limit of normal value of the laboratory, or,


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- within the normal range of the laboratory under standard of care
If historical laboratory analysis (≥12 months) is not available, an additional 
recent concomitant laboratory measurement is required (with a minimum of 
3 weeks testing interval). 
-
Requirement for therapy with calcitriol ≥0.25 μg per day or alphacalcidol
≥0.50 μg per day (both are active vitamin D supplements), and requirement
for supplemental oral calcium treatment ≥1000 mg per day over and above
normal dietary calcium intake prior to baseline measurements.
-
Part C (Extension phase): Patients entering the extension phase need to
have completed the Day 28 visit of the Main treatment period and sign the
ICF before entering the extension phase.
Sex 
: Male or female 
Age 
: 18 to 75 years, inclusive, at screening 
Study Drug 
Active medication 
Drug product 
: AZP-3601 
Activity 
: PTH analog 
In development for 
: HP 
Strength 
: 40 µg of AZP-3601 per vial 
Dosage form 
: Powder for solution for injection 
Route of administration 
: sc abdominal injection (with rotation of injection sites every dosing day for Parts 
B and C) 
Manufacturer 
: NUVISAN GmbH, Neu-Ulm, Germany 
Active medication (additional batch for Part C) 
Drug product 
: AZP-3601 
Activity 
: PTH analog 
In development for 
: HP 
Strength 
: 100 µg of AZP-3601 per vial * 
Dosage form 
: Powder for solution for injection 
Route of administration 
: sc abdominal injection (with rotation of injection sites every dosing day) 
Manufacturer 
: NUVISAN GmbH, Neu-Ulm, Germany 
 
 
 
 
 
 
 
 
 
 
 
 
Variables* 
Safety and Tolerability 
Variables 
: Adverse events, clinical laboratory (clinical chemistry, hematology, coagulation, 
and urinalysis), vital signs (systolic and diastolic blood pressure, pulse rate, and 
body temperature), 12-lead electrocardiogram and time-matched with PK 
sampling (
 Part C), continuous cardiac monitoring (
 
, body weight, physical examination (full or abbreviated), injection site 
reaction, and presence of antidrug antibodies (ADA) in plasma (ADA for Part C 
only) 


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For hypocalcemia and hypercalcemia events, time of onset, amount of 
supplements administered, and timing will be recorded. 
PK Variables 
: - 
Plasma AZP-3601 concentrations 
-
Plasma PK parameters estimated using noncompartmental analysis, as
appropriate.
Day 1 of Part
 C: Cmax, tmax, AUC0-t, AUC0-12, and AUC0-24.
 Day 28 of Part C (Main treatment period) and Day 84 of
Part C (Extension phase): Cmax, Ctrough, Cmin, tmax, kel, t1/2, AUC0­12, AUC0-24,
CLss/F, Vz/F, and Rac
PD and Other 
Variables 
: Parts 
 C:  
-
Levels of serum total calcium, albumin­corrected serum calcium, and serum
phosphate.
-
24-hour urine calcium, phosphate, renal clearance of calcium and
phosphate, fractional excretion (FECa) of calcium and phosphate, 
 magnesium,
renal tubular maximum reabsorption of phosphate/glomerular filtration rate
(TMP/GFR).
-
Endogenous serum PTH(1-84) levels.
: Parts 
 C only: 
-
Bone turnover biomarkers (serum bone­specific alkaline phosphatase
[BSAP], serum carboxy-terminal telopeptide of type I collagen [s-CTx],
serum procollagen type 1 amino-terminal propeptide [P1NP], and serum
osteocalcin).
-
Serum magnesium.
-
Serum 25­hydroxy vitamin D and serum 1,25­dihydroxy vitamin D.
Part C only:
-
Reduction in daily dose of calcium and active vitamin D supplementation
(number of patients achieving a reduction of 50% and more in daily doses of
calcium and active vitamin D supplementation at the end of the treatment
period will be calculated).
-
EQ-5D questionnaire and short form health survey 36 (SF-36) questionnaire.
-
Bone mineral density as assessed by DXA
* The timing, type, and number of safety, PK, PD, and additional assessments may be changed during the
study depending on emerging study results. 
Statistical Methods 
Sample Size Calculation : The sample size and design for each part is based on the desire to obtain 
adequate safety, tolerability, PK, and PD data to achieve the objectives of the 
study while exposing as few subjects as possible to the investigational product 
and study procedures. This sample is typical for a FIH study. Any p-values to 
be calculated according to the statistical analysis plan will be interpreted in the 
perspective of the exploratory character of this study. 
Safety 
: Descriptive statistics 
PK 
: Descriptive statistics for all relevant PK parameters: n, mean, SD, minimum, 
median, maximum, geometric mean, and CV%; analysis of variance on Cmax 
and AUC parameters to determine dose-proportionality  
PD and Additional 
: Descriptive statistics. 
 
 


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Further details will be provided 
in the statistical analysis plan. 


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VERSION 7.0_FR –  08APR2022 
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Page 20 of 24 
Table 3 
Schedule of Assessments – Part C (MAD Part in Patients with HP – Main Treatment Period) 
Assessment 
Screening/Optimization 
Main Treatment Period (4 weeks treatment) 
Follow-up 
(Week) Day 
(-8) 
(-6) 
a,b
(-4) 
a,b
(-2) 
a,b
-4 b
-1
1 
3 b 
5 b 
8 b 
11 b 
14 
15 
16 
21 b 
28/
ET 
29 
30 
b
37 
Visit Window (days) 
±2 
±2 
±2 
±2 
±1 
±1 
±1 
±1 
±1 
±1 
±2 
Informed Consent 
X 
X p 
Medical History 
X 
Demography 
X 
Dispensing and Training of Diary 
X 
Completion of Diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination c 
F 
A 
A 
A 
F 
A 
A 
Body Weight and Height 
X 
X q 
Serum Pregnancy Test 
(Females of childbearing 
potential Only) 
X 
X 
X 
X 
Clinical Laboratory (Clinical 
Chemistry, Hematology, 
Coagulation, and Urinalysis) 
(Fasted) 
X 
X 
X 
X 
12-Lead ECG d
X 
Vital Signs e 
X 
X 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 test 
X 
X 
Inclusion and Exclusion Criteria 
X 
X 
Study Drug Administration f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Accountability 
X 
X r 
Blood Sampling for ADA g 
X 
X 
X 
Injection Site Reaction h 
X 
X 
X 
X 
X 
X 
X 
Blood Sampling for PK i 
X 
X 
X 
Blood Sampling: Total Calcium, 
Albumin­Corrected Calcium, and 
Phosphate in Serum j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Active Vitamin D and Oral 
Calcium Supplementation 
Adjustment k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Magnesium and Native Vitamin 
D Supplementation Adjustment, 
if needed  
X 
X 
X 
X 
X 
X 
Blood Sampling: Endogenous 
Serum PTH(1-84) 
X 
X 
X 
X 
X 
Blood Sampling: Bone Turnover 
Biomarkers l 
X 
X 
X 
X 
X 


CLINICAL STUDY PROTOCOL 
AZP-3601-CLI-001/AZP20005-20005X 
VERSION 7.0_FR –  08APR2022 
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Page 21 of 24 
Assessment 
Screening/Optimization 
Main Treatment Period (4 weeks treatment) 
Follow-up 
(Week) Day 
(-8) 
(-6) 
a,b
(-4) 
a,b
(-2) 
a,b
-4 b
-1
1 
3 b 
5 b 
8 b 
11 b 
14 
15 
16 
21 b 
28/
ET 
29 
30 
b
37 
Visit Window (days) 
±2 
±2 
±2 
±2 
±1 
±1 
±1 
±1 
±1 
±1 
±2 
Blood Sampling: 25­Hydroxy 
Vitamin D (Native Vitamin D) 
and 1,25­Dihydroxy Vitamin D in 
Serum 
X 
X 
X 
Blood Sampling: Serum 
Magnesium 
X 
X 
X 
Blood Sampling: Serum 
Creatinine o 
X 
X 
X 
X 
X 
X 
24-Hour Urine Collection:
Calcium, Phosphate, Creatinine
(for Calculation of FECa of
Calcium and Phosphate and for
Calculation of TMP/GFR), and
Magnesium m
X 
X 
X 
X 
EQ-5D questionnaire 
X 
X 
SF-36 questionnaire 
X 
X 
DXA (bone mineral density) n 
X 
Previous and Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
A=abbreviated physical examination; ADA=antidrug antibodies; AE=adverse event; ECG=electrocardiogram; F=full physical examination; FECa=fractional excretion; PD=pharmacodynamic(s); 
PK=pharmacokinetic(s); PTH=parathyroid hormone; sc=subcutaneous; SF-36=short form health survey 36; TMP/GFR=tubular maximum reabsorption of phosphate/glomerular filtration rate; DXA=dual-
energy x-ray absorptiometry 
a 
Weeks -6, -4, and -2 visits are mandatory but may be combined when albumin-corrected serum calcium is within the target range. 
b 
These visits are mandatory. As an alternative, these visits may be performed off-site; for instance, blood sampling may be performed at a local laboratory or at home by a study nurse. In 
addition, during the optimization period, there may be optional weekly visits. 
c 
A full physical examination will be done at screening, and on Day 28 (predose). An abbreviated physical examination will be done on Days 1, 14, and 16 (at predose), and 29, and at follow-up. 
Unscheduled symptom­directed physical examinations may be conducted at any time per the Investigator’s discretion.  
d 
Single 12-lead ECG: at screening. The ECG will be recorded after the subject has been resting for at least 5 minutes in the supine position.  
e 
Supine systolic and diastolic blood pressure, pulse rate, and body temperature: at screening, on Day -1, on Days 1, 14, 15, and 28 at predose, on Day 29, and at follow­up. Vital signs will be 
recorded after the subject has been resting for at least 5 minutes in the supine position. 
f 
Subjects in Part C will receive AZP-3601 for 28 days as daily sc abdominal injections (with rotation of injection sites every dosing day). During the study visit the injection will be performed at 
the clinical site. 
g 
Blood sampling for ADA: on Day -1, on Day 28, and at follow-up. All samples will be analyzed. In case of positive ADA, patients will be monitored until the levels return to normal. 
h 
Injection site reaction: postdose on Day 1, predose and 1 hour postdose (when dosing) on Days 14, 15, 16, and 28, on Day 29, and at follow­up. 
i 
Blood sampling for PK of AZP-3601 in plasma: serial samplings on Days 1, 14, and 28 (predose, 5min, 10min, 20min, 30min, 1 hour and 2 hours post dose).  
j 
Serial sampling on Days 1, 14, and 28 (predose, 2 hours and 6 hours post dose). Samples will be taken fasting and pre-dose, except when profile where pre- and post-doses are taken 
k 
At any time during the study, hypercalcemia and hypocalcemia will be managed by adjustment in active vitamin D and/or oral calcium supplementation. Adjustments will be based on laboratory 
values including albumin-corrected serum calcium and serum phosphate as well as on symptoms and will be performed at the Investigator’s judgment.  
l
Bone turnover biomarkers include serum bone­specific alkaline phosphatase, serum carboxy-terminal telopeptide of type I collagen, serum procollagen type 1 amino-terminal propeptide, and
serum osteocalcin.


CLINICAL STUDY PROTOCOL 
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VERSION 7.0_FR –  08APR2022 
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Page 22 of 24 
m 
The schedule of assessment indicates the end of collection day of each 24h collection.Refer to Section 3.5.1.3.2 and Figure 4 for more details. 
n 
DXA scans can be obtained within 2 weeks prior to the Day 1 visit 
o
Sample will be taken predose and fasting
p 
For patients willing to enter the extension phase, an ICF should be signed on Day 28 at the latest 
q 
Only weight is measured at Day 28 
r 
Day 28: Dispense study drug to the patients participating to the extension phase 


CLINICAL STUDY PROTOCOL 
AZP-3601-CLI-001/AZP20005-20005X 
VERSION 7.0_FR –  08APR2022 
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Page 23 of 24 
Table 4    Schedule of Assessments - Part C Extension Phase 
Assessment 
Extension Phase (2 months treatment) d 
Follow-up 
Day (Month) 
D29-D30 p 
42 b 
56 
(Month 1) 
70 b 
84/Early 
termination 
(Month 2) 
85 
(D84+1d) 
86 b 
D84+2d) 
98 
Visit Window (days) 
±4 
±4 
±4 
±4 
±4 
Informed Consent a 
Completion of Diary 
X 
X 
X 
X 
X 
X 
X 
Physical Examination c 
A 
F 
A 
A 
Body Weight 
X 
Serum Pregnancy Test (Females of childbearing potential Only) 
X 
X 
Clinical Laboratory (Clinical Chemistry, Hematology, 
Coagulation, and Urinalysis) (Fasted) 
X 
X 
X 
Vital Signs e 
X 
X 
X 
X 
SARS-CoV-2 test m 
Study Drug Administration f 
X 
X 
X 
X 
Drug Accountability o 
X 
X 
Blood Sampling for ADA g 
X 
X 
X 
Injection Site Reaction h 
X 
X 
X 
X 
Blood Sampling for PK r 
X 
Blood Sampling: Total Calcium, Albumin Corrected Calcium, and 
Phosphate in Serum i 
X 
X 
X 
X 
X 
X 
X 
Active Vitamin D and Oral Calcium Supplementation Adjustment 
j
X 
X 
X 
X 
X 
X 
X 
Blood Sampling: Endogenous Serum PTH(1-84) 
X 
X 
X 
Blood Sampling: Bone Turnover Biomarkers k 
X 
X 
X 
Blood Sampling: 25Hydroxy Vitamin D (Native Vitamin D) and 
1,25Dihydroxy Vitamin D in Serum 
X 
X 
Blood Sampling: Serum Magnesium 
X 
X 
Blood Sampling: Serum Creatinine n 
X 
X 
X 
X 
24-Hour Urine Collection: Calcium, Phosphate, Creatinine (for
Calculation of FECa of Calcium and Phosphate and for
Calculation of TMP/GFR), and Magnesium l
X 
X 
X 
EQ-5D questionnaire 
X 
SF-36 questionnaire 
X 
DXA (bone mineral density) q 
X 
Previous and Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
AE Monitoring 
X 
X 
X 
X 
X 
X 
X 


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VERSION 7.0_FR –  08APR2022 
PRA-QMS-02701 5.0 
Page 24 of 24 
A=abbreviated physical examination; ADA=antidrug antibodies; AE=adverse event; ECG=electrocardiogram; F=full physical examination; FECa=fractional excretion; PD=pharmacodynamic(s); 
PK=pharmacokinetic(s); PTH=parathyroid hormone; sc=subcutaneous; SF-36=short form health survey 36; TMP/GFR=tubular maximum reabsorption of phosphate/glomerular filtration rate; DXA=dual-
energy x-ray absorptiometry 
a 
For patients willing to enter the extension phase, an ICF should be signed on Day 28 at the latest 
b 
These visits are mandatory. As an alternative, these visits may be performed off-site; for instance, blood sampling may be performed at a local laboratory or at home by a study nurse. 
c 
F=Full physical examination. A=Abbreviated examination. Physical Examination are done predose at visits when there is a dosing. Unscheduled symptom-directed physical examinations may be 
conducted at any time per the Investigator’s discretion.  
d 
The 2 month open label treatment extension phase will start immediately following Day 28 visit of the Main treatment period. Patients will complete study assessments up to Day 28 as described in 
Table 3, and from Day 29 onwards as described in Table 4. 
e 
Supine systolic and diastolic blood pressure, pulse rate, and body temperature. Vital signs will be recorded after the subject has been resting for at least 5 minutes in the supine position. Vital Signs 
are done predose at visits when there is a dosing. 
f 
Subjects will receive AZP-3601 for 56 days (2 months), as daily sc abdominal injections (with rotation of injection sites every day of administration) from Day 29 onwards. On Day 29 onwards, patients 
will continue on the same dose of AZP-3601 as on Day 28 then individual titration may start as early as Day 30, and patients may have their dose of AZP-3601 adjusted at any time during the 
extension phase.  
During study visits, the injection will be performed at the clinical site. 
g 
All blood sampling for ADA will be analyzed. In case of positive ADA, patients will be monitored until the levels return to normal. 
h 
Injection site reaction: predose and 1 hour postdose when there is a dosing 
i 
Serial sampling on Days 56 and 84 (predose, 2 hours and 6 hours postdose). Samples will be taken fasting and pre-dose, except when profile where pre- and post-doses are taken. 
j 
At any time during the study, hypercalcemia and hypocalcemia will be managed by adjustment in active vitamin D and/or oral calcium supplementation. Adjustments will be based on laboratory 
values including albumin-corrected serum calcium and serum phosphate as well as on symptoms and will be performed at the Investigator’s judgment.  
k 
Bone turnover biomarkers include serum bone-specific alkaline phosphatase, serum carboxy-terminal telopeptide of type I collagen, serum procollagen type 1 amino-terminal propeptide, and serum 
osteocalcin. 
l
The schedule of assessment indicates the end of collection day of each 24h collection. Refer to Section 3.5.1.3.2 and Figure 4 for more details.
m 
Testing may be performed at the discretion of the Investigator. Testing will be performed using a country registered detection test 
n 
Samples will be taken predose and fasting 
o
Dispense the study drug to the patients on Day 28. Study drug return/dispense on Day 56 and Study drug return on Day 84
p 
On Day 29 and Day 30, the subjects will follow the same assessments than ones listed in Table 3, except: 
-
Blood Sampling: Total Calcium/Albumin- Corrected Calcium/Phosphate and Creatinine in Serum, taken predose in addition to fasting
-
Physical Exam and Vital signs at predose
-
Injection site reaction at pre-dose and at 1-hour postdose.
q 
DXA scans can be obtained within 2 weeks prior to the end of the extension phase visit (Day 84 visit). 
r 
Blood sampling for PK of AZP-3601 in plasma: serial samplings on Day 84 (predose, 5min, 10min, 20min, 30min, 1 hour and 2 hours post dose). 

SAP_001.pdf: 
Statistical Analysis Plan 
AZP20005-20005X  
Protocol: AZP-3601-CLI-001 
Version Date: 26-Aug-2022  
EDSREP 009 T 01 G 
Page 1 of 53 
Statistical Analysis Plan 
Sponsor: 
Amolyt Pharma 
Protocol No: 
AZP-3601-CLI-001 
Protocol Title: 
A SINGLE AND MULTIPLE ASCENDING DOSE STUDY TO 
INVESTIGATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND PHARMACODYNAMICS OF AZP-3601, 
A SYNTHETIC PARATHYROID HORMONE ANALOG, IN HEALTHY 
SUBJECTS AND IN SUBJECTS WITH HYPOPARATHYROIDISM 
PRA Project ID: 
AZP20005-20005X 
Version Date: 
26-Aug-2022 (SAP V3) 
1.0 Approvals 
The undersigned have approved this Statistical Analysis Plan for use in this study. 
Name of Sponsor 
Representative / 
Title: 
Soraya Allas, MD, PhD / 
VP Clinical Development and Regulatory Affairs, Amolyt Pharma 
Signature of 
Sponsor 
Representative / 
Date: 
 
Name of Author / 
Title: 
Director Biostatistics, Early Phase ICON plc. 
Signature of Author / 
Date: 
 
30/08/2022


Statistical Analysis Plan 
AZP20005-20005X  
Protocol: AZP-3601-CLI-001 
Version Date: 26-Aug-2022  
EDSREP 009 T 01 G 
Page 2 of 53 
2.0 Table of Contents 
1.0 Approvals ................................................................................................................................................ 1 
2.0 Table of Contents .................................................................................................................................... 2 
3.0 Introduction ............................................................................................................................................. 4 
4.0 Changes from Previous Version of Approved SAP ................................................................................ 4 
5.0 Study Objectives ..................................................................................................................................... 4 
5.1 Primary ................................................................................................................................................ 4 
5.2 Secondary ........................................................................................................................................... 5 
5.3 Exploratory .......................................................................................................................................... 5 
6.0 Study Design ........................................................................................................................................... 5 
6.1 Sample Size Considerations ............................................................................................................. 11 
6.2 Randomization .................................................................................................................................. 11 
7.0 Overview of Planned Analysis .............................................................................................................. 12 
7.1 Changes from Protocol ..................................................................................................................... 12 
7.2 Interim Analysis ................................................................................................................................. 12 
7.3 Final Analysis .................................................................................................................................... 13 
8.0 Definitions and General Analysis Methods ........................................................................................... 13 
8.1 Analysis Data Presentation ............................................................................................................... 13 
8.1.1 Rounding .................................................................................................................................... 13 
8.1.2 Imputation .................................................................................................................................. 13 
8.1.3 Descriptive Statistics .................................................................................................................. 13 
8.1.4 Pooling ....................................................................................................................................... 14 
8.1.5 Unscheduled Measurements ..................................................................................................... 14 
8.2 Analysis Data Definitions .................................................................................................................. 14 
8.2.1 Baseline Definition ..................................................................................................................... 14 
8.2.2 Treatment/Subject Grouping ...................................................................................................... 15 
8.2.3 Common Variable Derivations ................................................................................................... 15 
8.2.4 ADaM Datasets and Metadata ................................................................................................... 15 
8.3 Software ............................................................................................................................................ 16 
8.4 Statistical Methods ............................................................................................................................ 16 
8.4.1 Statistical Outlier Determination ................................................................................................. 16 
8.4.2 Predetermined Covariates and Prognostic Factors ................................................................... 16 
8.4.3 Hypothesis Testing ..................................................................................................................... 16 
8.5 TFL Layout ........................................................................................................................................ 16 
9.0 Analysis Sets ......................................................................................................................................... 17 
9.1 Safety Set .......................................................................................................................................... 17 
9.2 Pharmacokinetic Set ......................................................................................................................... 17 
9.3 Pharmacodynamic Set ...................................................................................................................... 17 
9.4 Enrolled Set (Part C only) ................................................................................................................. 17 
10.0 Subject Disposition .............................................................................................................................. 17 
11.0 Protocol Deviations and Violations ..................................................................................................... 18 
12.0 Demographic and Baseline Characteristics ........................................................................................ 18 
12.1 Demographics ................................................................................................................................. 18 
12.2 Medical History and Disease under Study ...................................................................................... 18 
12.3 Other Baseline Characteristics ....................................................................................................... 18 
13.0 Concomitant Medications .................................................................................................................... 19 
14.0 Treatment Compliance and Exposure ................................................................................................ 19 
15.0 Pharmacokinetic Analyses .................................................................................................................. 20 
15.1 Pharmacokinetic Variables ............................................................................................................. 20 
15.1.1 Plasma Variables ..................................................................................................................... 20 
15.2 Pharmacokinetic Summaries .......................................................................................................... 24 
15.2.1 Pharmacokinetic Concentrations ............................................................................................. 24 
15.2.2 Pharmacokinetic Parameters ................................................................................................... 24 


Statistical Analysis Plan 
AZP20005-20005X  
Protocol: AZP-3601-CLI-001 
Version Date: 26-Aug-2022  
EDSREP 009 T 01 G 
Page 3 of 53 
16.0 Pharmacodynamic and other Analysis ................................................................................................ 25 
16.1 Pharmacodynamic and other Variables .......................................................................................... 25 
16.1.1 Serum PD Concentrations and Parameters............................................................................. 25 
16.1.2 Urine PD Concentrations and Parameters............................................................................... 26 
16.1.3 Standard of Care ...................................................................................................................... 27 
16.1.4 EQ-5D Questionnaire ............................................................................................................... 27 
16.1.5 SF-36 Questionnaire ................................................................................................................ 28 
16.1.6 DXA Analysis ........................................................................................................................... 28 
16.2 Pharmacodynamic Evaluation ........................................................................................................ 28 
16.2.1 Main PD Analysis ..................................................................................................................... 29 
16.2.2 Exploratory Analysis for other PDs and other Measurements ................................................. 29 
17.0 Safety Analyses .................................................................................................................................. 30 
17.1 Safety Variables .............................................................................................................................. 30 
17.1.1 Adverse Events ........................................................................................................................ 31 
17.1.2 Deaths and Serious Adverse Events ....................................................................................... 32 
17.1.3 Injection Site Reactions ............................................................................................................ 32 
17.1.4 Laboratory Data ....................................................................................................................... 32 
17.1.5 Vital Signs ................................................................................................................................ 32 
17.1.6 Body Weights and BMI............................................................................................................. 32 
17.1.7 Electrocardiograms .................................................................................................................. 32 
17.1.8 Telemetry ................................................................................................................................. 32 
17.1.9 Physical Examination ............................................................................................................... 32 
17.1.10 ADA in Plasma ....................................................................................................................... 33 
18.0 References .......................................................................................................................................... 33 
Appendix 1: Glossary of Abbreviations ....................................................................................................... 34 
Appendix 2: Schedule of Assessments ....................................................................................................... 36 
Appendix 3: List of End of Text Outputs ..................................................................................................... 46 
Appendix 4: Shells for Post-Text Tables, Figures and Listings .................................................................. 52 
Document History ........................................................................................................................................ 53 
 


Statistical Analysis Plan 
AZP20005-20005X  
Protocol: AZP-3601-CLI-001 
Version Date: 26-Aug-2022  
EDSREP 009 T 01 G 
Page 4 of 53 
3.0 Introduction 
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the analysis 
and reporting of data collected under Amolyt Pharma Protocol AZP-3601-CLI-001. This SAP covers
 and the analyses to 
be performed for Part C (study conducted in patients with hypoparathyroidism).  
This SAP should be read in conjunction with the study protocol. This version of the SAP has been 
developed using the global protocol version 5.0 dated 12-May-2021, and the country specific protocol 
amendments dated 17-Mar-2021 for Netherlands, 8-Apr-2022 for France (Version 7.0) and 11-Apr-2022 
for Hungary and Spain (Version 7.0) (including all amendments up to this protocol date). 
An approved and signed SAP is a requirement for database lock. An approved SAP is also required for 
unblinding of the study treatments. 
This SAP only covers the results that will be processed by the PRA Early Development Services (EDS) 
Biostatistics Department. 
PRA EDS will perform the pharmacokinetic (PK), pharmacodynamic (PD), and safety and tolerability 
evaluation.  
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be identified. Any post-hoc or unplanned analyses, or significant changes 
from the planned analysis in this SAP performed to provide results for inclusion in the clinical study report 
(CSR) but not included in this SAP, will be clearly identified in the CSR. Changes to planned analyses do 
not require an updated SAP but should be included in the CSR if significant. 
4.0 Changes from Previous Version of Approved SAP 
Version 2.0: 
 
Overall changes based on updated versions of the protocol. 
 
Inclusion of the analyses related to Part C (Main treatment period and Extension phase) 
Version 3.0: 
 
Inclusion of additional PK samplings of AZP-3601 in plasma at D84, during the Extension phase 
of part C according to protocol version 7.0 
 
Added listing of SF-36 Questionnaire - Physical and Mental Component Score (Part C only) 
5.0 Study Objectives 
5.1 Primary 
 
 
To assess the safety and tolerability of AZP-3601 following single and 4-week multiple ascending 
doses administered by sc injection to patients with hypoparathyroidism (HP) (Part C, Main 
Treatment Period) 
 
To assess the safety and tolerability of AZP-3601 during a 2-month treatment extension period 
(Part C, Extension Phase) in patients with HP 
 


Statistical Analysis Plan 
AZP20005-20005X  
Protocol: AZP-3601-CLI-001 
Version Date: 26-Aug-2022  
EDSREP 009 T 01 G 
Page 5 of 53 
5.2 Secondary 
 
 
To assess the PD response of AZP-3601 on maintenance of serum calcium and phosphate levels 
within a target range while oral calcium and active vitamin D are progressively reduced, following 
multiple ascending doses administered by sc injection to patients with HP (Part C, Main 
Treatment Period) 
 
To assess the PK of AZP-3601 following single and multiple ascending doses administered by sc 
injection to patients with HP (Part C) 
 
To assess the feasibility of individual titration of AZP3601 during a 2-month treatment extension 
period (Part C, Extension Phase) in patients with HP (ie if individual dosing across a dose range 
can be implemented in a safe and effective manner and can be maintained throughout the 
treatment period) 
 
5.3 Exploratory 
 
 
To assess the effect of AZP-3601 on urinary excretion of calcium and phosphate as well as on 
bone turnover biomarkers following multiple ascending doses administered by sc injection to 
patients with HP (Part C, Main Treatment period) 
 
To assess the effect of AZP-3601 on urinary excretion of calcium and phosphate as well as on 
bone biomarker and Bone Mineral Density (BMD) as assessed by Dual-Energy X-Ray 
absorptiometry (DXA) during a 2-month treatment extension period (Part C, Extension Phase) 
 
6.0 Study Design 
This is a first-in-human (FIH) study in healthy subjects followed by a study in patients with HP combined 
in a single protocol. 
 
Part B will be 
followed by a MAD part in patients with HP who will receive AZP3601 for 4 weeks (Part C). 
Patient completing the 4 weeks Main Treatment Period of Part C, will be offered to enter a 2-month open 
label treatment extension phase. Together with the initial 4-weeks treatment period, this extension phase 
will allow the collection of safety and PD data over a total of 3 months of treatment. 
In all study parts, safety, tolerability, PK (Part 
 C), and PD of sc doses of AZP - 3601 will be 
assessed.  
 
The overall study schematic is presented in the figure below: 
 
 


Statistical Analysis Plan 
AZP20005-20005X  
Protocol: AZP-3601-CLI-001 
Version Date: 26-Aug-2022  
EDSREP 009 T 01 G 
Page 6 of 53 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
AZP20005-20005X  
Protocol: AZP-3601-CLI-001 
Version Date: 26-Aug-2022  
EDSREP 009 T 01 G 
Page 7 of 53 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part C (MAD part in patients with HP)  
Part C will be an open-label MAD study in male or female patients with HP who are on treatment with oral 
calcium and active vitamin D to evaluate the safety and tolerability, PK, and PD of AZP-3601. Up to 2 
cohorts of approximately 12 patients each are planned for this part of the study.  
 
Part C, Main Treatment Period 
The figure below illustrates the study design for Part C for the Main Treatment Period. 
 
 
 
Prior to the treatment period, there will be an optimization period of up to 8 weeks during which doses of 
oral calcium and active vitamin D will be adjusted to achieve a baseline target range of albumin-corrected 
serum calcium (7.8 to 9.0 mg/dL) and therefore ensuring a common baseline for all patients. 
  
During this optimization period, any serum 25hydroxy vitamin D (native vitamin D) and/or magnesium 
deficiencies will be corrected. 
 


Statistical Analysis Plan 
AZP20005-20005X  
Protocol: AZP-3601-CLI-001 
Version Date: 26-Aug-2022  
EDSREP 009 T 01 G 
Page 8 of 53 
During the main treatment period, patients in Part C will receive AZP-3601 for 28 days as daily sc 
abdominal injections (with rotation of injection sites every dosing day). Doses of oral calcium and active 
vitamin D supplements will be carefully reduced during the initial 14 days of treatment while maintaining 
albumin-corrected serum calcium in the target range (7.8 to 9.0 mg/dL). Reductions of both oral calcium 
and active vitamin D supplements will be performed using a staged approach until the active vitamin D 
dose can be eliminated and the oral calcium dose can be reduced to or below 500 mg/day (please note 
that throughout this protocol doses of oral calcium refer to doses of elemental calcium). Based on animal 
data, serum calcium is expected to increase progressively following repeated administration of AZP-
3601 and PD steady state is expected to be observed within the first 5 days of dosing. Staggered 
reductions of doses of oral calcium and active vitamin D supplements will therefore be performed at 
near-steady state based on the predose albumin-corrected serum calcium value. It is anticipated to 
perform reduction of supplements on Day 5, 8, and 11. The days of dose reduction of supplements may 
change based on data from Part B; they may be advanced or delayed based on (but not limited to) when 
the PD steady state is observed.  
  
If independence from active vitamin D and reduction of oral calcium is not achieved on Day 14 (ie, 
elimination of active vitamine D and reduction of oral calcium to or below 500 mg/day), the AZP-3601 
dose will be increased and patients will be treated at this dose for the remaining duration of the treatment 
period (up to Day 28). Patients achieving independence from active vitamin D and reduction of oral 
calcium on Day 14 will remain at the same dose level. The last remaining daily dose of oral calcium, if 
any, may be removed on Day 17 based on the predose albumin-corrected value of serum calcium. 
  
Patients will undergo frequent testing for albumin-corrected serum calcium and phosphate during the 
initial 14-day treatment period and again following increase of the dose. In addition, there may be 
additional and unscheduled checks for albumin-corrected serum calcium and phosphate at the discretion 
of the Investigator. 
 
At any time during the study, hypercalcemia and hypocalcemia will be managed by adjustment in active 
vitamin D and/or oral calcium supplementation. Adjustments will be based on laboratory values including 
albumin-corrected serum calcium and serum phosphate as well as on symptoms and will be performed at 
the Investigator’s judgment. As a general guidance, adjustments should be performed when calcium 
values are outside the target range of 7.8 to 9.0 mg/dL. 
 
The following treatments are planned to be administered in Part C in an open-label fashion: 
Cohort C1: 
sc doses of 20 µg AZP-3601 (n=12) qd from Day 1 to Day 28 (dose of AZP-3601 may be 
increased to 40 µg from Day 14 onwards) 
Cohort C2: 
sc doses of a fixed dose up to 40a µg AZP-3601 (n=12) qd from Day 1 to Day 28 (dose of 
AZP-3601 may be increased at a fixed dose up to 60 µg from Day 14 onwards) 
During the extension phase, patients may have their AZP-3601 dose increased in increments of 10a µg 
to a maximum dose of 60a µg (Cohort 1) and of 80a µg (Cohort 2). 
 
a The planned dose levels (including the dose levels allowed to increase the dose in the same cohort) 
may be changed following review of data from Parts A and B, and the emerging data from Part C. 
However, for each of the cohorts the doses will not exceed the doses previously tested in Part A and 


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Part B. In addition, the increase from one dose level to the next dose level within the same cohort or 
between cohorts will not be more than 3-fold. 
 
Part C may commence after the first 3 cohorts of Part B have been completed, providing there is 
sufficient appropriate data available (safety and tolerability, PK, and PD) to enable determination of 
dose levels.  
 
The following table provides an overview of the doses (µg) planned to be adminstered in Part C 
 
. 
 
 
Part C Cohort 
 
 
 
 
 
 
C1b 
20 (dose 1) 
40 (dose 2) 
C2b 
fixed dose 
up to 40 
(dose 1) 
fixed dose 
up to 60 
(dose 2) 
a Part B may commence following completion of the first 3 cohorts of Part A. 
b Part C may commence after completion of the first 3 cohorts of Part B. 
 
Although this is an ascending dose study, a lower dose may be administered in the second cohort 
based on the safety, tolerability, or available PD and plasma PK results of the first cohort. Also, the 
same dose may be tested or an intermediate dose may be tested to gain more information on safety, 
tolerability, PD, and/or PK.  
 
There will be an interval of at least 7 days between the last dose in the first cohort and the first dose in 
the second cohort. Patients included in the first cohort cannot participate in the second cohort. 
 
Part C, Extension Phase  
The figure below illustrates the study design for Part C for the Extension Phase. 


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Patients completing the 4 weeks Main Treatment Period of Part C, will be offered to enter a 2-month 
open label treatment extension phase. For patients willing to enter the extension phase, an informed 
consent form (ICF) should be signed on Day 28 at the latest. 
 
Patients will have to complete study assessments up to Day 28, as described in Schedule of 
Assessments Table 4 (in the Appendix 2) and from Day 29 onwards, as described in Table 5 (in the 
Appendix 2). 
 
Patients who will not participate to the Extension phase will have to complete study assessments as 
described in Table 4 (in the Appendix 2). 
 
The 2-month open label treatment extension phase will start immediately following Day 28 visit of the 
Main treatment period. Patients will receive AZP-3601 for 56 days (2 months) as daily sc injections from 
Day 29 onwards (with rotation of injection sites each day of administration). 
 
The goal is to optimize AZP-3601 dosing across a dose range while doses of oral calcium and active 
vitamin D are as low as safely possible and albumin-corrected serum calcium is maintained within the 
target range of 7.8 to 9.0 mg/dL (1.95 to 2.25 mmol/L) together with an optimal control of the symptoms of 
hypoparathyroidism. 
 
For patients who are taking minimal or no supplemental calcium (≤500 mg/day) and no vitamin D on Day 
28, the AZP-3601 dose from the previous 14 days of treatment (Part C, Main Treatment Period) can be 
maintained and adjusted when needed during the Extension Phase.  
For patients who are still taking active vitamin D and/or more than 500 mg/day of oral calcium on Day 28, 
a progressive reduction of supplements will be carried out while increasing the dose of AZP-3601. 
 
On Day 29 onwards, patients will continue on the same dose of AZP-3601 as on Day 28, then individual 
titration of AZP-3601 may start as early as Day 30 and patients may have their dose of AZP-3601 
adjusted at any time during the Extension Phase. Patients may have their AZP-3601 dose increased, as 


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defined in previous section, with the goal of achieving or maintaining albumin-corrected serum calcium in 
the target range of 7.8 to 9.0 mg/dL. 
 
The AZP-3601 dose may be adjusted downward at any time as needed to maintain albumin-corrected 
serum calcium within the target range or for any safety concerns. 
 
Once patients achieve a stable albumin-corrected serum calcium with the minimum doses of 
supplements, they will be maintained at that dose of AZP-3601. A separate titration guideline to help the 
investigator and to facilitate a standardized approach to dose adjustment, will be provided to the clinical 
site. 
 
Patients will have their serum calcium/Albumin levels measured within 5 days after any adjustment of 
AZP-3601 and any other time at the discretion of the investigator. The investigator will be free to perform 
any other serum or urine test if needed. 
 
In addition, there may be additional and unscheduled checks for serum calcium and phosphate at the 
discretion of the investigator. 
 
At any time during the study, hypercalcemia and hypocalcemia will be managed by adjustment in active 
vitamin D and/or oral calcium supplementation. Adjustments will be based on laboratory values including 
albumin-corrected serum calcium and serum phosphate as well as on symptoms and will be performed 
at the Investigator’s judgment.  
6.1 Sample Size Considerations 
This is an exploratory trial for which no formal statistical hypothesis testing will be performed and 
therefore no formal sample size calculations have been done. The sample size is based on the desire to 
obtain adequate safety, tolerability, PK and PD data and is considered sufficient to achieve the objectives 
of the study while exposing as few subjects as possible to the investigational product and study 
procedures. This sample is typical for a FIH study. Any p-values to be calculated according to the SAP 
will be interpreted in the perspective of the exploratory character of this study. 
6.2 Randomization 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Part C is not randomized. All patients will receive AZP-3601 and no placebo will be administered. patients 
will be assigned to a cohort based on their availability. After obtaining written informed consent, patients 
will be screened according to the inclusion and exclusion criteria. Patients will be assigned unique patient 
numbers allocated in ascending order within the clinical site, that identify the study site and the individual 
subject. The patient number will be as follows: XXX-YYY, with XXX for country and site number, and YYY 
for patient counter. Any replacement patient will receive the number of the patient to be replaced, 
increased by 500 (thus XXX-501 as replacement for XXX-001).  
7.0 Overview of Planned Analysis 
7.1 Changes from Protocol 
The PK parameter AUC0-6 will be provided whereas AUC0-12 and AUC0-24 will not be provided, because the 
drug is expected to eliminate quickly and because of the scheduled timepoints of PK assessments.  
The PK parameter AUC0-inf will be calculated at Day 1 for 
 C, therefore kel will be also calculated 
at this timepoint as well as Adj R2.  
An additional analysis set (Enrolled Set) will be derived for Part C. The adverse events (AEs) in Part C will 
also be summarized for Enrolled Set. 
7.2 Interim Analysis 
 
 
 
 
 
       
 
       
 
 
 
 
 
 
 
 
 
For Par C, following completion of Cohort C1, an interim PK/PD report will be provided in a descriptive 
way, along with a dose escalation report (DER) describing the safety and tolerability, and available 
pharmacodynamic and pharmacokinetic data, to assist the SRC in dose escalation decision from Cohort 
C1 to Cohort C2.  


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The following PK/PD data will be included in the interim reports:  
• 
PK: AZP-3601 plasma (pg/mL)  
• 
PD: Serum Calcium (mg/dL)  
 
Serum Calcium corrected for Albumin (mg/dL)  
 
Serum Inorganic Phosphorus (mg/dL)  
 
Serum PTH, Intact (pg/mL)  
 
Urine Calcium excretion rate (estimated, mg/24h)  
 
Urinary fractional excretion of calcium (%)  
 
Urinary fractional excretion of inorganic phosphorus (%) 
 
ADAs 
 
The interim safety reports will be generated by Principal Investigator (data is extracted from the system 
Oracle EDC).  
7.3 Final Analysis 
Draft TFLs will be provided 
 
 after the database lock of Part C. 
After Sponsor comments have been incorporated, the TFLs will be finalized and incorporated in the final 
CSR. 
8.0 Definitions and General Analysis Methods 
8.1 Analysis Data Presentation 
8.1.1 Rounding 
In listings, data will be presented with the same precision as the original data. Derived data will be 
rounded for presentation purposes.  
For all summaries, except PK data summaries, the mean and median will be presented to one decimal 
place greater than the listed data, standard deviation (SD) to two greater than the listed data, and the 
minimum and maximum will be presented to the same number of decimal places as the listed data. 
Frequency percentages will be presented with one decimal. 
For all PK data (i.e. concentrations and derived parameters) summaries, descriptive statistics will be 
presented as integers when values are ≥100 or presented with 3 significant figures when values are 
<100. The tmax values and descriptive statistics thereof will be reported with 2 decimals. Ratios will be 
presented with 1 decimal. The coefficient of variation (CV%) will be reported with 1 decimal. 
  
P-values will be reported to four decimal places; p-value less than 0.0001 will be reported as p <0.0001. 
8.1.2 Imputation 
Unless otherwise noted, data will not be imputed. Exceptions are missing start and end times of adverse 
events (AEs), see Section 17.1.1, PK concentrations below lower limit of quantification (LLOQ), see 
Section 15.2, PTH(1-84) concentrations below LLOQ, see Section 16.2.2.1, and missing score in SF-36 
Questionnaire, see section 16.1.5. 
8.1.3 Descriptive Statistics 
Unless otherwise indicated, continuous variables will be summarized with the following descriptive 
statistics: number of observations (n), (arithmetic) mean, SD, minimum (min) value, median, and 
maximum (max) value. For PK data, geometric mean and geometric CV will be presented in addition. 
 
Geometric mean = exp(m), where m is the arithmetic mean of the log-transformed data. 


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 
Geometric CV (%): sqrt(exp(s*s)-1)*100, where s*s is the variance of the log-transformed data. 
Categorical data will be summarized with frequencies and percentages. Percentages by categories will be 
based on the number of subjects exposed within a treatment. 
For categorical data, the categories will be presented in the tables exactly as they appear in the electronic 
case report form (eCRF) / Database. No data manipulation will be done for presentation purposes. 
8.1.4 Pooling 
For each part, summary statistics will be calculated by treatment (and time point, if applicable).  
8.1.5 Unscheduled Measurements 
Unscheduled measurements will be included in the listings. Except for unscheduled measurements used 
for baseline, unscheduled measurements will be excluded from the descriptive statistics and statistical 
analysis. 
8.2 Analysis Data Definitions 
8.2.1 Baseline Definition 
Unless otherwise stated, baseline for post-dose evaluations is defined as the last observation recorded 
before the first study drug administration in each study part. The last observation can be an unscheduled / 
repeated measurement. If a pre-treatment observation is missing then the screening value may be used. 
 
 
 Another exception is 
the baseline definition for the main PD analysis due to the potential batch effect (see Section 16.2.1). 


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8.2.2 Treatment/Subject Grouping  
Label 
Grouping 
Study Drug 
AZP-3601 and Placebo  
Treatment 
 
   
 
   
Part C (MAD Part in Subjects with HP) 
multiple sc AZP-3601 
Dose Level a 
 
 
 
 
Part C (MAD Part in patients with HP, Main Treatment Period) 
Cohort 1: 20µg qd from Day 1 to Day 28 (may be increased to 40 µg from 
Day 14 onwards) 
Cohort 2: 40µg qd from Day 1 to Day 28 (may be increased to 60 µg from 
Day 14 onwards) 
Part C (MAD in patients with HP, Extension Phase) 
During the extension phase, patients may have their AZP-3601 dose 
increased in increments of 10a µg to a maximum dose of 60a µg (Cohort 1) 
and of 80a µg (Cohort 2) 
a The planned dose levels may change following review of the emerging data.  
8.2.3 Common Variable Derivations 
Variable 
Definition/Calculation 
Analysis Study Day 
(Prior to Dose) 
Date of Measurement minus First Dose Date in each study part 
Analysis Study Day 
(Post Dose) 
Date of Measurement minus First Dose Date +1 in each study part 
Scheduled time 
Planned time of the assessment. Time in hours of the assessment relative to 
the planned time of the first drug administration in each study part 
Actual Time 
Actual time in hours calculated as the sampling data/time minus the date/time 
of the first drug administration in each study part 
Change from Baseline 
Post-dose observation minus baseline observation 
8.2.4 ADaM Datasets and Metadata 
The analysis datasets will be generated in accordance with Clinical Data Interchange Standard 
Consortium (CDISC) Analysis Data Model (ADaM) Version 2.1.  
ADaM compliant datasets will be delivered to the Sponsor. A define.xml file version 2 with the 
corresponding metadata will be included. Analysis results metadata will be excluded. 
At least the following datasets will be generated: 
 
Subject-level Analysis Dataset (ADSL) 
 
AEs Analysis Dataset (ADAE) 


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 
Exposure Analysis Dataset (ADEX) 
 
Concomitant Medications Analysis Dataset (ADCM) 
 
Medical History Analysis Dataset (ADMH) 
 
Laboratory Analysis Dataset (ADLB) 
 
Vital Signs Analysis Dataset (ADVS)  
 
ECG Analysis Dataset (ADEG) 
 
PK Concentrations Analysis Dataset (ADPC) 
 
PK Parameters Analysis Dataset (ADPP) 
 
Pharmacodynamic Analysis Dataset (ADPD) 
8.3 Software 
The statistical analysis and reporting will be done using SAS® for WindowsTM Version 9.4 or higher (SAS 
Institute, Inc.). 
PK parameter calculations will primarily be done using Phoenix® WinNonlin® (WNL) version 8.1 or higher 
(Certara, Inc.). Additional PK computations may be performed in SAS®. 
8.4 Statistical Methods 
8.4.1 Statistical Outlier Determination 
No statistical outlier analysis is planned. 
8.4.2 Predetermined Covariates and Prognostic Factors 
There are no predetermined covariates or prognostic factors. 
8.4.3 Hypothesis Testing 
No formal hypothesis testing will be done. 
8.5 TFL Layout 
Report layout will be according to the PRA EDS – International Council for Harmonisation (ICH) E3 
compliant – CSR Template. The layout of TFLs will be according to the PRA EDS standards. 
Format: 
 
Page size: A4 
 
Data in listings will be sorted by study part, subject number, 
 /cohort 
(for Part C) and time point. 
 
Data in tables will be sorted by study part, 
 /cohort (for Part C) and 
time point. 
 
Column titles will be in title case letters. 
 
All tables and listings will be in landscape format. 
 
Study part refers to 
 ‘Part C Main’, and ‘Part C Extension’ if applicable: “Treatment” refers 
to placebo and various dose levels of study drug in the TFL. 
 
Table, listing and figure shells will be provided together with the SAP. 


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9.0 Analysis Sets 
Analyses 
Safety Set 
Pharmacokinetic 
Set 
Pharmacodyna
mic Set 
Enrolled Set 
(Part C only) 
Disposition 
Summaries 
 
 
 
 
Demographics    
 
 
 
 
Baseline 
Characteristics 
 
 
 
 
Medical History 
 
 
 
 
Treatment 
Exposure 
 
 
 
 
AE Summaries 
 
 
 
 
CM Summaries 
 
 
 
 
Other Safety 
Assessments 
 
 
 
 
PK Concentrations 
Summaries 
 
 
 
 
PK Parameters 
Summaries 
 
 
  
 
PD Parameters 
Summaries 
 
 
 
 
9.1 Safety Set 
All subjects who have received at least 1 dose of AZP-3601 or placebo. 
9.2 Pharmacokinetic Set 
All subjects who have received at least 1 dose of AZP-3601 and provided sufficient bioanalytical 
assessment results to calculate reliable estimates of the PK parameters. 
9.3 Pharmacodynamic Set 
All subjects belonging to the safety set and for whom the PD data are considered to be sufficient and 
interpretable. 
9.4 Enrolled Set (Part C only) 
All patients who sign the informed consent form. 
The table of “Disposition Summaries” will be presented from “All Subjects”, including summarizing the 
members of each analysis set. Moreover, all the listings will also be presented from “All Subjects”. 
10.0 Subject Disposition 
All disposition data will be listed. 


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 members of each analysis set 
will be presented. The number and percentage of subjects who withdrew from the study prematurely and 
a breakdown of the corresponding reasons for withdrawal will also be presented. Summaries will be 
reported by study part and treatment, as well as overall within each part. 
11.0 Protocol Deviations and Violations 
Protocol deviations will be collected and entered into the Clinical Trial Management System (CTMS) per 
clinical monitoring Standard Operating Procedures. From CTMS, protocol deviations will be pulled into 
study data tabulation model (SDTM). Important protocol deviation data will be listed by subject. 
12.0 Demographic and Baseline Characteristics 
12.1 Demographics 
All demographic data will be listed by subject. 
Subject demographics will be summarized descriptively for all subjects by study part and 
 
 /cohort (for Part C) as well as overall within each part. The summary will include the 
subjects’ age (in years), gender, race (if available), ethnicity, weight (in kg), height (in cm), and body mass 
index (BMI) (in kg/m2) at baseline. In addition, for Part C, the number and percentage of subjects will be 
summarized by age group ‘<45 years’, ‘≥ 45 and <65 years’ and ‘≥65 years’. Demographics will be 
summarized for the safety, PK, PD and enrolled sets if applicable. 
12.2 Medical History and Disease under Study 
Medical history will be listed by subject. Medical history data will be coded according to the Medical 
Dictionary for Regulatory Activities (MedDRA) version 23.1. 
Medical history will be summarized by system organ class (SOC) and preferred term (PT). The number 
and percentage of subjects will be presented by study part and 
 /cohort (for 
Part C). 
For Part C, all the information related to disease under study will be listed by patient. A summary table will 
be provided for the duration (in years) and the etiology of hypoparathyroidism. Furthermore, menopause 
status will be summarized using the frequency of patients with or without menopause based on the total 
number of female patients, and using the time since menopause (years). 
12.3 Other Baseline Characteristics 
 
 
For Part C, a summary table and a listing will be provided for the following baseline values:  
- 
Prescribed active vitamin D 
- 
Prescribed active vitamin D in category (low, medium, high): 
o 
Calcitriol: low dose 0-0.25 μg/day, medium dose >0.25-0.5 μg/day, high dose >0.5 
μg/day. 
o 
Alfacalcidiol: low dose 0-0.50 μg/day, medium dose >0.50-1.0 μg/day, high dose >1.0 
μg/day 
- 
Prescribed calcium 
- 
Prescribed calcium in category: 
o 
0-2000 mg/day 
o 
>2000 mg/day 
- 
Serum total calcium 
- 
Serum phosphate 


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- 
Albumin-adjusted serum calcium 
- 
Serum 25-Hydroxyvitamin D 
- 
Serum 1,25-Dihydroxyvitamin D 
- 
24-Hour urinary calcium (mg/24h) 
- 
24-Hour urinary calcium adjusted by creatinine 
- 
FECa of calcium  
- 
FECa of calcium in category  
o 
0-2% 
o 
> 2% 
- 
Bone turnover biomarkers 
- 
e-GFR 
 
The other baseline characteristics will be listed, including results of pregnancy tests, serology tests, drug 
and alcohol screen, SARS-CoV-2 Polymerase Chain Reaction (PCR) test and childbearing potential (Part 
C only).   
13.0 Concomitant Medications 
Prior and concomitant medications (drug treatment), categorized by standardized medication group 
according to the World Health Organization (WHO) Drug Dictionary (WHODrug Global B3 SEP2020), will 
be listed by subject. Medications with an end date prior to the first dose of study drug within each study 
part will be considered prior medications and will be identified in the listing. Any medication taken after the 
first dose of study drug, including those who started prior to the first dose of study and continued past that 
date will be considered concomitant medications. If a partial date allows a medication to be considered 
concomitant it will be categorized as such.  
Concomitant medications (drug treatment) will be summarized by standardized medication group and 
 /cohort (for Part C) in each study part. The number and percentage of 
subjects using at least one medication within each standardized medication group will be presented by 
 /cohort (for Part C) in each study part. 
In addition, prior and concomitant medications (non-drug treatment) will also be listed.  
14.0 Treatment Compliance and Exposure 
Exposure data of study drug, collected by CRF, will be listed by subject. In Part C, exposure data of study 
drug, collected by diary, will also be listed by subject. If applicable, date and time of meal intake and 
comments will be listed. 
   
 
 
 
   
 
 
 
For Part C, exposure data of study drug will be summarized by cohort for 
 
Dose exposure parameters separately by main treatment period and extension phase include: 
o 
Total actual dose received (μg) (Sum of all doses administered) 
o 
Number of doses received 
o 
Duration of exposure (in days) = last dose date - first dose date + 1   
o 
Dose Intensity (μg/day) = total actual dose received / duration of exposure 
o 
Relative Dose Intensity (ratio) = total actual dose received / total planned dose 
 
Dose increases during the main treatment period include: 
o 
Doses increases at Day 15 = Yes / No (doses at Day 15 versus doses at Day 1) 


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o 
Doses increases after Day 15  = Yes / No (doses at Day 16 or later up to Day 28 versus 
doses at Day 1) 
 
Doses increases or decreases during the extension phase (versus actual dose at Day 28) 
include: 
o 
Number of patients with one increase only (without decrease)   
o 
Number of patients with at least two increases (without decrease) 
o 
Number of patients with one decrease only (without increase) 
o 
Number of patients with at least two decreases (without increase) 
o 
Number of patients with both increase and decrease 
o 
Number of patients with no change in dose 
 
Study drug dispensing and returning will be listed by subject.   
15.0 Pharmacokinetic Analyses  
15.1 Pharmacokinetic Variables 
15.1.1 Plasma Variables 
15.1.1.1 Plasma PK Concentrations 
 
Plasma AZP-3601 concentrations 
15.1.1.2 Plasma PK Parameters 
 
PK Parameters for AZP-3601 as defined in Table 1 


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Table 1  
Plasma AZP-3601 PK Parameters 
Parameter 
 
 
AND 
C 
Day 
1  
 
  
 
AND 
PART C 
DAY 28 
and DAY 
84 
Description 
SAS Programming Notes 
Cmax 
X 
X 
Maximum plasma concentration. Observed peak analyte concentration 
obtained directly from the experimental data without interpolation, 
expressed in concentration units. 
Cmax from WNL.  
Cmax will be presented as “Cmax” in 
the TFL. 
Ctrough 
 
X 
Trough plasma concentration. 
Derived in SAS 
Ctrough will be presented as “Ctrough” in 
the TFL. 
Cmin 
 
X 
Minimum plasma concentration (predose concentration excluded) 
Cmin from WNL.  
Cmin will be presented as “Cmin” in the 
TFL. 
tmax 
X 
X 
Time to maximum plasma concentration. First observed time to reach 
peak analyte concentration obtained directly from the experimental 
data without interpolation, expressed in time units. 
Tmax from WNL.   
tmax will be presented as “Tmax” in the 
TFL. 
AUC0-t   
X 
 
Area under the plasma concentration-time curve (time 0 to time of last 
quantifiable concentration). 
AUClast from WNL.  
AUC0-t will be presented as “AUClast” 
in the TFL. 
AUC0-inf 
X 
 
Area under the plasma concentration-time curve (time 0 to infinity). 
Calculated as: AUC0-inf = AUC0-t + Clast/kel, where Clast is the observed 
concentration at time t, where t is the last point with a concentration 
above the lower limit of quantification.  
 
Percent extrapolation less than or equal to 20% and an adjusted r2 
greater than 0.80 are required to obtain a reliable AUC0-inf. 
AUCINF_obs from WNL.  
AUC0-inf will be presented as “AUCinf” 
in the TFL. 
If %AUCextra >20% then parameter is 
flagged. 
If  Adj R2  ≤ 0.80 then parameter is 


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Parameter 
 
 
AND 
C 
Day 
1  
 
  
 
AND 
PART C 
DAY 28 
and DAY 
84 
Description 
SAS Programming Notes 
flagged. 
%AUCextra 
 
 
Percentage of estimated part for the calculation of AUCinf: Calculated 
as: 
([AUC0-inf – AUC0-t]/ AUC0-inf)*100%. 
AUC_%Extrap_obs from WNL.  
%AUCextra will be presented as 
“AUC%extrap” in the TFL, and listed 
only.  
AUC0-6 
X 
X 
Area under the plasma concentration-time curve from time zero up to 
6 hours. 
  
AUC0-6 from WNL  
AUC0-6 will be presented as 
“AUC(0-6)” in the TFL. 
AUC0-12 
 
X 
Area under the plasma concentration-time curve from time zero up to 
12 hours. 
  
AUC0-12 from WNL  
AUC0-12 will be presented as 
“AUC(0-12)” in the TFL. 
AUC0-24 
 
X 
Area under the plasma concentration-time curve from time zero up to 
24 hours. 
  
AUC0-24 from WNL  
AUC0-24 will be presented as 
“AUC(0-24)” in the TFL. 
kel 
X 
 
Terminal phase rate constant calculated by linear regression of the 
terminal log-linear portion of the concentration vs. time curve.  
Linear regression of at least three points and an adjusted r2 greater 
than 0.80 are required to obtain a reliable kel. 
Lambda_z from WNL.   
kel will be presented as “Kel” in the 
TFL, and listed only 
If  Adj R2  ≤ 0.80 then parameter is 
flagged. 
t1/2 
X 
 
Terminal phase half-life expressed in time units.  
adjusted r2 greater than 0.80 is required to obtain a reliable t1/2. 
HL_Lambda_z from WNL. 
t1/2 will be presented as “t1/2” in the 
TFL. 
If Adj R2 ≤ 0.80 then parameter is 
flagged. 


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Note: AUCs will be calculated using linear up / log down, expressed in units of concentration x time. 
 
Parameter 
 
 
AND 
C 
Day 
1  
 
  
 
AND 
PART C 
DAY 28 
and DAY 
84 
Description 
SAS Programming Notes 
CL/F 
 
  
Apparent oral clearance, calculated as dose/AUC0-inf. 
 
CL_F_obs from WNL. 
If %AUCextra >20% or Adj R2 ≤ 0.80 
then parameter is flagged. 
CLss/F 
 
X 
Apparent oral clearance at steady state, calculated as dose/AUC0-tau 
where tau =6h (Parts B and C). 
 
CLss_F from WNL 
CLss/F will be presented as “CLss/F” in 
the TFL.  
 
 
Vz/F 
 
X 
Apparent volume of distribution at terminal phase, calculated as 
(CL/F)/kel (Part A), or as (CLss/F)/kel (Parts B and C). 
  
VZ_F_obs from WNL. 
If %AUCextra >20% or Adj R2 ≤ 0.80 
then parameter is flagged.  
Rac 
 
X 
Accumulation ratio, based on AUC0-tau of Day 14 (Part B) or Day 28 
(Part C) vs Day 1 where tau = 6h (Parts B and C).  
Calculated in SAS. 
Rac will be presented as “Rac” in the 
TFL. 
 
Adj R2  
 
X 
 
Goodness of fit statistic for the log-linear terminal elimination phase of 
the concentration-time profile identified by least-squares linear 
regression and adjusted for the number of points (minimum of 3) used 
in the estimation of kel. 
“Rsq_adjusted” from WNL. 
Adj R2 will be presented as “Adj R2” in 
the TFL and listed only.  


Statistical Analysis Plan 
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15.2 Pharmacokinetic Summaries 
15.2.1 Pharmacokinetic Concentrations 
All AZP-3601 plasma concentrations will be reported under PK population set with data handling of PK 
Data Set and PK Data Set Info (for information only). Under PK Data Set, analyses on the concentrations 
will be performed with values under LLOQ set as “BQL”. Under PK Data Set Info, AZP-3601 plasma 
concentration will include the concentrations extrapolated from the analyte response under the LLOQ (for 
information purpose); values under LLOQ will either be a “No peak” or an actual value between 0 and the 
LLOQ value (i.e. 50 pg/mL). The Inclusion of the informative PK concentrations ("No peak” and actual 
value between 0 and the LLOQ) in the analyses under PK Data Set Info will be performed for information 
only. The conventions to be applied for “No peak” under PK Data Set Info will be the same as the one use 
for BQL under PK Data Set. Descriptive statistics and PK concentration plots will be conducted on both 
data sets.  
Descriptive statistics (n, 0<n<LLOQ, n with imputed 0, arithmetic mean, SD, geometric mean, geometric 
CV(%), median, min, and max) will be used to summarize the plasma concentrations for AZP-3601 by 
scheduled time point by study part and treatment (for Parts A and B)/cohort (for Part C). Plasma 
concentrations for AZP-3601 below the quantifiable limit (BQL) will be set to zero in the computation of 
descriptive statistics. Geometric means and geometric CV(%) will be presented as ‘NC’ (not calculable) if 
there is at least one BQL value imputed by zero.  
Linear and semi-logarithmic plots of the arithmetic mean plasma concentration with SD by scheduled 
sampling time will be provided by study part and 
/cohort (for Part C). These 
plots will show time in hours. 
 In Part
 
C, the MAD treatments will be presented in one plot per day. In addition, overlay plots for the MAD 
treatments will be presented, 
 
showing Day 1, Day 14 and Day 28 in one plot for Part C (one plot per cohort). If more than half of the 
subjects for a given timepoint have BQL values, then no mean profiles will be provided.  
Combined individual concentration-time profiles will be presented graphically on both a linear and a 
semi-logarithmic scale for each 
/cohort (for Part C). MAD plots will show the 
profiles for each day. 
Linear and semi-logarithmic plots of the individual plasma concentrations by actual sampling times will be 
provided by subject. These plots will show time in hours. MAD plots will show the complete profile. 
Individual plots will use the BQL handling procedure described below for “Pharmacokinetic Parameters”.  
All individual subject plasma concentration data will be listed, including time deviations and comments. 
15.2.2 Pharmacokinetic Parameters 
PK parameters for AZP-3601 will be estimated using non-compartmental methods with WNL under PK 
population set with data handling of PK Data Set and PK Data Set Info (if meaningful by the data 
obtained). Parameters will first be derived with values under LLOQ set as “BQL” (i.e. using PK Data Set). 
The inclusion of the informative PK concentrations ("No peak” and actual value between 0 and the LLOQ) 
in the calculation of the parameters will be performed for information only (i.e. using PK Data Set Info). 
Descriptive statistics will be conducted on both data sets if meaningful by the data obtained. 
The plasma PK parameters will be estimated from the concentration-time profiles. In estimating the PK 
parameters, BQL values at the beginning of the profile will be set to zero. BQL values that occur after the 
first quantifiable point will be considered missing. Values that are embedded between BQLs, or 
quantifiable values occurring after two or more BQLs, will be set to missing at the discretion of the 
pharmacokineticist. Actual sampling times, rather than scheduled sampling times, will be used in all 
computations involving sampling times. If the actual time or dose time is missing, the scheduled time may 
be substituted in order to calculate the PK parameter. 


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The points to be included in the kel range will be determined by the pharmacokineticist after inspection of 
the semi-log concentration-time profiles. At least 3 points will be required to be used. The Cmax data point 
will not be included. 
Parameters based on %AUCextra>20% or Adj R2 ≤ 0.80 will be flagged but not excluded from statistical 
analysis.  
Descriptive statistics (n, arithmetic mean, SD, geometric mean, geometric CV(%), median, min, and max) 
will be used to summarize the calculated PK parameters by study part and treatment (for Parts A and B) 
/cohort (for Part C). For tmax, only n, median, min and max will be presented. 
15.2.2.1 Dose-Proportionality 
 
 
 
 
  
 
 
  
 
 
16.0 Pharmacodynamic and other Analysis 
16.1 Pharmacodynamic and other Variables 
16.1.1 Serum PD Concentrations and Parameters 
Part
 C: 
At the time points defined in the schedules of assessments, blood samples will be taken for the 
measurements of serum total calcium, serum albumin, albumin-corrected serum calcium, serum 
phosphate, serum creatinine (to calculate the fractional excretion (FECa) of calcium and phosphate), and 
endogenous serum PTH(1-84). 
 
Serum PD variables include level/concentration of  
 
Serum total calcium 
 
Albumin-corrected serum calcium  
o Albumin-corrected serum calcium (mmol/L) = serum total calcium (mmol/L) + 0.020 (40 - serum 
albumin [g/L]) 
 
Serum phosphate  
 
Endogenous serum PTH(1-84).  
Furthermore, serum AUC0-24 for albumin-corrected calcium is a serum PD variable, which is defined as 
area under the serum concentration-time curve from time zero up to 24 hours for albumin-corrected 
calcium. 
 


Statistical Analysis Plan 
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Version Date: 26-Aug-2022  
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Page 26 of 53 
Part
 only: 
In addition to the PD variables listed above, at the time points defined in the schedules of assessments, 
blood samples will be taken for the measurements of serum 25-hydroxy vitamin D, serum 1.25-dihydroxy 
vitamin D, serum magnesium and serum bone turnover biomarkers. 
 
Serum PD variables include level/concentration of  
 
Serum 1.25-dihydroxy vitamin D 
 
Serum Magnesium 
 
Serum bone turnover biomarkers: 
o 
Serum bone-specific alkaline phosphatase (BSAP) 
o 
Serum carboxy-terminal telopeptide of type I collagen (s-CTx) 
o 
Serum procollagen type 1 amino-terminal propeptide (P1NP) 
o 
Serum osteocalcin 
 
Part C only: 
In addition to the PD variables listed above, the following serum PD variables will be calculated:  
 
Serum calcium phosphate product 
o Serum calcium phospate product (mg2/dL2) = serum total calcium (mg/dL) * serum phosphate 
(mg/dL)   
 
Number of patients within the target range of albumin-corrected serum calcium 
 
Number of patients within the normal range of albumin-corrected serum calcium 
 
Number of patients within target range of albumin-corrected serum calcium who taking no vitamin D 
and taking <=500mg of oral calcium 
 
Number of patients within normal range of albumin-corrected serum calcium who taking no vitamin 
D and taking <=500mg of oral calcium, 
where target range refers to 7.8 to 9.0 mg/dL and normal range refers to 8.3 to 10.6 mg/dL. 
 
16.1.2 Urine PD Concentrations and Parameters 
Part
 C:  
Urine will be collected during 24-hour collection intervals as defined in the schedules of assessments for 
the analysis of urine calcium, phosphate, creatinine (to calculate the FECa of calcium and phosphate and 
renal tubular maximum reabsorption of phosphate/glomerular filtration rate [TMP/GFR]) , 
 
 and magnesium. 
 
The urine PD variables include  
 
24-hour urine calcium (calcium excretion rate) =  concentration of urine calcium * volume 24h 
sample 
 
24-hour urine calcium adjusted by creatinine =   concentration of urine calcium in the 24h urine/ 
concentration of urine creatinine in the 24h urine 
 
24-hour urine calcium adjusted by body weight 1 = concentration of urine calcium * volume 24h 
sample / body weight  
 
24-hour urine phosphate (phosphate excretion rate)  =  concentration of urine phosphate * volume 
24h sample 
 
24-hour urine cAMP (cAMP excretion rate) =  concentration of urine cAMP * volume 24h sample 


Statistical Analysis Plan 
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 
Renal clearance of calcium =  Urine Ae0-24 / Serum AUC0-24 for albumin-corrected calcium, where  
Ae0-24 is the total amount of calcium excreted unchanged into urine from time 0 to 24h  
 
Renal clearance of phosphate =  Urine Ae0-24 / Serum AUC0-24 for phosphate, where Ae0-24 is the 
total amount of phosphate excreted unchanged into urine from time 0 to 24h  
 
FECa of calcium (%)2 = 100 * urine calcium * serum creatinine / (serum calcium * urine creatinine) 
 
FECa of phosphate (%)3 = 100 * urine phosphate * serum creatinine / (serum phosphate * urine 
creatinine) 
 
Tubular reabsorption of phosphate (TRP) = 1 - {(urine phosphate/serum phosphate) × (serum 
creatinine/urine creatinine)} 
 
Renal TMP/GFR = TRP × serum phosphate if TRP was ≤0.86;  Renal TMP/GFR =  0.3 × TRP/[1 – 
(0.8*TRP)] × serum phosphate 
 
24-hour urine magnesium (magnesium excretion rate) =  concentration of urine magnesium * 
volume 24h sample (Only for Part C) 
Note 1: for 24-hour urine calcium adjusted by body weight:  “body weight” refers to the last measurement of body weight before the 
start of 24-hour interval of urine collection for each day.  
Note 2: for FECa of calcium (%): “serum calcium” refers to the measurement at start of 24-hour interval of urine collection for each 
day. 
Note 3: for FECa of phosphate (%): “serum phosphate” refers to the measurement at start of 24-hour interval of urine collection for 
each day. 
16.1.3 Standard of Care 
Part C only: 
Standard of care will be evaluated at Baseline, at Day 14, at the end of the main treatment period (Day 
28) and after 2 weeks during the extension period.  
Variables for Standard of Care includes the following: 
 
Mean active vitamin D dose 
 
Mean calcium dose 
 
Number of patients 
o 
Taking neither vitamin D nor calcium  
o 
Taking no vitamin D and ≤1000 mg/day of calcium 
o 
Taking no vitamin D and ≤500 mg/day of calcium 
o 
Taking no vitamin D 
o 
Taking no calcium  
o 
Taking ≤500 mg/day of calcium 
o 
Taking ≤1000 mg/day of calcium 
 
16.1.4 EQ-5D Questionnaire 
Part C only: 
EQ-5D will be used as a self-administered questionnaire measuring generic health status. The EQ-5D 
questionnaire has 2 components: health state description (using five-level scale) and evaluation (using a 
visual analogue scale). 
Parameters from EQ-5D questionnaire 
 
Health state description 
o 
Mobility 
o 
Self-care 
o 
Usual activities 
o 
Pain/discomfort 


Statistical Analysis Plan 
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o 
Anxiety/depression 
 
Health state evaluation 
o 
Overall health status 
16.1.5 SF-36 Questionnaire 
Part C only: 
Short form health survey 36 (SF-36) will be used as a self-administered questionnaire measuring generic 
health status. 
The SF-36 consists of 8 scaled scores, which are based on the sums of the questions in their section. 
Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal 
weight. The lower the score, the more disability. The higher the score, the greater level of functioning  i.e. 
a score of 0 is equivalent to worst functioning and a score of 100 is equivalent to best functioning. The 
health domain scales will be transformed to T Scores (refer to “User’s Manual for the SF-36v2 Health 
Survey, 3rd Edition”). The 8 scaled scores will be calculated by PRO CoRe 2.0 Smart Measurement 
System. Missing data will be dealt with using Missing Data Estimation (MDE).  Using MDE, the software 
applies a value to a scale item rendered missing if at least one of the items in that scale has valid data. A 
scale receives a “missing” score (“.”) only if all the items in that scale are missing. 
 
Parameters from short form health survey 36 (SF-36) questionnaire 
o 
Vitality 
o 
Physical functioning 
o 
Bodily pain 
o 
General health perceptions 
o 
Physical role functioning 
o 
Emotional role functioning 
o 
Social role functioning 
o 
Mental health 
 
In addition to display of separate scales, component summaries will be shown:  
o 
Physical Component Summary (PCS), summarizing Physical functioning, Physical role 
functioning, Bodily pain, and General health perceptions 
and  
o 
Mental Component Summary (MCS), summarizing Vitality, Social role functioning, 
Emotional role functioning, and Mental health 
16.1.6 DXA Analysis 
Part C only: 
Bone mineral density (BMD) and Trabecurlar Bone Score will be assessed by DXA. DXA scans will be 
conducted using standardized procedures and settings. DXAs image will be read using independent 
central reading. 
 
Parameters from DXA Analysis 
o 
BMD (T Score and Z Score) 
o 
Trabecular Bone Score 
16.2 Pharmacodynamic Evaluation 
All individual concentration data for the PD assessments and all PD variables will be listed by subject. 


Statistical Analysis Plan 
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Protocol: AZP-3601-CLI-001 
Version Date: 26-Aug-2022  
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16.2.1 Main PD Analysis 
The main PD variables refer to the concentration of serum total calcium, albumin-corrected serum calcium 
and serum phosphate, as well as to the serum AUC0-24 for albumin-corrected calcium. The main PD 
variables will be summarized and listed in US standard units.   
Descriptive statistics (n, arithmetic mean, SD, median, min, and max) summarizing the serum 
concentration for main PD variables (absolute observed value and change from baseline) will be 
presented by study part and 
/cohort (for Part C) at each scheduled 
timepoint/day. Taking potential batch effect into consideration, the change from baseline will be calculated 
with corresponding baseline per batch if applicable; for different batches, all the assessments (absolute 
observed value and change from baseline (when possible)) will be presented with corresponding batch 
information separately. For the daily pre-dose timepoints, if a repeat/retest result is available, then the 
repeat/retest (Batch R) result will be used for the calculations. 
 
 
 
 
 
 
 
  
 
 
 
 
Descriptive statistics (n, arithmetic mean, SD, median, min, and max) will also be used to summarize the 
serum AUC0-24 for albumin-corrected calcium. Change from baseline for that AUC will be listed and 
summarized, which is defined as area under the serum concentration-time curve from time zero up to 24 
hours for change from baseline of albumin-corrected calcium.  
In Part A, linear plots of the arithmetic mean serum concentrations of main PD variables (absolute 
observed value and change from baseline) with SD over all scheduled timepoints will be presented by 
treatment. In Part B, similar linear plots (absolute observed value and change from baseline) will also be 
provided for each summary tables of serum concentration as described above and presenting only the 
24h profile versus time on Day 1, Day 7 and Day 14 (separately). In part C, similar linear plots will be 
provided by cohort for the main treatment period and for the extension phase separately.  
16.2.2 Exploratory Analysis for other PDs and other Measurements 
16.2.2.1 Serum 
As to the other serum concentration of PD variables (endogenous serum PTH(1-84), serum 25-hydroxy 
vitamin D, serum 1.25-dihydroxy vitamin D, and serum bone turnover biomarkers), descriptive statistics 
(n, arithmetic mean, SD, median, min, and max) summarizing the panel data (absolute observed values 
and change from baseline) will be presented by study part, 
) /cohort (for Part 
C) at each scheduled timepoint/day. For PTH(1-84), BQL values will be set to half of the LLOQ value. 
 
As to the derived PD serum variables in Part C (serum calcium phosphate product, number of patients 
within the target range of albumin-corrected serum calcium, number of patients within the normal range of 
albumin-corrected serum calcium, number of patients within target range of albumin-corrected serum 
calcium who taking no vitamin D and taking <=500mg of oral calcium, number of patients within normal 
range of albumin-corrected serum calcium who taking no vitamin D and taking <=500mg of oral calcium) 
will be summarized descriptively by cohort and timepoint. The corresponding numbers and percentages 
of patients will be summarized at Baseline, Day 14, and Day 28.  


Statistical Analysis Plan 
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Version Date: 26-Aug-2022  
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Page 30 of 53 
16.2.2.2 Urine 
As to the derived PD urine variables, descriptive statistics (n, arithmetic mean, SD, median, min, and 
max) will be used to summarize by study part, 
 /cohort (for Part C) and 
scheduled timepoint. For 24-hour urine calcium, 24-hour urine phosphate and 24-hour urine magnesium 
(for Part C only), descriptive statistics will also be provided for change from baseline.  
In addition, linear plots will be provided for bone turnover biomarkers, in a way similarly as the linear plots 
mentioned above for main PD analysis. 
16.2.2.3 Standard of Care 
Summary and frequency table will be provided for each variable of standard of care by cohort at baseline, 
at day 14, at the end of main treatment period and every two weeks during extension.  
Dosing amounts of supplements prescribed by investigators will be listed and used for the analysis of 
standard of care. 
16.2.2.4 EQ-5D and SF-36 
Descriptive statistics (n, arithmetic mean, SD, median, min, and max) will be used to summarize scores 
(absolute values and changes from baseline) for the parameters of these questionnaires by cohort at 
each scheduled day. 
16.2.2.5 DXA Analysis 
Descriptive statistics (n, arithmetic mean, SD, median, min, and max) will be used to summarize BMD and 
Trabecular Bone Score (absolute values and changes from baseline) by treatment dose level and at each 
scheduled day.  
17.0 Safety Analyses  
17.1 Safety Variables 
The following safety variables will be summarized by study part (Part
 C main, or C extension) if 
applicable: 
 
AEs 
 
Injection Site Reaction  
 
Clinical Laboratory Evaluations 
o 
Clinical Chemistry  
o 
Hematology  
o 
Coagulation 
o 
Urinalysis 
 
Vital Signs 
o 
Systolic Blood Pressure 
o 
Diastolic Blood Pressure  
o 
Pulse rate 
o 
Body temperature 
 
Electrocardiograms (ECG) 
o 
Heart Rate 
o 
PR-Interval 
o 
QRS-Duration 
o 
QT-Interval 
o 
QTc Friderica  
 
Part A only: Continuous cardiac monitoring (telemetry) 
 
Physical Examination 
 
Body Weight and BMI 


Statistical Analysis Plan 
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 
Antidrug antibodies (ADA) in plasma 
 
17.1.1 Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to (the first) 
administration of the study drug or any event already present that worsens in either severity or frequency 
following exposure to the study drug.  
An overall summary table will be provided by treatment and overall for each study part with the number of 
subjects and events reporting, AEs, TEAEs, treatment-emergent SAEs, treatment-emergent AEs of 
special interest (AESIs), and TEAEs leading study drug discontinuation. 
Based on the pharmacology of AZP-3601 as well as other PTH analogs, and the pathophysiology of HP, 
AESIs are as follows:  
 
Hypocalcemia (including the following symptoms: agitation, anxiety, hypoestesia, paresthesia, 
muscle cramping, muscle fatigue, musculoskeletal pain, musculoskeletal stiffness, myalgia, 
tetany, seizure, tremor, brain fog). 
 
Hypercalcemia (including the following symptoms: thirst, frequent urination, abdominal pain, 
nausea, vomiting, fatigue). 
 
Hypercalciuria. 
 
Orthostatic hypotension and vasodilatory symptoms (including postural/orthostatic dizziness, 
syncope, tachycardia/palpitations). 
A summary table with the number of subjects reporting TEAEs and the number of events, categorized by 
system organ class (SOC) and preferred term (PT) coded according to the MedDRA, will be presented by 
 /cohort (for Part C)  and overall for each study part. Subjects will only be 
counted once within each system organ class or preferred term. 
A summary table with the number of subjects reporting TEAEs, categorized by SOC, PT and relationship  
to study drug (Related or Not Related), will be provided by 
 /cohort (for Part 
C)  and overall for each study part. A treatment-related TEAE is defined as any TEAE that is assessed by 
the investigator as definitely, likely, possibly or unlikely related to study treatment. TEAE that is assessed 
as Not Related will be defined as not treatment-related. Subjects with multiple events within a particular 
body system or preferred term will be counted under the category of their most drug-related event within 
that body system or preferred term.  
A summary table with the number of subjects reporting TEAEs, categorized by SOC, PT and severity as 
recorded on eCRF (Mild, Moderate, Severe, Life-threatening or Death), will also be provided by 
 
/cohort (for Part C) and overall for each study part. Subjects with multiple events within 
a particular body system or preferred term will be counted under the category of their most severe event 
within that body system or preferred term. 
A summary table with the number of subjects reporting treatment-emergent AESIs and the number of 
events, categorized by SOC and PT coded according to the MedDRA, will be presented by treatment (for 
Parts A and B)/cohort (for Part C) and overall per for each study part. Subjects will only be counted once 
within each body system or preferred term. 
The following missing data will be imputed as defined (for calculations only / will not be presented): 
 
Missing AE severity or relationship will be assumed to be severe or related, respectively 
 
Missing AE start times for the determination of treatment emergence will be assumed to occur 
after treatment unless partial date documents the AE as happening prior to treatment 
 
Missing AE start date will be assumed to be after treatment for the determination of TEAE unless 
partial or complete end date documents the AE as happening prior to treatment 
All AEs (including non-treatment-emergent events) recorded on the eCRF will be listed, with a flag to 
indicate whether the AEs are AESIs.  
A separate listing of TEAEs leading to study drug discontinuation will be provided. 


Statistical Analysis Plan 
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Page 32 of 53 
17.1.2 Deaths and Serious Adverse Events 
A listing of deaths and other serious adverse events (SAE) will be provided by subject. 
17.1.3 Injection Site Reactions   
Injection site reactions as collected on the CRF will be listed per subject. 
A summary table with the number and percentage of subjects reporting injection site reactions, 
categorized by severity evaluation, will be presented by 
 /cohort (for Part C) 
and overall at each scheduled assessment timepoint for each study part.  
17.1.4 Laboratory Data 
Clinical laboratory data will be presented using standard units from the SDTM Controlled Terminology. 
Descriptive statistics summarizing continuous laboratory results of clinical chemistry, hematology and 
coagulation (absolute observed and derived changes from baseline) for each study part by 
 
 /cohort (for Part C) and scheduled time will be presented.  
Frequency table summarizing categorical laboratory results of urinalysis for each study part by 
 
 /cohort (for Part C)  and scheduled time will be presented, if appropriate. 
All laboratory data will be listed by subject. 
A separate listing of clinically significant abnormal values will also be provided. 
17.1.5 Vital Signs 
Descriptive statistics summary of vital signs and derived changes from baseline will be provided for each 
study part by 
 /cohort (for Part C) and scheduled time point. 
All vital signs data (including changes from baseline) will be listed by subject. 
17.1.6 Body Weights and BMI 
Descriptive statistics summary of body weights and BMI and derived changes from baseline will be 
provided for each study part by 
 /cohort (for Part C) and scheduled time 
point. 
All body weights and BMI data (including changes from baseline) will be listed by subject. 
17.1.7 Electrocardiograms 
A descriptive statistics summary of continuous 12-lead ECG parameters and derived changes from 
baseline will be provided for each study part by 
 /cohort (for Part C) and 
scheduled time.  
 
 
 
All ECG parameters (including changes from baseline) and the corresponding abnormalities and 
physician’s conclusions will be listed by subject. 
 
 
 
17.1.9 Physical Examination 
The physical examination findings (abnormalities) at screening and changes /new findings after screening 
will be listed. 


Statistical Analysis Plan 
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17.1.10 ADA in Plasma 
The presence of ADA in plasma will be listed if applicable. 
18.0 References 
Clinical Study Protocol: A SINGLE AND MULTIPLE ASCENDING DOSE STUDY TO INVESTIGATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF AZP-3601, A 
SYNTHETIC PARATHYROID HORMONE ANALOG, IN HEALTHY SUBJECTS AND IN SUBJECTS 
WITH HYPOPARATHYROIDISM. Global Version 5.0, 12May2021. 
Clinical Study Protocol: A SINGLE AND MULTIPLE ASCENDING DOSE STUDY TO INVESTIGATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF AZP-3601, A 
SYNTHETIC PARATHYROID HORMONE ANALOG, IN HEALTHY SUBJECTS AND IN SUBJECTS 
WITH HYPOPARATHYROIDISM. Netherlands specific version 3.3, 17Mar2021. 
Blinding Plan: A SINGLE AND MULTIPLE ASCENDING DOSE STUDY TO INVESTIGATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF AZP-3601, A 
SYNTHETIC PARATHYROID HORMONE ANALOG, IN HEALTHY SUBJECTS AND IN SUBJECTS 
WITH HYPOPARATHYROIDISM. Version 15Jan2021.  
User’s Manual for the SF-36v2 Health Survey, QualityMetric Incorporated, 3rd Edition, 2011 (ISBN: 1-
891810-28-6) 
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