A Phase 2b, Open-label Dose-ranging Study Evaluating the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy of CLTX-305 (Encaleret) in Autosomal Dominant Hypocalcemia (ADH) Type 1
Phase: PHASE2
Conditions: Autosomal Dominant Hypocalcemia (ADH), Autosomal Dominant Hypocalcemia Type 1 (ADH1)
Sponsor: Calcilytix Therapeutics, Inc., a BridgeBio company

Confidential 
CALCILYTIX THERAPEUTICS, INC 
Abbreviated Title 
CLTX-305 for treatment of ADH1 
Protocol Number: 
CLTX-305-201 
NIH 20-D-0122 
IND Number: 
143347 
Version Dates: 
30 October 2019 (original) 
Amendment 6: 03 June 2021 
Amendment 1: 16 April 2020 
Amendment 7: 12 November 2021 
Amendment 2: 10 June 2020 
Amendment 3: 24 June 2020 
Amendment 4: 24 August 2020 
Amendment 5: 09 February 2021 
Amendment 8: 16 August 2022 
Amendment 9: 25 April 2023 
Amendment 10: 18 May 2023 
Protocol Title: 
A Phase 2b, Open-label Dose-ranging Study Evaluating the Safety, 
Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy 
of CLTX-305 (encaleret) in Autosomal Dominant Hypocalcemia Type 
1 (ADH1). 
Indication: 
Autosomal Dominant Hypocalcemia Type 1 (ADH1) 
Investigational Medicinal 
Product: 
CLTX-305 (encaleret)  
Sponsor/Manufacturer: 
Calcilytix Therapeutics, Inc. 
1800 Owens Street Suite C-1200 
San Francisco CA, 94158 
Key Sponsor Contacts: 
 
 
Confidentiality Statement 
This document contains information proprietary to Calcilytix Therapeutics, Inc. The information is being provided to you for the purpose of 
conducting a clinical trial for Calcilytix Therapeutics, Inc. You may disclose the contents of this document to study personnel under your 
supervision who need to know for the purpose, provided such study personnel are bound by confidentiality obligations to keep this document and 
its contents confidential. You are allowed to disclose the contents of this document to your Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC) as required for the purpose. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Calcilytix Therapeutics, Inc. and that it may not be further disclosed to third parties. You may not disclose the 
contents of this document to any other party, unless government regulations or laws require such disclosure, without prior written permission 
from Calcilytix Therapeutics, Inc. Any supplemental information that may be added to this document is proprietary to Calcilytix Therapeutics, 
Inc. and should be handled in accordance with the conditions described above. 
NCT #: NCT04581629

CLTX-305 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201: Amendment 10: 18 May 2023 NIH 20-D-0122  
Page 2 
 
Confidential 
 
INVESTIGATOR’S STATEMENT 
I agree to conduct the study (Study CLTX-305-201) in accordance with the protocol and with 
all applicable government regulations and Good Clinical Practice (GCP) guidance. 
 
 
 
 
 
Principal Investigator’s Signature  
 
Date 
 
 
 
 
 
  
 
National Institutes of Health  
Building 30, Rm 218 
30 Convent Dr. MSC 4320 
Bethesda, MD 20892-4320 
 
 
 
  
 
 

CLTX-305 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201: Amendment 10: 18 May 2023 NIH 20-D-0122  
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Confidential 
 
SPONSOR’S AGREEMENT 
I approve the attached protocol entitled “A Phase 2b, Open-label Dose-ranging Study 
Evaluating the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy 
of CLTX-305 (encaleret) in Autosomal Dominant Hypocalcemia Type 1 (ADH1)" and agree 
to abide by all provisions set forth therein. 
 
 
 
 
 
 
 
 
 
 
   
Calcilytix Therapeutics, Inc. 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
5/19/2023 | 10:46 AM PDT

CLTX-305 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201: Amendment 10: 18 May 2023 NIH 20-D-0122  
Page 4 
 
Confidential 
 
TABLE OF CONTENTS 
INVESTIGATOR’S STATEMENT ..........................................................................................2 
SPONSOR’S AGREEMENT ....................................................................................................3 
TABLE OF CONTENTS ...........................................................................................................4 
LIST OF TABLES .....................................................................................................................7 
LIST OF FIGURES ...................................................................................................................8 
LIST OF ABBREVIATIONS ....................................................................................................9 
STATEMENT OF COMPLIANCE .........................................................................................11 
1 
PROTOCOL SUMMARY .....................................................................................12 
1.1 
Synopsis ...........................................................................................................12 
1.2 
Schema .............................................................................................................16 
1.3 
Schedule of Activities (SOA) ..........................................................................19 
1.3.1 
Pharmacokinetic, Pharmacodynamic, and Urine Sampling Times ......27 
2 
INTRODUCTION .................................................................................................32 
2.1 
Study Rationale ................................................................................................32 
2.2 
Background ......................................................................................................34 
2.2.1 
Pharmacokinetics and Product Metabolism .........................................34 
2.2.2 
Efficacy of CLTX-305 (encaleret) in Prior Clinical Trials ..................35 
2.2.3 
Autosomal Dominant Hypocalcemia, Type 1 ......................................35 
2.3 
Risk/Benefit Assessment .................................................................................37 
2.3.1 
Known Potential Risks .........................................................................37 
2.3.2 
Known Potential Benefits ....................................................................39 
2.3.3 
Assessment of Potential Risks and Benefits ........................................39 
3 
OBJECTIVES AND ENDPOINTS .......................................................................41 
4 
STUDY DESIGN...................................................................................................44 
4.1 
Overall Design .................................................................................................44 
4.2 
Scientific Rationale for Study Design ..............................................................47 
4.3 
Justification for Dose .......................................................................................48 
5 
STUDY POPULATION ........................................................................................49 
5.1 
Inclusion Criteria .............................................................................................49 
5.2 
Exclusion Criteria ............................................................................................50 
5.3 
Inclusion of Vulnerable Participants ................................................................52 
5.4 
Lifestyle Considerations ..................................................................................52 
5.5 
Screen Failures .................................................................................................52 
5.6 
Strategies for Recruitment and Retention ........................................................52 
5.6.1 
Costs .....................................................................................................53 
5.6.2 
Compensation ......................................................................................53 
6 
STUDY INTERVENTION ....................................................................................54 

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6.1 
Study Interventions(s) Administration .............................................................54 
6.1.1 
Study Intervention Description ............................................................54 
6.1.2 
Dosing and Administration ..................................................................54 
6.1.3 
Period 1 (Single Ascending Dose Escalation and BID PK/PD 
profile) – Cohort 1 ...............................................................................56 
6.1.4 
Period 2 (BID Dosing) – Cohorts 1 and 2............................................56 
6.1.5 
Period 3 (Cohort 1 and Cohort 2) – Outpatient Dosing .......................57 
6.1.6 
Long-term Extension (Cohort 1 and Cohort 2) – Outpatient Dosing ..57 
6.1.7 
Dose Limiting Toxicity ........................................................................57 
6.1.8 
Dose Modifications ..............................................................................59 
6.1.9 
Drug Administration ............................................................................59 
6.2 
Preparation/Handling/Storage/Accountability .................................................60 
6.2.1 
Acquisition and Accountability ...........................................................60 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ...........................60 
6.2.3 
Product Storage and Stability...............................................................60 
6.2.4 
Preparation ...........................................................................................61 
6.3 
Measures to Minimize Bias: Randomization and Blinding .............................61 
6.4 
Study Intervention Compliance .......................................................................61 
6.5 
Concomitant Therapy.......................................................................................61 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..............................................................63 
7.1 
Discontinuation of Study Intervention .............................................................63 
7.2 
Participant Discontinuation/Withdrawal from the Study .................................63 
7.3 
Lost to Follow-up .............................................................................................64 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................65 
8.1 
Screening Procedures .......................................................................................65 
8.2 
Treatment Period ..............................................................................................65 
8.2.1 
Period 1 (Single Ascending Dose Escalation and BID PK/PD 
profile) – Cohort 1 ...............................................................................65 
8.2.2 
Period 2 (BID Dosing) - Cohorts 1 and 2 ............................................68 
8.2.3 
Period 3 (Cohort 1 and Cohort 2) - Outpatient Dosing ........................71 
8.2.4 
Long-term Extension (LTE) ................................................................72 
8.2.5 
Follow-up and Early Termination ........................................................73 
8.3 
Efficacy Assessments .......................................................................................74 
8.3.1 
Pharmacokinetic and Pharmacodynamic Blood Sampling ..................74 
8.3.2 
Timed Interval and 24-hour urine ........................................................74 
8.3.3 
Clinical Evaluations .............................................................................74 
8.3.4 
Samples for Genetic/Genomic Analysis ..............................................74 
8.3.5 
Description of the Scope of Genetic/Genomic Analysis .....................74 

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8.3.6 
Description of how Privacy and Confidentiality of Medical 
Information/Biological Specimens will be Maximized .......................75 
8.3.7 
Management of Results ........................................................................75 
8.3.8 
Genetic counseling ...............................................................................75 
8.4 
Safety and Other Assessments .........................................................................76 
8.4.1 
Physical Examinations .........................................................................76 
8.4.2 
Vital Signs ............................................................................................76 
8.4.3 
Clinical Laboratory Determinations ....................................................76 
8.4.4 
Electrocardiograms ..............................................................................77 
8.4.5 
Dual-energy X-Ray Absorptiometry (DXA) .......................................77 
8.4.6 
Renal Ultrasound .................................................................................77 
8.5 
Adverse Events and Serious Adverse Events ..................................................78 
8.5.1 
Definition of Adverse Event ................................................................78 
8.5.2 
Definition of Serious Adverse Events (SAE) ......................................78 
8.5.3 
Classification of an Adverse Event ......................................................78 
8.5.4 
Time Period and Frequency for Event Assessment and Follow-Up ....79 
8.5.5 
Adverse Event Reporting .....................................................................80 
8.5.6 
Serious Adverse Event Reporting ........................................................81 
8.5.7 
Events of Special Interest.....................................................................82 
8.5.8 
Reporting of Pregnancy .......................................................................84 
8.6 
Unanticipated Problems ...................................................................................85 
8.6.1 
Definition of Unanticipated Problems (UP) ........................................85 
8.6.2 
Unanticipated Problem Reporting ........................................................85 
8.6.3 
NIH Intramural IRB Reporting of IND Safety Reports .......................85 
9 
STATISTICAL CONSIDERATIONS...................................................................86 
9.1 
Statistical Hypothesis .......................................................................................86 
9.2 
Sample Size Determination ..............................................................................86 
9.3 
Populations for Analyses .................................................................................86 
9.4 
Statistical Analyses ..........................................................................................86 
9.5 
Demographics and Other Baseline Characteristics ..........................................86 
9.6 
Safety Analyses ................................................................................................87 
9.7 
Pharmacokinetic Analyses ...............................................................................87 
9.8 
Pharmacodynamic Analyses ............................................................................87 
9.9 
Interim Analysis ...............................................................................................87 
10 
REGULATORY AND OPERATIONAL CONSIDERATIONS ..........................88 
10.1 
Informed Consent Process ...............................................................................88 
10.1.1 
Consent/Assent Procedures and Documentation .................................89 
10.2 
Study Discontinuation and Closure .................................................................90 

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10.3 
Confidentiality and Privacy .............................................................................90 
10.4 
Future Use of Stored Specimens and Data ......................................................92 
10.5 
Safety Oversight...............................................................................................92 
10.6 
Clinical Monitoring ..........................................................................................93 
10.7 
Quality Assurance and Quality Control ...........................................................93 
10.8 
Data Handling and Record Keeping ................................................................94 
10.8.1 
Data Collection and Management Responsibilities .............................94 
10.8.2 
Study Records Retention ......................................................................94 
10.8.3 
LTE Electronic Data Capture ...............................................................95 
10.9 
Protocol Deviations ..........................................................................................95 
10.9.1 
NIH Definition of Protocol Deviation .................................................95 
10.10 
Publication and Data Sharing Policy ...............................................................95 
10.10.1 
Human Data Sharing Plan ....................................................................95 
10.10.2 
Genomic Data Sharing Plan .................................................................96 
10.10.3 
Agreement Type ...................................................................................96 
10.11 
Conflict of Interest Policy ................................................................................96 
11 
REFERENCES ......................................................................................................97 
Appendix 1  
Summary of Changes ...........................................................................99 
 
LIST OF TABLES 
Table A 
Period 1 Schedule of Activities ..................................................................19 
Table B 
Period 2 Schedule of Activities ..................................................................21 
Table C 
Period 3 Schedule of Activities ..................................................................23 
Table D 
Long-term Extension Schedule of Activities .............................................25 
Table E 
Non-intensive BID Sampling Days ...........................................................27 
Table F 
Non-intensive BID Sampling Days - (if CLTX-305 (encaleret) dose is 
≤ 180 mg BID) ...........................................................................................27 
Table G 
Non-intensive BID Sampling Days - (if CLTX-305 (encaleret) dose is 
> 180 mg BID) ...........................................................................................28 
Table H 
Intensive Sampling Days for QD dosing ...................................................28 
Table I 
Intensive Sampling Days for BID dosing ..................................................29 
Table J 
Intensive Sampling Days for BID dosing - (if CLTX-305 (encaleret) 
dose is > 180 mg BID) ...............................................................................30 
Table K 
Intensive Sampling Days for BID dosing- (if CLTX-305 (encaleret) 
dose is ≤ 180 mg BID) ...............................................................................31 
Table L 
Research Sample Collection Timepoints in Periods 1 and 3 .....................31 
 

CLTX-305 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201: Amendment 10: 18 May 2023 NIH 20-D-0122  
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LIST OF FIGURES 
Figure A 
Study Overview Schematic ........................................................................45 
Figure B 
Detailed Schematic for Periods 1 and 2 (Single and Multiple 
Ascending Dose Testing) ...........................................................................45 
Figure C 
Detailed Schematic for Period 3 ................................................................46 
Figure D 
Detailed Schematic for Long-term Extension (LTE) .................................46 
Figure E 
Dosing Guidance Algorithm for Period 1 ..................................................67 
Figure F 
Dosing Guidance Algorithm for Period 2 – Cohort 1 ................................70 

CLTX-305 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201: Amendment 10: 18 May 2023 NIH 20-D-0122  
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADH1 
Autosomal dominant hypocalcemia type 1 (ADH1) 
AE 
Adverse event 
AESI 
Adverse event of Special Interest 
Alb 
Albumin 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC(0-24) 
Area under the concentration-time curve from time 0 to 24 hours 
AUC(0-inf) 
AUC extrapolated to infinity 
AUC(0-t) 
Area under the concentration-time curve from time 0 to the last 
measurable time point 
AUC(0-tau) 
AUC over the dosing interval 
BID 
Twice daily 
BMI 
Body mass index 
Ca 
Calcium 
CaSR 
Calcium-sensing receptor 
CaSR 
Human gene encoding the CaSR 
cCa 
Albumin-corrected blood calcium 
Cmax 
Maximum plasma concentration 
Cr 
Creatinine 
Ctrough 
Trough concentration 
CTx 
Collagen cross-linked C-telopeptide 
DL 
Dose Level 
DMC 
Data Monitoring Committee  
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
ET 
Early termination 
EoT 
End of Treatment  
FDA 
Food and Drug Administration 
FGF23 
Fibroblast growth factor-23 
FSH 
Follicle stimulating hormone 
FU 
Follow-up 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
Hr, hrs 
Hour, Hours 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgM 
Immunoglobulin M 
IND 
Investigational New Drug application 
IMP 
Investigational medicinal product: CLTX-305 (encaleret) 
iPTH 
Intact PTH 
Kd 
Dissociation constant 

CLTX-305 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201: Amendment 10: 18 May 2023 NIH 20-D-0122  
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Abbreviation 
Definition 
LTE 
Long-term Extension 
M1 
Metabolite of CLTX-305 (encaleret), ether glucuronide of the parent drug 
M3 
Metabolite of CLTX-305 (encaleret), acyl glucuronide of the parent drug 
NIH 
National Institutes of Health 
P1NP 
Procollagen type 1 N-propeptide 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/pharmacodynamic 
PTH 
Parathyroid hormone 
QD 
Once daily 
QTc 
QT interval corrected for changes in the heart rate 
SOC 
System organ class 
t½ 
Apparent terminal half-life 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum plasma concentration 
UVA/B 
Ultraviolet A or B light 
WOCBP 
Women of childbearing potential 

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Protocol: CLTX-305-201: Amendment 10: 18 May 2023 NIH 20-D-0122  
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the Institutional Review Board (IRB) for review and approval. Approval 
of both the protocol and the consent form must be obtained before any participant is enrolled. 
Any amendment to the protocol will require review and approval by the IRB before the 
changes are implemented to the study. In addition, all changes to the consent form will be 
IRB-approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 

CLTX-305 
 
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Protocol: CLTX-305-201: Amendment 10: 18 May 2023 NIH 20-D-0122  
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Title: 
A Phase 2b, Open-label Dose-ranging Study Evaluating the Safety, 
Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy 
of CLTX-305 (encaleret) in Autosomal Dominant Hypocalcemia 
Type 1 (ADH1) 
Study Description: 
This will be a single-site, open-label, dose-ranging study to evaluate 
the safety, tolerability, and efficacy of CLTX-305 (encaleret) to 
maintain normalized albumin-corrected blood calcium (cCa) in 
participants with hypocalcemia due to ADH1. The study consists of 
2 cohorts and 3 periods, followed by a Long-term Extension. 
Objectives: 
Primary: 
Periods 1 and 2: Evaluate the safety and tolerability of single and multiple 
doses of CLTX-305 (encaleret) in participants with ADH1 
Period 3: Evaluate the safety, tolerability, and efficacy of CLTX-305 
(encaleret) in participants with ADH1 for 24 weeks  
Long-term Extension (LTE) following Period 3: Evaluate the longer-term 
(25 months or about 2 years) safety and tolerability of CLTX-305 
(encaleret) 
 
Secondary: 
Periods 1 and 2:  
• 
Evaluate the effect of CLTX-305 (encaleret) to increase serum 
iPTH levels after both single and multiple doses across a dose 
range in participants with ADH1 
Periods 1, 2, and 3:  
• 
Evaluate the pharmacodynamic (PD) effects of CLTX-305 
(encaleret) on blood calcium concentrations 
• 
Evaluate the PD effects of CLTX-305 (encaleret) on associated 
measures of calcium homeostasis including 1,25-(OH)2 Vitamin D 
levels and urinary calcium excretion 
• 
Evaluate the PD effects of CLTX-305 (encaleret) on bone turnover 
markers including C-telopeptide (CTx) and procollagen type 1 N-
propeptide (P1NP)  
• 
Evaluate the PK of both single and multiple ascending doses of 
CLTX-305 (encaleret) in participants with ADH1. 
 
 

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LTE: 
• 
Obtain long-term data on efficacy (durability) of CLTX-305 
(encaleret) on blood calcium concentrations 
• 
Evaluate the long-term PD effects of CLTX-305 (encaleret) on 
associated measures of mineral homeostasis including iPTH, 1,25-
(OH)2 Vitamin D levels and urinary calcium excretion  
• 
Evaluate the long-term PD effects of CLTX-305 (encaleret) on 
bone turnover markers including C-telopeptide (CTx) and 
procollagen type 1 N-propeptide (P1NP)  
Endpoints: 
Primary: 
Periods 1, 2, and 3: Adverse events (AEs), clinical safety laboratory tests, 
vital signs, and electrocardiograms (ECGs) 
Period 3: Albumin-corrected blood calcium concentrations (cCa) and 24-hr 
urinary calcium excretion after treatment with CLTX-305 (encaleret) for 
24 weeks 
LTE: 
Adverse events (AEs), clinical safety laboratory tests, vital signs for 
approximately 25 months (approximately 2 years) 
Secondary:  
Periods 1 and 2: iPTH blood concentration profiles (24-hours) over time 
after single and multiple doses of CLTX-305 (encaleret) 
Periods 1, 2, and 3:  
• PK parameters: maximum plasma concentration (Cmax), time to 
maximum plasma concentration (tmax), apparent terminal half-life 
(t½), area under the concentration-time curve (AUC) from time 0 to 
the last measurable time point (AUC(0-t)), AUC from time 0 to 
24 hours (AUC(0-24)), AUC extrapolated to infinity (AUC(0-inf)) 
following single-doses.  
• Determination of the steady state PK parameters: Cmax, trough 
concentration (Ctrough), and AUC over the dosing interval AUC(0-
tau) 
 
 

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Periods 1, 2, 3, and LTE:  
• 
Pharmacodynamic endpoints measured over time: 
• 
Blood calcium - Absolute levels and change from baseline in cCa  
• 
Urinary calcium clearance (fractional excretion and 24-hour total 
excretion) 
• 
Renal function (eGFR) 
• 
Serum levels of 1,25-(OH)2 Vitamin D 
• 
Blood samples for magnesium, phosphate, creatinine 
• 
Urine samples for pH, magnesium, phosphate, sodium, potassium, 
creatinine, cAMP, citrate 
• 
Bone resorption markers collagen cross-linked C-telopeptide 
(CTx) 
• 
Bone formation markers – blood procollagen type 1 N-propeptide 
(P1NP) 

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Study Population: 
Up to 20 male or female participants (up to 16 to enter the treatment phase) 
with Autosomal Dominant Hypocalcemia Type 1 (ADH1) 
Phase: 
Phase 2b 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
National Institutes of Health (NIH) Clinical Center (CC) 
Description of 
Study Intervention: 
CLTX-305 (encaleret) is an oral tablet containing the active ingredient 
encaleret provided in 5, 10, 30 and 60 mg doses. 
Primary Study 
Duration: 
Estimated time from when the study opens to enrollment until completion 
of Period 3 is approximately 16 months. 
Participant 
Duration: 
Total maximum duration of study participation, including Periods 1, 2, and 
3, will be approximately 16 months for each participant, which includes up 
to 60 days between the screening visit and study drug initiation and up to 
16 weeks between Periods 1 and 2. Participants who elect to continue in 
LTE will receive CLTX-305 (encaleret) for an additional period of time, 
up to 25 months (approximately 2 years) or until they transition to the 
CLTX-305-302/CALIBRATE Phase 3 LTE, whichever occurs first. 

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Calcilytix Therapeutics, Inc. 
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1.2 
Schema 
 Overall Study Design 
 
 

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Schematic for Periods 1, 2, and 3 
 
 
Period 3 
 
 
 
 
 
 
 
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
X
X
X
X
X
X
X
Wk 8
Wk 16
Wk 24
Period 3:Study week
Telephone Contact Visit 
(with local labs)  
NIH Inpatient visit
(PK/PD, 24-hr urine, safety measures) 
Titration
Maintenance
Wk= Week
Shading to help visualization - Dark Grey (NIH visit), Light Grey (Telephone contact), as indicated 
NIH
NIH
NIH

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Long-term Extension (LTE) 
 
 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
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1.3 
Schedule of Activities (SOA) 
Table A 
Period 1 Schedule of Activities 
Period 1 
Screening1 
Interval 
labs12 
NIH CC inpatient Period 1 
Discharge/ 
EoT/ET2 
FU Lab3 
FU Post last 
dose 
Admission 
QD Dosing 
BID Dosing 
Days 
-60 to -2 
-14 to-10 
-1 
1 
2 
3 
4 
5 
6 
7–8 
9-11 
30 ± 7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Admission to clinic 
X 
 
X 
 
 
 
 
 
 
 
 
Demographics, Medical history4 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
 
 
 
 
 
 
 
 
 
 
Safety Lab Tests5  
X 
 
X 
 
 
 
 
 
 
 
 
Height6 and weight 
X 
 
X 
 
 
 
 
X 
X 
 
 
Vital signs7 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical examination 
X 
 
X 
 
 
 
 
 
X 
 
 
Renal Ultrasound, DXA Scan 
X 
 
 
 
 
 
 
 
 
 
 
FSH level test (postmenopausal women) 
X 
 
 
 
 
 
 
 
 
 
 
Blood β-HCG pregnancy test (WOCBP only) 
X 
 
X 
 
 
 
 
X 
 
 
 
ECG, 12-lead 
X 
 
X 
 
 
 
 
X 
 
 
 
AEs and SAEs, Prior/Concomitant meds8 
X 
 
X 
--------------------------------------------------------------------------------------------
→ 
Study drug administration9 
 
 
 
X 
X 
X 
X 
X 
 
 
 
PK/PD blood sample collection 
 
 
 
Tables E, H, I, L 
 
X 
 
24 hr. Urine10 
X 
X 
 
 
 
 
Outpatient laboratory testing  
 
X11 
 
 
 
X3 
 
Discharge13 
 
 
 
 
X 
 
 
Telephone Contact14, 15 
 
 
 
 
 
 
X 
Abbreviations: Adverse Event = AE; Albumin = Alb; Alanine aminotransferase = ALT Blood urea nitrogen = BUN; Aspartate aminotransferase = AST; Alkaline Phosphatase = Alk 
Phos;Electrocardiogram = ECG; BID = Twice daily; Blood Pressure = BP; Calcium = Ca; Calcium Sensing Receptor = CASR; Chloride = Cl; Concomitant Medication = Con. Meds; 
Creatinine = Cr; Dual-energy X-ray Absorptiometry = DXA; Early Termination = (ET); End of Treatment = EoT; Follow-up = FU; Follicle-Stimulating Hormone = FSH; Glucose = Glu; 
Heart Rate = HR; Hematocrit = Hct; Hemoglobin = Hgb; Lactate Dehydrogenase = LDH; Intact Parathyroid Hormone = iPTH; Magnesium = Mg; National Institute of Health Clinical 
Center = NIH CC; Parathyroid Hormone = PTH; Phosphate = PO4; Phosphorus = P; Potassium = K; Pharmacodynamic = PD; Pharmacokinetic = PK; Prothrombin Time/ Prothrombin Time 
= PT/INR; Red Blood Cell Count = RBC; Thromboplastin Time = PTT; Serious Adverse Event = SAE; QD = Once daily; Total Bilirubin = Tbili; Triglycerides = TGL; White Blood Count 
= WBC; Women Of Child Bearing Potential = WOCBP 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122 
Page 20 
 
Confidential 
 
1. 
Screening Visit at NIH Clinical Center.  
2. 
If participant discontinues from the study early (ET) or withdraws from taking the CLTX-305 (encaleret) (EoT), perform related assessments, resume prior medication 
regimen, arrange FU labs within 1-2 days, and a FU call within 30 ± 7 days after last dose of the CLTX-305 (encaleret). 
3. 
Outpatient laboratory testing includes blood Cr, Ca, Alb, Mg, PO4, iPTH, and PK sample collection on Day 7 or 8 after discharge from NIH CC on Day 6.  
4. 
Including CaSR mutational analysis (if not documented). 
5. 
Safety Labs – Chemistry (Na, K, Cl, bicarbonate, Glu, BUN, Cr, Alb, total protein, Ca, Mg, PO4, iPTH, 25-OH Vitamin D, cholesterol, TG, AST, ALT, Tbili, Alk phos, LDH, 
amylase, lipase, uric acid), Hematology (RBC, Hgb, Hct, RBC indices, WBC, differential), Coagulation (PT/PTT/INR), urinalysis. HIV, viral hepatitis panel to be done at 
screening visit only. 
6. 
Height measured at screening only. 
7. 
Vital signs include supine or sitting blood pressure (BP) by automated cuff, heart rate (HR), and respiratory rate, to be collected q8 hours during in-patient days. Orthostatic 
BP and HR will be assessed once at screening and once daily during Period 1. 
8. 
Discontinue calcitriol on Day -1 during the admission. 
9. 
On Days 1, 2, & 3 participants receive CLTX-305 (encaleret) per the dosing algorithm. On Day 4 & 5 participants receive BID doses based on Days 1-3. 
10. 24-hour urine at the screening visit and 10-14 days prior to Day 1 dosing (Ca, Mg, PO4, Cr, Na, K, Citrate, pH). 
11. Outpatient laboratory testing on day -14-10 includes: blood Cr, calcium, albumin, magnesium, phosphate, 25-OH Vitamin D. 
12. Interval lab tests at outpatient laboratory will be done in those for whom the screening visit is >21 days prior to Period 1. 
13. After the last dose of CLTX-305 (encaleret), participants resume prior outpatient conventional treatment regimen prior to discharge. 
14. Telephone contact: should occur on days 9 to 11 or once calcium results are available. PI/study staff to review results with participant.  
15. Telephone contact: 30 ± 7 days after last dose of CLTX-305 (encaleret) in Period 1 to review AEs/Con meds 
 
 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122 
Page 21 
 
Confidential 
 
Table B 
Period 2 Schedule of Activities 
Period 2 
Screening1 
Interval Labs 11 
NIH CC inpatient Period 2 
Discharge/EoT/ET2 
FU Post last 
dose 
Admission 
BID Dosing 
Days 
-60 to -2 
-14 to -10 
-1 
1 
2 
3 
4 
5 
6 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Admission to clinic 
X 
 
X 
 
 
 
 
 
 
 
Demographics, Medical history3 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
 
 
 
 
 
 
 
 
 
Safety Lab Tests4  
X 
 
X 
 
 
 
 
 
 
 
Height5 and weight 
X 
 
X 
 
 
 
 
X 
X 
 
Vital signs6 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
 
X 
 
 
 
 
 
X 
 
Renal Ultrasound, DXA Scan 
X 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal women) 
X 
 
 
 
 
 
 
 
 
 
Blood β-HCG pregnancy test (WOCBP only) 
X 
 
X 
 
 
 
 
X 
 
 
ECG, 12-lead 
X 
 
X 
X14 
 
X14 
 
X14 
 
 
AEs and SAEs, Prior/Concomitant meds7 
X 
 
X 
 ------------------------------------------------------------------------→  
Study drug administration8 
 
 
 
X 
X 
X 
X 
X 
 
 
PK/PD blood sample collection 
 
 
 
Tables F, G, J, K 
 
 
24 hr. Urine9 
X 
X 
 
 
 
Outpatient laboratory testing 
 
X10 
 
 
X2 
 
Dispense study drug for Period 3, Discharge12 
 
 
 
 
X 
 
Telephone Contact13 
 
 
 
 
 
X 
Abbreviations: Adverse Event = AE; Albumin = Alb; Alanine aminotransferase = ALT; Blood urea nitrogen = BUN; Aspartate aminotransferase = AST; Alkaline Phosphatase = 
Alk Phos; Electrocardiogram = ECG; BID = Twice daily; Blood Pressure = BP; Calcium = Ca; Calcium Sensing Receptor = CaSR; Chloride = Cl; Concomitant medication = 
Con. meds; Creatinine = Cr ; Dual-energy X-ray Absorptiometry = DXA; Early Termination =  (ET); End of Treatment = EoT; Follow-up = FU; Follicle-Stimulating Hormone 
= FSH; Glucose = Glu; Heart Rate = HR; Hematocrit = Hct; Hemoglobin = Hgb; Lactate Dehydrogenase = LDH; Intact Parathyroid Hormone = iPTH; Magnesium = Mg; 
National Institute of Health Clinical Center = NIH CC; Parathyroid Hormone = PTH; Phosphate = PO4; Phosphorus = P; Potassium = K; Pharmacodynamic = PD; 
Pharmacokinetic = PK; Prothrombin Time/ Prothrombin Time = PT/INR; Red Blood Cell Count = RBC; Thromboplastin Time = PTT; Serious Adverse Event = SAE; QD = 
Once daily; Total Bilirubin = Tbili; Triglycerides = TGL; White Blood Count = WBC; Women Of Child Bearing Potential = WOCBP 
1 
Screening Visit at NIH CC for Cohort 2 participants. Participants may complete the Screening Visit as outpatients or be housed overnight at NIH CC. Cohort 1 participants do 
not require re-screening assessments. Participants who complete the screening visit midweek have the option to stay overnight at NIH CC during the intervening days prior to 
the start of Period 2, Day -1. 
2 
If participant discontinues from the study early (ET) or withdraws from taking CLTX-305 (encaleret) (EoT), perform related assessments, resume prior medication regimen, 
arrange FU labs within 1-2 days. Participants instructed to obtain outpatient laboratory testing (See Footnote 10) approximately 1-2 days after discharge from NIH CC. PI/Site 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122 
Page 22 
 
Confidential 
 
staff should contact the participant within 3-5 days to review test results and provide guidance regarding clinical management as they transition to prior clinical care providers. 
Optionally, participants may stay in the NIH CC overnight to complete assessments. 
3 
Including CaSR mutational analysis (if not documented). 
4 
Safety Labs – Chemistry (Na, K, Cl, bicarbonate, Glu, BUN, Cr, alb, total protein, Ca, Mg, PO4, iPTH, 25-OH Vitamin D, cholesterol, TG, AST, ALT, Tbili, Alk phos, LDH, 
amylase, lipase, uric acid), Hematology (RBC, Hgb, Hct, RBC indices, WBC, diff), Coagulation (PT/PTT/INR), urinalysis. HIV, viral hepatitis panel, and iron panel to be 
done at screening visit only unless repeat measures are clinically indicated. 
5 
Height measured at screening only. 
6 
Vital signs include supine or sitting blood pressure (BP) by automated cuff, heart rate (HR), and respiratory rate, to be collected q8 hours during in-patient days. Orthostatic 
BP and HR will be assessed once at screening and once daily during Period 2. 
7 
Discontinue calcitriol on Day -1 during the admission. 
8 
Initial dose (Days 1 & 2) of CLTX-305 (encaleret) BID based on results from Period 1. If calcium has not increased into the normal range, then the CLTX-305 (encaleret) 
dose will be increased for Days 3-5. Participants will undergo frequent PK/PD sampling over 24h on Day 5. 
9 
24-hour urine at the screening visit 14 to 10 days prior to Day 1 dosing (Ca, Mg, PO4, Cr, Na, K, Citrate, pH) 
10 
For cohorts 1 and 2: outpatient laboratory testing on days -14 to -10 before admission include: blood Cr, Ca, Alb, Mg, PO4, 25-OH Vitamin D, Hematology (RBC, Hgb, Hct, 
RBC indices, WBC)  
11 
Interval lab tests at outpatient laboratory will be done in those for whom the screening visit is >21 days prior to Period 2. 
12 
After the last dose of CLTX-305 (encaleret), for participants continuing to Period 3, dispense supply of CLTX-305 (encaleret) before discharge.  
13 
ET and EoT - a final FU call should occur within 30 ±7 days from the date of the last dose of CLTX-305 (encaleret) in Period 2.  
14 
ECG assessments: Day 1, 3 and 5 each at 3 hrs ± 30 min post dose (AM) 
 
 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122 
Page 23 
 
Confidential 
 
Table C 
Period 3 Schedule of Activities 
Period 3 - After discharge in Period 2 (Day 6) 
FU outpatient labs2 
2 to 3 ± 2days 
FU outpatient labs2 
7 ± 2 days 
FU- after last dose 
30 ± 7 days 
Un-scheduled visit3 
Study Dosing Period 
Weeks 
1, 2, 3, 4 
6 
NIH CC 
12 
NIH CC 
20 
NIH CC 
EoT/ET1 
 
 
 
 
8 
16 
24 
Days (windows) 
± 2 
± 5 
± 5 
± 5 
± 5 
± 5 
± 5 
Telephone Contact (NIH PI/Study Staff) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
AEs and SAEs, Con meds 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Review compliance4/Titration 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Outpatient laboratory5 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
NIH CC visit 
 
 
X 
 
X 
 
X 
 
 
 
 
Renal ultrasound, DXA scan 
 
 
 
 
 
 
X 
 
 
 
 
Dispense study drug  
 
 
X 
 
X 
 
X15 
 
 
 
 
Height6 and weight 
 
 
X 
 
X 
 
X 
 
 
 
 
Vital signs7 
 
 
X 
 
X 
 
X 
 
 
 
 
Physical examination8 
 
 
X 
 
X 
 
X 
 
 
 
 
Safety Laboratory 9 
 
 
X 
 
X 
 
X 
 
 
 
 
Blood β-HCG pregnancy test (WOCBP only) 
 
 
X 
 
X 
 
X 
 
 
 
 
ECG, 12-lead 
 
 
X 
 
X 
 
X 
 
 
 
 
Study drug administration10 
 
 
X 
 
X 
 
X 
 
 
 
 
PD blood collection11 
 
 
X 
 
X 
 
X 
 
 
 
 
PK blood collection12 
 
 
 
 
 
 
X 
 
 
 
 
Timed Interval & 24-hour Urine13,14 
 
 
X 
 
X 
X14 
X 
 
 
X14 
 
Abbreviations: Adverse Event = AE; Albumin = Alb; Alanine aminotransferase = ALT; Blood urea nitrogen = BUN; Aspartate aminotransferase = AST; Alkaline Phosphatase = 
Alk Phos; Electrocardiogram = ECG; BID = Twice daily; Blood Pressure = BP; Calcium = Ca; Calcium Sensing Receptor = CaSR; Chloride = Cl; Concomitant medication = 
Con. meds; Creatinine = Cr; C-telopeptide = CTX; Dual-energy X-ray Absorptiometry = DXA; Early Termination = (ET); End of Treatment = EoT; Follow-up = FU; Follicle-
Stimulating Hormone = FSH; Glucose = Glu; Heart Rate = HR; Hematocrit = Hct; Hemoglobin = Hgb; Lactate Dehydrogenase = LDH; Intact Parathyroid Hormone = iPTH; 
Magnesium = Mg; National Institute of Health Clinical Center = NIH CC; Parathyroid Hormone = PTH; Phosphate = PO4; Phosphorus = P; Potassium = K; Pharmacodynamic = 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122 
Page 24 
 
Confidential 
 
PD; Pharmacokinetic = PK; Procollagen type 1 N-propeptide = P1NP; Prothrombin Time/ Prothrombin Time = PT/INR; Red Blood Cell Count = RBC; Thromboplastin Time = 
PTT; Serious Adverse Event = SAE; QD = Once daily; Total Bilirubin = Tbili; Triglycerides = TGL; White Blood Count = WBC; Women Of Child Bearing Potential = 
WOCBP  
1 
If participant discontinues from the study early (ET) or withdraws from taking CLTX-305 (encaleret) (EoT), before completing Period 3 per protocol, participant will be 
asked to return to the NIH CC as soon as possible for the ET/EoT visit assessments and return the unused CLTX-305 (encaleret). Participant should revert to their outpatient 
regimen of oral calcium and active vitamin D. Participants will go through FU activities as stated in table and footnote 2, and then will have a safety FU call 30 day ± 7 days. 
2 
Participants who withdraw from taking CLTX-305 (encaleret) (EoT) before completing Period 3 per protocol or who elect not to continue into the LTE will obtain the 
following outpatient laboratory assessments after the last dose of CLTX-305 (encaleret) and after re-starting their prior regimen of oral calcium and active vitamin D: blood 
Cr, Ca, Alb, Mg, PO4. Follow-up (FU) call should occur within 3-5 days to review the lab results and receive guidance on clinical management of their ADH1 as they 
transition to their prior clinical care providers. 
3 
Unscheduled visits: For laboratory evaluation following dose adjustment or assessment or follow-up of an AE, in which clinically indicated procedures will be performed.  
4 
Document current CLTX-305 (encaleret) dose and calcium dosing regimen, any modifications, and reason for modifications. 
5 
Outpatient laboratory testing: Blood samples for clinical laboratory panels (Na, Cl, bicarbonate, K, BUN, Cr and including Alb, Ca, Mg, PO4, iPTH, CTX and P1NP).  
6 
Height measured only at ET visit. 
7 
Vital signs include supine or sitting blood pressure (BP) by automated cuff, heart rate (HR), and respiratory rate.  
8 
Focused Physical exams: weight measurement at all visits. 
9 
Safety Labs collected at the NIH CC visits– Chemistry (Na, K, Cl, bicarbonate, Glu, BUN, Cr, Alb, total protein, Ca, Mg, PO4, 25-OH Vitamin D, Cholesterol, TG, AST, 
ALT, Tbili, Alk phos, LDH, amylase, lipase, uric acid), Hematology (RBC, Hgb, Hct, RBC indices, WBC, diff), Coagulation (PT/PTT/INR). 
10 
CLTX-305 (encaleret) administered and recorded during the NIH CC visit/in-house PK/PD collection days. 
11 
See Table E : Non-intensive Sampling Days for PD measures and timepoints and Table L : Research Sample Collection. 
12 
See Table E : Use Non-intensive Sampling Days schedule for PK timepoints. 
13 
See Table E : see time intervals for urine collections for calculation of fractional excretion rates and 24-hour total excretion of urine Ca, Mg, PO4, Cr, cAMP, citrate, Na, K, 
pH during the NIH CC visits 
14 
Outpatient 24-hr urine Ca, Mg, PO4, Cr, Na, K, citrate, pH at 20 weeks. Participants who withdraw from taking CLTX-305 (encaleret) (EoT) before completing Period 3 per 
protocol or chose not to continue into the LTE will obtain 24-hr urine at 30 ± 7 days follow-up.  
15 
Week 24 drug dispensing is only for participants who continue into the LTE; If a participant is not immediately continuing into the LTE, no drug will be dispensed. 
 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122 
Page 25 
 
Confidential 
 
Table D 
Long-term Extension Schedule of Activities 
LTE - After last day in week 24 in Period 3 
FU outpatient labs2, 14 
2 to 3 ± 2 days 
FU outpatient labs2, 14 
7 ± 2 days 
FU- after last dose12, 14 
30 ± 7 days 
Un-scheduled visit3 
Study Dosing Period 
Months 14 
NIH 
CC 
3 
NIH 
CC 
9 
NIH 
CC 
15 
NIH 
CC 
21 
NIH CC 
EoT/ET1  
 
 
 
 
013 
6 
12 
18 
24 
Days (windows) 
 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
+30 
Reconsent13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone Contact (NIH PI/Study Staff) 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
AEs and SAEs, Con meds 
X 
----------------------------------------------------------------------→ 
X 
X 
X 
X 
Review compliance4/dose adjustment as needed 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Outpatient laboratory5 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
NIH CC visit 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Renal ultrasound, DXA scan 
 
 
 
 
X 
 
 
 
X15 
 
 
 
 
Dispense study drug  
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Height6 and weight 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Vital signs7 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Physical examination 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Safety and Drug Monitoring Laboratory8 
X13 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Blood β-HCG pregnancy test (WOCBP only)9 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
ECG, 12-lead 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Study drug administration10 
X 
----------------------------------------------------------------------→ 
 
 
 
 
24-hour Urine11 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X12 
 
Abbreviations: Adverse Event = AE; Albumin = Alb; Alanine aminotransferase = ALT; Blood urea nitrogen = BUN; Aspartate aminotransferase = AST; Alkaline Phosphatase = 
Alk Phos; Electrocardiogram = ECG; BID = Twice daily; Blood Pressure = BP; Calcium = Ca; Calcium Sensing Receptor = CaSR; Chloride = Cl; Concomitant medication =  
Con. meds; Creatine Kinase = CK; Creatinine = Cr; C-telopeptide = CTX; Dual-energy X-ray Absorptiometry = DXA; Early Termination =  (ET); End of Treatment = EoT; 
Follow-up = FU; Follicle-Stimulating Hormone = FSH; Glucose = Glu; Heart Rate = HR; Hematocrit = Hct; Hemoglobin = Hgb; Lactate Dehydrogenase = LDH; Intact 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122 
Page 26 
 
Confidential 
 
Parathyroid Hormone = iPTH; Magnesium = Mg; National Institute of Health Clinical Center = NIH CC; Parathyroid Hormone = PTH; Phosphate = PO4; Phosphorus = P; 
Potassium = K; Pharmacodynamic = PD; Pharmacokinetic = PK; Procollagen type 1 N-propeptide = P1NP; Prothrombin Time/ Prothrombin Time = PT/INR; Red Blood Cell 
Count = RBC; Thromboplastin Time = PTT; Serious Adverse Event = SAE; QD = Once daily; Total Bilirubin = Tbili; Triglycerides = TGL; White Blood Count = WBC; 
Women Of Child Bearing Potential = WOCBP 
1 
If participant discontinues from the study early (ET) or withdraws from taking CLTX-305 (encaleret) (EoT), before completing LTE per protocol, participant will be asked to 
return to the NIH CC within 30 days following the last dose for the ET/EoT visit assessments and return the unused CLTX-305 (encaleret). Participant should resume oral 
calcium and active vitamin D under the supervision of the study team while the encaleret is being safely discontinued. Follow-up labs should beperformed per this Schedule 
of Assessments. 
2 
Participants who withdraw from taking CLTX-305 (encaleret) (EoT) before transitioning to the CLTX-305-302/CALIBRATE LTE per protocol will obtain the following 
outpatient laboratory assessments after the last dose of CLTX-305 (encaleret) and after re-starting their prior regimen of oral calcium and active vitamin D: blood Cr, Ca, Alb, 
Mg, iPTH, PO4. Follow-up (FU) call should occur within 3-5 days to review the lab results and receive guidance on clinical management of their ADH1 as participants 
transition to prior standard of care. 
3 
Unscheduled visits: For laboratory evaluation following dose adjustment or assessment or follow-up of an AE, in which clinically indicated procedures will be performed 
4 
Document current CLTX-305 (encaleret) dose and calcium dosing regimen, any modifications, and reason for modifications 
5 
Outpatient laboratory testing: Blood samples for clinical laboratory panels (Na, Cl, bicarbonate, K, BUN, Cr and including Alb, Ca, Mg, PO4, iPTH, CTX, and P1NP).  
6 
Height measured only at month 24/final visit or ET visit 
7 
Vital signs include supine or sitting blood pressure (BP) by automated cuff, heart rate (HR), and respiratory rate.  
8 
Safety and Drug Monitoring Labs collected at the NIH CC visits approximately 4 hours after the morning encaleret dose – Chemistry (Na, K, Cl, bicarbonate, Glu, BUN, Cr, 
Alb, total protein, Ca, Mg, PO4, iPTH, 25-OH Vitamin D, CTX, P1NP, Cholesterol, TG, AST, ALT, Tbili, Alk phos, LDH, amylase, lipase, uric acid, CK), Hematology 
(RBC, Hgb, Hct, RBC indices, WBC, diff), Coagulation (PT/PTT/INR), Research labs (FGF23 and mid-molecule PTH). HIV, viral hepatitis panel should be repeated within 
3 months prior to transition to CLTX-305-302/CALIBRATE. 
9 
Blood β-HCG pregnancy test can be performed at the NIH CC on the day of transition to CLTX-305-302/CALIBRATE Phase 3 LTE, and an aliquot will also be sent to the 
central lab for the CLTX-305-302/CALIBRATE Phase 3 LTE. 
10 
CLTX-305 (encaleret) administered and recorded during the NIH CC visit/in-house days. 
11 
Outpatient 24-hr urine collection for Ca, Mg, PO4, Cr, Na, K, citrate, pH 
12 
A final follow-up safety telephone call and outpatient labs will occur 30 ± 7 days after the last dose of CLTX-305 (encaleret). 
13 
If a participant is not able to enter the LTE immediately following Period 3, then participant will be reconsented to and may restart CLTX-305 (encaleret) at the previous 
therapeutic dose determined in Period 3. Safety and Drug Monitoring Laboratory tests should be done while participant is at the NIH CC.   
14 
When participant transitions to CLTX-305-302/CALIBRATE Phase 3 LTE, participant will be asked to return to the NIH CC to return the unused CLTX-305 (encaleret), and 
complete any remaining eligibility assessments for the CLTX-305-302/CALIBRATE Phase 3 LTE study.  
15 
If the Month 24 visit aligns with the transition to the CLTX-305-302/CALIBRATE Phase 3 LTE, then the renal ultrasound and DXA scan will be performed once as part of 
the CLTX-305-302/CALIBRATE Phase 3 LTE.   

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
Page 27 
 
Confidential 
 
1.3.1 
Pharmacokinetic, Pharmacodynamic, and Urine Sampling Times 
Table E 
Non-intensive BID Sampling Days 
Period 1: Day 4 (BID Dosing) 
Period 3: PK/PD sampling days  
Timepoint ± 20 min. (relative to AM 
dose) 
Blood Assays 
PK1 samples 
-15 min, +30 min, 2, 4, 8, 11, 13 hrs 
Intact PTH 
-15 min, +30 min*, 2, 4, 8, 11, 13, 17 hrs 
Serum bone markers: CTX, P1NP 
-15 min,                                   13 hrs 
1, 25-(OH)2 Vitamin D, cAMP 
-15 min,                    4, 8,        13,17, 24 hrs2 
Ca, PO4, Mg, Cr, albumin 
-15 min, +30 min*, 2, 4, 8, 11, 13, 17, 24 hrs2 
K, CK 
-15 min,                                   13 hrs 
Urine Assays:   
Timed Interval Urine Collections: 
Ca, Mg, PO4, Cr, cAMP, pH  
 
-15 min 0-4 h, 4-8 h, 8-13 h, 13-17 h, 17-24 h 
24-Hour urine: 
Ca, Mg, PO4, Cr, Na, K, Citrate, pH  
0, 24 hrs (Start collection after first morning 
void and end 24 hours later) 
1 
PK in Period 3 only collected at 24 weeks;  
2 
24 hour timepoint only collected in Period 3 
* 
+30 min timepoint only collected in Period 3 at 24 weeks 
 
Table F 
Non-intensive BID Sampling Days - (if CLTX-305 (encaleret) dose is 
≤ 180 mg BID) 
Period 2: Days 1, 2, 3 & 4  
Timepoint ± 20 min. (relative to AM 
dose) 
Blood Assays 
PK samples 
-15 min,                 2, 4 hrs 
Intact PTH 
-15 min, +30 min, 2, 4, 8, 11, 13, 17 hrs 
1, 25-(OH)2 Vitamin D  
-15 min,                    4, 8,        hrs 
Ca, PO4, Mg, Cr, albumin 
-15 min, +30 min, 2, 4, 8, 11, 13, 17 hrs 
K, CK 
-15 min,                                   13 hrs 
Urine Assays:   
Timed Interval Urine Collections: 
Ca, Mg, PO4, Cr, pH  
-15 min1, 0-4 h, 4-8 h, 8-13 h, 13-17 h, 17-24 h 
24-Hour urine: 
Ca, Mg, PO4, Cr, Na, K, Citrate, pH  
0, 24 hrs (Start collection after first morning 
void and end 24 hours later) 
1 
-15 min urine is done on Period 2 (Day 1) only 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Confidential 
 
 
Table G 
Non-intensive BID Sampling Days - (if CLTX-305 (encaleret) dose is 
> 180 mg BID) 
Period 2: Days 2, 3 & 4 
Timepoint ± 20 min. (relative to AM 
dose) 
Blood Assays 
PK samples 
15 min, +30 min, 2, 4, 8, 11, 13 hrs 
Intact PTH 
-15 min, +30 min, 2, 4, 8, 11, 13, 17 hrs 
1, 25-(OH)2 Vitamin D 
-15 min,                    4, 8,         
Ca, PO4, Mg, Cr, albumin 
-15 min, +30 min, 2, 4, 8, 11, 13, 17 hrs 
K, CK 
-15 min,                                   13 hrs 
Urine Assays:   
Timed Interval Urine Collections: 
Ca, Mg, P, Cr, pH  
   0-4 h, 4-8 h, 8-13 h, 13-17 h, 17-24 h 
24-Hour urine: 
Ca, Mg, PO4, Cr, Na, K, Citrate, pH  
0, 24 hrs (Start collection after first morning 
void and end 24 hours later) 
 
Table H 
Intensive Sampling Days for QD dosing  
Period 1: Days 1, 2, 3 
 
Timepoint ± 10 min (relative to AM dose) 
Blood Assays: 
PK samples 
-15 min, +30 min, 1, 1.5, 2, 3, 4, 6, 8, 13 hrs 
Intact PTH 
-15 min, +30 min, 1, 1.5, 2, 3, 4, 6, 8, 13, 17 hrs 
Serum bone markers: CTX, P1NP 
-15 min,                                                13 hrs  
1, 25-(OH)2 Vitamin D, cAMP 
-15 min,                                    4,    8,  13, 17 hrs  
Ca, PO4, Mg, Cr, albumin 
-15 min, +30 min, 1,        2, 3, 4, 6, 8, 13, 17 hrs 
K, CK 
-15 min,                                                13 hrs  
Urine Assays 
Timed Interval Urine Collections: 
Ca, Mg, PO4, Cr, cAMP, pH 
-15 min1, 0-4 h, 4-8h, 8-13h, 13-17h, 17-24 h 
24-Hour urine: 
Ca, Mg, PO4, Cr, Citrate, Na, K, pH  
0, 24 hrs (Start collection after first morning 
void and end 24 hours later) 
1 
-15 min urine is done on Period 1 (Day 1) only 
 
 
 
 

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Table I 
Intensive Sampling Days for BID dosing 
Period 1: Day 5 
Timepoints ± 10 min (relative to AM & PM doses) 
Blood Assays 
PK samples 
TRT AM Dose: -15 min, +30 min, 1, 1.5, 2, 3, 4, 6, 8 hrs 
TRT PM Dose:                +30 min, 1, 1.5, 2, 3, 4, 6, 15 hrs 
Intact PTH 
TRT AM Dose: -15 min, +30 min, 1, 1.5, 2, 3, 4, 6, 8 hrs 
TRT PM Dose:                +30 min, 1, 1.5, 2, 3, 4, 6, 8, 15 
hrs 
Serum bone markers: CTX, P1NP 
TRT AM Dose: -15 min,                                           8 hrs 
1, 25-(OH)2 Vitamin D, cAMP 
TRT AM Dose: -15 min,                                       4, 8 hrs 
TRT PM Dose:                                                      4, 8, 15 
hrs 
Ca, P, Mg, Cr, albumin 
TRT AM Dose: -15 min, +30 min, 1, 1.5, 2, 3, 4, 6, 8 hrs 
TRT PM Dose:                +30 min, 1, 1.5, 2, 3, 4, 6, 8, 15 
hrs 
K, CK 
TRT AM Dose: -15 min,                                           8 hrs 
Urine Assays 
Timed Interval Urine Collections: 
Ca, Mg, PO4, Cr, cAMP, pH 
0-4 h, 4-8h, 8-13h, 13-17h, 17-24 h 
24-Hour urine: 
Ca, Mg, PO4, Cr, Citrate, Na, K, pH  
0-24 hrs (Start collection after first morning void and end 24 
hours later) 
Abbreviation: Time Relative To = TRT 
 
 

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 Table J 
Intensive Sampling Days for BID dosing - (if CLTX-305 (encaleret) 
dose is > 180 mg BID) 
Period 2: Day 5  
Timepoints ± 10 min (relative to AM & PM doses) 
Blood Assays 
PK samples 
TRT AM Dose: -15 min, +30 min,  1.5, 2,   4, 6, 8 hrs 
TRT PM Dose:                +30 min,  1.5, 2,    4, 6, 15 hrs 
Intact PTH 
TRT AM Dose: -15 min, +30 min,  1.5, 2,   4, 6, 8 hrs 
TRT PM Dose:                +30 min,  1.5, 2,   4, 6, 8, 15 hrs 
Ca, PO4, Mg, Cr, albumin 
TRT AM Dose: -15 min, +30 min, 1.5, 2,    4, 6, 8 hrs 
TRT PM Dose:                +30 min, 1.5, 2,    4, 6, 8, 15 hrs 
K, CK 
TRT AM Dose: -15 min,                                           8 hrs 
Urine Assays 
Timed Interval Urine Collections: 
Ca, Mg, PO4, Cr, pH 
0-4 h, 4-8h, 8-13h, 13-17h, 17-24 h 
24-Hour urine: 
Ca, Mg, PO4, Cr, Citrate, Na, K, pH  
0-24 h (Start collection after first morning void and end 24 
hours later) 
Abbreviation: Time Relative To = TRT  
 
 

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Table K 
Intensive Sampling Days for BID dosing- (if CLTX-305 (encaleret) 
dose is ≤ 180 mg BID) 
Period 2: Day 5  
Timepoints ± 10 min (relative to AM & PM doses) 
Blood Assays 
PK samples 
TRT AM Dose: -15 min,               1.5, 4 h  
TRT PM Dose:               +30 min, 1.5, 4,         15 h 
Intact PTH 
TRT AM Dose: -15 min,               1.5,  4, 8 hrs 
TRT PM Dose:               +30 min, 1.5,  4,  8,      15 hrs. 
Serum bone markers: CTX, P1NP 
TRT AM Dose: -15 min                            8 hrs. 
1, 25-(OH)2 Vitamin D, cAMP 
TRT AM Dose: -15 min                        4, 8 hrs. 
TRT PM Dose:                                       4, 8,     15 hrs. 
Ca, PO4, Mg, Cr, albumin 
TRT AM Dose: -15 min,                1.5,  4,  8 hrs.  
TRT PM Dose:                +30 min, 1.5, 4, 8, 15 hrs. 
K, CK 
TRT AM Dose: -15 min,                            8 hrs. 
Urine Assays 
Timed Interval Urine Collections: 
Ca, Mg, PO4, Cr, cAMP, pH 
0-4 h, 4-8h, 8-13h, 13-17h, 17-24 h 
24-Hour urine: 
Ca, Mg, PO4, Cr, Citrate, Na, K, pH  
0-24 h (Start collection after first morning void and end 24 
hours later) 
Abbreviation: Time Relative To = TRT 
 
Table L 
Research Sample Collection Timepoints in Periods 1 and 3 
Period 1: Day 1 and Day 4 
Period 3: Weeks 8, 16, and 24  
 
Timepoint ± 10 min (relative to AM dose) 
Research Specimens: 
Including FGF23 and mid-molecule PTH  
-15 min, +30 min, 2, 4, 8, 11, 13 hrs 

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2 
INTRODUCTION 
2.1 
Study Rationale 
The rationale for developing CLTX-305 (encaleret) as a potential treatment for hypocalcemia 
in patients with ADH1 is based on both preclinical and clinical data. CLTX-305 (encaleret) is 
a CaSR antagonist (calcilytic). CLTX-305 (encaleret) interfered with the effect of 
extracellular calcium to suppress PTH secretion from isolated bovine parathyroid cells at 
physiological calcium concentrations and shifted the IC50 of the calcium-PTH curve 
rightward (See Investigator Brochure). Calcilytics in general have been shown, in both in 
vitro and vivo models, to shift the aberrant CaSR “set-point” back towards a normal IC50 for 
calcium, resulting in increased PTH secretion and elevation of blood calcium concentrations 
in cellular and animal models of ADH1 (Dong et al, 2015; Hannan et al, 2015). 
Preliminary clinical data also support potential utility of calcilytics to treat humans with 
ADH1. Intravenous administration of a structurally related small molecule calcilytic, 
NPSP795, in five patients with ADH1, was associated with dose-related increased plasma 
PTH levels and decreased urinary fractional calcium excretion, although without a clear 
increase in cCa (Roberts et al, 2019). This small proof-of-concept study utilized a very 
rapid-acting but short-lived calcilytic agent and was further limited in the dose range tested. 
However, taken together with in vitro and in vivo data, the study is supportive of further 
testing of calcilytics in ADH1. Of note, the systemic exposures achieved in the ADH1 
participants across 3 doses tested, were comparable to doses that caused hypercalcemia in 
healthy volunteers with presumed normal CaSR function during a separate single 
ascending-dose study. This suggests that patients with ADH1 may require larger doses of a 
calcilytic, compared to euparathyroid individuals, to achieve similar increases in calcium 
levels. 
CLTX-305 (encaleret) can cause hypercalcemia acutely, in healthy volunteers and 
postmenopausal women, at doses of 30 mg, with some additional effect at doses of 50 and 
100 mg. At doses higher than 30 mg, the primary effect was to increase the duration of PTH 
and calcium elevation. Chronically, CLTX-305 (encaleret) doses of 7.5, 10 and 15 mg were 
associated with an increased propensity for hypercalcemia. Taken together these data from 
euparathyroid participants suggest that the steep portion of the dose-response curve for 
CLTX-305 (encaleret) effects on calcium concentrations occurs over approximately a one log 
range (10–100 mg) with a definitive efficacy to raise calcium acutely at 30 mg (for review of 
CLTX-305 (encaleret) dose-response for PTH, calcium and calcium-related hormones see 
Investigator Brochure). 
Rationale for Periods 1, 2 and 3 (dose exploration, dose consolidation, and dose 
stabilization) 
Given the lack of any prior data on the safety and dose-response to CLTX-305 (encaleret) in 
ADH1 patients, this initial part of the study is designed as a Phase 2b, safety, tolerability and 
dose-ranging exercise that will be conducted in 3 steps. The initial Period 1 is to be 
conducted entirely on an inpatient basis, exploring the safety and efficacy-related dose-
response to CLTX-305 (encaleret) administered as escalating doses given once or twice daily 

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over 5 days. All participants will be instructed to stop taking calcitriol on Day -1, the day of 
admission, but continue their oral calcium supplement regimen until admitted. Magnesium 
supplements and potassium citrate will be discontinued starting the morning of Day 1. 
Calcium supplements will be discontinued or decreased starting on Day 1, based on the 
estimated dietary calcium intake, targeting a combined calcium intake of >1000 mg/day. 
Following Period 1 participants will resume oral calcium, calcitriol, and other held 
supplements, upon discharge from the study center. 
 
Following an interval of sufficient duration (NIH Guidelines for Blood Draw Limits for 
Research Purposes (M95-9, June 2009)) to ensure that participants have adequately 
recovered the Hgb levels following the intensive blood sampling of Period 1, they will return 
to the study center for Period 2, which will also be conducted entirely on an inpatient basis. 
By initiating Period 2 dosing with CLTX-305 (encaleret) at a well-tolerated dose already 
studied in Period 1, further adjustments can be made at steady-state over the 5-day duration 
of Period 2 (“dose consolidation”). A second group of individuals with ADH1 (Cohort 2) 
who are naïve to CLTX-305 (encaleret) will be invited to join the study beginning with 
Period 2, drawing on the experience with starting doses and dose adjustment in the 
participants in Period 1 and their initial experience in Period 2. 
Following the completion of Period 2, eligible participants will be discharged from the NIH 
CC and enter into Period 3 where they will receive CLTX-305 (encaleret) as an outpatient 
with close safety and laboratory monitoring for a period up to 24 weeks. Participants are 
considered to have completed the study once they complete 24 weeks of Period 3 and the 
safety follow-up visit. Following the outpatient treatment in Period 3, participants may 
continue into a Long-term Extension. 
 
Rationale for the Long-term Extension (LTE) 
Participants who have completed Period 3 and continue to meet study eligibility criteria may 
continue in a Long-term Extension (LTE) for continuous safety evaluation of CLTX-305 
(encaleret). The primary objective of LTE is to assess the longer-term safety and tolerability 
of CLTX-305 (encaleret) in ADH1 participants. The secondary objective will be to obtain 
long-term efficacy (durability) data of CLTX-305 (encaleret) treatment with respect to 
mineral homeostasis and related measures.  
The LTE is designed to obtain additional safety data for CLTX-305 (encaleret). Participants 
who elect to continue in LTE will receive CLTX-305 (encaleret) for an additional period of 
time, up to 25 months (approximately 2 years) or until they transition to the CLTX-305-
302/CALIBRATE Phase 3 LTE, whichever occurs first. 
 
At any point during the LTE, and before transition to the CLTX-305-302/CALIBRATE 
Phase 3 LTE, participants can choose to stop participation and be placed back on the 
conventional therapy. Follow-up assessments should be completed per Schedule of 
Assessments (see Section 1.3 Table D). 
 

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2.2 
Background 
CLTX-305 (encaleret) (known previously as JTT-305 or MK-5442), is an oral calcium-
sensing receptor (CaSR) antagonist (calcilytic), originally developed for the treatment of 
osteoporosis, that is now being evaluated as a potential treatment for autosomal dominant 
hypocalcemia type 1 (ADH1) in this dose finding proof-of-concept trial. 
Previously, CLTX-305 (encaleret) was developed as a treatment for osteoporosis by Japan 
Tobacco Inc., (JTI) and Merck, Sharp & Dohme Corp., (Merck); Healthy volunteers and 
postmenopausal women with osteoporosis participated in a 1,766-participant program of 
which 1,280 were exposed to CLTX-305 (encaleret) in eight phase 1 and four phase 2 studies 
including exposures up to 52 weeks. Despite early data demonstrating a potential net benefit 
on bone formation, late phase trials failed to demonstrate efficacy on endpoints of bone 
mineral density (BMD) in postmenopausal women with osteoporosis.  
Hypercalcemia was identified as an on-target but dose-limiting side effect in the osteoporosis 
program as reviewed below. Hypercalcemia was a safety issue in the osteoporosis program, 
whereas it is considered a marker for efficacy in the ADH1 program. The goal of the current 
program is to develop CLTX-305 (encaleret) as a targeted therapy to treat hypocalcemia and 
disturbed calcium homeostasis in patients with chronic hypocalcemia due to activating 
mutations in the calcium sensing receptor (CaSR). 
2.2.1 
Pharmacokinetics and Product Metabolism 
CLTX-305 (Nonproprietary name: encaleret, molecular formula 
(C29H33ClFNO4)2·H2SO4·H2O, molecular weight 1144.15) is formulated as 5, 10, 30 and 60 
mg white film coated tablets for the current clinical trial. The 10 and 30 mg dosage strengths 
are round tablet presentations; the 60 mg dosage strength can be round or a modified oval 
tablet presentation. The active agent inhibits the CaSR, via allosteric modulation, with an 
IC50 of 86.2 + 6.2 nM (in cell-based assays at 2 mM extracellular calcium). In humans, two 
major glucuronide metabolites (M1 and M3) occur. M1 (IC50 > 3000 nM) is inactive and M3 
(IC50 67.3 + 6.6 nM) is active. 
CLTX-305 (encaleret) is rapidly absorbed in humans (tmax median 1.5 hr. (range 0.75–3 h at 
most single doses or at steady-state). The elimination half-life (t1/2) is approximately 11-14 
hours at steady state (14 days). Dose-proportional increases in plasma CLTX-305 (encaleret) 
concentrations were documented over the dose range (5, 15, 30, 50 and 100 mg) in the fasted 
state without significant food effect. CLTX-305 (encaleret) showed minimal accumulation 
when administered once daily (QD) for two weeks in Japanese postmenopausal women. 
Based on non-clinical data, fecal excretion was the main route of elimination. In humans, 
excretion of unchanged CLTX-305 (encaleret) and metabolites into urine was minimal (< 5% 
as total of parent and metabolite). 
The two major glucuronide metabolites showed similar pharmacokinetics as the parent drug, 
with M1 median tmax approximately 2 hr. and M3 median tmax approximately 1.5 hr. For M1 
(inactive), concentrations in plasma were approximately 2-fold higher than those of parent 

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drug; M3 (active) concentrations were low (10% compared to parent). Neither M1 nor M3 
showed prolonged elimination. 
No significant age-related or race differences (US population vs. Japanese participants) were 
observed in CLTX-305 (encaleret) pharmacokinetics. AUC and Cmax values may be 
approximately 37% and 30% higher in females but these differences were not significant 
when body weight was taken into account. Hepatic and renal impairment studies have not 
been conducted. 
In a drug interaction study, co-administration with ketoconazole, a potent CYP3A4 inhibitor, 
resulted in approximately 1.67x increase in Cmax and approximately 2x increase in AUC0-24 
with slightly less effect on M1 and M3. 
For additional information see Investigator’s Brochure, Section 4.3 and Section 5.2. 
2.2.2 
Efficacy of CLTX-305 (encaleret) in Prior Clinical Trials 
During the prior development program in osteoporosis, dose-related increases of endogenous 
serum parathyroid hormone (PTH) and calcium (Ca) were observed in participants with 
presumed normal CaSR function (i.e., healthy volunteers and postmenopausal women with 
osteoporosis). In healthy postmenopausal women, repeat CLTX-305 (encaleret) doses of 15 
or 20 mg resulted in consistent elevations in intact PTH (iPTH) over 3-4 hours post single 
daily dosing. The stimulatory effect on iPTH was consistent, without evidence for 
tachyphylaxis, after 6 and 12 months of once daily administration. CLTX-305 (encaleret) 
dosing in phase 2 studies was limited to 15 mg once daily (QD) to minimize hypercalcemia. 
With chronic once-daily dosing up to 15 mg, albumin-corrected blood calcium (cCa) levels 
reached a plateau with up to 30% of participants registering an elevated blood calcium above 
the upper limit of the laboratory reference range during long-term trials in postmenopausal 
women with normal systemic calcium homeostasis (normal CaSR sensitivity). Such 
hypercalcemia was asymptomatic, modifiable by decreasing calcium/vitamin D 
supplementation, and/or resolved after stopping CLTX-305 (encaleret) dosing. No serious 
adverse events (SAEs) related to either hyper- or hypocalcemia were observed in the CLTX-
305 (encaleret) program for osteoporosis in postmenopausal women (See IB Section 5.2). 
In summary, extensive data from the prior osteoporosis development program demonstrated 
that CLTX-305 (encaleret) is associated with dose-proportional increases in peak serum 
iPTH levels in participants presumably expressing wild-type CaSR, with iPTH elevations 
lasting less than 8-12 hours but associated with elevations in cCa at chronic daily oral doses 
of 15 mg or above. 
2.2.3 
Autosomal Dominant Hypocalcemia, Type 1 
ADH1 is a rare disorder of systemic calcium homeostasis caused by activating mutations of 
the CaSR gene leading to hypocalcemia (Hannan 2012, Hofer 2003). The CaSR plays the 
dominant role in regulating systemic calcium homeostasis by controlling PTH secretion and 
urinary calcium excretion in response to variations in blood calcium levels (Hofer 2003, 

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Gunn 2004). Negative allosteric modulators of the CaSR, (so-called calcilytic agents) may 
represent a potential targeted therapy for ADH1. 
The prevalence of ADH1 is uncertain (Lienhardt A, 2001) and has previously been estimated 
to occur in 1 in 70,000 (Gunn 2004); however, the disease is recognized as rare by the 
National Institutes of Health (NIH) Office of Rare Disease Research (Genetic and Rare 
Disease (GARD) Number: 2877) and Orphanet (Orpha Number: 428).  
ADH1 is characterized by variable degrees of hypocalcemia with abnormally low levels of 
parathyroid hormone (PTH), hyperphosphatemia and low magnesium levels usually with 
persistent hypercalciuria (Roszko 2016). Symptoms of hypocalcemia most commonly 
include paresthesia, muscle spasms, cramps, tetany, circumoral numbness, and can be of 
variable intensity including inducing seizures. Hypocalcemia can also present with 
laryngospasm, neuromuscular irritability, cognitive impairment, personality disturbances, 
prolonged QT intervals, electrocardiographic changes that mimic myocardial infarction, or 
heart failure. 
In patients with ADH1, hypocalcemia occurs primarily due to increased sensitivity of the 
CaSR to extracellular ionized calcium which suppresses iPTH-secretion and leads to lower 
levels of endogenous 1,25-(OH)2 Vitamin D (decreasing calcium absorption from the gut) 
and lower levels of calcium reabsorption in the kidney (leading to hypercalciuria). 
Hypercalciuria is therefore worse in patients with ADH1 compared with other forms of 
hypoparathyroidism because of two mechanisms contributing to decreased renal calcium 
reabsorption: 1. reduced PTH-mediated reabsorption of calcium from the primary renal 
filtrate, 2. the presence of hyperactive CaSRs in the distal renal tubules preventing 
appropriate calcium reabsorption. Furthermore, standard treatment with oral calcium and 
calcitriol supplementation tends to worsen hypercalciuria which is associated with long-term 
morbidity such as nephrolithiasis, nephrocalcinosis and chronic kidney disease that can 
progress to renal failure (Khan 2018, Li 2018). 
For this reason, the consensus approach to management of ADH1 is to balance oral 
supplementation of calcium and calcitriol with the known high risk for renal calcifications, 
kidney stones and kidney failure (Roszko et al, 2016). This means the healthcare provider 
must help the patient find a regimen that can maintain the lowest serum calcium 
concentrations compatible with symptom relief to minimize hypercalciuria. Thiazide 
diuretics are sometimes added for their modest urinary calcium lowering effects.  
Experimental treatment with PTH(1-34) in ADH1 participants was able to correct serum 
calcium but did not abrogate hypercalciuria (Winer 2012, Winer 2014, Gafni 2015). 
Exogenous PTH(1-84) is approved for the orphan indication of hypoparathyroidism but the 
clinical study in patients with established hypoparathyroidism that supported approval 
excluded patients with hypoparathyroidism due to calcium sensing receptor mutations 
(Mannstadt, 2013).  
CLTX-305 (encaleret) may prove to be a therapy uniquely targeted to the underlying 
pathogenesis of altered calcium homeostasis in patients with ADH1 where resetting the 
CaSR “set-point” might normalize serum calcium and lower requirements for oral 

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supplementation with calcium and active vitamin D and without increasing the risk of 
iatrogenic chronic hypercalciuria. 
2.3 
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
CLTX-305 (encaleret) has been generally well tolerated in humans during chronic treatment 
up to and beyond 12 months. In a prior osteoporosis development program, CLTX-305 
(encaleret) was administered to over 1280 healthy men and post-menopausal women; no 
specific safety issues or signals were seen with acute dosing up to 100 mg and chronic dosing 
up to 15 mg QD. No distinct patterns of adverse events (AEs), to suggest intolerance nor 
evidence of toxicity (on- or off-target), were seen with CLTX-305 (encaleret), except for its 
known, on-target pharmacological effect to stimulate endogenous PTH hormone release and 
dose-related hypercalcemia (in euparathyroid participants) as described above. Details for all 
previous non-clinical and clinical studies with CLTX-305 (encaleret) can be found in the 
CLTX-305 (encaleret) Investigator’s Brochure. 
The most common adverse events reported in early phase trials included constipation, 
headache, dizziness, nausea, vomiting, abdominal pain, back pain and dermatitis in addition 
to increased blood calcium concentrations. None of these adverse events occurred with 
differential frequency in the larger phase 2 trials where no specific pattern of adverse events 
or clear differences were evident in AEs by System, Organ, Class between CLTX-305 
(encaleret) and placebo or comparator arms (other than differences in calcium levels). 
A thorough QT study in healthy participants showed no clinically meaningful QTc 
prolongation following a single oral dose of up to 100 mg CLTX-305 (encaleret) at any of 
the examined timepoints. 
In preclinical safety and toxicology studies the dose-limiting effects of CLTX-305 (encaleret) 
were related to mechanism-based elevations in serum calcium concentrations and effects on 
calcium homeostasis. In contrast, no off-target or other tissue or organ-specific toxicities 
were identified. 
The metabolism and elimination of CLTX-305 (encaleret) in preclinical studies has been 
conducted. Based on non-clinical data, fecal excretion was the main route of elimination. In 
humans, excretion of unchanged CLTX-305 (encaleret) and metabolites into urine was 
minimal (< 5% as total of parent and metabolite). The two major glucuronide metabolites 
(M1, M3) showed similar pharmacokinetics as the parent drug, with M1 median tmax ~2 hr. 
and M3 median tmax ~1.5 hr. For M1 (inactive), concentrations in plasma were approximately 
2-fold higher than those of parent drug; M3 (active) concentrations were low (10% compared 
to parent). Neither M1 nor M3 showed prolonged elimination (see Investigator Brochure for 
details). CLTX-305 (encaleret) has not been formally studied in patients with severe to 
moderate renal impairment but significant dose adjustments in this population are not 
expected given elimination pathway and in the setting of the protocol dose escalation safety 
review process. 

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In a human drug interaction study, CLTX-305 (encaleret) co-administration with ketoconazole, 
a potent CYP3A4 inhibitor, resulted in ~1.67x increase in Cmax and ~2x increase in AUC0-24 
with slightly less effect on M1 and M3. 
The potential for skin phototoxicity in humans is expected to be minimal based on the tissue 
distribution in rats and estimated human dosage, but participants may be at increased risk to 
natural or artificial sunlight (tanning beds or ultraviolet A/B light (UVA/B) treatment). 
Participants at increased risk to UV injury are encouraged to minimize or avoid exposure to 
natural or artificial sunlight (tanning beds or UVA/B treatment), wear sun-protective 
clothing, and use sunscreen that strongly absorbs ultraviolet A light (UVA). 
It is not known if CLTX-305 (encaleret) could have an effect on pregnancy or breastfeeding 
in humans. CLTX-305 (encaleret) may have potential teratogenic effects in humans based on 
the results of a reproductive toxicity study in rabbits where the incidence of skeletal 
anomalies (fusion of the sternebra) was increased in the fetuses at 30 mg/kg and above. 
Currently, Women of child-Bearing Potential (WOCBP) will be consented to receive 
pregnancy testing at screening and at intervals throughout the trial and required to utilize 
contraception and agree to avoid pregnancy during the experimental treatment. 
There are currently no approved alternative therapies for people with ADH1 to maintain 
blood calcium levels in the normal or low-normal range other than oral calcium and active 
vitamin D supplementation. The activating mutation in the CaSR leads to an insufficient 
iPTH response to low blood levels of calcium such that these patients are hypocalcemic 
without therapy. The goal of therapy is to raise blood calcium concentrations sufficiently to 
improve/abrogate symptoms and improve function and well-being. Current therapy with oral 
supplements presents challenges due to the frequency and pill-burden of using calcium and 
active vitamin D as well as the iatrogenic complication related to hypercalciuria which 
results from increasing the overall calcium load. These complications of current therapy 
often include nephrocalcinosis, progressive renal dysfunction and can result in renal failure. 
Treatment with CLTX-305 (encaleret) is being explored as a potential alternative or 
adjunctive treatment to maintain blood calcium levels while minimizing hypercalciuria. 
In the dose-escalating and dose-finding components of Periods 1, 2 and 3, participants may 
experience fluctuations in their blood calcium and phosphate levels including the potential 
for hypocalcemia, hypercalcemia, and/or hypophosphatemia. The long-term risk of such 
fluctuations with CLTX-305 (encaleret) are not expected to be larger than the risk of current 
therapy however such fluctuations may be more frequent during the initial dose-
escalating/dose finding portions of the clinical study. The clinical study is designed to 
minimize the risk of untoward fluctuations in blood calcium, phosphate and related serum 
chemistries: During the dose-finding Periods 1 and 2, participants will be supervised with 
frequent monitoring of blood calcium and phosphate levels multiple times per day and may 
receive treatment for hypocalcemia, hypercalcemia, or hypophosphatemia as required while 
effective doses of CLTX-305 (encaleret) are being identified. Each participant is assessed for 
evidence of an individualized effective dose of CLTX-305 (encaleret) during the in-house 
periods before entering outpatient Period 3. During Period 3 participants continue a 
combination of their oral calcium supplements and individualized starting dose of CLTX-305 
(encaleret) and will undergo at least weekly re-assessment and dose-titration based on 

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outpatient laboratory monitoring results and telephone contact visits with the investigative 
site staff. The outpatient approach to dose and regimen modification is similar to the current 
practice for optimizing conventional treatment with oral calcium and active vitamin D. 
Additional risks and potential discomforts related to the frequent blood and urine sampling 
procedures in the supervised setting of the in-house stays during Periods 1 and Periods 2 are 
addressed in the Informed Consent Document and include evaluations of medical history, 
physical examination, renal ultrasound and EKG. During test days multiple blood and urine 
collections will occur introducing known common risks (discomfort, bruising) for blood 
draws and/or intravenous catheter placement introducing smaller risks of complications 
including fainting (usually a vasovagal response to sight or insertion of needles) or 
inflammation of the insertion site (including potentially pain and swelling) and the potential 
for infection or venous thrombosis. Central catheters (inserted via the arm or the neck) may 
be used during Periods 1 and 2 to reduce participant burden during intensive sampling 
requirements. Adjustments in sampling may be necessary to reduce the burden of sampling if 
blood losses from either central or peripheral catheters breach NIH Guidelines for Blood 
Draw Limits for Research Purposes (M95-9, June 2009). 
Based on the totality of the evidence acquired to date, no other organ-specific or adverse 
safety signals of potential clinical concern have been identified. Clinical trials in the new 
target population of patients with ADH1 will closely evaluate dose-related effects on calcium 
and phosphate homeostasis and otherwise employ routine safety monitoring (For details on 
CLTX-305 (encaleret) safety data, see IB Section 5.3).  
2.3.2 
Known Potential Benefits 
There are no definitive currently known benefits of CLTX-305 (encaleret) in the target 
population of patients with hypocalcemia due to ADH1. In vitro and in vivo studies, 
including preclinical data in mouse models suggest that calcilytic agents including CLTX-
305 (encaleret) may shift the sensitivity of the ADH1-mutated CaSR back towards “normal” 
resulting in normalization of blood calcium levels. In a pilot study in humans with ADH1, an 
investigational calcilytic was shown to dose-dependently stimulate PTH acutely associated 
with transient suppression of urinary calcium excretion although the doses and times tested 
may have been insufficient to demonstrate definitive changes in serum calcium levels 
(Roberts et al 2019). 
2.3.3 
Assessment of Potential Risks and Benefits 
Taken together, both preclinical and available clinical data support further clinical 
development of CLTX-305 (encaleret) as a potential therapy targeted to the molecular 
defects in ADH1. Current standard of care, which includes oral calcium and active vitamin D 
supplementation, is complicated by the increased sensitivity of the CaSR to exogenous 
calcium which leads to an exaggerated urinary calcium excretion in response to small 
increases in blood calcium. This augmented urinary calcium excretion occurs both because 
iPTH levels are sub-optimal due to the altered CaSR function in the parathyroid glands, and 
due to the over-stimulation of the CaSR in the distal renal tubules, both of which contribute 
to enhanced urinary calcium loss and are associated with chronic complications of renal 

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function. CLTX-305 (encaleret), as a calcilytic agent, may dampen the CaSR to facilitate 
achievement and maintenance of the therapeutic targets of normalized blood calcium 
concentrations while also avoiding or minimizing hypercalciuria. 
One challenge to clinical development of CLTX-305 (encaleret) is that the doses of CLTX-
305 (encaleret) that will be effective in patients with ADH1 may be higher than the doses 
previously identified as raising blood calcium in extensive clinical experience in 
euparathyroid participants (postmenopausal women in the prior osteoporosis program). 
Effective doses of CLTX-305 (encaleret) for patients with ADH1 cannot be determined 
without execution of a specifically designed clinical trial. The current proposed clinical trial 
is designed to utilize conventional early drug development approaches, including single and 
multiple-ascending doses, while leveraging prior safety exposure data, to address the 
important questions of dose-response, acute safety and tolerability, and definitive proof-of-
concept regarding the extent to which CLTX-305 (encaleret) can act to normalize blood 
calcium in participants with ADH1. 
The study is designed to minimize known potential risks (as described above) while 
maximizing the range of doses studied to increase the probability of establishing a definitive 
proof-of-concept of the potential utility of CLTX-305 (encaleret) as a treatment for 
hypocalcemia in patients with ADH1. 
Patients with renal impairment due to ADH1 have been described but there are no dedicated 
studies addressing all aspects of this disease complication and its progression over time. In 
patients with post-surgical hypoparathyroidism who have no detectable PTH or low normal 
residual iPTH, there are case series that show that renal impairment with a decrease of > 25% 
eGFR and chronic kidney disease impairment have been described. The dose of calcium 
supplementation was significantly related to the decrease in renal function in these reports 
(Ponce de León-Ballesteros G., et al, 2020). Based on this important implication, participants 
with evidence of renal impairment, eGFR ≥ 25 mL/minute/1.73 m2 using CKD-EPI (for 
participants < 18 years old the Schwartz equation will be calculated) may be enrolled. 
 

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3 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
Periods 1 and 2 
• Evaluate the safety and tolerability of 
single and multiple doses of CLTX-
305 (encaleret) in participants with 
ADH1 
Period 3:  
• Evaluate the safety, tolerability and 
efficacy of CLTX-305 (encaleret) in 
participants with ADH1 for 24 weeks  
LTE: 
• Evaluate the longer-term safety and 
tolerability of CLTX-305 (encaleret) in 
ADH1 participants from Period 3 for 
approximately 25 months 
(approximately 2 years) 
Periods 1, 2, and 3:  
• Adverse events (AEs), clinical safety 
laboratory tests, vital signs, and 
electrocardiograms (ECGs) 
Period 3: 
• Albumin-corrected blood calcium 
concentrations (cCa) and 24-hr 
urinary calcium excretion after 
treatment with CLTX-305 (encaleret) 
for 24 weeks  
LTE: 
• Adverse events (AEs), clinical safety 
laboratory tests, vital signs for 
approximately 25 months 
(approximately 2 years) 
Secondary 
Periods 1 and 2: 
• Evaluate the effect of CLTX-305 
(encaleret) to increase serum iPTH 
levels after both single and multiple 
doses across a dose range in 
participants with ADH1 
Periods 1 and 2: 
• iPTH blood concentrations profiles 
(24-hours) over time after single and 
multiple doses of CLTX-305 
(encaleret) 
Periods 1, 2, and 3: 
• Evaluate the pharmacodynamic (PD) 
effects of CLTX-305 (encaleret) on 
blood calcium concentrations 
• Evaluate the PD effects of CLTX-305 
(encaleret) on associated measures of 
calcium homeostasis including 1,25-
(OH)2 Vitamin D levels and urinary 
calcium excretion  
• Evaluate the PD effects of CLTX-305 
(encaleret) on bone turnover markers 
including C-telopeptide (CTx) and 
procollagen type 1 N-propeptide 
(P1NP)  
Periods 1, 2, and 3: 
Pharmacodynamic endpoints measured over 
time up to 24 weeks (final visit): 
• Blood calcium - Absolute levels and 
change from baseline in cCa  
• Urinary calcium clearance (fractional 
excretion and 24-hour total excretion) 
• Renal function (eGFR) 
• Serum levels of 1,25-(OH)2 Vitamin 
D 
• Blood samples for magnesium, 
phosphate, creatinine 
• Urine samples for pH, magnesium, 
phosphate, sodium, potassium, 
creatinine, cAMP, citrate 

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• Bone resorption markers collagen 
cross-linked C-telopeptide (CTx)  
• Bone formation markers – blood 
procollagen type 1 N-propeptide 
(P1NP)   
• Evaluate the PK of both single and 
multiple ascending doses of CLTX-
305 (encaleret) in participants with 
ADH1. 
• PK parameters: maximum plasma 
concentration (Cmax), time to 
maximum plasma concentration 
(tmax), apparent terminal half-life (t½), 
area under the concentration-time 
curve (AUC) from time 0 to the last 
measurable time point (AUC(0-t)), 
AUC from time 0 to 24 hours 
(AUC(0-24)), AUC extrapolated to 
infinity (AUC(0-inf)) following single-
doses.  
• Determination of the steady state PK 
parameters: Cmax, trough 
concentration (Ctrough), and AUC over 
the dosing interval AUC(0-tau) 
LTE: 
• Obtain long-term data on efficacy 
(durability) of CLTX-305 (encaleret) 
on blood calcium concentrations 
• Evaluate the long-term PD effects of 
CLTX-305 (encaleret) on associated 
measures of mineral homeostasis 
including, iPTH, 1,25-(OH)2 Vitamin 
D levels and urinary calcium excretion 
• Evaluate the long-term PD effects of 
CLTX-305 (encaleret) on bone 
turnover markers including C-
telopeptide (CTx) and procollagen 
type 1 N-propeptide (P1NP)  
 
LTE: 
• Blood calcium - Absolute levels and 
change from baseline in cCa  
• Urinary calcium clearance (fractional 
excretion and 24-hour total 
excretion) 
• Blood levels of iPTH 
• Renal function (eGFR) 
• Serum levels of 1,25-(OH)2 Vitamin 
D 
• Blood samples for magnesium, 
phosphate, creatinine 
• Urine samples for pH, magnesium, 
phosphate, sodium, potassium, 
creatinine, cAMP, citrate 
• Bone resorption markers collagen 
cross-linked C-telopeptide (CTx)  
• Bone formation markers – blood 
procollagen type 1 N-propeptide 
(P1NP)   
 

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4 
STUDY DESIGN 
4.1 
Overall Design 
This will be a single-site, open-label, dose-ranging and dose maintenance study to evaluate 
the safety, tolerability and efficacy of CLTX-305 (encaleret) to maintain normal albumin-
corrected blood calcium (cCa) in participants with hypocalcemia due to ADH1. It will consist 
of two inpatient periods of dose initiation, escalation and steady-state adjustment (Periods 1 
and 2), an outpatient dose stabilization and maintenance period including NIH clinical visits 
(Period 3), and a long-term extension (LTE). 
The LTE is designed to obtain additional safety data and evaluate durability of efficacy for 
CLTX-305 (encaleret). The LTE also allows for continued treatment of enrolled participants 
with CLTX-305 (encaleret). Participants who elect to continue in LTE will receive CLTX-
305 (encaleret) for an additional period of time, up to 25 months (approximately 2 years) or 
until they transition to the CLTX-305-302/CALIBRATE Phase 3 LTE, whichever occurs 
first. 
Two principal cohorts are planned: 
• Cohort 1: up to 8 participants (minimum of 5) will initially be enrolled into Period 1 
(inpatient), after which they may return to participate in Period 2 (inpatient, after at 
least an 8-week interval). Participants who complete Period 2 will be eligible to enter 
Period 3 (outpatient) for up to 24 weeks of dosing with CLTX-305 (encaleret). 
• Cohort 2: up to 10 additional participants (minimum of 5) will enroll directly into 
Period 2 (inpatient). The initiation of Cohort 2 will be based on evaluation of 
accumulated data from Cohort 1. Cohort 2 participants who complete Period 2 will be 
eligible to enter Period 3 (outpatient) to receive up to 24 weeks of CLTX-305 
(encaleret). 
Participants from both cohorts who complete Period 2 will be eligible to enter Period 3. 
Outpatient dosing with CLTX-305 (encaleret) will be determined from review of individual 
dose-response data from Periods 1 and/or 2 based on identifying well-tolerated BID doses 
with preliminary evidence for efficacy. During the initial outpatient period (Period 3), 
participants will undergo additional individualized dose titration as necessary in response to 
safety data and the results of key efficacy measures. Participants who complete Period 3 (up 
to Week 24) and who elect to continue in the LTE will receive CLTX-305 (encaleret) for 
additional period of time, up to 25 months (approximately 2 years) or until they transition to 
the CLTX-305-302/CALIBRATE Phase 3 LTE, whichever occurs first. 
 

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Figure A 
Study Overview Schematic 
 
   
Figure B 
Detailed Schematic for Periods 1 and 2 (Single and Multiple 
Ascending Dose Testing) 
 

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A schematic of Period 3 is shown in Figure C. 
Figure C 
Detailed Schematic for Period 3 
 
Figure D 
Detailed Schematic for Long-term Extension (LTE) 
 
 
• Period 1 - Is an inpatient stay that consists of 5 dosing days during which participants 
will undergo a once-daily (QD) dose escalation for 3 days followed by 2 days of 
twice daily (BID) dosing at an individualized test dose of CLTX-305 (encaleret). 
• Period 2 - Is an inpatient stay that consists of 5 dosing days during which participants 
will receive BID doses of CLTX-305 (encaleret) based on individual responses from 
Period 1 (for participants who complete Period 1) or review of aggregate data from 
Period 1 (for participants in Cohort 2 entering Period 2 without prior exposure to 
CLTX-305 (encaleret)). The initial dose, dose level 1 (DL1) will be administered for 
approximately 2 days (48 hours) with cCa monitoring.  Participants will undergo 
encaleret dose up- or down-titration depending on cCa levels, with a potential 
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
X
X
X
X
X
X
X
Wk 8
Wk 16
Wk 24
Period 3:Study week
Telephone Contact Visit 
(with local labs)  
NIH Inpatient visit
(PK/PD, 24-hr urine, safety measures) 
Titration
Maintenance
Wk= Week
Shading to help visualization - Dark Grey (NIH visit), Light Grey (Telephone contact), as indicated 
NIH
NIH
NIH

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increase in dose if cCa remains below the lower limit of normal and potential 
decrease in dose if cCa is greater than or equal to the upper limit of normal. A final 
test day (Day 5) will include frequent blood and urine sampling to collect 24-hour 
PK/PD profiles. 
• Period 3 - Is an outpatient dosing period that consists of administration of CLTX-305 
(encaleret) for up to 24 weeks. Participants completing Period 2 will continue to self-
administer CLTX-305 (encaleret) at an initial BID dose based on their tolerance and 
response to BID dosing during Period 2. Initial titration will be based on each 
participant’s need for symptom control and ongoing monitoring of efficacy endpoints 
(primarily cCa and urine calcium excretion) with a goal to optimize cCa in the normal 
range while minimizing hypercalciuria. Participants will not take calcitriol but may 
take calcium supplementation as needed to ensure a minimum daily dietary intake of 
1000 mg. Participants may receive oral calcium supplements as directed by the 
investigative site if they are not able to achieve a minimum of 1000 mg per day of 
dietary calcium intake. Guidance on overall outpatient titration is discussed in Section 
6.1.5 and in Section 8.2.3. The need for additional dose adjustments may depend on 
factors potentially related to the time course of changes in parathyroid gland function, 
intestinal calcium absorption, bone resorption, and kidney function, all of which will 
be monitored. Participants are considered to have completed the study once they 
complete 24 weeks of Period 3 and the safety follow-up visit. 
Long-term Extension (LTE) - Outpatient dosing with CLTX-305 (encaleret) will continue 
for an additional period of time, up to 25 months (approximately 2 years), or until they 
transition to the CLTX-305-302/CALIBRATE Phase 3 LTE, whichever comes first, after 
completion of the Week 24 visit in Period 3. Participants completing Period 3 will continue 
to receive clinical supplies of CLTX-305 (encaleret) at the same BID dose based on their 
tolerance and response to BID dosing during CLTX-305 (encaleret) dosing in Period 3. 
Participants will not take calcitriol but may take calcium supplementation as needed to 
achieve a minimum daily intake of 1000 mg. Participants may receive oral calcium 
supplements as directed by the investigative site if they are not able to achieve a minimum of 
1000 mg per day of dietary calcium intake. A final follow-up safety visit in the LTE will 
occur 30 ± 7 days after the last dose of CLTX-305 (encaleret) is taken as part of this protocol 
for participants who withdraw from the study or CLTX-305 (encaleret) before transitioning 
to the CLTX-305-302/CALIBRATE Phase 3 LTE. 
At any point during the LTE, and before transition to the CLTX-305-302/CALIBRATE 
Phase 3 LTE, participants can choose to stop participation and be placed back on the 
conventional therapy. Follow-up assessments should be completed per Schedule of 
Assessments (see Section 1.3 Table D) and clinical supply of CLTX-305 (encaleret) should 
be returned to the investigative site. 
4.2 
Scientific Rationale for Study Design 
For detailed background on the study rationale see Section 2.1 (Study Rationale). The current 
Add clinical trial is designed to test CLTX-305 (encaleret) across a range of doses 
administered both once and twice daily to determine the ability of a calcilytic to raise blood 
calcium in patients with ADH1. 

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The current study is designed to confirm the utility of the calcilytic agent, CLTX-305 
(encaleret), to treat hypocalcemia due to ADH1 through allosteric antagonism of the mutated 
CaSR in these patients. The study is designed to identify minimally effective doses, steady 
state pharmacokinetic/pharmacodynamic (PK/PD) relationships, and/or maximally tolerated 
doses in the target population of people with confirmed ADH1. Such data will be established 
during in-house periods 1 & 2 resulting in individualized dosing that will inform starting 
doses for outpatient exposure during Period 3. Initial outpatient dosing may be further 
titrated, along with oral calcium supplements, with the goal of optimizing blood calcium 
without the need for calcitriol while minimizing urinary Ca excretion. 
Due to the orphan nature of ADH1, and the rarity of available participants for participation in 
this clinical trial, the Sponsor believes it is reasonable to anticipate extending the study into 
an outpatient Period 3 based on the expectation that Periods 1 and 2 will identify both 
individualized and rational average effective doses across both Cohorts 1 and 2. 
4.3 
Justification for Dose 
The current study proposes to initiate first-in-patient dosing in the new target population of 
participants with ADH1, at 30 mg of CLTX-305 (encaleret). This dose has been shown 
previously to be safe and well tolerated in non-ADH1 participants (i.e., people not harboring 
pathogenic, gain-of-function variants that drive ADH1) and was unequivocally associated 
with increased plasma iPTH and elevation of cCa. It is expected that this may be an 
ineffective or minimally effective dose in ADH1 and therefore represents a logical starting 
dose upon which to base dose-escalation and dose-finding. For details of the PK/PD 
relationship of CLTX-305 (encaleret) in euparathyroid participants with presumed normal 
CaSR function, See the Investigator’s Brochure. 
Using both single ascending and multiple-ascending dose paradigms, the proposed study will 
explore the PK-PD relationship of CLTX-305 (encaleret) in participants with ADH1. 
Because ADH1 is an orphan disease with few identified potential participants, and because of 
the well characterized safety data available from the prior development program, we propose 
to conduct individualized dose escalation in a cohort of approximately 16 participants. It is 
not possible to predict what dose of CLTX-305 (encaleret), on average, will result in elevated 
calcium in ADH1 but it is anticipated that dosing may need to proceed from 30 mg through 
at least a log increase. The supervised in-house testing during Periods 1 and 2 will allow 
dosing to proceed based on safety and tolerability with close monitoring for evidence of 
efficacy based on changes in iPTH and cCa for each participant. Doses that elevate cCa, for 
example > 1mg/dL, within 1-5 days, would establish a definitive proof-of-concept for CLTX-
305 (encaleret) as a potential treatment for ADH1. Doses that are associated with 
hypercalcemia would establish an upper bound or maximally tolerated dose. 
Given that Periods 1 and 2 are designed to identify individually effective doses of CLTX-305 
(encaleret), as well as potential upper bounds, these results should facilitate the choice of 
outpatient starting doses, likely at lower doses, as well as inform the initial approach to 
outpatient dose adjustment and optimization during Period 3. 

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Period 3 is designed to identify individualized chronic doses. Due to the different timeframes 
for PTH action (relatively immediately limiting calcium loss in the urine, followed by 
increasing endogenous 1,25-(OH)2 Vitamin D effects on GI absorption, and eventually 
mobilizing bone calcium), chronic outpatient doses may be lower than doses shown to be 
acutely effective. The dose-response curves for both iPTH stimulation and cCa elevation 
from Periods 1 and 2 may also inform updated PK-PD models which are currently based on 
non-ADH1 participants (Cabal 2013, Shrestha 2010). Taken together, individualized 
participant data and the ongoing accrual of data on all participants should facilitate rational 
outpatient dosing and titration. 
The LTE is designed to obtain additional safety data for CLTX-305 (encaleret). Participants 
who elect to continue in LTE will receive CLTX-305 (encaleret) for an additional period of 
time, up to 25 months (approximately 2 years) or until they transition to the CLTX-305-
302/CALIBRATE Phase 3 LTE, whichever occurs first. Participants who transfer to the 
CLTX-305-302/CALIBRATE Phase 3 LTE will continue encaleret dosing at their prescribed 
dose until enrolled into the CLTX-305-302/CALIBRATE Phase 3 LTE. 
At any point during the LTE, and before transition to the CLTX-305-302/CALIBRATE 
Phase 3 LTE, participants can choose to stop participation and be placed back on the 
conventional. Follow-up assessments are to be completed per Schedule of Assessments (see 
Section 1.3 Table D) and clinical supply of CLTX-305 (encaleret) should be returned to the 
investigative site. 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Participants must meet the following criteria for inclusion during screening: 
1. Be able to understand and sign a written informed consent or assent form, which must 
be obtained prior to initiation of study procedures. 
2. Age ≥ 16 years  
3. Postmenopausal women are allowed to participate in this study: 
a. Women are considered postmenopausal and not of childbearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least 6 weeks prior to start of the study. In 
the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment, shall she 
be considered not of childbearing potential. 
4. Body mass index (BMI) ≥ 18.5 to < 39 kg/m2 
5. Have an activating mutation of the CaSR gene 
6. Participants being treated with thiazide diuretics may be enrolled if they are willing 
and able to discontinue thiazides for at least 5 half-lives prior to initiation of CLTX-

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305 (encaleret) and during the study treatment period. When the thiazide is being 
used as an antihypertensive, alternative therapy will be offered. 
7. Participants being treated with strong CYP3A4 inhibitors (including clarithromycin, 
telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, 
indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) should ideally, if 
clinically appropriate, discontinue these medications during the screening period for 
at least 5 half-lives prior to initiation of CLTX-305 (encaleret). Participants who must 
remain on strong CYP3A4 inhibitors may still enroll if they are able to remain on 
their medications at stable doses throughout the trial. 
8. Participants being treated with magnesium or potassium citrate supplements should 
discontinue such treatment starting on Day -1 during Period 1 and Period 2 and may 
be asked to discontinue treatment during Period 3 if the blood magnesium and urine 
citrate are within the normal ranges during Period 1 and Period 2. 
5.2 
Exclusion Criteria 
Participants who meet any of the following criteria during Screening will not be eligible to 
participate in the study: 
1. History of treatment with PTH 1-84 or 1-34 within the previous 3 months 
2. History of hypocalcemic seizure within the past 3 months 
3. Blood 25-OH Vitamin D level < 25 ng/mL 
a. If participant has a blood 25-OH Vitamin D level < 25 ng/mL at the screening 
visit, they will be prescribed cholecalciferol or ergocalciferol supplementation. 
Once the 25-OH Vitamin D level is > 25 ng/mL, the participant will be eligible to 
continue to the treatment phase of the study. 
4. Participants with hemoglobin (Hgb) < 13 g/dL for men and < 12 g/dL for women  
a. If participant has a low Hgb at the screening visit due to iron, B12, or folate 
deficiency, they will be prescribed supplementation. Once the Hgb level is 
> 13 in men or > 12 in women, the participants will be eligible to continue to 
the treatment phase of the study. 
5. Abnormal laboratory values which in the opinion of the investigator, would make the 
participant not suitable for participation in the study 
6. Estimated glomerular filtration rate (eGFR) < 25 mL/minute/1.73 m2 using CKD-EPI 
(for participants < 18 years old the Schwartz equation will be calculated) 
7. 12-lead resting electrocardiogram (ECG) with clinically significant abnormalities 
8. Participants with positive hepatitis B surface antigen (HBsAg), Hepatitis A 
immunoglobulin M (IgM), or human immunodeficiency virus (HIV) viral serology test 
results at the Screening Visit. Participants who are in complete remission from 
Hepatitis C as evidence by sensitive assay ≥12 weeks after completion of HCV 
therapy are allowed to participate in the study. 

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9. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
serum hCG laboratory test 
10. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 months following the discontinuation of study treatment. 
Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 
In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female participants 
on the study the vasectomized male partner should be the sole partner for that 
participant. 
• Combination of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or 
other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal 
suppository 
11. Sexually active male participants who are unwilling to use a condom during vaginal 
intercourse while taking the CLTX-305 (encaleret) (study drug) and for 3 months after 
the last dose of the study drug. Participants should not father a child during active 
participation in the study starting with the first CLTX-305 (encaleret) dose in Period 1, 
Period 2 (for Cohort 2) until the end of study participation. Condoms are not required if 
the participant is vasectomized or if the participant’s partner is not a woman of child-
bearing potential. 
12. Hypersensitivity to any active substance or excipient of CLTX-305 (encaleret) 
13. History of drug or alcohol dependency within 12 months preceding the Screening Visit 
14. History of thyroid or parathyroid surgery 
15. Current participation in other investigational drug studies 
16. Unwillingness to refrain from blood donation within 12 weeks prior to screening visit 
from the start of the study enrollment through one year after the last dose of the study 
drug 

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5.3 
Inclusion of Vulnerable Participants 
Participants between 16 and 18 years of age may be enrolled in this study. Older adolescents 
have the capacity to provide adequate assent in an intensive Phase 2a study for which benefit 
in this disorder remains uncertain. Younger children are excluded because of the intensity of 
the procedures with uncertain clinical benefit. 
5.4 
Lifestyle Considerations 
Not applicable. 
5.5 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently assigned to the study intervention or entered in the study. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). Due to the ultra-orphan nature of ADH1, all data derived from participants during 
screening will be entered into the clinical trial database regardless of whether an individual 
participant is included or excluded from the active treatment periods. 
Individuals who do not meet the criteria for participation in this trial (screen failure) because 
of a failing to meet criteria outlined in Section 5 may be rescreened once. The PI will discuss 
with Sponsor if additional screening attempts are warranted so that a joint decision can be 
made and recorded if necessary for a specific participant. Rescreened participants should be 
assigned the same participant number as for the initial screening. 
5.6 
Strategies for Recruitment and Retention 
ADH1 is a rare disease with varying estimates on the order of 1500 patient prevalence in the 
United States. ADH1 is designated as an orphan disease consistent with this ultra-rare 
prevalence. A number of participants are identified and known to NIH investigators, some of 
whom have participated in prior clinical evaluations at the NIH in a prior pilot study utilizing 
a related calcilytic compound, NPSP795 (Roberts et al 2019). Initial recruitment will include 
contacting known potential participants with ADH1. Additional recruitment may proceed 
through referrals from worldwide clinical and research experts involved in this specialized 
area of mineral metabolism. Finally, outreach through patient advocacy organizations 
worldwide will also be pursued. 
While most established ADH1 patients aged > 16 years old will likely be eligible to 
participate according to protocol inclusion/exclusion criterion, it is estimated that up to 20 
potential participants may be enrolled to support up to 16 participants entering the treatment 
phase of the study. 

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Potential participants will undergo the informed consent/assent process and be screened 
during an admission to the NIH, when they will receive explanation of the clinical trial 
procedures and requirements. Participants will receive expert clinical oversight of their 
outpatient therapeutic regimen and management from NIH investigators during the period 
from screening to the first in-house admission and throughout the clinical trial to encourage 
and enhance retention. 
5.6.1 
Costs 
Compensation (see below) for participation in the trial will be per NIH guidelines as 
described in the Informed Consent and related attachments. Participants will not be billed by 
NIH and the Sponsor for any research or related clinical care that participants will receive at 
the NIH Clinical Center for this study. The NIH Clinical Center will provide short-term 
medical care for any injury resulting from participation in this clinical trial. Costs for local 
medical care related to the clinical trial but not otherwise covered by participant’s own 
insurance may be compensated by the Sponsor. 
5.6.2 
Compensation 
Participants will be compensated for participation in this clinical trial via check or direct 
deposit to the adult or minor participant. If the minor does not have a bank account or is 
unable to deposit checks, an alternative arrangement will be made with the participant and 
parent/guardian. 
Maximum compensation will be $2550, paid in $850 installments at the completion of the 
first three study periods. Participants will not be compensated for participation in the LTE. 
If participant is unable to finish the study, he/she will receive adjusted compensation for 
part(s) completed also in accordance with NIH HRPP policy 3014-302 Subject Recruitment 
and Compensation. 
Air/train/bus travel will be arranged by the NIH travel agency unless there are extenuating 
circumstances requiring the participant to book his/her own travel. For minor participants, 
travel and Children’s Inn/hotel accommodation will also be provided for 1 parent or legal 
guardian. Miscellaneous out-of-pocket travel expenses (e.g., baggage receipts, airport 
parking, taxis) will be reimbursed if a receipt is provided. Participants traveling by car from 
> 50 miles will be reimbursed mileage per NIH policies. Participant copays or co-insurance 
for local laboratories will be paid or reimbursed if an invoice or receipt is provided. 

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6 
STUDY INTERVENTION 
6.1 
Study Interventions(s) Administration 
During Period 1 participants from Cohort 1 will receive CLTX-305 (encaleret) QD and BID 
per protocol with water as described in Section 8.2.1. 
During Period 2 participants from both Cohort 1 and Cohort 2 will receive CLTX-305 
(encaleret) BID with water as described in Section 8.2.2 
During Period 3 participants from both Cohort 1 and Cohort 2 who enter Period 3 will be 
discharged home to continue taking CLTX-305 (encaleret) BID with water as described in 
Section 8.2.3. 
During LTE participants who have completed Period 3 will continue taking CLTX-305 
(encaleret) BID with water as an outpatient as described in Section 8.2.4. 
6.1.1 
Study Intervention Description 
The investigational medicinal product (IMP), CLTX-305 (encaleret), will be provided as 
white film-coated tablets containing encaleret sulfate drug substance (active ingredient 
encaleret) and may be provided in 5, 10, 30 and 60 mg doses in bottles. If the 5mg tablet is 
not available for use, then the 10 mg tablets may be split according to the related 
specifications indicated in the Pharmacy manual provided by the Sponsor. No other dose 
strength may be split. 
If the 10 mg tablet needs to be split, the participant should cut one 10 mg encaleret tablet 
each day and take half of the tablet in the morning and the other half of the split tablet in the 
evening, assuring that the participant receives a full 10 mg dose per day. Participant should 
follow the manufacturer instructions for use included with the pill cutter. In the event that 
half of the split 10 mg tablet is lost, the participant should cut a new tablet in half for the 
evening dose and discard the remaining half. The participant should start with a new 10 mg 
tablet the following morning. 
Full details regarding CLTX-305 (encaleret) packaging are provided in the Pharmacy 
Manual. 
6.1.2 
Dosing and Administration 
For details on Dosing of CLTX-305 (encaleret) see Section 8.2. 
For additional background on Dose Justification see Section 4.3. 
Dosing of CLTX-305 (encaleret) in participants with ADH1 is informed by prior experience 
of both acute and chronic dosing of CLTX-305 (encaleret) in the osteoporosis program that 
included exposures up to 1 year primarily in postmenopausal women with presumed normal 
CaSR function. The proposed starting dose is 30 mg in ADH1 because this is a dose proven 
to result in acute elevations in cCa in euparathyroid participants without an ADH1 mutations. 

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Based on peer-reviewed data from a pilot human study of a related calcilytic agent, NPSP795 
(Roberts et al 2019), which also studied a top dose known to cause a rise in calcium in 
euparathyroid participants but not in ADH1 participants, we anticipate that the starting dose 
of 30 mg may be ineffective or minimally effective but represents a rational initial dose that 
has been demonstrated as safe and well tolerated previously. 
Because a comprehensive safety database exists from the prior osteoporosis development 
program, including 12 months or more duration of safety exposure, the current first-in-ADH1 
study will include repeat dosing, dose-escalation and dose individualization over time in 
individual ADH1 participants. Similar to cross-over designs, conducting dose-escalation 
within participants should reduce variability and increase the precision of dose/response 
modeling compared to an approach that might use separate parallel or sequential cohorts. Up 
to 16 participants studied should be feasible and allow characterization of individual and 
group mean dose-exposure-response profiles as well as proof-of-concept on elevation of cCa. 
Our approach is preferable since the ultra-orphan nature of the disease makes conventional 
parallel group dose finding not feasible. 
CLTX-305 (encaleret) will be tested both as a single daily dose and as a twice daily dose. In 
the prior osteoporosis program CLTX-305 (encaleret) was administered once daily and this 
was seen to stimulate a transient increase (spike) in iPTH levels secretion within 2 hours and 
a second lower plateau level of iPTH (still elevated compared to baseline) for up to 12 hours 
at doses of 30 mg and above. Despite both PK (drug exposure) and PD (increased iPTH 
levels) lasting less than 24 hours, some evidence for increased trough cCa (measured 24 
hours after last dose) suggests that once daily dosing and once-daily dose escalation should 
be tested in ADH1 participants. 
CLTX-305 (encaleret) may be administered within 30 minutes prior to meals. Administration 
with meals was shown in prior Phase 1 trials to be associated with adequate systemic 
absorption, prompt increases in plasma levels of iPTH but with a slightly blunted PTH Cmax 
compared to administration while fasted (See Investigator’s Brochure for details and results 
of Phase I trials). Recommendation for administration within 30 minutes prior to meals was 
chosen as the paradigm for ADH1 dosing because, unlike in the osteoporosis program, the 
goal in ADH1 patients is not to maximize PTH Cmax but to facilitate increased iPTH levels 
above baseline throughout the day, adequate to raise blood cCa levels into the normal range. 
It is anticipated, however, that twice daily dosing may result in lower iPTH levels Cmax and 
more stable iPTH level over the course of 24 hours versus single daily dosing. The protocol 
is designed to test this hypothesis by conducting both once-daily and twice daily dose 
escalation in Period 1 and twice-daily dose escalations in Period 2. 
An overview and general description of the study strategy for intervention CLTX-305 
(encaleret) administration is presented below. Additional detail on doses, regimens and 
titration algorithm/guidance for each Period can be found under the appropriate sub-section 
of Section 8.2, including flowcharts for dosing in Period 1 (Figure E) and Period 2 
(Figure F). 

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6.1.3 
Period 1 (Single Ascending Dose Escalation and BID PK/PD profile) – 
Cohort 1 
In Period 1, eligible Cohort 1 participants are admitted to the NIH CC after completing 
screening tests. On days 1-3 of admission, Cohort 1 participants will undergo single daily 
dosing and protocol-specified dose-escalation of CLTX-305 (encaleret) from the initial dose 
of 30 mg on Day 1, increasing to a maximum dose of 180 mg on Day 3. Based on the 
individualized responses to QD dose escalation an individualized dose of CLTX-305 
(encaleret) will be chosen for BID administration on Days 4 and 5. 
Days 1, 2 and 3 (QD Dose Escalations): Up to 8 participants (minimum of 5) will undergo a 
single-dose, dose-escalation over the first 3 days of admission in Period 1. Morning doses 
will be administered on Days 1, 2 and 3, respectively, accompanied by frequent blood and 
urine sampling for 24-hours for PK/PD measures. CLTX-305 (encaleret) will be 
administered in the morning within 30 minutes prior to breakfast. If dose escalation is limited 
due to tolerability or hypercalcemia, then the investigator, in consultation with the Sponsor, 
may choose to interrupt the pre-specified dose escalation (for example see Section 6.1.7 and 
Section 8.2.1). In this case, the investigator, in consultation with sponsor, may choose to 
repeat the last well-tolerated dose on Days 2 and 3, or titrate down as appropriate. 
Dose-escalation will take place sequentially on Days 1, 2 and 3 without interim wash-out 
because prior extensive PK-PD data supports minimal drug accumulation over 24 hours 
when dosed once daily (for details see the Investigator’s Brochure). Similarly, it is expected 
that iPTH levels will not remain elevated for 24 hours after dosing when CLTX-305 
(encaleret) is administered once-daily. However, any carryover effects that may occur should 
not confound the objective of demonstrating an acutely efficacious dose of CLTX-305 
(encaleret). For any given participant, cCa values > 10.5 mg/dL, during a dosing interval, 
will indicate that a top dose of CLTX-305 (encaleret) has been reached for that individual 
and further dose escalation will not be necessary. In this scenario, the investigator, in 
consultation with the Sponsor, may choose to repeat the last well-tolerated dose on the 
remaining QD testing days (e.g., Days 2 and 3), as appropriate. Detailed examples of dose 
and titration modifications based on the cCa response are shown in Figure E in Section 8.2. 
Days 4 and 5 (BID Dose Escalation): Based on each participant’s individual PD responses 
to QD dose-escalation, an individualized dose of CLTX-305 (encaleret) will be chosen for 
BID dosing on Days 4 and 5. CLTX-305 (encaleret) will be administered once in the 
morning and once in the evening, within 30 minutes prior to breakfast and dinner. The dose 
selected should be based on each participant’s response in cCa and/or PTH levels during the 
prior QD dosing (Days 1-3). A guidance algorithm for BID dosing, based on the individual 
response to QD dosing in Period 1, is presented in Figure E in Section 8.2. 
6.1.4 
Period 2 (BID Dosing) – Cohorts 1 and 2 
In Period 2, eligible Cohort 1 participants, who have completed Period 1, may return after at 
least 8 weeks for admission to NIH for Period 2. After all Cohort 1 participants have finished 
Period 1 and the data analyzed, the Sponsor will open enrolment for Cohort 2 participants. 
Eligible Cohort 2 participants may enroll directly into Period 2, after completing the consent 

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and screening process per protocol. In Period 2 all participants will initiate CLTX-305 
(encaleret) BID dosing given within 30 minutes prior to breakfast and dinner on Days 1 and 
2. cCa concentrations will be monitored frequently throughout Period 2, and CLTX-305 
(encaleret) doses will be up- or down-titrated as needed to target normal cCa concentrations. 
Assessment of the 24-hour PK/PD profile of CLTX-305 (encaleret) with BID dosing will be 
conducted on Day 5. A guidance algorithm for initiating and titrating BID dosing during 
Period 2 is presented in Section 8.2.2, and in the algorithm/guidance in Figure F. 
6.1.5 
Period 3 (Cohort 1 and Cohort 2) – Outpatient Dosing 
In Period 3, the initial outpatient dose of CLTX-305 (encaleret) will be individualized based 
on the results from inpatient Periods 1 and/or 2 as described in greater detail in Section 8.2.3. 
Period 3 will include a titration phase of approximately 12 weeks and a maintenance phase of 
approximately 12 weeks for a total outpatient exposure to CLTX-305 (encaleret) of 24 
weeks. Titration will be conducted by the NIH investigators at scheduled or unscheduled 
telephone contact visits based on review of outpatient chemistry results for cCa, Mg, 
phosphorous at NIH CC visits (approximately every 8 weeks) based on assessment of both 
blood and urine calcium results as described, with the goal of optimizing the CLTX-305 
(encaleret) dose without calcitriol, targeting normal cCa and phosphorus concentrations, 
avoiding symptoms of hypo- or hypercalcemia, and minimizing the extent of hypercalciuria. 
Oral calcium supplementation may be used as needed on top of a minimum daily dietary 
intake of at least 1000 mg. 
6.1.6 
Long-term Extension (Cohort 1 and Cohort 2) – Outpatient Dosing 
In the Long-term Extension (LTE), participants will continue CLTX-305 (encaleret) per the 
dosing regimen established in the maintenance phase of Period 3. Telephone contacts along 
with outpatient laboratory assessments will be performed every 6 months starting at Month 3 
with NIH CC visits occurring every 6 months starting at Month 6. CLTX-305 (encaleret) 
doses may be titrated as needed based on assessment of both blood and urine results as 
described, with the goal of optimizing the CLTX-305 (encaleret) dose without calcitriol, 
targeting normal cCa and phosphorus concentrations, avoiding symptoms of hypo- or 
hypercalcemia, and minimizing the extent of hypercalciuria. Oral calcium supplementation 
may be used as needed on top of a minimum daily dietary intake of at least 1000 mg. 
6.1.7 
Dose Limiting Toxicity 
The goal of the current study in participants with ADH1, is to elevate cCa concentrations, 
including identifying doses capable of raising cCa beyond the normal range. It is important to 
establish if an allosteric modulator of the CaSR is capable of causing hypercalcemia at all, in 
patients with activating mutations of the CaSR. The study is designed to monitor for cCa 
elevations in a closely supervised and expert setting familiar with acute treatment and 
intervention, if necessary. In the prior osteoporosis program, hypercalcemia, identified by 
laboratory testing, was confirmed as a dose-limiting effect in presumed euthyroid participants 
without CaSR mutations, however, of note, laboratory hypercalcemia was not clearly 
associated with hypercalcemic symptoms; the events were detected in routine laboratory 

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monitoring and were managed by withholding or lowering the dose of CLTX-305 
(encaleret). 
Another inherent study objective is assessment of safety and tolerability across different 
doses and regimens including characterizing dose-limiting adverse events, determining 
maximum doses associated with acceptable safety risk, as well as determining doses that can 
effectively raise or maintain stable normal cCa concentrations.  
Based on experience accumulated in human clinical testing, from the prior osteoporosis 
program, no specific safety signal or adverse event profile was identified with acute or 
chronic dosing with CLTX-305 (encaleret). Dose-limiting hypercalcemia was the only signal 
that required chronic doses to be limited to 15 mg QD in an otherwise healthy population of 
postmenopausal women treated for up to 12 months. 
Since there is no specifically expected adverse event profile or anticipated dose-limiting 
toxicity in humans, safety monitoring for CLTX-305 (encaleret) will be based on established 
approaches and principles. Protocol-specified safety measures based on adverse event 
monitoring, safety laboratories, vital signs, physical exam, and EKGs will be assessed during 
the NIH visits. For any individual participant, the experience of an adverse event will be 
evaluated and recorded according to the guidance given in Section 8.5.3, and appropriate 
action with respect to study drug administration will be made according to the judgment and 
assessment of the investigator. 
It is expected that higher doses of CLTX-305 (encaleret) will be necessary to see comparable 
changes in cCa in participants with ADH1 compared to previously tested participants with 
normal CaSR function and therefore the current protocol stipulates potential dose escalation 
higher than 100 mg including doses possibly > 400 mg acutely in order to identify effective 
doses in the new target population of participants with abnormal CaSR function where cCa 
elevations would represent efficacy and not a safety side-effect. 
The proposed starting dose for participants with ADH1 is 30 mg, which was well tolerated, 
in healthy normal volunteers, without a specific safety signal, but was also rapidly effective 
in raising cCa. It is expected that this dose will not be effective or may be minimally 
effective in raising cCa in ADH1 participants. Therefore, based on known safety and efficacy 
on cCa, CLTX-305 (encaleret) 30 mg represents a rational initial dose for this first-in-ADH1 
trial. Moreover, CLTX-305 (encaleret) was acutely safe and well tolerated across a range 
from 5-100 mg in non-ADH1 participants (approximately 10-fold range). Original Phase 1, 
single-escalating dose trials in healthy humans with presumed normal CaSR function, were 
designed to escalate up to 400 mg CLTX-305 (encaleret); however, a top dose of 100 mg was 
identified based on rising cCa concentrations. The top dose in people with presumed normal 
CaSR function was chosen as 100 mg, to avoid excessive cCa elevations, and was used 
safely as the top dose in a Phase I thorough QTc study. 
Of note, although people with ADH1 may show a right-shifted dose-response compared to 
healthy non-ADH1 people, there is no biological reason to expect the dose-response 
trajectory to be significantly steeper in participants with ADH1. Therefore, it is important to 
plan for appropriate dose-escalation in this first-in-ADH1 trial, to focus on proof-of-calcium-

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raising effect. The planned dose range for QD exploration in ADH1 participants includes a 
range from 30 to 180 mg (approximately 6-fold range). If higher doses are required to 
confirm efficacy on cCa, dose escalation will continue but switch to BID regimens as 
specified in greater detail in the algorithm/guidance in Section 8.2. 
In the prior osteoporosis program, hypercalcemia adverse events were not symptomatic and 
were identified based on scheduled periodic laboratory assessments. Dose-limiting thresholds 
for post- CLTX-305 (encaleret) cCa levels are specified as part of the dosing and titration 
algorithms in Section 8.2. In Summary, participants who achieve a post-dose cCa > 10-10.5 
mg/dL (in Period 1) and cCa > 10 mg/dL (in Period 2) during the dose escalation will not 
proceed to higher CLTX-305 (encaleret) doses. Participants with cCa values between 10-10.5 
mg/dL during dose escalation in Period 1, will have their doses increased by 30 mg only. 
Participants who achieve cCa > 10-10.5 mg/dL in Period 1 and >10 mg/dL in Period 2 will 
have their dose maintained or reduced and undergo final frequent sampling as appropriate. 
6.1.8 
Dose Modifications 
See above for general principles of dosing and titration limitations based on toxicity or 
hypercalcemia. See Section 8.2 for details of the dosing guidance algorithm for each Period. 
Dose modifications should be made according to the protocol-specified guidance/algorithm 
described in Section 8.2 based on cCa thresholds of > 10-10.5 mg/dL in Period 1 and > 10 
mg/dL in Period 2. Similarly, titration in outpatient Period 3 and the LTE will be based 
primarily on periodic assessment of cCa and where cCa > 10 mg/dL would also require dose 
modification.  
For participants who develop clinical laboratory abnormalities unrelated to the dosing 
algorithm parameters (e.g., corrected calcium) indicating that further conduct of per protocol 
clinical assessments/procedures may put the participant at risk may have their CLTX-305 
(encaleret) dosing interrupted at the discretion of the principal investigator and should be 
captured as adverse events. Because of the intensive sampling required during the conduct of 
the in-hospital assessments, procedures related to the collection of blood in terms of sampling 
technique or frequency of sampling and/or blood volume may have their scheduled dosing 
interrupted so as to allow the patient to recover and continue the study treatment at a later 
date (re-initiation). The time interval separating the day of the interrupted dose and the day to 
re-initiate dosing will be less than or equal to 56 days. The participant with an interrupted 
dose may be re-initiated at the next protocol-specified dose level of CLTX-305 (encaleret) at 
the discretion of the principal investigator. A participant with a dose interruption shall 
continue to meet eligibility criteria for the study. 
6.1.9 
Drug Administration 
During Period 1 and Period 2 inpatient NIH CC stays, on days CLTX-305 (encaleret) is 
given once a day, participants will receive one dose in the morning that may be administrated 
within 30 minutes prior to breakfast with about 8 ounces of water. On days CLTX-305 
(encaleret) is given twice a day, participants will receive one dose in the morning and the 

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second dose in the evening and can be administered within 30 minutes prior to breakfast and 
dinner with about 8 ounces of water. 
During Period 3 and the LTE, participants will be instructed by the investigator/designee to 
take one dose of CLTX-305 (encaleret) in the morning and the second dose in the evening. 
Taking the dose within 30 minutes of breakfast and dinner is suggested but not required. 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and Accountability 
The site research pharmacist or delegated personnel will maintain an accurate record of the 
receipt of the CLTX-305 (encaleret) shipped by the Sponsor, including the date and quantity 
received. In addition, an accurate drug disposition record will be kept that specifies the 
amount to be administered to each participant, the date of dispensation, and any amount 
returned. This inventory record must be available for inspection at any time, and copies of 
this record will be provided to the Sponsor at the conclusion of the study. At the completion 
of the study, the site research pharmacist or delegated personnel will provide the Sponsor 
with a complete record of CLTX-305 (encaleret) accountability. 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
The CLTX-305 (encaleret) will be provided as white film-coated tablets containing the active 
ingredient CLTX-305 (encaleret) provided in 5, 10, 30 and 60 mg doses. 
The tablets contain the following excipients: mannitol, microcrystalline cellulose, colloidal 
silicon dioxide, croscarmellose sodium, sucrose fatty acid esters, hydroxypropyl 
methylcellulose, magnesium stearate, macrogol, and titanium oxide. 
6.2.3 
Product Storage and Stability 
The Sponsor will provide the study center with drug supplies. The CLTX-305 (encaleret) is 
to be stored at controlled room temperature between 20°C and 25°C with excursions 
permitted between 15°C and 30°C in the Sponsor provided bottles. 
In Periods 1 and 2, all participants will receive CLTX-305 (encaleret) only as dispensed and 
administered by investigative site staff at the NIH CC. All unused CLTX-305 (encaleret) 
must be returned to the Sponsor or destroyed on-site with approval by the Sponsor, after a 
final CLTX-305 (encaleret) accountability has been completed. If unused CLTX-305 
(encaleret) is not returned to the Sponsor, proof of destruction must be provided to the 
Sponsor. 
In Period 3 and LTE participants will be given CLTX-305 (encaleret) to allow outpatient 
BID self-administration at an individualized starting dose with overage to allow for dose up-
titration at the discretion of the investigator, between NIH CC visits. If needed, additional 
CLTX-305 (encaleret) may be mailed to the participant by the NIH CC pharmacy per 
standard NIH CC pharmacy procedures. Participants will return unused CLTX-305 
(encaleret) at each designated NIH CC visit which will be reviewed for accountability and an 

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estimate of compliance. Participants must return unused CLTX-305 (encaleret) to the NIH 
CC at their next visit. CLTX-305 (encaleret) accountability will be performed by the NIH 
pharmacist or delegated personnel. After a final CLTX-305 (encaleret) accountability is 
completed any unused CLTX-305 (encaleret) must be returned to the Sponsor or destroyed 
on-site with approval by the Sponsor and in accordance with procedure at NIH. If unused 
CLTX-305 (encaleret) is not returned to the Sponsor, proof of destruction must be provided 
to the Sponsor. 
6.2.4 
Preparation 
Not applicable. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable. This is an open-label study. 
6.4 
Study Intervention Compliance 
For inpatient Periods 1 and 2, CLTX-305 (encaleret) will be administered by site staff and 
recorded. The time of CLTX-305 (encaleret) administration will be documented in the 
appropriate CRF. Scheduled oral administration of study drug will occur at the study site 
under observation by study staff or designee, thus ensuring study drug compliance. During 
outpatient Period 3 and LTE, participants will self-administer CLTX-305 (encaleret) and 
should be giving instruction on dosing. In respect to CLTX-305 (encaleret) administration 
refer to section: “Drug Administration.” At each study visit and during telephone contacts, 
site staff will review and record compliance (e.g., document missed doses) and review and 
record any dose changes. 
6.5 
Concomitant Therapy  
At Screening, the study staff at NIH will question each participant specifically on the use of 
all concomitant medications and record the medication, dosage, and duration of use in the 
appropriate CRF. In general, upon admission and throughout the study, site staff will 
monitor, record, and administer all concomitant medications during the inpatient stay.  
All participants will be instructed to stop taking calcitriol on Day -1, the day of admission, 
but continue their oral calcium supplement regimen. Participants will receive at least 1,000 
mg total daily calcium derived from diet and supplementation throughout the treatment 
period. 
Participants being treated with thiazide diuretics may be enrolled if they are willing and able 
to discontinue thiazides 5 half-lives prior to initiation of CLTX-305 (encaleret) and during 
the study treatment period. When the thiazide is being used an antihypertensive, alternative 
therapy will be offered. 
Participants being treated with strong CYP3A4 inhibitors (including clarithromycin, 
telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir), if clinically appropriate, should 

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discontinue these medications during the screening period at least 5 half-lives prior to 
initiation of CLTX-305 (encaleret) and during the study treatment period. Otherwise, 
participants being treated with strong CYP3A4 inhibitors should remain on stable doses 
throughout the trial. 
Participants being treated with nirmatrelvir/ritonavir for COVID-19 may decrease the 
encaleret dosing to once daily during the 5-day treatment course given that ritonavir is a 
strong CYP3A4 inhibitor. Participants may take calcium supplementation as needed if they 
experience symptoms of hypocalcemia during this time. After completion of the 5-day 
nirmatrelvir/ritonavir treatment course, participants may resume twice daily encaleret. 

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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
An early termination (premature discontinuation) will occur if a participant who signs the 
informed consent/assent form (ICF) and is dosed ceases participation in the study, regardless 
of circumstances, before the completion of the protocol-defined study procedures. 
Participants can be early terminated from the study for any of the reasons to include the 
following: 
• AEs 
• Protocol violation 
• If it is discovered that the participants did not meet protocol entry criteria, and 
continued participation would present unacceptable risk to participant’s health 
• Non-compliance with administration of the investigational medicinal product CLTX-
305 (encaleret/IMP). 
• Withdrawal of consent: study participants may withdraw consent at any time for any 
reason without prejudice to future treatment. In the event of study withdrawal, the 
participant will be encouraged to undergo ET procedures as a final visit.  
• Lost to follow-up (site should attempt at least 3 documented phone calls, followed by 
a registered letter to the participant’s last known mailing address) 
• Pregnancy at any time after signing the ICF. CLTX-305 (encaleret) should be 
discontinued immediately, and pregnancy reported (Section 8.5.8) 
• Participant transitions to the CLTX-305-302/CALIBRATE Phase 3 LTE 
• Study terminated by the Sponsor 
• Site closed by the Sponsor/designee 
• PI’s decision based on participants’ safety 
7.2 
Participant Discontinuation/Withdrawal from the Study 
During Periods 1 and 2, if participants discontinue participation or are terminated early from 
the study, they should have all safety assessments for Early Termination (ET) as listed in the 
Schedule of Activities. When participants are discontinued from study medication, as 
described above in Section 7.1, they should be converted back to their outpatient regimen of 
oral calcium and active Vitamin D. Participants will be instructed to undergo outpatient  
laboratory testing of their blood calcium within 1-3 days of discontinuing study medication 
and to have those results sent to NIH investigators for review. A telephone contact should be 
arranged for the investigative staff to review the blood calcium results and advise on 
optimizing their outpatient clinical management. 

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During Period 3 and LTE, participants receive CLTX-305 (encaleret) to self-administer in 
the outpatient setting. A process for returning and reconciling CLTX-305 (encaleret) will be 
followed. When a participant discontinues the study or withdraws from taking study 
medication, they will revert to their prior outpatient regimen of oral calcium and active 
Vitamin D to address their underlying ADH1 and maintain cCa blood concentrations as they 
return to their prior clinical care providers. Participants will be instructed to undergo 
outpatient laboratory testing of their blood calcium within 1–3 days of discontinuing study 
medication and to have those results sent to NIH investigators for review. Study investigator 
should contact the participant to review the blood calcium results and advise on optimizing 
their outpatient clinical management. Arrangements will be made to return study medication 
to the study site for proper reconciliation and disposal. 
Participants who transfer to the CLTX-305-302/CALIBRATE Phase 3 LTE will continue 
encaleret dosing at their prescribed dose until enrolled into the CLTX-305-302/CALIBRATE 
Phase 3 LTE. When a participant transitions to CLTX-305-302/CALIBRATE Phase 3 LTE, 
participant will be asked to return to the NIH CC to return the unused CLTX-305 (encaleret), 
and complete any remaining eligibility assessments for the CLTX-305-302/CALIBRATE 
Phase 3 LTE study. 
All participants who received CLTX-305 (encaleret) and terminate early from the study, 
regardless of cause, with exception of transition to the CLTX-305-302/CALIBRATE Phase 3 
LTE, should undergo follow-up procedures according to Section 1.3 Table D SOA. The 
reason for early termination from the study will be reflected in the CRF. If a participant 
terminates early from the study because of an AE, the PI/study staff must record the AE as 
the reason for discontinuation. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she missed at least 3 documented 
phone calls, followed by no response after a registered letter to the participant’s last known 
mailing address is received. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant and reschedule the missed visit and 
counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record or study file. 
• Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Screening Procedures 
All participants must sign the Informed Consent Form (ICF) prior to any study-related 
procedures. Screening must be completed within 60 days prior to admission to the NIH CC 
(See Table A and Table B for Period 1 and Period 2 Schedule of Activities and Section 1.3 
for details on Screening Assessments). 
The first screening visit will be conducted at the NIH CC to determine participant eligibility, 
document current metabolic status, assess dietary calcium intake, and perform genotyping to 
confirm the type of ADH gene mutation (if specific information is not available; See Section 
8.3.4). Participants may complete the screening assessments as outpatients or be housed 
overnight at NIH CC. Participants who complete the screening visit midweek have the option 
to stay overnight at NIH CC during the intervening days prior to the start of Period 1 or 
Period 2, Day -1. Each participant’s current treatment regimen will be assessed by NIH 
investigators in relation to presence/absence and control of hypocalcemia-related complaints 
and symptoms, and assessment of blood and urine analytes including blood and urine 
calcium and phosphate. The total blood volume collected during the screening visit for each 
participant will be less than the blood volume limits per participant as per NIH Guidelines for 
Blood Draw Limits for Research Purposes (M95-9, June 2009). NIH investigators may 
recommend adjustments to a participant’s outpatient regimen during the screening period, in 
accordance with the accepted goals of achieving cCa in the low normal range, while 
minimizing hypercalciuria. Unscheduled outpatient laboratory assessments, if required, will 
be arranged through outpatient laboratories with results transmitted to and reviewed by the 
investigators as standard of care. Participants who complete the screening process and meet 
inclusion/exclusion criteria, may be scheduled for admission to Period 1 or Period 2 per 
protocol. 
After completing screening assessments, any AE/SAE reported by a study participant, 
whether or not CLTX-305 (encaleret) has been administered, will be recorded by the 
investigators. Any AE/SAE prior to dosing will be categorized as “Baseline” and any 
AE/SAE after dosing will be categorized as “treatment-emergent.” 
8.2 
Treatment Period 
8.2.1 
Period 1 (Single Ascending Dose Escalation and BID PK/PD profile) – 
Cohort 1 
For participants whose screening visit is > 21 days before initiation of study drug, outpatient 
laboratory testing will be performed 10-14 days prior to admission for blood and urine 
chemistry to be reviewed by the NIH investigators.  
All participants will be instructed to stop taking calcitriol on Day -1, the day of admission, 
but continue their oral calcium supplement regimen until admitted. 
Day -1 (Admission): Eligible participants in Cohort 1 will be admitted to the NIH CC the 
day prior to dosing in Period 1. 

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Days 1, 2 and 3 (QD Dose Escalations): Up to 8 participants (minimum of 5) will undergo a 
single-dose, dose-escalation over the first 3 days of admission. Morning doses with a starting 
dose of 30 mg will be administered on Days 1, 2 and 3, respectively, accompanied by 
frequent blood and urine sampling for 24-hours for PK/PD measures (For details of PK/PD 
assays and timepoints see Section 1.3.1, including Table E, Table H, Table I, and Table L. 
CLTX-305 (encaleret) will be administered in the morning, with water, within 30 minutes 
prior to breakfast. If dose escalation is limited due to tolerability or hypercalcemia (Also see 
Section 6.1.3), the investigator, in consultation with the Sponsor, may choose to repeat the 
last well-tolerated dose on Days 2 and 3, or down-titrate, as appropriate (See below for 
dosing guidance algorithm). 
Days 4 and 5 (BID Dose Escalation): Based on each participant’s individual PD responses 
to QD dose-escalation, an individualized dose of CLTX-305 (encaleret) will be chosen for 
BID dosing on Days 4 and 5. CLTX-305 (encaleret) will be administered once in the 
morning and once in the evening, within 30 minutes prior to breakfast and dinner. The dose 
selected should be based on each participant’s response in cCa and/or PTH levels during the 
prior QD dosing (Days 1–3). The investigator, in consultation with the Sponsor, will likely 
choose either 90 or 180 mg administered BID (for total daily doses of 180 and 360 mg, 
respectively) but will decide according to the following criteria for each participant: 
The lowest dose that resulted in an increase in cCa by ≥ 1 mg/dL during the dosing 
interval, or the lowest dose that maintained cCa in the normal range without 
exceeding the upper limit of the reference range over the dosing interval 
AND / OR: 
Peak iPTH 150–300 pg/mL and/or 
Sustained elevations in iPTH levels ≥ 50 pg/ml (ideally for up to 12 hours) 
If no single QD dose meets the above criteria for a given participant, then the investigator 
should choose the highest QD dose that was well tolerated and begin administration of that 
dose given once in the morning and once in the evening recommended within 30 minutes 
prior to meals (BID) starting on the morning of Day 4. 
Monitoring of cCa and iPTH will occur during BID dosing on Days 4 and 5 with frequent 
blood and urine sampling for PK/PD. For details on the timepoints and assays for PK/PD 
samples on Day 5 see Section 1.3.1 and specifically Table I. The total blood volume 
collected during Period 1 for each participant will be less than the blood volume limits per 
participant as per NIH Guidelines for Blood Draw Limits for Research Purposes (M95-9, 
June 2009). If a participant has a low body weight (<50 kg for adults or <55 kg for 
adolescents), the blood volume taken will be reduced to remain within the NIH guidelines of 
10.5mL/kg/8w (adult) and 9.5 mL/kg/8w (pediatric). The last dose of study medication will 
occur in the evening of Day 5. 
A schematic of dose modifications based on the guidance described above is shown below in 
Figure E: 
 

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Figure E 
Dosing Guidance Algorithm for Period 1 

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Day 6 (Discharge): After the PK/PD blood sampling is collected on the morning of Day 6 all 
participants will resume their prior conventional treatment regimen. During Day 6, cCa levels 
will be monitored throughout the day. This period can be extended if additional monitoring 
or treatment (e.g., to stabilize calcium) is needed prior to discharge. 
Outpatient testing done in Period 1 on day 7-8 (~ 24-48 hours after expected discharge from 
the NIH clinical center) will ideally be collected at the NIH CC. If this is not practical, with 
the participant’s permission, contact information for the participant will be provided to a 
sponsor-contracted healthcare service to schedule a mutually agreeable time for sample 
collection in the home. Blood samples collected will be evaluated for CLTX-305 (encaleret) 
concentrations as well as for blood creatinine, albumin, calcium, magnesium, phosphate, and 
PTH. This will allow both an evaluation of calcium homeostasis as well as a final PK sample 
while CLTX-305 (encaleret) concentrations are washing-out after Period 1. Given that the 
half-life of CLTX-305 (encaleret) at steady state is ~ 10-14 hours, the PK sample will 
represent a timepoint between 40-70 hours after the last dose of CLTX-305 (encaleret) 
(administered in the evening of Day 5). A telephone contact will be conducted on day 9-11 or 
once the calcium results are available to be reviewed with investigative site staff. 
In order to characterize both the pre-study calcemic status as well as changes associated with 
experimental interventions, the protocol will rely on frequent measurement of albumin-
corrected blood calcium concentrations. Assays will be conducted according to specifications 
of the NIH Clinical Center Laboratory, Bethesda, MD. The main indicator of normal versus 
abnormal blood calcium levels will be based on the correction for serum or plasma albumin 
according to the formula corrected calcium (cCa) = measured total calcium (mg/dL) + 0.8(4 
–albumin (g/dL)) OR measured total calcium (mmol/L) + 0.2(4 –albumin (g/dL)), 
recognizing that the total calcium reported in SI units (mmol/L) can be converted to 
conventional units (mg/dL) by multiplying by 4. Given that enrolled participants are 
expected to have both normal and stable albumin levels, the measures of total calcium and 
cCa are likely to be similar throughout the time course of this study. Ionized calcium assays 
will also be available at the NIH Clinical Center investigative site and can be measured either 
in the event of severe hypocalcemia or if there is any question about the accuracy of the cCa 
measure. Collection of ionized calcium will occur at the discretion of the expert investigators 
based on the clinical scenario on a case-by-case basis. 
8.2.2 
Period 2 (BID Dosing) - Cohorts 1 and 2 
For cohort 1, 10-14 days before admission to the NIH CC, participants will undergo 
outpatient laboratory testing for blood and urine chemistry (Table B). For cohort 2 
participants whose screening visit is > 21 days before initiation of study drug, outpatient 
laboratory testing will be performed 10-14 days prior to admission for blood and urine 
chemistry.  
Results will be reviewed by the NIH investigators. 
Participants who complete the screening visit midweek have the option to stay overnight at 
NIH CC during the intervening days prior to the start of Period 2, Day -1. 

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All participants will be instructed to stop taking calcitriol on Day -1, the day of admission, 
but continue their oral calcium supplement regimen until admitted. Magnesium supplements 
and potassium citrate will be discontinued starting the morning of Day 1. Calcium 
supplements will be discontinued or decreased starting on Day 1, based on the estimate 
dietary calcium intake, targeting a combined calcium intake of > 1000 mg/day. 
Day -1 (Admission): Eligible participants will be admitted to the NIH Clinical Center the day 
prior to dosing. 
Cohort 1- Participants in Cohort 1 who complete Period 1 will be scheduled to return for 
Period 2 after at least 8 weeks and up to 16 weeks (minimum of 8 weeks between Period 1 
and 2 for participant participating in both Periods to recover blood volume and hematocrit 
levels). BID dosing will be individualized based on each participant’s prior responses to 
CLTX-305 (encaleret) during Period 1. 
The first 7 participants who have completed CLTX-305-201 Period 2 and entered into Period 
3 have had a wide range of CLTX-305 (encaleret) dose requirements from 10 mg once daily 
to 180 mg BID suggesting that CLTX-305 (encaleret) dosing is highly individualized. As a 
result, all remaining participants in Period 2 will receive an initial CLTX-305 (encaleret) 90 
mg BID dose for at least 3-4 doses for evaluation of safety, tolerability and the ability to 
modulate cCa levels. The CLTX-305 (encaleret) dose will be up- or down-titrated as needed 
to maintain cCa levels below 10 mg/dL and blood phosphorus levels above the lower limit of 
normal. Dosing will be adjusted in 5, 10, 30, or 60 mg increments based on the available 
CLTX-305 (encaleret) tablet strengths. A frequent sampling test day with additional serial 
blood and urine sampling to assess 24-hour PK/PD profiles will be performed on Day 5. For 
details on the PK/PD timepoints during frequent sampling on Day 5 see Section 1.3.1 
specifically Table J and Table K.  
The total blood volume collected during Period 2 for Cohort 1 participants will be less than 
the blood volume limits per participant as per NIH Guidelines for Blood Draw Limits for 
Research Purposes (M95-9, June 2009). These volumes include the cumulative potential 
collection over an 8-week period: -10-14-day labs, Day -1 safety labs, Period 2 inpatient 
week, and 4 weeks of outpatient labs in Period 3. If a participant has a low body weight (<43 
kg for adults or <48 kg for adolescents), the blood volume taken will be reduced to remain 
within the NIH guidelines of 10.5mL/kg/8w (adult) and 9.5 mL/kg/8w (pediatric). If, at any 
time, the CLTX-305 (encaleret) dose is associated with a cCa > 10 mg/dL, then the dose 
should be reduced to a lower dose level. An example of how CLTX-305 (encaleret) dosing 
may be adjusted is provided in Figure F below. 
 
 

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Figure F 
Dosing Guidance Algorithm for Period 2 – Cohort 1 
 
Cohort 2 – Cohort 2 will commence after Cohort 1 has completed Period 1 and the PD dose 
responses and safety have been reviewed. Participants will receive an initial CLTX-305 
(encaleret) 90 mg BID dose for at least 3-4 doses for evaluation of safety, tolerability and the 
ability to modulate cCa levels. The CLTX-305 (encaleret) dose will be up- or down-titrated 
as needed to maintain cCa levels below 10 mg/dL and blood phosphorus levels above the 
lower limit of normal. Dosing will be adjusted in 5, 10, 30, or 60 mg increments based on the 
available CLTX-305 (encaleret) tablet strengths. The total blood volume collected during 
Period 2 for Cohort 2 participants will be less than the blood volume limits per participant as 
per NIH Guidelines for Blood Draw Limits for Research Purposes (M95-9, June 2009). 
These volumes include the cumulative potential collection over an 8-week period: screening 
visit labs, -10-14 day labs, Day -1 safety labs, Period 2 inpatient week, and 4 weeks of 
outpatient labs in Period 3. 
Participants will take the final dose of study medication in the evening of Day 5. After the 
final serial PK/PD blood sampling on the morning of Day 6, all participants completing 
Period 2 will be eligible for participation in Period 3 to receive CLTX-305 (encaleret) at the 
same BID dose (or lower) in an outpatient setting. Participants entering Period 3 will be 
discharged from NIH Clinical Center on the dose determined by the investigators to be 
effective and tolerated for each individual during Period 2. 
If a participant does not participate in Period 3, the participant will resume their prior 
conventional outpatient treatment regimen on Day 6 prior to discharge. 
In order to characterize both the pre-study calcemic status as well as changes associated with 
experimental interventions, the protocol will rely on frequent measurement of albumin-

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corrected blood calcium concentrations. Assays will be conducted according to specifications 
of the NIH Clinical Center Laboratory, Bethesda, MD. The main indicator of normal versus 
abnormal blood calcium levels will be based on the correction for serum or plasma albumin 
according to the formula corrected calcium (cCa) = measured total calcium (mg/dL) + 0.8(4 
–albumin (g/dL)) OR measured total calcium (mmol/L) + 0.2(4 –albumin (g/dL)), 
recognizing that the total calcium reported in SI units (mmol/L) can be converted to 
conventional units (mg/dL) by multiplying by 4. Given that enrolled participants are 
expected to have both normal and stable albumin levels, the measures of total calcium and 
cCa are likely to be similar throughout the time course of this study. Ionized calcium assays 
will also be available at the NIH Clinical Center investigative site and can be measured either 
in the event of severe hypocalcemia or if there is any question about the accuracy of the cCa 
measure. Collection of ionized calcium will occur at the discretion of the expert investigators 
based on the clinical scenario on a case-by-case basis. 
8.2.3 
Period 3 (Cohort 1 and Cohort 2) - Outpatient Dosing 
Period 3 will include a titration phase of approximately 12 weeks and a maintenance phase of 
approximately 12 weeks for a total outpatient exposure to CLTX-305 (encaleret) of 
approximately 24 weeks. In Period 3, the initial outpatient dose of CLTX-305 (encaleret) will 
be based on the results from inpatient Periods 1 and 2. Outpatient titration will be conducted 
by the NIH investigators with the goal of optimizing the CLTX-305 (encaleret) dose without 
calcitriol, targeting normal cCa and phosphorus concentrations while minimizing the need for 
calcium supplements, avoiding symptoms of hypo- or hypercalcemia, and minimizing the 
extent of hypercalciuria. If blood cCa levels are > 10.5 mg/dL, the NIH investigators can 
consider holding the CLTX-305 (encaleret) dose and restarting CLTX-305 (encaleret) at a 
lower dose after blood cCa has decreased to < 10 mg/dL. Oral calcium supplementation may 
be used as needed on top of a minimum dietary intake of at least 1000 mg daily. Participants 
previously treated with magnesium and potassium citrate supplements when not on CLTX-
305 (encaleret) may not be restarted on treatment during Period 3, if the blood magnesium 
and urine citrate are within the normal ranges during Period 2. 
For participants who require CLTX-305 (encaleret) doses < 10 mg BID to achieve the 
treatment goals described above, and the 5 mg tablets are not available, the 10 mg tablets 
may be split according to the related specifications indicated in the Pharmacy manual 
provided by the Sponsor in order to receive 5 mg BID dosing. Of note, no other dose strength 
besides the 10 mg tablet may be split. If the 10 mg tablet needs to be split, the participant 
should cut one 10 mg encaleret tablet each day and take half of the tablet in the morning and 
the other half of the split tablet in the evening, assuring that the participant receives a full 10 
mg dose per day. Participant should follow the manufacturer instructions for use included 
with the pill cutter. In the event that half of the split 10 mg tablet is lost, the participant 
should cut a new tablet in half for the evening dose and discard the remaining half. The 
participant should start with a new 10 mg tablet the following morning. 
Study visits include inpatient NIH Clinical Center visits every 8 weeks. PK assessments will 
be done at week 24 only; PD assessment will be done at weeks 8, 16 and 24 for evaluation of 
safety. AEs and concomitant medications will be recorded during these visits. Participants 
will be contacted by telephone per protocol at intervals during titration and maintenance, to 

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review the results of outpatient laboratory blood and urine assessments, confirm adequacy of 
the current regimen of study medication (including supplements), inquire about 
hypo/hypercalcemia symptoms, and assess for AEs. Participants are considered to have 
completed the study once they complete 24 weeks of Period 3 and the safety follow-up visit. 
For details on the visit schedule and assessments in Period 3 see Section 1.3. 
The total blood volume collected over 24 weeks during Period 3 for each participant will be 
less than the blood volume limits per participant as per NIH Guidelines for Blood Draw 
Limits for Research Purposes (M95-9, June 2009). This includes the 3 inpatient NIH visits. 
If a participant reaches week 24 prior to the LTE being in place, the participant can 
discontinue CLTX-305 (encaleret) and restart calcitriol and/or calcium supplements until the 
LTE is implemented. Upon entry into the LTE, the participant will be reconsented to and 
may restart CLTX-305 (encaleret) at the previous therapeutic dose determined in Period 3. 
8.2.4 
Long-term Extension (LTE) 
LTE will include continuation of outpatient treatment with CLTX-305 (encaleret) at the dose 
established in the maintenance phase of Period 3. CLTX-305 (encaleret) doses may be 
titrated as needed during LTE based on assessment of both blood and urine calcium results as 
described, with the goal maintaining optimal CLTX-305 (encaleret) dose without calcitriol, 
targeting normal cCa and phosphorus concentrations, avoiding symptoms of hypo- or 
hypercalcemia, and minimizing the extent of hypercalciuria. Oral calcium supplementation 
may be used as needed on top of a minimum daily dietary intake of at least 1000 mg. 
Participants previously treated with magnesium and potassium citrate supplements when not 
on CLTX-305 (encaleret) may not be restarted on treatment during LTE, if the blood 
magnesium and urine citrate are within the normal ranges during Period 3. 
Study visits include inpatient or outpatient NIH CC visits every 6 months starting at Month 6 
and telephone contacts along with outpatient laboratory assessments every 6 months starting 
at Month 3. Laboratory assessments will be performed every 3 months for evaluation of 
efficacy and safety. Laboratory assessments at the NIH CC will be collected approximately 
4-hours post-AM CLTX-305 (encaleret) dose. AEs and concomitant medications will be 
recorded during these visits. Participants will be contacted by telephone per protocol at 
intervals during LTE to review the results of outpatient laboratory blood and urine 
assessments, confirm adequacy of the current regimen of study medication (including 
supplements), inquire about hypo/hypercalcemia symptoms, and assess for AEs. The LTE is 
designed to obtain additional long-term safety data for CLTX-305 (encaleret). Participants 
who elect to continue in LTE will receive CLTX-305 (encaleret) for an additional period of 
time, up to 25 months (approximately 2 years) or until they transition to the CLTX-305-
302/CALIBRATE Phase 3 LTE, whichever occurs first. 
For details on the visit schedule and activities in LTE see Section 1.3. 
The total blood volume collected over approximately 25 months during LTE for each 
participant will be less than the blood volume limits per participant as per NIH Guidelines for 
Blood Draw Limits for Research Purposes (M95-9, June 2009). This includes the 4 inpatient 
or outpatient NIH CC visits. 

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Participants are considered to have completed the study once they complete 24 weeks of 
Period 3 and the safety follow-up visit. If a participant ends involvement in the study before 
completing the Period 3 activities, steps outlined in Schedule of Activities will be followed, 
see Section 1.3 Table C. 
At any point during the LTE, and before transition to the CLTX-305-302/CALIBRATE 
Phase 3 LTE, participants can choose to stop participation and be placed back on the 
conventional therapy. Follow-up assessments are to be completed (see Section 1.3 Table D) 
and clinical supply of CLTX-305 (encaleret) needs to be returned to the investigative site. 
 
8.2.5 
Follow-up and Early Termination 
Participants will receive a follow-up call 30 ± 7 days after their last dose of the study 
medication for assessment of AEs. 
If participants discontinue from taking part in the study or are terminated early from the 
study, they should have all safety assessments for Early Termination (ET) as listed in the 
Schedule of Activities (Section 1.3). 
When a participant discontinues or withdraws from taking study medication, they will revert 
to their prior outpatient regimen of oral calcium and active Vitamin D to address their 
underlying ADH1 and maintain cCa blood concentrations as they return to their prior clinical 
care providers. Participants will be instructed to undergo outpatient laboratory testing of their 
blood calcium within 1–3 days of discontinuing study medication and to have those results 
sent to NIH investigators for review. Study investigator should contact the participants to 
review the blood calcium results and advise on optimizing their outpatient clinical 
management. 
Participants who transfer to the CLTX-305-302/CALIBRATE Phase 3 LTE will continue 
encaleret dosing at their prescribed dose until enrolled into the CLTX-305-302/CALIBRATE 
Phase 3 LTE. When a participant transitions to CLTX-305-302/CALIBRATE Phase 3 LTE, 
participant will be asked to return to the NIH CC to return the unused CLTX-305 (encaleret), 
and complete any remaining eligibility assessments for the CLTX-305-302/CALIBRATE 
Phase 3 LTE study. 
Transition to CLTX-305-302/CALIBRATE Phase 3 Long Term Extension 
Participants from CLTX-305-201 who meet the study screening eligibility criteria of the 
CLTX-305-302/CALIBRATE Phase 3 study will enroll directly into the CLTX-305-
302/CALIBRATE Phase 3 LTE. If assessments for 25-OH Vitamin D, eGFR, 12-lead resting 
ECG, viral hepatits panel and HIV have been completed either at the NIH CC or via 
outpatient lab within the 3 months prior to transitioning into the CLTX-305-
302/CALIBRATE LTE, they do not need to be repeated for eligibility purposes. Other 
assessments performed during the final CLTX-305-201 ET/EoT study visit will be 
acceptable for assessment of CLTX-305-302/CALIBRATE eligibility criteria. Blood β-HCG 
pregnancy test can be performed at the NIH CC on the day of transition to CLTX-305-

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302/CALIBRATE Phase 3 LTE, and an aliquot will also be sent to the central lab for the 
CLTX-305-302/CALIBRATE Phase 3 LTE. 
If a participant discontinued encaleret during the CLTX-305-201 LTE for family planning 
purposes, the participant may enroll directly into the CLTX-305-302/CALIBRATE Phase 3 
LTE once family planning is complete if he/she meets the study eligibility criteria per the 
CLTX-305-302/CALIBRATE protocol and the CLTX-305-302/CALIBRATE Encaleret 
Resumption Criteria. Participants will resume encaleret as described in the CLTX-305-
302/CALIBRATE protocol. 
Assessments in the CLTX-305-302/CALIBRATE Phase 3 LTE will be conducted 
approximately every 3 months as described in CLTX-305-302/CALIBRATE protocol’s 
Schedule of Assessments. Participants who transfer to the CLTX-305-302/CALIBRATE 
Phase 3 LTE will receive encaleret for an additional period of approximately 48 months or 
until participant has access to commercial encaleret, or the Sponsor decides to end the study, 
whichever occurs first. 
8.3 
Efficacy Assessments 
8.3.1 
Pharmacokinetic and Pharmacodynamic Blood Sampling 
All PK blood samples will be analyzed by the CRO contracted by the Sponsor. All PD blood 
samples will be managed by the NIH laboratory. Details for sample processing and handling 
are provided in the Study Procedures Manual. The times for collection of these samples are 
detailed in the Schedule of Activities in Section 1.3.1. 
The efficacy assessments include evaluations of serum cCa concentrations over time and 
urinary excretion of calcium over time. 
For a tabular listing of PK/PD and safety analytes in Blood and Urine, See Section 1.3.1. 
8.3.2 
Timed Interval and 24-hour urine 
The times for collection of these samples are detailed in the Schedule of Activities in 
Section 1.3 and in a tabular listing of PK/PD and safety analytes in Blood and Urine Section 
1.3.1. 
8.3.3 
Clinical Evaluations 
Not applicable. 
8.3.4 
Samples for Genetic/Genomic Analysis 
8.3.5 
Description of the Scope of Genetic/Genomic Analysis 
For participants with no prior documented activating mutation in the CaSR or an affected 
first-degree relative (with associated documentation collected and filed in participant’s study 
binder), the diagnosis of ADH1 will be confirmed by genetic testing at screening. 

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If a participant’s CaSR mutation has not been confirmed at Screening, blood samples will be 
collected for somatic analysis of the CaSR gene. 
If no pathogenic variant in the CaSR is identified, additional testing for other genetic forms 
of hypoparathyroidism may be offered to the participant. 
No additional genetic testing is required as part of this protocol. 
8.3.6 
Description of how Privacy and Confidentiality of Medical 
Information/Biological Specimens will be Maximized 
CaSR gene mutation analyses will be conducted according to a somatic analysis assay 
performed at a certified genetics lab. Participant samples will be anonymized using a 
designated participant number and initials. 
Since all participant data in this clinical trial will be anonymized using the same system, each 
participant’s identity will remain anonymous in the clinical trial database. 
The clinical trial database, which may be shared with appropriate regulatory agencies, in 
addition to access from the Sponsor and investigators, will contain clinical/demographic data 
on participant’s age, ethnicity, sex, diagnosis, treatment, response to treatment, adverse 
events as per the standards of human clinical research, however, all the data will be 
anonymized without any link to individual identifying information. 
8.3.7 
Management of Results 
The anonymized results of a participant’s CaSR mutational analysis will be kept in a secured 
manner at the NIH. Participants who wish to receive the results of their CaSR gene mutation 
analysis may do so. This is a research-related test. 
Genetic counseling will be made available. Most participants eligible to participate will 
already be aware of their CaSR mutational status and aware of the diagnosis of ADH1. 
Consent for mutational analysis including receipt of information on the results will take place 
under the auspices of an experimental clinical research study filed with the FDA under an 
Investigational New Drug submission. 
If no pathogenic variant in the CaSR is identified, additional testing for other genetic forms 
of hypoparathyroidism may be offered to the participant. 
8.3.8 
Genetic counseling 
For participants who have not already had confirmation of their specific genetic mutation and 
who therefore submit to genetic mutation analysis, discussion of the results will be conducted 
by the expert investigators at the NIH and may also be conducted in conjunction with 
professional genetic counseling by associated staff with appropriate expertise to provide 
participants with sufficient interpretive information. 

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8.4 
Safety and Other Assessments 
8.4.1 
Physical Examinations 
At the times detailed in the Schedule of Activities in Section 1.3, participants will undergo a 
complete physical examination (PE), which is to be completed by a physician or an 
appropriately trained health professional. Any abnormal physical examination finding that is 
deemed clinically important (i.e., is associated with symptoms and/or requires medical 
intervention) will be recorded as an AE as described in Section 8.5.1. 
8.4.2 
Vital Signs 
Vital signs will be assessed in accordance to times and details indicated in the Schedule of 
Activities tables in Section 1.3. Any abnormal vital sign that is deemed clinically significant 
(i.e., is associated with symptoms and/or requires medical intervention) will be recorded as 
an AE as described in Section 8.5.1. 
8.4.3 
Clinical Laboratory Determinations 
Blood and urine samples for clinical laboratory tests will be collected at the times detailed in 
the Schedule of Activities (Section 1.3). At Screening, the samples will be collected at the 
NIH Clinical Center. Additional testing during the Screening period may be conducted at an 
outpatient laboratory near the participant. All laboratory tests (PD and safety) during the 
Dosing Periods 1 and 2 will be measured at the NIH Clinical Center.  
Outpatient testing done in Period 1 on day 7–8 (~ 24–48 hours after expected discharge from 
the NIH clinical center) will ideally be collected at the NIH CC. If this is not practical, with 
the participant’s permission, contact information for the participant will be provided to a 
sponsor-contracted healthcare service to schedule a mutually agreeable time for sample 
collection in the home. Blood samples collected will be evaluated for CLTX-305 (encaleret) 
concentrations as well as for blood creatinine, albumin, calcium, magnesium, phosphate, and 
PTH. This will allow both an evaluation of calcium homeostasis as well as a final PK 
parameter while CLTX-305 (encaleret) concentrations are washing-out after Period 1. Given 
that the half-life of CLTX-305 (encaleret) at steady state is ~ 10–14 hours, the PK sample 
will represent a timepoint between 40-70 hours after the last dose of CLTX-305 (encaleret) 
(administered in the evening of Day 5). A telephone contact will be conducted on day 9-11 or 
once the calcium results are available to be reviewed with investigative site staff. 
Laboratory testing during outpatient Period 3 and LTE will include outpatient laboratory 
collection of blood and urine for calcium and calcium-related analytes including safety 
laboratory tests. 
At any time during the study, abnormal laboratory parameters which are clinically relevant 
(e.g., require dose interruption of study treatment, lead to clinical symptoms or signs, or 
require therapeutic intervention), whether specifically requested in the protocol or not, will 
be recorded on the Adverse Events eCRF page. 

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The investigator will assess the clinical significance of values outside the reference ranges 
provided by the laboratory. 
Samples will be collected, processed, and stored according to the instructions provided in the 
Laboratory Manual. 
The investigator or qualified sub-investigator will review all laboratory results for clinical 
significance. Any laboratory result deemed clinically significant (i.e., is associated with signs 
and symptoms and/or requires medical intervention) will be recorded as an AE as described 
in Section 8.5.5. 
8.4.4 
Electrocardiograms 
A standard 12-lead ECG will be assessed at the times detailed in the Schedule of Activities, 
Section 1.3. ECGs will be performed in the supine position after a 5-minute rest. The 
investigator or qualified sub-investigator will review all ECG interpretations and interval 
duration measurements for clinical significance. Any ECG interpretation deemed to be 
clinically significant (i.e., is associated with symptoms and/or requires medical intervention) 
will be reported as an AE as described in Section 8.5.5. 
8.4.5 
Dual-energy X-Ray Absorptiometry (DXA) 
Bone densitometry of the spine, hip, distal radius, and total body will be performed by DXA 
at Screening during Periods 1 and 2, at Week 24 during Period 3, and at Month 12 and Month 
24 during the LTE (see Schedule of Activities tables in Section 1.3). If the Month 24 visit 
aligns with the transition to the CLTX-305-302/CALIBRATE Phase 3 LTE, then the DXA 
scan will be performed once as part of the CLTX-305-302/CALIBRATE Phase 3 LTE. 
Radiation exposure. This research study involves exposure to radiation from four DXA 
scans performed at the screening visit, Week 24 during Period 3, and Months 12 and 24 
during the LTE. This radiation exposure is not necessary for medical care and is for research 
purposes only. The amount of radiation participants will receive in this study is well below 
the dose guidelines established by the NIH Radiation Safety Committee for child (less than 
500 mrem per year) or adult (less than 5000 mrem per year) research participants. The 
effective dose that participants will receive from participation in this research study is less 
than four millirem. This protocol has been approved by the Radiation Safety Committee. 
8.4.6 
Renal Ultrasound 
Renal ultrasound will be performed at Screening during Periods 1 and 2, at Week 24 during 
Period 3, and at Month 12 and Month 24 during LTE (see Schedule of Activities tables in 
Section 1.3). If the Month 24 visit aligns with the transition to the CLTX-305-
302/CALIBRATE Phase 3 LTE, then the renal ultrasound will be performed once as part of 
the CLTX-305-302/CALIBRATE Phase 3 LTE. 

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8.5 
Adverse Events and Serious Adverse Events 
8.5.1 
Definition of Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
8.5.2 
Definition of Serious Adverse Events (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening; i.e., in the opinion of the investigator, the AE places the study 
participant at immediate risk of death from the event as it occurred; it does not 
include a reaction that, had it occurred in a more severe form, might have caused 
death. 
• Results in study participant hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, or 
• Results in a congenital anomaly or birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based on appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
Emergency room visits that do not result in hospitalization should be evaluated for one of the 
other seriousness outcomes to determine whether they qualify as SAEs. 
Preplanned hospitalizations (e.g., elective procedures for preexisting conditions that did not 
worsen) are excluded from SAE reporting. 
Note that death is an outcome of an AE and not an AE in itself. The event that was the 
proximate cause of death should be reported as the AE term. 
8.5.3 
Classification of an Adverse Event 
8.5.3.1  
Severity of Event 
The investigator will provide an assessment of the severity of each AE by recording a 
severity rating on the appropriate AE reporting page of the participant’s CRF. Severity, 
which is a description of the intensity of manifestation of the AE, is distinct from 
seriousness, which implies a participant outcome or AE-required treatment measure 
associated with a threat to life or functionality. Severity will be assessed according to the 
following scale: 

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Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living. 
Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
8.5.3.2  
Relationship to Study Intervention 
The investigator must assess the relationship of the event to the study drug. The causal 
relationship of the AE is assessed using a binary system, and AEs are classified as either 
‘related’ or ‘unrelated’ as defined below. 
• Related: The available evidence suggests the adverse event is most likely due to the 
study drug. For example, a temporal relationship exists between the AE onset and 
administration of the study drug that cannot be readily explained by the study 
participant’s clinical state, concurrent disease or concomitant therapies.  
• Not related: The available evidence suggests the adverse event is most likely related 
to factors other than the administration of the study drug. Such other factors may 
include the underlying disease state, comorbidities, an intercurrent illness, 
concomitant medication(s) or procedures. 
• The investigator may change the causality assessment at any time based on new 
accumulated information. 
• An AE with causal relationship not initially determined will require follow-up to 
assign causality. 
8.5.3.3  
Expectedness  
The investigator will be responsible for determining whether an adverse event (AE) is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
study intervention. 
8.5.4 
Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate case report form (CRF). Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, relationship to study 
product (assessed only by those with the training and authority to make a diagnosis), and 
time of resolution/stabilization of the event. All AEs occurring while on study must be 

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documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
8.5.5 
Adverse Event Reporting  
Any untoward event that is reported from the time that the study participant signs the ICF 
until 30 ± 7 days after the last dose of CLTX-305 (encaleret) must be collected. Thus, any 
untoward medical occurrences or unfavorable and unintended signs, symptoms, or diseases 
that occur in the pretreatment, treatment, or posttreatment period are to be considered AEs 
(and SAEs if appropriate), and consequently recorded and reported as such. 
Participants are to be queried regarding any AEs or SAEs at the time of each vital sign 
assessment, as well as at each visit, according to the Schedule of Activities (Section 1.3). 
Participants will be asked to volunteer information with a nonleading question such as, “How 
do you feel?” Study center personnel will then record all pertinent information in the 
participant’s CRF. 
All AEs and SAEs reported by the participant (or participant’s legal representative) or 
observed or otherwise identified by the investigator (or other study center personnel) at a 
defined study visit or during any communication with the participant (or participant’s legal 
representative) occurring outside a defined study visit (from the time the participant signs the 
ICF to 30 ± 7 days after the last dose of CLTX-305 (encaleret) must be documented. 
All AEs must be recorded on the appropriate AE reporting page of the participant’s CRF 
whether or not they are considered causally related to the CLTX-305 (encaleret). 
For every AE, the investigator must: 
• Provide an assessment of the severity, causal relationship to CLTX-305 (encaleret), 
and seriousness of the event (i.e., whether it is a SAE) 
• Document all actions taken with regard to CLTX-305 (encaleret) 
• Detail any other treatment measures taken for the AE 
Document resolution of the AE (with or without sequelae); ongoing; or lost to follow-up. 

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8.5.6 
Serious Adverse Event Reporting 
The Sponsor is required to inform worldwide regulatory authorities of SAEs that meet 
specific criteria. Therefore, the Sponsor or its designated representative must be notified 
immediately regarding any SAE that occurs after informed consent is obtained. 
Within 24 hours of learning of any AE that meets one of the criteria for an SAE, the study 
center personnel must report the event to the Sponsor/designee on the SAE Form. The 
Sponsor’s Medical Monitor may also be notified by telephone. 
In addition, SAEs that are assessed by the investigator as related to study drug(s) and 
occurring after 30 days post the last dose of CLTX-305 (encaleret) will also be reported to 
the Sponsor/designee within 24 hours of when the site becomes aware of the event. 
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an 
SAE, that AE should be recorded as a new SAE. 
The study center staff must transmit the SAE Form to the Sponsor/designee. Even if an initial 
report is made by telephone, the study center staff must still complete the SAE Form with all 
available details and send the form within 24 hours of knowledge of the event. 
Supplemental information shall be submitted as soon as available and may include laboratory 
results, radiology reports, progress notes, hospital admission and emergency room notes, 
holding and observation notes, discharge summaries, autopsy reports, and death certificates. 
The investigator is expected to take all therapeutic measures necessary to treat and promote 
resolution of the SAE. Any medications or procedures necessary for treatment of the SAE 
must be recorded on the appropriate pages of the participant’s CRF. The study center staff 
must follow all SAEs until resolution or until the SAE is deemed stable. The 
Sponsor/designee may contact the study center to solicit additional information or follow-up 
on the event. 
Email all relevant SAE or pregnancy report forms to the Sponsor/designee at the following 
email address: 
Email for SAEs and pregnancy: 
CLTX-305-201@prahs.com  
 

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Contact information for the Sponsor’s Medical Monitor is as follows: 
 
 
Email: 
  
Telephone: 
 
Calcilytix Therapeutics, Inc. 
1800 Owens Street, Suite C-1200 
San Francisco, CA 94158 
 
 
Backup contact: 
 
  
Email: 
  
Telephone: 
  
Calcilytix Therapeutics, Inc. 
1800 Owens Street, Suite C-1200 
San Francisco, CA 94158 
 
All SAEs (except deaths due to progressive disease) will be reported to the NIDCR Office of 
the Clinical Director no later than 7 days after the PI first learns of the event. 
8.5.7 
Events of Special Interest 
Hypocalcemia in ADH1 
The main goal of CLTX-305 (encaleret) treatment in participants with ADH1 is to raise 
serum calcium levels. Hypocalcemia is not an expected side-effect of treatment with CLTX-
305 (encaleret) but it is a complication of the underlying disease being treated. As such, 
hypocalcemia may develop whenever the underlying disease is inadequately treated and 
might occur due to either inadequate or missed doses of a specific, effective medication. 
The current study involves reducing the dose of current maintenance medications or 
suspending their use entirely (i.e., oral calcium supplements and calcitriol), to facilitate dose-
finding with the CLTX-305 (encaleret) and potentially establishing clinical proof-of-concept. 
Under these circumstances there is a risk that participants could experience symptoms of 
hypocalcemia prior to achieving an effective dose of CLTX-305 (encaleret). In order to 
mitigate this risk, the study design emphasizes safety foremost. All changes to oral 
maintenance medications in conjunction with CLTX-305 (encaleret) dosing will be 
conducted with participants in residence at the NIH Clinical Center in the first two periods, 
with multiple daily measurements of blood calcium and close supervision by health 
professionals with experience caring for individuals with ADH1. In addition to these 
precautions, monitoring for and capture of events suggestive of or consistent with 
hypocalcemia will be reviewed as an AE of special interest as described below. 

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Assessment of Blood Calcium Concentrations 
In order to characterize both the pre-study calcemic status as well as changes associated with 
experimental interventions, the protocol will rely on frequent measurement of albumin-
corrected blood calcium concentrations. Assays will be conducted according to specifications 
of the NIH Clinical Center Laboratory, Bethesda, MD. The main indicator of normal versus 
abnormal blood calcium levels will be based on the correction for serum or plasma albumin 
according to the formula corrected calcium (cCa) = measured total calcium (mg/dL) + 0.8(4–
albumin (g/dL)) OR measured total calcium (mmol/L) + 0.2(4 –albumin (g/dL)), recognizing 
that the total calcium reported in SI units (mmol/L) can be converted to conventional units 
(mg/dL) by multiplying by 4. Given that enrolled participants are expected to have both 
normal and stable albumin levels, the measures of total calcium and cCa are likely to be 
similar throughout the time course of this study. Ionized calcium assays will also be available 
at the NIH Clinical Center investigative site and can be measured either in the event of severe 
hypocalcemia or if there is any question about the accuracy of the cCa measure. Collection of 
ionized calcium will occur at the discretion of the expert investigators based on the clinical 
scenario on a case-by-case basis. 
Adverse Events of Hypocalcemia: Symptomatic and Asymptomatic 
Adverse events consistent with hypocalcemia will be classified as either symptomatic or 
asymptomatic, and assessed for severity, recognizing that there is a spectrum of clinical 
manifestations. Symptomatic hypocalcemia will be based on identification of symptoms 
consistent with hypocalcemia such as numbness/tingling of hands, feet or lips, muscle 
cramps/spasms/twitching, other weakness or lightheadedness and/or new or worsening 
anxiety, including anger or depression and neurocognitive signs of confusion/hallucinations 
accompanied by laboratory evidence of a drop in cCa. Relevant symptoms will be 
documented as blood calcium levels are checked to confirm calcium status. A Case Report 
Form (CRF) for symptomatic hypocalcemia as an AE of special interest will capture the 
details of each hypocalcemic event including but not limited to symptoms, concomitant cCa 
concentrations, precipitating factors, treatment, resolution, and action taken regarding study 
medication. 
Asymptomatic hypocalcemia will also be captured as an AE of special interest based on 
defining a threshold value for cCa < 7 mg/dL. Since cCa levels are sampled frequently 
throughout the inpatient period, asymptomatic low cCa results will be identified during 
routine cCa monitoring. 
Clinical Evaluation and Treatment of Hypocalcemia: 
Hypocalcemia can range in symptom severity from asymptomatic to life-threatening. 
Appropriate treatment and action regarding study medication and/or other interventions (e.g., 
urgent calcium supplementation) will primarily be based on clinical evaluation of severity 
and acuity. Cases of hypocalcemia in this trial, if they occur, are expected to be manageable 
with supportive treatment. 
Different patients may have different sensitivities to low calcium levels but one advantage of 
conducting this initial safety and proof-of-concept trial at the NIH is that the expert 
investigators have significant experience in managing these patients as well as specific 

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historical knowledge about the clinical course and management of many members of the 
expected cohort to be studied.  The investigators performing the current study have decades 
of accumulated and institutional experience caring for these patients including management 
of hypocalcemia that is a consequence of the underlying disorder. This includes experience 
managing outpatient regimens of oral calcium and calcitriol to ensure patient functioning, 
well-being and quality of life, based on outpatient laboratory monitoring and assessment of 
symptoms. 
Appropriate evaluations may include serial cCa measures, an initial and follow-up ECG as 
appropriate based on clinical assessment (bradycardia e.g.) and/or if cCa is < 7 mg/dL. 
Graded interventions according to the expert judgment of the NIH investigators will include 
standard measures such as oral calcium and/or calcitriol supplementation (see below) for 
mild-moderate events. In the case on unresolving or worsening hypocalcemia with more 
acute clinical manifestations including worsening neurocognitive deficits, seizures, tetany, 
hypotension or cardiac dysfunction, for example, appropriate urgent intervention, also 
according with standards of care, will be undertaken by the site, including administration of 
intravenous calcium gluconate (see below). 
Addition of Oral Calcium Supplements and/or Calcitriol 
Since all participants will be attempting to consume at least 1000 mg dietary calcium per day 
throughout the trial, additional supplemental oral calcium in the range of 1,000–2,000 mg 
additional supplement may be given as required with close follow-up of cCa. Transient 
requirements for calcium supplementation and/or 1-2 doses of calcitriol (at doses based on 
each participant’s prior known sensitivity and dosing of outpatient calcitriol, if known, e.g., 
likely in the range of 0.5-2 mcg) resulting in stabilized calcium levels, need not interfere with 
per protocol dose escalation, particularly if required on Days 1 and 2 before CLTX-305 
(encaleret) effective doses may have been achieved. More severe or prolonged hypocalcemia 
unresponsive to oral supplementation may require early termination from the study period at 
the judgement of the investigator. If calcium levels are not stable and if evidence of clinically 
significant hypocalcemia precludes further dosing in the study period, CLTX-305 (encaleret) 
dosing will be stopped and participants may be re-started on their prior outpatient regimen of 
oral calcium and calcitriol and discharged when stable, with close follow-up. Such 
participants may be eligible to return for either a repeat of the study period or to the next per 
protocol study period, at the discretion of the investigator and the Sponsor. 
Intravenous Calcium supplementation: 
In the event of severe hypocalcemia, the NIH Clinical Center has the facilities to conduct 
advanced supportive care including intravenous fluid replacement, supplemental oxygen, 
continuous ECG monitoring, and bedside ionized calcium monitoring if required. 
Intravenous calcium may be given as clinically indicated. 
8.5.8 
Reporting of Pregnancy  
Study center personnel must report every pregnancy from the time study participant signs the 
ICF until 30 ± 7 days after the last dose of CLTX-305 (encaleret). Within 24 hours of 

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learning of the pregnancy, study center personnel must report the event to the Sponsor or its 
designated representative on the Clinical Trial Pregnancy Form, even if no AE has occurred. 
The study team will make every effort to follow the pregnancy to its conclusion and report 
the outcome on the follow-up Clinical Trial Pregnancy Form. If the pregnancy is associated 
with an SAE (e.g., if the female participant is hospitalized for hemorrhage), a separate SAE 
Form must be completed (in addition to the Pregnancy Form) as described in Section 8.5.5 
and Section 8.5.6, with the appropriate serious criterion (e.g., hospitalization) indicated. 
In the event that a participant becomes pregnant, the investigator is required to contact the 
Sponsor Medical Monitor/designee within 24 hours of awareness. 
If a participant becomes pregnant, administration of the study drug(s) must be discontinued 
immediately. 
If the partner of a male participant becomes pregnant after initiation of CLTX-305 (encaleret) 
and within 30 ± 7 days of the last dose, the study team will inform the Sponsor Medical 
Monitor/designee. If the partner agrees, the study team will amend the protocol to allow for 
follow-up of the pregnancy. 
8.6 
Unanticipated Problems 
8.6.1 
Definition of Unanticipated Problems (UP) 
Any incident, experience, or outcome that meets all the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
Institutional Review Board (IRB)-approved research protocol and informed consent 
document; and (b) the characteristics of the participant population being studied; and 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at 
a greater risk of harm (including physical, psychological, economic, or social harm) 
than was previously known or expected. 
8.6.2 
Unanticipated Problem Reporting 
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review 
Board (IRB) as per Policy 801 and to the Sponsor. 
8.6.3 
NIH Intramural IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NIH Intramural IRB. 

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9 
STATISTICAL CONSIDERATIONS 
All analysis details will be provided in a formal statistical analysis plan (SAP). 
9.1 
Statistical Hypothesis 
All data will be descriptively analyzed with no hypothesis testing. 
9.2 
Sample Size Determination 
The sample size of up to 8 participants in Period 1 (Cohort 1) and up to 10 additional 
participants in Period 2 (Cohort 2), is consistent with conventional first-in-human single and 
multiple ascending studies (SAD and MAD) that generally enroll between 8–10 participants 
per dose arm with escalation being based on safety and tolerability. 
The sample size for the current study is not based on statistical testing of a formal powered 
hypothesis. The proposed clinical trial represents a re-purposing of CLTX-305 (encaleret), 
leveraging extensive exposure and safety data from the prior osteoporosis program, to 
conduct a modified single and multiple-ascending dose study in a new target population of 
patients with ADH1. However, a recent publication of a different experimental calcilytic 
agent, NPSP795 (Roberts 2019), reported preliminary evidence for a dose-response on iPTH 
in participants with ADH1 with a sample size of 5 study participants. The authors speculated 
that despite testing doses known to raise iPTH robustly in non-ADH1 study participants, 
larger doses would have been required to stimulate iPTH in ADH1 participants sufficiently to 
also see elevations in cCa. The current protocol is designed to explore a broad potential dose 
range for safety and tolerability, however, the proposed sample size of approximately 16 
participants may be sufficient to confirm a definitive proof-of-concept on either iPTH and/or 
cCa if effective doses are achieved. 
9.3 
Populations for Analyses 
Safety Population:  All study participants who received at least one dose of study drug 
CLTX-305 (encaleret) 
PK Population:  
All participants who received at least one dose of study drug CLTX-305 
(encaleret) and who have sufficient PK samples drawn to enable the 
calculation of PK parameters for CLTX-305 (encaleret). 
PD Population:  
All study participants with PD data. 
9.4 
Statistical Analyses 
All analysis details will be provided in a formal statistical analysis plan (SAP). 
9.5 
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment. 

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9.6 
Safety Analyses 
Safety and tolerability parameters will be summarized using descriptive statistics, where 
appropriate. All safety data will be provided in data listings. 
AEs will be coded using the MedDRA dictionary. The incidence of each treatment-emergent 
AE (TEAE) will be summarized by system organ class, preferred term and treatment 
assignment. Multiple AEs mapped to the same preferred term will be counted once per 
participant. Concomitant medications will be coded using the WHO Drug Dictionary with 
generic term and Anatomical Therapeutic Chemical (ATC) code and summarized by ATC 
code, WHO Drug generic name, and treatment. Reasons for early termination will be 
summarized by treatment group assignment. Safety laboratory findings, vital signs, and 
12-lead ECGs will be summarized descriptively and listed by treatment assignment and visit. 
Values and changes from baseline at scheduled time points will be summarized. Laboratory 
data will be listed and values and changes from baseline at each visit will be summarized. An 
additional listing of treatment-emergent laboratory abnormalities will be provided. 
An AE (classified by preferred term) that occurs during the treatment period will be 
considered a TEAE if it was not present before the first dose of CLTX-305 (encaleret) or if it 
was present before the first dose of CLTX-305 (encaleret) but increased in severity during 
the treatment period. If more than 1 AE is reported before the first dose of CLTX-305 
(encaleret) and is coded to the same preferred term, the AE with the greatest severity will be 
used as the benchmark for comparison with the AEs that were also coded to that preferred 
term and that occurred during the period. An AE that occurs more than 30 ± 7 days after the 
last dose of CLTX-305 (encaleret) will not be counted as a TEAE. 
9.7 
Pharmacokinetic Analyses 
PK parameters will be calculated for each participant and summarized by treatment. Only 
participants with sufficient data to calculate each PK parameter will be included in the 
summary of each PK endpoint. 
9.8 
Pharmacodynamic Analyses 
PD parameters will be calculated for each participant and summarized by treatment. Only 
participants with sufficient data to calculate each PD parameter will be included in the 
analysis. 
9.9 
Interim Analysis 
Due to the open-label study design and quantitative laboratory analytes used to derive PK 
and PD endpoints, both the Sponsor and NIH investigator will be able to conduct joint 
periodic data reviews on an ongoing basis throughout the study. 
Review of safety, tolerability, and effects on iPTH and cCa will be conducted on Period 1 
single-dose and multiple-dose (QD and BID) responses prior to commencement of Period 2. 

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10 
REGULATORY AND OPERATIONAL CONSIDERATIONS 
10.1 
Informed Consent Process 
Consent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant and written documentation of informed consent is required prior to 
starting intervention/administrating study intervention. Study ICF will be submitted with this 
protocol as appropriate.  
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee as applicable for review prior to consenting. A designated 
study investigator will carefully explain the procedures and tests involved in this study, and 
the associated risks, discomfort and benefits. In order to minimize potential coercion, as 
much time as is needed to review the document will be given, including an opportunity to 
discuss it with friends, family members and/or other advisors, and to ask questions of any 
designated study investigator. A signed informed consent document will be obtained prior to 
any research activities taking place. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance 
with policy, including HRPP Policy 303) per discretion of the designated study investigator 
and with the agreement of the participant/consent designee(s). Whether in person or remote, 
the privacy of the subject will be maintained. Consenting investigators (and 
participant/consent designee, when in person) will be located in a private area (e.g., clinic 
consult room). When consent is conducted remotely, the participant/consent designee will be 
informed of the private nature of the discussion and will be encouraged to relocate to a more 
private setting if needed. If the consent process is occurring remotely, participants and 
investigators will view individual copies of the approved consent document on screens at 
their respective locations; the same screen may be used when both the investigator and the 
participant are co-located but this is not required. 
Note: When required, the witness signature will be obtained similarly as described for the 
investigator and participant below. 
Consent will be documented with required signatures on the physical document (which 
includes the printout of an electronic document sent to the participant) or on the electronic 
document. The process for documenting signatures on an electronic document is described 
below. 
For electronic consent: 
The study team will confirm with the subject that they are comfortable using the electronic 
consenting before proceeding with obtaining consent. If not, other methods will be utilized. 
When an electronic document with a digital signature is used for the documentation of 
consent, this study will use the iMedConsent™ platform which is 21 CFR, Part 11 compliant 
to obtain the required signatures. During the consent process, subjects/LARs and 
investigators will view the same approved consent document simultaneously in their 
respective locations.  The identity of the subject will be determined by verifying a 

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government issued identification card via the telehealth platform, prior to obtaining the 
signature. 
iMED consent will capture electronic signatures via the methods listed below: 
• Using a smartphone: participants will be registering their signatures using their finger. 
Participants will receive a secure link that leads them to secure “web pages” that will 
capture their electronic signatures using their finger. 
• Using a computer/tablet/laptop: participants will be registering their signatures using 
a computer mouse or their finger/stylus (for touch/stylus enabled tablets and 
computer screens). Participants will receive a secure link that leads them to secure 
“web pages” that will capture their electronic signatures using the aforementioned 
methods. 
Once the completed consent has been saved, it will post to CRIS within a few minutes. All 
consents completed in iMedConsent™ will post to both the Documents tab and the Consents 
tab in CRIS.  If the research participant has a FollowMyHealth™ account a copy of the 
completed consent will be posted to their account within two business days. The study team 
will provide the research participant with a printed copy of the signed document. 
If a participant reaches week 24 of Period 3 prior to the LTE being in place, upon entry into 
the LTE, the participant will be reconsented to and may restart CLTX-305 (encaleret) at the 
previous therapeutic dose determined in Period 3. 
10.1.1 
Consent/Assent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate 
in the study and continues throughout the individual’s study participation. Consent forms will 
be Institutional Review Board (IRB)-approved and the participant will be asked to read and 
review the document. Participants who are 16 or 17 at the time of enrollment will use the 
same consent form and be asked to sign in the assent section of the signature page, in 
addition to having a parent/Legally Authorized Representative (LAR) sign. If a participant 
becomes an adult (18 years of age) while participating in the study, the participant will be re-
consented at their next NIH CC visit. 
If a participant does not read and write in English, the short-form ICF in the participant’s 
preferred language will be utilized per NIH policies. 
The investigator will explain the research study to the participant and answer any questions 
that may arise. A verbal explanation will be provided in terms suited to the participant’s 
comprehension of the purposes, procedures, and potential risks of the study and of their 
rights as research participants. Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to 
agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. Participants must be informed that 
participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their 
records. The informed consent process will be conducted and documented in the source 

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document (including the date), and the form signed, before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if 
they decline to participate in this study. 
10.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, the Investigational New Drug (IND) the Sponsor and regulatory authorities as 
appropriate. If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and the 
Sponsor (as appropriate) and will provide the reason(s) for the termination or suspension. 
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor, IRB and/or Food and Drug Administration (FDA). 
10.3 
Confidentiality and Privacy 
All research activities will be conducted in as private a setting as possible. 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, study staff, and sponsor/and designee. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating 
to participants. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. 
All participants’ records will only be identified by participant initials and participant number. 
Participants’ names are not to be transmitted to the Sponsor. The investigator will keep a 
master participant list on which the participant number and the full name, address, and 
telephone number of each participant are listed. The study participant’s contact information 
will be securely stored at NIH Clinical Center for internal use during the study. At the end of 

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the study, all records will continue to be kept in a secure location for as long a period as 
dictated by the reviewing IRB, Institutional policies, or the Sponsor requirements. 
Data collection will involve the use of a 21 CFR part 11 compliant EDC system, only 
authorized personnel will have access to the EDC system. The study authorized 
representatives of the Sponsor, representatives of the Institutional Review Board (IRB), 
regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The NIH Clinical Center will permit 
access to such records. 
In addition to periodic monitoring occurring within the system by the Sponsor personnel 
and/or authorized Sponsor representatives, programmatic edit checks will be used to review 
the data for completeness, logic, and adherence to study protocol. As a result of this 
monitoring and these checks, queries may be issued electronically to the clinical study center 
and answered electronically by NIH Clinical Center. The identifying information (assigned 
username, date, and time) for both the originator of the query (if created during the 
monitoring process) and the originator of the data change (if applicable), as well as the 
investigator’s approval of all changes performed on his or her participants’ data, will be 
collected. 
All data collected in the context of this study will be stored in a secure location and evaluated 
according to regulatory requirements and applicable guidance for electronic records. Data 
will be stored and evaluated in such a way as to guarantee participant confidentiality in 
accordance with the legal stipulations applying to confidentiality of data. Study records 
(e.g., copies of CRFs, regulatory documents) will be retained at the NIH Clinical Center, 
along with adequate source documentation, according to local regulatory requirements and 
ICH requirements. All study records must be available for inspection by the Sponsor, its 
authorized representatives, and regulatory officials. 
The investigator must retain a copy of all records that support CRFs for this study (e.g., ICFs, 
clinical laboratory reports, source documents, CLTX-305 (encaleret) dispensing records) for 
a period of at least 15 years after study completion unless local regulations or NIH Clinical 
Center policies require a longer retention period or otherwise notified in writing by the 
Sponsor. 
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a suitable alternate custodian 
employee of the study center or to a suitably qualified and responsible third party. The 
Sponsor must be notified in writing of the name and address of the new custodian before 
such transfer is made. 
No study records shall be destroyed without notifying the Sponsor and giving the Sponsor the 
opportunity to arrange long-term storage for such study records or to authorize in writing the 
destruction of records after the required retention period. 

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10.4 
Future Use of Stored Specimens and Data 
A unique participant code, as opposed to personal identifiers, will be used on the CRFs, and 
in the study database. A participant code log that links the names to identification numbers 
will be securely maintained at the NIH. 
Data collected for this study will be analyzed and transmitted to Calcilytix via a secure, 
encrypted Internet connection and stored on a secure server. 
All stored samples are coded and do not have personal identifiers. The codes for identifiers 
are contained in a participant code log that is maintained in secure research files at the NIH. 
Samples received for PK analysis by Calcilytix/or designee from participants consented to 
this protocol, may be destroyed or unused samples sent back to the NIH for additional 
research purposes. Additional research samples collected for FGF23 and mid-molecule PTH 
may be stored at the NIH for use in future studies, with the participants’ consent.  
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), 
de-identified biological samples will be stored at the NIH. These samples could be used to 
research the causes of ADH1, its complications and other conditions for which individuals 
with ADH1 are at increased risk, and to improve treatment. 
During the conduct of the study, an individual participant can choose to withdraw consent to 
have biological specimens stored for future research. However, withdrawal of consent with 
regard to biological sample storage may not be possible after the study is completed. 
10.5 
Safety Oversight 
Safety monitoring for this study will be the responsibility of the investigator along with the 
NIDCR Clinical Director and the Calcilytix (the Sponsor) Medical Monitor with support 
from the Sponsor’s designee (contract-research organization (CRO) Medical Monitor and 
safety/pharmacovigilance groups). Serious adverse events will be reported directly to the 
Sponsor/designee (CRO) and reviewed by the Calcilytix Medical Monitor. 
The investigator will be responsible for monitoring the data and accruing safety information. 
The investigator is responsible for monitoring the study progress and study data. The 
investigator will also maintain responsibility for ensuring the accuracy, completeness, 
timeliness, and legibility of the data. The investigator and associate investigators are also 
required to keep accurate and timely records to ensure that the conduct of the study is fully 
documented. The investigator will review individual study participant data upon each patient 
encounter. The investigator will review aggregate data reports quarterly to review enrollment 
progress and AEs. Trends will be discussed with the NIH and Calcilytix study teams to 
ensure participant safety; study compliance and recruitment goals are met. 
This study will have a Data and Safety Monitoring Committee (DSMC), that is monitored by 
the NIDCR Division of Intramural Research. The DSMC will operate in accordance with the 
approved charter. 

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Serious adverse event monitoring will be supported by the Sponsor’s designee (CRO safety 
and pharmacovigilance group), the Calcilytix Medical Monitor and Calcilytix/designee site 
study monitor. The investigator will review the SAE report, request additional information 
about the event if necessary and provide a medical monitor assessment within 2 business 
days of receipt of the SAE report. The investigator and the Sponsor/designee Medical 
Monitor may discuss specific events or trends if noted. The investigator will determine the 
appropriate clinical action for the participant. 
Because the study is an open-label, dose finding, proof-of-concept trial, data review will be 
performed on an ongoing basis as each participant proceeds throughout all Periods of the 
study with respect to identifying individualized effective doses of CLTX-305 (encaleret). 
Dosing decisions based on blood corrected calcium concentrations will be the responsibility 
of the NIH investigators in consultation with the Sponsor on an ongoing basis guided by the 
dosing algorithm described in the protocol. The Sponsor and NIH investigators will conduct 
a review of available data from Cohort 1 once at least 5 participants have completed Period 1 
and as required thereafter, prior to opening enrolment of Cohort 2. These reviews will be 
documented and will include determinations of accumulated risk/benefit, tolerability and 
efficacy on normalizing blood corrected calcium concentrations as they inform potential 
starting doses for participants in Cohort 2 entering Period 2. 
Additional details of the process and procedures for safety monitoring will be documented in 
the Safety Monitoring Plan prepared in collaboration with the Sponsor’s designated CRO. 
10.6 
Clinical Monitoring 
Before the first participant is dosed in the study, the Sponsor/designee (CRO) will meet with 
the investigator and the investigator’s staff to review the procedures for conducting the study 
and to train the staff on recording the data on the eCRF. The Sponsor/designee (CRO) will 
routinely monitor the progress of the study by conducting on-site or virtual/remote visits 
thereafter. The Sponsor/designee (CRO) will also be able to review query statuses remotely, 
which may warrant more frequent communication with the NIH investigator and study staff. 
The investigator will make available to the Sponsor/designee (CRO) the source documents, 
the signed consent forms, and all other study-related documents. The investigator will be 
responsible for reviewing eCRFs, resolving data queries generated by the Sponsor/designee 
(CRO) via the system, providing missing or corrected data, approving all changes performed 
on the data, and endorsing the participants data within the EDC system. This approval 
method will include applying an electronic signature, a uniquely assigned username and a 
password that together will represent a traditional handwritten signature. 
Additional details of the process and procedures for Clinical study research site monitoring 
will be documented in the Clinical Monitoring Plan prepared in collaboration with the 
Sponsor’s designated CRO. 
10.7 
Quality Assurance and Quality Control 
Following written Standard Operating Procedures (SOPs), the clinical trial monitors will 
verify that the clinical trial is conducted, and data are generated, and biological specimens are 

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collected, documented (recorded), and reported in compliance with the protocol, 
International Council on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)). Additional details of monitoring (including Clinical, Safety, Data, Quality, 
and overall Trial monitoring) will be available in designated monitoring plan documents. 
Quality control (QC) procedures will be implemented beginning with the data entry system 
and data QC checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/resolution. 
The Sponsor/designee will conduct site audits as stipulated in study-related plan(s). The 
investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the Sponsor, and inspection by 
local and regulatory authorities. 
10.8 
Data Handling and Record Keeping 
10.8.1 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the site investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
Hardcopies or electronic copies of the study visit serial test worksheets will be provided for 
use as source document worksheets for recording data for each participant enrolled in the 
study. Data recorded in the electronic case report form (eCRF) derived from source 
documents should be consistent with the data recorded on the source documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected 
adverse reactions data) and clinical laboratory data will be entered into Medidata RAVE, a 
21 CFR Part 11-compliant data capture system provided by the CRO. The data system 
includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. 
10.8.2 
Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Council on Harmonisation (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at 
least 2 years have elapsed since the formal discontinuation of clinical development of the 
study intervention, or as per the NIH Intramural Records Retention Schedule. No records will 
be destroyed without the written consent of the Sponsor, if applicable. It is the responsibility 
of the Sponsor to inform the investigator when these documents no longer need to be 
retained. 

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10.8.3 
LTE Electronic Data Capture 
For administrative purposes, LTE data for participants may be housed in the eCRF for 
CLTX-305-201 and in the eCRF for CLTX-305-302/CALIBRATE. When the NIH site is 
activated in CLTX-305-302/CALIBRATE, the database for CLTX-305-201 will be cleaned 
and closed. LTE participants will be able to consent to the LTE portion of the CLTX-305-
302/CALIBRATE study for the purpose of data capture to support the LTE summary of the 
CLTX-305-201 CSR. LTE data captured in CLTX-305-201 and CLTX-305-
302/CALIBRATE for these participants will be summarized in the CSR for CLTX-305-201. 
The CSR for CLTX-305-302/CALIBRATE will not include data from the subjects 
originating from CLTX-305-201. 
10.9 
Protocol Deviations 
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations to the NIH Institutional Review Board as per Policy 801. Deviations must be 
addressed in study source documents and reported to the Sponsor. The investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. Additional details 
on the process and procedures of identifying and managing protocol deviations will be 
available in the Sponsor/designee (CRO) data monitoring plan. 
10.9.1 
NIH Definition of Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the IRB-approved research 
protocol. 
• Major deviations: Deviations from the IRB approved protocol that have or may have 
the potential to negatively impact the rights, welfare or safety of the participant, or to 
substantially negatively impact the scientific integrity or validity of the study. 
• Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety or welfare of participants or others, or the scientific integrity or validity 
of the study. 
10.10 
Publication and Data Sharing Policy 
10.10.1 
Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
This study is sponsored by Calcilytix Therapeutic Inc., and publications of data from this 
study will be in alignment with the NIH and Calcilytix Therapeutics Inc. Cooperative 
Research and Development Agreement (CRADA). 
National Institutes of Health (NIH) Public Access Policy ensures that the public has access to 
the published results. NIH funded research requires that NIH scientists submit final peer-

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reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
This study will comply with the NIH Data Sharing Policy and the Clinical Trials Registration 
and Results Information Submission rule. As such, this trial will be registered at 
ClinicalTrials.gov, and results information from this trial will be submitted to 
ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals. Results from this trial will be made available 12 months after the primary 
study completion date. Calcilytix will consider requests from qualified researchers for access 
to Calcilytix clinical Data. 
10.10.2 
Genomic Data Sharing Plan 
Not applicable. See Section 10.3 (Confidentiality and Privacy) 
10.10.3 
Agreement Type 
The NIDCR investigator(s) and Calcilytix will sign the protocol and Cooperative Research 
and Development Agreement, (CRADA) to confirm agreement. The investigator(s) will not 
implement any amendment (deviation or changes of the protocol) without agreement by the 
Calcilytix (the Sponsor) and IRB approval, except where necessary to eliminate immediate 
hazard(s) to study participants, or when change(s) involve only logistical or administrative 
aspects of the study. Any logistical or administrative changes will be done in agreement with 
Calcilytix and documented within 30 days on implementation. 
10.11 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the design and conduct of this trial. The study leadership at sponsor/and designee in 
conjunction with the NIH NIDCR has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 

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11 
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Thyroidectomy. World Journal of Surgery 44, 2692–2698 (2020). DOI: 10.1007/S00268-
020-05531-0. 
Roberts, Mary Scott; Gafni, Rachel I.; Brillante, Beth; Guthrie, Lori C.; Streit, Jamie; Gash, 
David et al. (2019): Treatment of Autosomal Dominant Hypocalcemia Type 1 with the 
Calcilytic NPSP795 (SHP635). In Journal of bone and mineral research: the official journal 
of the American Society for Bone and Mineral Research. DOI: 10.1002/jbmr.3747. 
Roszko, Kelly L.; Bi, Ruiye D.; Mannstadt, Michael (2016): Autosomal Dominant 
Hypocalcemia (Hypoparathyroidism) Types 1 and 2. In Frontiers in physiology 7, p. 458. 
DOI: 10.3389/fphys.2016.00458. 
Shrestha, Rajiv P.; Hollot, Christopher V.; Chipkin, Stuart R.; Schmitt, Claus P.; Chait, Yossi 
(2010): A mathematical model of parathyroid hormone response to acute changes in plasma 
ionized calcium concentration in humans. In Mathematical biosciences 226 (1), pp. 46–57. 
DOI: 10.1016/j.mbs.2010.04.001. 
Winer, Karen K.; Fulton, Kara A.; Albert, Paul S.; Cutler, Gordon B. (2014): Effects of 
pump versus twice-daily injection delivery of synthetic parathyroid hormone 1-34 in children 
with severe congenital hypoparathyroidism. In The Journal of pediatrics 165 (3), 556-63.e1. 
DOI: 10.1016/j.jpeds.2014.04.060. 
Winer, Karen K.; Zhang, Bo; Shrader, Joseph A.; Peterson, Donna; Smith, Michaele; Albert, 
Paul S.; Cutler, Gordon B. (2012): Synthetic human parathyroid hormone 1-34 replacement 
therapy: a randomized crossover trial comparing pump versus injections in the treatment of 
chronic hypoparathyroidism. In The Journal of clinical endocrinology and metabolism 97 
(2), pp. 391–399. DOI: 10.1210/jc.2011-1908. 
 

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Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Appendix 1  Summary of Changes 
SUMMARY OF CHANGES 
Section No./Title 
Changes  
Rationale 
Original Protocol Vs. Amendment 1 
Cover page  
1. Update cover page and Protocol version.  
2. Added IND number.  
3. Changes in Key Sponsor Contact information  
4. Updated list of abbreviation. 
 
Administrative change  
 
1.1 Synopsis 
Updated for consistency with 3 Objectives and Endpoints 
Administrative change and/or 
typographical 
1.2 Schema; 1.3/Tables A & 
B: SOAs  
Change footnote numbering to reflect update tables.  
Administrative change and/or 
typographical  
1.3 Tables A & B: SOAs; 
Schema 
“Baseline” replaced with “Admission” 
Arrow moved to between Period 1 Period 2 Boxes 
Changes for clarification only  
1.3 Tables A, B and C: 
SOAs 
 
Update footnotes and tables: 
1. Table: A, B, C: Added treatment discontinuation rules. 
2. Table A: Added local labs and PK sample collection on 
Day 7 or 8 after discharge from the NIH CC in Period 1. 
3. Table A: Added telephone contact during Day 9 to 11 to 
review labs results with PI and to review AEs/Con meds. 
30 ± 7 days after discharge. 
4. Tables A & B: Added DXA scan. 
5. Table: A, B &, C: added reference to PK/PD blood sample 
collection Tables in footnotes. 
6. Tables A & B:  Added clarification related to the 
frequency for height measurement.  
7. Tables A, B & C: Added clarification about vital signs 
assessment.  
Changes in response to Agency 
advice and for clarification  

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Section No./Title 
Changes  
Rationale 
8. Tables A, B, & C: footnote referring to table D, E and F: 
Changed 24-hour urine interval lab sample collection 
added Na and K. 
 
1.3.1 Table D, E & F 
1. Table D: Removed PK Samples timepoint at 17hrs. 
2. Tables D, E & F: Removed parenthesis related to 
calculations related information for Timed Interval Urine 
collection and 24-hour urine. 
3. Tables D, E & F: Added Na, and K to 24-hour urine 
collection list of tests.  
4. Table D and E: Timed Interval Urine collection: Added -15 
min. timepoint and related footnotes. Modified 9hrs. to 
8hrs. timepoints  
5. Table F: Addition of -15 min. timepoint sample collection 
for PM dose for: PK, Intact PTH, 1, 25-(OH)2 Vitamin D, 
cAMP and Ca, P, Mg, Cr, albumin. 
 
Reassessment and revision of 
timepoints and testing  
1.3.1 Table G 
Added new table for Research Sample collection & associated 
timepoint during Periods 1,2, and 3.  
Additional sample collection for 
research testing 
2.2.3 Background- 
Autosomal Dominant 
Hypocalcemia, Type 1 
 
Refined the description of Hypercalciuria is in patients with 
ADH1. 
 
Addition of language for 
clarification 
5.1 Inclusion criteria  
Added inclusion criteria 6 and 7: 
- 
Criteria 6: Instruction related to use of Thiazide  
- 
Criteria 7: Instruction related to use of CYP3A4 inhibitors  
Changes in response to Agency 
advice  
5.2 Exclusion criteria 3a 
Outlined cholecalciferol or ergocalciferol supplementation for 
a blood 25-OH Vitamin D level < 25 ng/mL at the screening 
visit. 
Addition of language for 
clarification 

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Section No./Title 
Changes  
Rationale 
6.5 Concomitant Therapy 
Added new text providing instructions and clarifications for 
concomitant medications use and/or discontinuation of 
thiazide and strong CYP3A4 inhibitors.  
Change in response to Agency 
advice 
7.1, 7.2 & 8.2.4 Participant 
Discontinuation/Withdrawal 
from the Study & Follow-up 
and Early Termination 
 
For clarity, information related to participant discontinuation 
in the study were moved from Section 7.1 to Section 7.2. 
Added instructions regarding safety follow- up, resuming 
prior medication in case of discontinuation from CLTX-305 
(encaleret), withdrawal or early termination from the study. 
Change in response to Agency 
advice and clarification 
8.2.1, 8.2.2, and 8.4.3 
Periods 1 and 2; Cohorts 1 
and 2 and, 
Clinical Laboratory 
Determinations 
 
Added clarifying language to indicate that for participants 
with screening visit > 21 days before initiation of study drug, 
outpatient laboratory testing will be performed 10-14 days 
prior to admission for blood and urine chemistry. 
Added Day 7-8 post discharge laboratory testing to allow 
evaluation of calcium homeostasis as well as a final PK 
considering the half-life of CLTX-305 (encaleret) is about 10 
to 14 hours to represent a timepoint between 40 to 70 hours 
after the last dose of CLTX-305 (encaleret) on the evening of 
Day 5. 
Added information to clarify how both pre-study calcemic 
status as well as changes associated with experimental 
interventions will be measured and calculated in accordance 
with the specification of the NIH Clinical Center laboratory 
Change in response to Agency 
advice and additional testing 
measurement clarification 
 
8.3.4.1 & 8.3.4.3 Description 
and Scope of Genetic 
Analysis & Management of 
Results 
Clarified ADH1 genetic testing at screening. 
Added- If no pathogenic variant in the CaSR is identified, 
testing for other genetic forms of hypoparathyroidism may be 
offered to the participant.  
Clarification and allowance of 
testing for other genetic forms of 
hypoparathyroidism 

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Section No./Title 
Changes  
Rationale 
8.4.5 Dual Energy X-Ray 
Absorptiometry (DXA) 
Added DXA at Screening for bone mineral density 
measurement. 
Change in response to Agency 
advice 
8.5.7 Events of Special 
Interest 
Added description of hypocalcemia due to ADH1 and 
algorithm to discriminate normal versus abnormal blood 
calcium levels. Clinical symptoms, evaluation and treatment 
hypocalcemia are added.  
Change in response to Agency 
advice 
8.5.8 Reporting of 
pregnancy  
Added information related partner pregnancy reporting.  
Addition of language for 
clarification 
10.4 Future use of Stored 
Specimens and Data  
Added clarification regarding sample storage. 
Addition of language for 
clarification 
10.10.1 Human Data Sharing 
Plan  
Added clarification regarding availability of results. 
Addition of language for 
clarification 
Section No./Title 
Amendment 2- Date 10 June 2020 
(Pre-IRB review changes) 
Rationale 
5.3 Inclusion of vulnerable 
participants  
Added rational for including 16- and 17-years old participants 
and not younger due to their capacity to provide assent. 
Addition of language for 
clarification 
5.6.2 Compensation 
Details added related to NIH Policy, amount, mode of 
payment, and travel arrangement. 
Addition of information  
10.1.1 Consent/Assent 
Procedures and 
Documentation 
Added information related to use of the same consent and 
signature process for 16- and 17-years old participants and 
parent/Legally Authorized Representative (LAR). 
Addition of information for 
clarification  
Section No./Title 
Amendment 3: Date 24 June 2020 
(response to IRB review) 
Rationale 
8  Study Assessments and 
Procedures- subsections: 8.1, 
8.2.1, 8.2.2 and 8.2.3  
Added details related to amount of blood volume to be 
collected during screening, Period 1, Period 2, and Period 3.  
Change in response to IRB 
feedback 

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Section No./Title 
Changes  
Rationale 
10.1.1 Consent/Assent 
Procedures and 
Documentation 
Added re-consenting process language for participants who 
reach 18 years of age during participation in the study. 
Change in response to IRB 
feedback 
Section No./Title 
Amendment 4: Date 24 August 2020 
(response to DSMC review) 
Rationale 
Sponsor Signature Page 
Incorporated as part of the document  
Administrative change 
1.2 Schema: 
 Periods 1,2, 3 and 3  
Modified to clarify Period 1, Day 1 and Day 2 doses could be 
up to 90 mg QD and up to 180 mg QD, respectively. 
Modified for Clarification 
1.3 Schedule of Assessment 
–Tables A, B, C- Footnotes 
Section 8.2.1  
Period 1 (single Ascending 
Dose Escalation and BID 
PK/PD profile)-Cohort 1  
 
1. Table A, B, and C- clarified safety lab tests  
2. Table A, and C, section 8.2.1, and 8.4.3- list outpatient 
laboratory testing specifically. 
3. Table A- clarified outpatient lab testing on day -14 to -10 
and removed PTH. 
4. Table A- clarified on Days 1, 2, 3 participants will receive 
BID doses based on Days 1 -3. 
Modified for Clarification  
1.3.1 Pharmacokinetic, 
Pharmacodynamic, and 
Urine Sampling Times, 
Table F 
Timepoints modified: 
- 
Eliminated all -15 min TRT PM blood draw. 
- 
Modified timed interval Urine collections to 4-8 h, and 8-
13. 
Clarifications in consideration to 
IP dosing time 
4 Study Design, 4.1 Overall 
Design- Figure A and B 
Modified to indicate in Period 1, Days 2 and 3 up to 90 mg 
QD, and 180 mg QD dose of the CLTX-305 (encaleret) may 
be administered.  
Change per NIDCR DSMC 
recommendation  
5 Study population 
5.2 Exclusion Criteria 7, 
subsection a 
Participants who are in complete remission from Hepatitis C 
as evidence by sensitive assay ≥12 weeks after completion of 
HCV therapy are allowed to participate in the study. 
Change per NIDCR DSMC 
recommendation 
6.1.2.1, Period 1 (Single 
Ascending Dose Escalation 
and BID PK/PD profile) 
Cohort 1  
Clarification added to indicate dose adjustment increasing 
CLTX-305 (encaleret)to a maximum of 180 mg on Day 3 may 
occur. 
Change per NIDCR DSMC 
recommendation 

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Section No./Title 
Changes  
Rationale 
6.1.2.4 Dose Limiting 
Toxicity 
6.1.2.5 Dose Modification 
Change the cCA threshold to 10 to 10.5 mg/dL in Periods 1 
and 2 and consideration related to dose escalation and/or 
adjustment accordingly.  
Change per NIDCR DSMC 
recommendation 
8 Treatment Period  
Figure D 
Modified Figure D and change the cCA from 11 mg/dL to 
10.5 mg/dL and consideration related to dose escalation by 30 
mg. 
Change per NIDCR DSMC 
recommendation 
8.2.1- Period 1 (Single 
Ascending Dose Escalation 
and BID PK/PD profile) – 
Cohort 1 
Clarified that on Days 1, 2, and 3 (QD dose Escalations: The 
starting dose on Day 1 is 30 mg.  
Addition of language for 
clarification  
8.2.1 - Figure D - Dosing 
Guidance Algorithm for 
Period 1 
Dosing Algorithm modified in consideration to changes in 
cCa threshold and dose adjustment.  
Change per NIDCR DSMC 
recommendation 
10.5 Safety Oversight 
Include the language outlining involvement of DSMC that is 
established by NIDCR.  
Addition of language for 
clarification 
8.4.3 Clinical Laboratory 
determination 
For outpatient labs, added creatinine and albumin 
Modification for clarification 
Section No./Title 
Amendment 5: Date 01 February 2021 
 
Rationale 
Key Sponsor Contact: 
8.5.9 Serious Adverse Event 
Reporting 
- 
New Contact and related information added:  
 
- 
Updated: Phone number for second contact 
 
- 
Contact information added, 
and updated  
Section 1.1 – Synopsis-
Objectives and Endpoints 
Section 3- Objectives and 
Endpoints 
- 
Moved evaluation of safety and tolerability for Period 3 
from Secondary to the Primary Objectives and Endpoint. 
- 
Added Periods 2 and 3 to the first Primary safety Endpoint  
- 
Added 24-hour urinary calcium excretion to primary 
endpoint for Period 3  
- 
Added: Renal function (eGFR) to secondary endpoint for 
Periods 1, 2 and 3 
- 
Clarification added, and 
modified the order of the 
Objectives and Endpoints 
- 
Added renal function 
measure to secondary 
endpoint for all study Periods 
 

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Section No./Title 
Changes  
Rationale 
1.2 – Schema-Schematic for 
Periods 1, 2, and 3 
4.1 Overall Design Figures 
A, B, and C 
8.2.2 – Period 2 (BID) – 
Cohorts 1 and 2 
- 
Time interval between Period 1 and Period 2 for 
participants in Cohort 1 changed from 8 to 12 to ≥ 8 to 16 
weeks. 
- 
Period 3 and figure: added asterisk to indicate PK at week 
24   
 
- 
Clarification and update on 
minimum and maximum time 
intervals between Periods 1 
and 2 
- 
Clarification of study visit 
week for PK measurement    
1.3 – Schedule of Activities 
Table B- Period 2 
8.1 Screening Procedures 
8.2.2 – Period 2 (BID 
Dosing) – Cohorts 1 and 2 
Section 8.2.2 – Figure E 
Dosing Guidance Algorithm 
for Period 2-Cohort 1  
  
- 
Table B- Added ECG measurement to Day 1, Day 3 and 
Day 5 
- 
Table B- Footnote 1- Added clarification for screening 
visit that may include inpatient overnight stay as well as 
option for additional overnight stay at NIH CC if 
participant is to start the study midweek. 
- 
Table B- Footnote 4- added iron panel to be done if 
clinically indicated   
- 
Footnote 10-assessments apply to Cohort 1 and 2 and 
added, Hematology (RBC, Hgb, Hct, RBC indices, WBC) 
- 
Added clarification to stop taking calcitriol on Day -1 until 
admitted  
- 
Added instruction for discontinuation of magnesium, 
potassium citrate on Day 1 and calcium based on estimate 
dietary calcium intake targeting a combined calcium 
intake of > 1000 mg/day  
- 
Update the limit of cCa from >10.5 to >10.0 for dose 
reduction 
- 
Update total blood volumes to be collected 
- 
Figure E – outlined normal rage to 7.5 to 10 mg/dL, and 
changed cCa from >10.5 to >10.0 for dose reduction 
- 
Additional ECG for QTC 
- 
 
- 
 analysis  
- 
Allowing flexibility in 
consideration to screening 
assessments and COVID-19 
pandemic travel limitations 
  
- 
Added as additional safety 
measure and clarification 
- 
Added supplement intake 
management on Day 1 
- 
Clarification, and correction 
of the cCa for dose reduction 
in text and related figure  
 
1.3- Schedule of Activities- 
 Table C- Period 3 
- Added ECG measures during Period 3 NIH CC visits.  
- Table column and Footnote 2, 5 and 14 updated: Follow-
up (FU) days for outpatient labs after last dose of CLTX-
305 (encaleret)  
- Additional ECG measures for 
QTC analysis 
- Harmonization with section 
8.4.4 of the protocol  

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Section No./Title 
Changes  
Rationale 
- changed FU days to 2 to 3 ± 2 days 
- 
added FU days of 7 ± 2 days  
- 
added Na, K, Cl, Ca, Mg, PO4, Cr, pH and 24-hour 
urine assessments to the 30 ± 7 days safety FU 
- 
Footnote 13: Clarification that related assessment to be 
done at the NIH CC 
- Addition of laboratory safety 
assessment and clarification 
related to assessments during 
the NIH CC visit   
2.3. Risk/Benefit 
Assessment 
2.3.1 Known Potential Risks 
2.3.2 Known Potential 
Benefits 
 
- Added preclinical metabolism and excretion information 
and citation related to eGFR threshold change 
consideration 
- Citation- Reference added to Section 11 
- Addition of risk for venous thrombosis procedure 
- Addition of blood collection method: central catheter 
- Providing rational in support 
of change in exclusion 
criteria related to eGFR 
- Addition of option for blood 
collection  
1.3.1 Pharmacokinetic, 
Pharmacodynamic, and 
Urine Sampling Times 
- Added tables to this section to modify timepoints and 
assessments– These changes are for Period 2 and 3  
- Changes in consideration to 
amount of blood volume 
collected  
5.1 Inclusion Criteria  
8.2.2 Period 2 (BID Dosing) 
– Cohorts 1 and 2 
8.2.3 Period 3 (Cohort 1 and 
Cohort 2) – Outpatient 
Dosing 
- New criteria # 8- instruction for discontinuation of 
magnesium, potassium citrate on Day 1 and calcium based 
on estimate dietary calcium intake targeting a combined 
calcium intake of > 1000 mg/day during and Period 2 and 
possible discontinuation of these supplement during 
Period 3 if blood Mg and urine citrate are within the 
normal range during previous Periods. 
- Updated Total volume of blood collected during Period 2 
- New inclusion criteria  
 
- To collect safety lab 
assessments and 24-hour 
urine information   
- Updated after recalculation of 
total blood volume collection  
5.2 Exclusion Criteria 4, 6, 
11 and 16 
 
- Criteria # 4 – Hemoglobin (Hgb) criteria for Male and 
Female included in for the study 
- Criteria # 6 – Added information related to rationale for 
eGFR threshold change. Citation- Reference added to 
section 11. Estimated glomerular filtration rate (eGFR) < 
25 mL/minute/1.73 m2.  
- Criteria # 11 – Condoms are not required if the participant 
has a female partner who is not of child-bearing potential. 
- Hemoglobin criteria 4 and 16 
related to participations’ 
safety  
- Expanded threshold for eGFR 
in the related exclusion 
criteria and added rationale 

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Section No./Title 
Changes  
Rationale 
- Criteria # 16 – exclusion of participants who donate blood 
during the study 
 
for this change in 
Risk/Benefit section  
- Revised to further clarify 
requirements for 
contraception 
4.1 Overall Study Design 
9.2 Sample size 
Change the maximum number of participants in Period 2 from 
up to 8 additional participants to up to 10 participants 
Increase the maximum number of 
participants in Period 2  
6.1.7 Dose Modifications 
 
Added guidance language for dose interruption and dose 
resumption  
Information added related to dose 
interruption and continuation 
8.4.3 Clinical Laboratory 
Determinations 
Information added on reporting of laboratory AEs resulting in 
clinical intervention 
Clarification related to reporting 
laboratory AEs 
8.4.4 Electrocardiograms 
added additional ECG measurement during Period 2  
Added additional ECG measures 
for safety 
10.6 Clinical Monitoring 
10.8.1 Data Collection and 
Management 
Responsibilities 
Option for virtual/remote monitoring visits added  
Flexibility for onsite or virtual 
study monitoring visits in 
consideration to COVID-19 
pandemic limitations 
Section No./Title 
Amendment 6: Date 03 June 2021 
 
Rationale 
All sections of the protocol  
Replaced: references of study subjects to study participants 
throughout the documents  
General Administrative change: 
Consistency of terms used 
throughout the protocol   
All sections of the protocol 
Replaced: CLTX-305 with CLTX-305 (encaleret) 
General Administrative change: 
Consistency of terms used 
throughout the protocol 
Protocol Cover page  
Calcilytix address has changed, new address is inserted as: 
1800 Owens Street, Suite C-1200 
San Francisco, CA 94158 
Updated- Sponsor change of 
address 
Protocol Cover page  
The Sponsor Signature page 
Contact Information for the new Sponsor 
 
added:  
Updated pertinent sections of the 
protocol to reflect name and 

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Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
Changes  
Rationale 
8 Study assessment and 
procedure 
8.5 Adverse Events and 
Serious Adverse Events 
 
 
 
Telephone: 
 
Calcilytix Therapeutics, Inc. 
1800 Owens Street, Suite C-1200 
San Francisco, CA 94158 
 
contact information for the 
 
1 Protocol Summary 
1.1  Protocol Summary 
Synopsis  
3 Objectives and Endpoints 
Primary Objective added (new texts):  
LTE: 
- Evaluate the longer-term (25 months or about 2 years) 
safety and tolerability of CLTX-305 (encaleret) 
Primary Endpoint for Period 3 reworded to: 
- Albumin-corrected blood calcium concentrations (cCa) 
and 24-hr urinary calcium excretion after treatment with 
CLTX-305 (encaleret) for 25 weeks 
Primary Endpoint added: 
LTE:  
- Adverse events (AEs), clinical safety laboratory tests, vital 
signs 
Secondary Objective added: 
Periods 1,2, and 3: 
- Evaluate the PD effects of CLTX-305 (encaleret) on bone 
turnover markers including C-telopeptide (CTx) and 
procollagen type 1 N-propeptide (P1NP)  
LTE: 
- Obtain long-term data on efficacy (durability) of CLTX-
305 (encaleret) on blood calcium concentrations 
- Evaluate the long-term PD effects of CLTX-305 
(encaleret) on associated measures of mineral homeostasis 
For addition of the LTE to the 
protocol to support participants’ 
continuation of dosing with 
CLTX-305 (encaleret) based on 
data to date and avoid 
interruption of IP if participants 
are benefiting from taking 
CLTX-305 (encaleret) and if 
elect to stay on the study.  
Added- Long-term safety and 
efficacy data will be collected 
during the LTE.  
Added- Related primary and 
secondary objective and endpoint 
assessments are outlined.  

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Section No./Title 
Changes  
Rationale 
including iPTH, 1,25-(OH)2 Vitamin D levels and urinary 
calcium excretion  
- Evaluate the long-term effects of CLTX-305 (encaleret) 
on bone turnover markers including C-telopeptide (CTx) 
and procollagen type 1 N-propeptide (P1NP)  
 
Secondary Endpoints updated: 
- Secondary Endpoints rearranged to clarify that PK 
assessments are only for Periods 1, 2, and 3, and PD 
assessments are for Periods 1, 2, 3, and LTE 
 

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Section No./Title 
Changes  
Rationale 
1 Protocol Summary 
1.1 Synopsis- Study duration 
and Participant Duration 
Changed:  Total duration of the study from approximately 24 
months to approximately 41 months 
Added: Participants that continue to meet study eligibility 
criteria after Period 3 may continue in the Long-term 
Extension (LTE) for approximately 25 additional months. 
Added total duration of study and 
duration of participants 
involvement in the study related 
to the addition of the LTE to the 
protocol 
1 Protocol Summary 
1.2 Schema  
4.1 Overall Design Figure C 
 
Period 3 schema correction- removed asterisk at 24-hour urine 
and week 24 (present in Amend. 5) as 24-hour urines are 
collected at all visits noted in schema 
Added the schema for LTE 
Correction for Period 3 schema 
to align 24-hour urine collection 
at all visits noted. 
Addition of the LTE to the list of 
schemata  
1 Protocol Summary 
1.3 Table C 
Added DXA scan for Week 24 NIH CC visit.  
Included the definition to the list of abbreviation under the 
table  
Table C: Added missing definition for C-telopeptide (CTx) and 
procollagen type 1 N-propeptide (P1NP) in the list of 
abbreviation under the table. 
Added telephone contact (NIH PI/Study Staff) under the FU 
outpatient labs 7±2 days column and associated Footnote 2: 
follow-up visits and instructions for testing changed added for 
participants who opt to leave the study after Period 3 and not 
continue participate in the LTE portion of the study. 
 
Table C Footnote 3: added unscheduled visits for laboratory 
evaluation following dose adjustment  
 
Table C Footnote 14: added 24-hr urine to be collected 30 
days after CLTX-305 (encaleret) withdrawal if ET prior to 
Period 3 completion or chose not to enter LTE 
 
Table C footnote 15: Week 24 study drug dispensing is only 
for participants who continue into the LTE; If a participant is 
Added DXA to the list of 
assessments to be done at week 
24, for continued safety 
monitoring. Added FU telephone 
contact and safety labs on days 
7± 2 after week 24 assessment 
visits and assessment for 
participants who opt not to 
continue in LTE after Period 3. 
Added steps in consideration to 
study drug dispensation for those 
participants who do not elect to 
go into LTE or unable to move to 
LTE immediately. Added 
laboratory evaluation following 
dose adjustment to the 
unscheduled visits 

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Section No./Title 
Changes  
Rationale 
not immediately continuing into the LTE, no drug will be 
dispensed. 
1.3 Table D 
Added Schedule of Activities (SOA) for LTE; relabeled 
previous tables D1 thru G to E thru L 
Added SOA for addition of the 
LTE to the protocol and relabeled 
other tables to provide further 
clarity  
1 Protocol Summary 
1.3.1 Pharmacokinetic and 
Pharmacodynamic -Table E 
Footnote number 1: removed superscript 1 corresponding to 
table footnote 1, in the row for Timed Interval Urine 
Collection,  
Correction 
2 Introduction- 
2.1 Study Rationale 
Added rationale for Periods 1, 2, 3 in this section in addition 
to the information in section 4.2  
Added rationale for the LTE 
Addition of rationale for the 
Periods 1 through 3 in this 
pertinent section 
Added the rationale for addition 
of LTE to the protocol 
 
2 Introduction 
2.2.1 Pharmacokinetics and 
Product Metabolism 
 
Added information on CLTX-305 (encaleret) dosing tablets: 
The 10 and 30 mg dosage strengths are round tablet 
presentations; the 60 mg dosage strength can be round or a 
modified oval tablet presentation.  
Updated information related to CLTX-305 (encaleret) half-life 
to provide clarity: The elimination half-life (t1/2) is 
approximately 11-14 hours at steady state (14 days).  
Updated information to provide 
clarity 
4 Study Design 
4.1 Overall Design 
Added the following language as last sentence to Period 3: 
Participants are considered to have completed the study once 
they complete 24 weeks of Period 3 and the safety follow-up 
visit. 
Added the following language to include LTE:  
It will consist of two inpatient periods of dose initiation, 
escalation and steady-state adjustment (Periods 1 and 2), an 
Clarification regarding 
participant status if participant 
elects not to participate in LTE 
Clarification, and addition of 
language/instructions related to 
the LTE in the protocol  

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Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
Changes  
Rationale 
outpatient dose stabilization and maintenance period including 
NIH clinical visits (Period 3), and a Long-term Extension 
(LTE).  
The LTE is designed to obtain additional safety data and 
evaluate durability of efficacy for CLTX-305 (encaleret). The 
LTE also allows for continued treatment of enrolled 
participants with CLTX-305 (encaleret). Participants who 
elect to continue in LTE will receive CLTX-305 (encaleret) 
for an additional period of approximately 25 months 
(approximately 2 years) or until they have access to CLTX-
305 (encaleret) via prescription, whichever occurs first. 
 
During the initial outpatient period (Period 3), participants 
will undergo additional individualized dose titration as 
necessary in response to safety data and the results of key 
efficacy measures. Participants who complete Period 3 (up to 
Week 24) and who elect to continue in the LTE will receive 
CLTX-305 (encaleret) for an additional period of 
approximately 25 months (approximately 2 years) or until 
they have access to CLTX-305 (encaleret) via prescription, 
whichever occurs first. 
4 Study Design 
4.1 Overall Design,    
Figure A and Figure D 
Figure A: added LTE after Period 3 
Figure D: Added a separate schema for the LTE 
Updated Period 2 dosing as follows:  
The initial dose, dose level 1 (DL1) will be administered for 
approximately 2 days (48 hours) with cCa monitoring. 
Participants will undergo CLTX-305 (encaleret) dose up- or 
down-titration depending on cCa levels, with a potential 
increase in dose if cCa remains below the lower limit of 
For addition of the LTE to the 
protocol and to the Overall Study 
Design Schema and a separate 
schema for LTE. 
Clarification to Period 2 CLTX-
305 (encaleret) dosing. 
Clarification of calcium 
supplementation in Period 3 

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Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
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Rationale 
normal and potential decrease in dose if cCa is greater than or 
equal to the upper limit of normal. 
Period 3 language on oral calcium supplements updated:  
Participants may receive oral calcium supplements as directed 
by the investigative site if they are not able to achieve a 
minimum of 1000 mg per day of dietary calcium intake.  
Added the following language as last sentence for Period 3: 
Participants are considered to have completed the study once 
they complete 24 weeks of Period 3 and the safety follow-up 
visit. 
Added Long-term Extension (LTE) description related to dose 
determination, instructions related to the supplement intake, 
and end of LTE planning if prescription encaleret is not 
available is added as two separate paragraphs at the end of this 
section  
Clarification regarding 
participant status if participant 
elects not to participate in LTE 
4 Study Design  
4.3 Justification for Dose 
Language related to the LTE is added as the last two 
paragraphs in this section 
For addition of the LTE to the 
protocol 
5 Study Population 
5.2 Exclusion Criteria 
Exclusion criteria #11 updated from condum use until the end 
of Period 3 to the end of study participation 
Updated to account for continued 
condum use if participating in 
LTE 
5 Study Population 
5.6 Strategies for 
Recruitment and Retention 
Updated information related to the number of participants 
identified to date (at the time of the protocol Amendment 6) 
Compensation update related to the LTE portion of the study 
For addition of the LTE to the 
protocol 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Confidential 
 
Section No./Title 
Changes  
Rationale 
5 Study Population 
5.6.2 Compensation 
Updated reference to NIH policy from “NIH Policy OHSRP 
SOP13, Appendix A” to “NIH HRPP policy 3014-302 Subject 
Recruitment and Compensation” 
Updated to reference current NIH 
HRPP policy 
6 Study Intervention 
6.1 Study Intervention(s) 
Administration 
Added language related to LTE: During LTE participants who 
have completed Period 3 will continue taking CLTX-305 
(encaleret) BID with water as an outpatient as described in 
Section 8.2.4 
For addition of the LTE to the 
protocol  
6 Study Intervention 
6.1.2 Dosing and 
Administration 
6.1.9 Drug administration 
Updated the language in both sections to indicate the timing 
of the meals in association with the CLTX-305 (encaleret) 
administration is a recommendation rather than a requirement.  
Updated to allow flexibility for 
mealtime in association with the 
CLTX-305 (encaleret) 
administration   
6 Study Intervention 
6.1.4 Period 2 (BID Dosing) 
– Cohorts 1 and 2 
6.1.5 Period 3 (Cohort 1 and 
Cohort 2) – Outpatient 
Dosing 
6.1.6 Long-term Extension 
(Cohort 1 and Cohort 2)- 
Outpatient Dosing 
Updated Period 2 dosing as follows:  
In Period 2 all participants will initiate CLTX-305 (encaleret) 
BID dosing given within 30 minutes prior to breakfast and 
dinner on Days 1 and 2. cCa concentrations will be monitored 
frequently throughout Period 2, and CLTX-305 (encaleret) 
doses will be up- or down-titrated as needed to target normal 
cCa concentrations. 
Updated Period 3 Outpatient Dosing, last two sentence to: 
Titration will be conducted by the NIH investigators at 
scheduled or unscheduled telephone contact visits based on 
review of outpatient chemistry results for cCa, Mg, 
phosphorous at NIH CC visits (approximately every 8 weeks) 
based on assessment of both blood and urine calcium results 
as described, with the goal of optimizing the CLTX-305 
(encaleret) dose without calcitriol, targeting normal cCa and 
phosphorus concentrations, avoiding symptoms of hypo- or 
Clarification on Period 2 and 
Period 3 CLTX-305 (encaleret) 
dosing and addition of the LTE to 
the protocol 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
Changes  
Rationale 
hypercalcemia, and minimizing the extent of hypercalciuria. 
Oral calcium supplementation may be used as needed on top 
of a minimum daily intake of at least 1000 mg. 
Added new paragraph with related LTE: 
In the Long-term Extension (LTE), participants will continue 
CLTX-305 (encaleret) per the dosing regimen established in 
the maintenance phase of Period 3. Telephone contacts along 
with outpatient laboratory assessments will be performed 
every 6 months starting at Month 3 with NIH CC visits 
occurring every 6 months starting at Month 6. CLTX-305 
(encaleret) doses may be titrated as needed based on 
assessment of both blood and urine calcium results as 
described, with the goal of optimizing the CLTX-305 
(encaleret) dose without calcitriol, targeting low normal cCa 
concentrations, avoiding symptoms of hypo- or 
hypercalcemia, and minimizing the extent of hypercalciuria. 
Oral calcium supplementation may be used as needed on top 
of a minimum daily intake of at least 1000 mg. 
6 Study Intervention 
6.1.7 Dose Limiting Toxicity 
Updated to reflect Periods 1 and 2 CLTX-305 (encaleret) dose 
adjustments in the setting of cCa > 10 mg/dL: 
In Summary, participants who achieve a post-dose cCa > 10-
10.5 mg/dL (in Period 1) and cCa > 10 mg/dL (in Period 2) 
during the dose escalation will not proceed to higher CLTX-
305 (encaleret) doses. Participants with cCa values between 
10-10.5 mg/dL during dose escalation in Period 1, will have 
their doses increased by 30 mg only. Participants who achieve 
cCa > 10-10.5 mg/dL in Period 1 and >10 mg/dL in Period 2 
Updated to reflect CLTX-305 
(encaleret) dose adjustments in 
the setting of increased cCa 
levels 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
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Rationale 
will have their dose maintained or reduced and undergo final 
frequent sampling as appropriate. 
8 Study Assessments and 
Procedures  
8.2.2 Period 2 (BID Dosing) 
– Cohorts 1 and 2 
Cohort 1 dosing language updated to reflect dosing experience 
from Periods 2 and 3:  
The first 7 participants who have completed CLTX-305-201 
Period 2 and entered into Period 3 have had a wide range of 
CLTX-305 (encaleret) dose requirements from 10 mg once 
daily to 180 mg BID suggesting that encaleret dosing is highly 
individualized. As a result, all remaining participants in 
Period 2 will receive an initial encaleret 90 mg BID dose for 
at least 3-4 doses for evaluation of safety, tolerability and the 
ability to modulate cCa levels. The encaleret dose will be up- 
or down-titrated as needed to maintain cCa levels below 10 
mg/dL and blood phosphorus levels above the lower limit of 
normal. Dosing will be adjusted in 10, 30, or 60 mg 
increments based on the available encaleret tablet strengths. A 
frequent sampling test day with additional serial blood and 
urine sampling to assess 24-hour PK/PD profiles will be 
performed on Day 5. 
If, at any time, the CLTX-305 (encaleret) dose is associated 
with a cCa > 10 mg/dL, then the dose should be reduced to a 
lower dose level. 
Clarified that Figure F is considered an example of how 
encaleret dosing may be adjusted.  
Cohort 2 dosing language updated to reflect dosing experience 
from Periods 2 and 3:  
CLTX-305 (encaleret) dosing 
updated to reflect experience 
from participants who have 
completed Period 2 and continue 
into Period 3 
 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
Changes  
Rationale 
Cohort 2 will commence after Cohort 1 has completed Period 
1 and the PD dose responses and safety have been reviewed. 
Participants will receive an initial encaleret 90 mg BID dose 
for at least 3-4 doses for evaluation of safety, tolerability and 
the ability to modulate cCa levels. The encaleret dose will be 
up- or down-titrated as needed to maintain cCa levels below 
10 mg/dL and blood phosphorus levels above the lower limit 
of normal. Dosing will be adjusted in 10, 30, or 60 mg 
increments based on the available encaleret tablet strengths. 
8 Study Assessments and 
Procedures  
8.2.3 Period 3 (Cohort 1 and 
Cohort 2) – Outpatient 
Dosing 
Added phosphorus to the following sentence: 
Outpatient titration will be conducted by the NIH 
investigators with the goal of optimizing the CLTX-305 
(encaleret) dose without calcitriol, targeting normal cCa and 
phosphorus concentrations while minimizing the need for 
calcium supplements, avoiding symptoms of hypo- or 
hypercalcemia, and minimizing the extent of hypercalciuria. 
Added sentence regarding CLTX-305 (encaleret) dosing 
consideration if blood cCa is > 10.5 mg/dL:  
If blood cCa levels are > 10.5 mg/dL, the NIH investigators 
can consider holding the CLTX-305 (encaleret) dose and 
restarting CLTX-305 (encaleret) at a lower dose after blood 
cCa has decreased to < 10 mg/dL. 
Added the following language to second paragraph, last 
sentence: 
Adding phosphorus keeps 
sentence consistent with section 
6.1.5 
For addition of guidance on 
CLTX-305 (encaleret) dosing 
should blood cCa be > 10.5 
mg/dL; Clarification regarding 
participant status if participant 
elects not to participate in LTE 
Addition of guidance if 
participants complete week 24 
prior to LTE being in place 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Confidential 
 
Section No./Title 
Changes  
Rationale 
Participants are considered to have completed the study once 
they complete 24 weeks of Period 3 and the safety follow-up 
visit. 
Added guidance language for participants should they reach 
week 24 prior to LTE being in place:  
If a participant reaches week 24 prior to the LTE being in 
place, the participant can discontinue CLTX-305 (encaleret) 
and restart calcitriol and/or calcium supplements until the 
LTE is implemented. Upon entry into the LTE, the participant 
will be reconsented to and may restart encaleret at the 
previous therapeutic dose determined in Period 3. 
8 Study Assessments and 
Procedures  
8.2.4 Long-term Extension 
Paragraph added related to language for the LTE: Describing 
visit timing, visit procedures  
For addition of the LTE to the 
protocol and the related visit 
timing and procedures  
8 Study Assessment and 
Procedures 
8.3.1 Pharmacokinetic and 
Pharmacodynamic Blood 
Sampling 
 
 
Clarifying text added to indicate PK analysis is done by the 
Sponsor contracted CRO/service provider 
Clarification related to 
contracting responsibility and 
management for the CRO/service 
provider performing the PK 
analysis 
8 Study Assessment and 
Procedures 
8.4.5 Dual-energy X-Ray 
Absorptiometry (DXA) 
8.4.6 Renal Ultrasound 
 
Added/updated/corrected procedure for Period 3 and LTE via 
the first paragraph of this section Period 3:  
-Bone densitometry of the spine, hip, distal radius, and total 
body will be performed by DXA at Screening per the 
Schedule of Activities Section 1.3, at Week 24 during Period 
3, at Month 12 during LTE, and the last NIH CC visit. 
Added, updated and corrected 
this section to clarify and include 
Period 3 DXA and add this 
assessment to the LTE. Added a 
separate procedure section 
related to the Renal Ultrasound  

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Confidential 
 
Section No./Title 
Changes  
Rationale 
-Added the amount of effective dose as 4 millirem 
8.4.6- added a paragraph related to the timing or Renal 
Ultrasound procedure and exposure information  
8 Study Assessment and 
Procedures 
8.5.6 Serious Adverse 
Events 
8.5.7 Events of Special 
Interest 
Sentence added: 
All SAEs (except deaths due to progressive disease) will be 
reported to the NIDCR Office of the Clinical Director no later 
than 7 days after the PI first learns of the event. 
In “Clinical Evaluation and Treatment of Hypocalcemia”, 
corrected “EKG” to “ECG” 
Added NIH process requirement 
Missed correction in previous 
revision 
8 Study Assessment and 
Procedures 
8.6.2 Unanticipated Problem 
Reporting (UPs) 
Added ‘the Sponsor’ to the end of the first paragraph for 
reporting of (UPs)- missed during the previous protocol 
revisions  
Clarification- Adding Sponsor to 
receive reports related to UPs as 
the IND holder accountable for 
FDA reporting as required and 
applicable 
9 Statistical Considerations 
9.6 Safety Analyses 
Corrected last sentence to: 
An AE that occurs more than 30 ± 7 days after the last dose of 
CLTX-305 (encaleret) will not be counted as a TEAE. 
Missed correction in previous 
revision 
10 Regulatory and 
Operational Considerations 
Added clarifying language for reporting to the 
 
 
Clarifying Calcilytix’s responsibilities and regulatory 
accountabilities as the Sponsor.  
Clarifying roles within the 
Sponsor whom to receive report 
and responsible and accountable 
for on the Sponsor side for the 
study 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Confidential 
 
Section No./Title 
Changes  
Rationale 
10.1 Informed Consent 
Process 
Added guidance language for informed consent process 
should participant reach week 24 prior to LTE being in place:  
If a participant reaches week 24 of Period 3 prior to the LTE 
being in place, upon entry into the LTE, the participant will be 
reconsented to and may restart CLTX-305 (encaleret) at the 
previous therapeutic dose determined in Period 3. 
Addition of consenting guidance 
if participants complete week 24 
prior to LTE being in place 
Section No./Title 
Amendment 7: Date 12 November 2021 
Rationale 
SPONSOR AGREEMENT-
page 
Edited language: 
Added: approval, to indicate Sponsor’s related language for 
Medical Director’s approval of the protocol is reflected 
Removed: I agree to comply with the International Council on 
Harmonisation (ICH) Tripartite Guideline on Good Clinical 
Practice (GCP) and applicable Food and Drug Administration 
(FDA) regulations/guidelines set forth in 21 CFR Parts 11, 50, 
54, 56, and 312 and all locally applicable laws. 
Adjustment of text to clarify 
Sponor’s role in protocol 
approval and documentation of 
the approval 
1 Protocol Summary  
1.2 Schema, Overall Design 
 
Added: Cohort 1 to Cohort 2 before the arrow for LTE to 
reflect that Cohort 1& 2 can participate in LTE  
Removed- Ph3 related text from the LTE text box 
Corrections on the overall study 
schema 
1 Protocol Summary  
1.3 Schedule of Activities, 
Table D Long-term 
Extension Schedule of 
Activities  
Removed – “Timed Interval” for urine collection.  
Added – “Creatine Kinase = CK” to the Abbreviations in the 
footnotes and to list of Safety and Drug Monitoring Labs in 
footnote 8  
Clarifications of urine and blood 
collections during LTE.  

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
Changes  
Rationale 
1 Protocol Summary  
1.3.1 Pharmacokinetic, 
Pharmacodynamic, and 
Urine Sampling Times 
Table E 
Added: Footnote 2 under table “24 hour timepoint only 
collected in Period 3” 
Further clarifies timepoint for 24 
hour sample collection 
6 Study Information 
6.1 Study Intervention(s) 
Administration 
6.1.1 Study Intervention 
Description 
8 Study Assessments and 
Procedures 
8.2.3 Period 3 (Cohort 1 and 
Cohort 2)-Outpatient dosing 
Updated study intervention description to match current IB, 
and adding 5mg dosage 
Added- If the 5mg tablet is not available for use, then the 10 
mg tablets may be split according to the related specifications 
indicated in the Pharmacy manual provided by the Sponsor. 
No other dose strength may be split. 
Added- If the 10 mg tablet needs to be split, the participant 
should cut one 10 mg encaleret tablet each day and take half 
of the tablet in the morning and the other half of the split 
tablet in the evening, assuring that the participant receives a 
full 10 mg dose per day. Participant should follow the 
manufacturer instructions for use included with the pill cutter. 
In the event that half of the split 10 mg tablet is lost, the 
participant should cut a new tablet in half for the evening dose 
and discard the remaining half. The participant should start 
with a new 10 mg tablet the following morning.   
Allowance for splitting 10 mg 
tablets only to provide provisions 
for 5 mg dosing with instructions 
for administration and related 
timing  

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
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Rationale 
6 Study Information 
6.1.5 Period 3 (Cohort 1 and 
Cohort 2)-Outpatient Dosing 
6.1.6 Long-term extension 
(Cohort 1 and Cohort 2)- 
Outpatient Dosing 
8 Study Assessments and 
Procedures  
8.2.3 Period 3 (Cohort 1 and 
Cohort 2)- Outpatient 
Dosing 
8.2.4 Long-term Extension 
(LTE) 
8.5.7 Events of Special 
Interest 
Addition of Oral Calcium 
Supplements and/or 
Calcitriol 
Added ‘dietary’ to following statements in multiple sections 
of the protocol:  
Oral calcium supplementation may be used as needed on top 
of a minimum dietary intake of at least 1000 mg daily. 
Since all participants will be receiving at least 1000 mg 
dietary calcium per day throughout the trial, additional 
supplemental oral calcium in the range of 1,000–2,000 mg 
additional supplement may be given as required with close 
follow-up of cCa. 
Clarification related to use of 
dietary calcium   
Section No./Title 
Amendment 8: 16 August 2022 
Rationale 
Title Page 
Key Sponsor Contacts 
Removed 
 
Personnel has departed from 
Calcilytix 
1 Protocol Summary 
1.1 Synopsis 
Changed “Study Duration” to “Primary Study Duration” 
 
Changed paragraph: 
“Estimated time from when the study opens to enrollment 
until completion or data analysis is approximately 41 months”  
To: 
“Estimated time from when the study opens to enrollment 
until completion of Period 3 is approximately 16 months.” 
 
 
Differentiate the core study from 
the Long-term extension and 
include the transition to the 
CLTX-305-302/CALIBRATE 
Phase 3 Long-term extension 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Confidential 
 
Section No./Title 
Changes  
Rationale 
Changed paragraph: 
“Total duration of study participation, including Periods 1, 2, 
and 3, will be approximately 12 months for each participant, 
including up to 60 days between the screening visit and study 
drug initiation. Participants that continue to meet study 
eligibility criteria after Period 3 may continue in the Long-
term Extension (LTE) for approximately 25 additional 
months” 
To: 
“Total maximum duration of study participation, including 
Periods 1, 2, and 3, will be approximately 16 months for each 
participant, which includes up to 60 days between the 
screening visit and study drug initiation and up to 16 weeks 
between Periods 1 and 2. Participants who elect to continue in 
LTE will receive CLTX-305 (encaleret) for an additional 
period of time, up to 25 months (approximately 2 years) or 
until they transition to the CLTX-305-302/CALIBRATE 
Phase 3 LTE, whichever occurs first.” 
1 Protocol Summary 
1.2 Synopsis: Overall Study 
Design 
Changed the LTE box from “(24 months or until encaleret 
approval)” to “(Up to 24 months, or until transition to Phase 
3)” 
Capture the transition planning to 
the CLTX-305-
302/CALIBRATE Phase 3 Long-
term extension 
1.3 Schedule of Activities 
(SOA) 
Table D Long-term 
Extension Schedule of 
Activities 
Changed Days (windows) of NIH CC EoT/ET from “± 7” to 
“+30”; 
 
Edited footnote 1 from: 
“If participant discontinues from the study early (ET) or 
withdraws from taking CLTX-305 (encaleret) (EoT), before 
completing LTE per protocol, participant will be asked to 
return to the NIH CC as soon as possible for the ET/EoT visit 
assessments and return the unused CLTX-305 (encaleret). 
Capture the transition planning to 
the CLTX-305-
302/CALIBRATE Phase 3 Long-
term extension 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
Page 124 
 
Confidential 
 
Section No./Title 
Changes  
Rationale 
Participant should revert to their outpatient regimen of oral 
calcium and active vitamin D.” 
To: 
“If participant discontinues from the study early (ET) or 
withdraws from taking CLTX-305 (encaleret) (EoT), before 
completing LTE per protocol, participant will be asked to 
return to the NIH CC within 30 days following the last dose 
for the ET/EoT visit assessments and return the unused 
CLTX-305 (encaleret). Participant should resume oral calcium 
and active vitamin D under the supervision of the study team 
while the encaleret is being safely discontinued. Follow-up 
labs should be performed per this Schedule of Assessments.” 
 
Edited footnote 2 from: 
“Participants who complete the LTE or withdraw from taking 
CLTX-305 (encaleret) (EoT) before completing LTE per 
protocol will obtain the following outpatient laboratory 
assessments after the last dose of CLTX-305 (encaleret) and 
after re-starting their prior regimen of oral calcium and active 
vitamin D: blood Cr, Ca, Alb, Mg, iPTH, PO4. Follow-up 
(FU) call should occur within 3-5 days to review the lab 
results and receive guidance on clinical management of their 
ADH1 as participants transition to prior standard of care.”  
To: 
“Participants who withdraw from taking CLTX-305 
(encaleret) (EoT) before transitioning to the CLTX-305-
302/CALIBRATE LTE per protocol will obtain the following 
outpatient laboratory assessments after the last dose of CLTX-
305 (encaleret) and after re-starting their prior regimen of oral 
calcium and active vitamin D: blood Cr, Ca, Alb, Mg, iPTH, 
PO4. Follow-up (FU) call should occur within 3-5 days to 
review the lab results and receive guidance on clinical 

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Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
Changes  
Rationale 
management of their ADH1 as participants transition to prior 
standard of care.” 
 
Added “HIV, viral hepatitis panel should be repeated within 3 
months prior to transition to CLTX-305-302/CALIBRATE.” 
To footnote 8. 
 
Added new footnote 13: “When participant transitions to 
CLTX-305-302/CALIBRATE, participant will be asked to 
return to the NIH CC to complete the ET/EoT visit 
assessments, return the unused CLTX-305 (encaleret), and 
complete the screening assessments for the CLTX-305-
302/CALIBRATE Phase 3 study. Follow-up labs will not be 
needed.” 
2 Introduction 
2.1 Study Rationale 
Changed paragraphs: 
“The LTE is designed to obtain additional safety data for 
CLTX-305 (encaleret). Participants who elect to continue in 
LTE will receive CLTX-305 (encaleret) for an additional 
period of approximately 25 months (approximately 2 years) or 
until they have access to CLTX-305 (encaleret) via 
prescription, whichever occurs first.  
  
If at the end of the LTE (duration of about 25 months, or 
approximately 2 years) prescription encaleret is not available, 
participants will be placed back on the conventional therapy 
after the follow-up assessments are completed (see Section 1.3 
Table D).” 
To: 
“The LTE is designed to obtain additional safety data for 
CLTX-305 (encaleret). Participants who elect to continue in 
LTE will receive CLTX-305 (encaleret) for an additional 
period of time, up to 25 months (approximately 2 years) or 
Capture the transition planning to 
the CLTX-305-
302/CALIBRATE Phase 3 Long-
term extension 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
Page 126 
 
Confidential 
 
Section No./Title 
Changes  
Rationale 
until they transition to the CLTX-305-302/CALIBRATE 
Phase 3 LTE, whichever occurs first. 
 
At any point during the LTE, and before transition to the 
CLTX-305-302/CALIBRATE Phase 3 LTE, participants can 
choose to stop participation and be placed back on the 
conventional therapy. Follow-up assessments should be 
completed per Schedule of Assessments (see Section 1.3 
Table D).” 
2.3.1 Known Potential Risks 
Added Paragraph: 
“The potential for skin phototoxicity in humans is expected to 
be minimal based on the tissue distribution in rats and 
estimated human dosage, but participants may be at increased 
risk to natural or artificial sunlight (tanning beds or ultraviolet 
A/B light (UVA/B) treatment). Participants at increased risk 
to UV injury are encouraged to minimize or avoid exposure to 
natural or artificial sunlight (tanning beds or UVA/B 
treatment), wear sun-protective clothing, and use sunscreen 
that strongly absorbs ultraviolet A light (UVA).” 
 
Changed Paragraph: 
“In the dose-escalating and dose-finding components of 
Periods 1, 2 and 3, participants may experience fluctuations in 
their blood calcium levels including the potential for 
hypocalcemia and/or hypercalcemia. The long-term risk of 
such fluctuations with CLTX-305 (encaleret) are not expected 
to be larger than the risk of current therapy however such 
fluctuations may be more frequent during the initial dose-
escalating/dose finding portions of the clinical study. The 
clinical study is designed to minimize the risk of untoward 
fluctuations in blood calcium and related serum chemistries: 
During the dose-finding Periods 1 and 2, participants will be 
Adding phototoxicity and 
hypophosphatemia as a potential 
known risks 

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supervised with frequent monitoring of blood calcium levels 
multiple times per day and may receive treatment for 
hypocalcemia or hypercalcemia as required while effective 
doses of CLTX-305 (encaleret) are being identified. Each 
participant is assessed for evidence of an individualized 
effective dose of CLTX-305 (encaleret) during the in-house 
periods before entering outpatient Period 3. During Period 3 
participants continue a combination of their oral calcium 
supplements and individualized starting dose of CLTX-305 
(encaleret) and will undergo at least weekly re-assessment and 
dose-titration based on outpatient laboratory monitoring 
results and telephone contact visits with the investigative site 
staff. The outpatient approach to dose and regimen 
modification is similar to the current practice for optimizing 
conventional treatment with oral calcium and active vitamin 
D.” 
To: 
“In the dose-escalating and dose-finding components of 
Periods 1, 2 and 3, participants may experience fluctuations in 
their blood calcium and phosphate levels including the 
potential for hypocalcemia, hypercalcemia, and/or 
hypophosphatemia. The long-term risk of such fluctuations 
with CLTX-305 (encaleret) are not expected to be larger than 
the risk of current therapy however such fluctuations may be 
more frequent during the initial dose-escalating/dose finding 
portions of the clinical study. The clinical study is designed to 
minimize the risk of untoward fluctuations in blood calcium, 
phosphate and related serum chemistries: During the dose-
finding Periods 1 and 2, participants will be supervised with 
frequent monitoring of blood calcium and phosphate levels 
multiple times per day and may receive treatment for 
hypocalcemia, hypercalcemia, or hypophosphatemia as 

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required while effective doses of CLTX-305 (encaleret) are 
being identified. Each participant is assessed for evidence of 
an individualized effective dose of CLTX-305 (encaleret) 
during the in-house periods before entering outpatient Period 
3. During Period 3 participants continue a combination of 
their oral calcium supplements and individualized starting 
dose of CLTX-305 (encaleret) and will undergo at least 
weekly re-assessment and dose-titration based on outpatient 
laboratory monitoring results and telephone contact visits with 
the investigative site staff. The outpatient approach to dose 
and regimen modification is similar to the current practice for 
optimizing conventional treatment with oral calcium and 
active vitamin D.” 
 
Changed paragraph: 
“Based on the totality of the evidence acquired to date, no 
other organ-specific or adverse safety signals of potential 
clinical concern have been identified. Clinical trials in the new 
target population of patients with ADH1 will closely evaluate 
dose-related effects on calcium homeostasis and otherwise 
employ routine safety monitoring (For details on CLTX-305 
(encaleret) safety data, see IB Section 5.3).” 
To: 
“Based on the totality of the evidence acquired to date, no 
other organ-specific or adverse safety signals of potential 
clinical concern have been identified. Clinical trials in the new 
target population of patients with ADH1 will closely evaluate 
dose-related effects on calcium and phosphate homeostasis 
and otherwise employ routine safety monitoring (For details 
on CLTX-305 (encaleret) safety data, see IB Section 5.3).” 

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4 Study Design 
4.1 Overall Design 
Changed paragraph: 
“The LTE is designed to obtain additional safety data and 
evaluate durability of efficacy for CLTX-305 (encaleret). The 
LTE also allows for continued treatment of enrolled 
participants with CLTX-305 (encaleret). Participants who 
elect to continue in LTE will receive CLTX-305 (encaleret) 
for an additional period of approximately 25 months 
(approximately 2 years) or until they have access to CLTX-
305 (encaleret) via prescription, whichever occurs first.” 
To: 
“The LTE is designed to obtain additional safety data and 
evaluate durability of efficacy for CLTX-305 (encaleret). The 
LTE also allows for continued treatment of enrolled 
participants with CLTX-305 (encaleret). Participants who 
elect to continue in LTE will receive CLTX-305 (encaleret) 
for an additional period of time, up to 25 months 
(approximately 2 years) or until they transition to the CLTX-
305-302/CALIBRATE Phase 3 LTE, whichever occurs first.” 
 
Changed paragraph: 
“Participants from both cohorts who complete Period 2 will be 
eligible to enter Period 3. Outpatient dosing with CLTX-305 
(encaleret) will be determined from review of individual dose-
response data from Periods 1 and/or 2 based on identifying 
well-tolerated BID doses with preliminary evidence for 
efficacy. During the initial outpatient period (Period 3), 
participants will undergo additional individualized dose 
titration as necessary in response to safety data and the results 
of key efficacy measures. Participants who complete Period 3 
(up to Week 24) and who elect to continue in the LTE will 
receive CLTX-305 (encaleret) for an additional period of 
approximately 25 months (approximately 2 years) or until 
Capture the transition planning to 
the CLTX-305-
302/CALIBRATE Phase 3 Long-
term extension 

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Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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they have access to CLTX-305 (encaleret) via prescription, 
whichever occurs first.” 
To: 
“Participants from both cohorts who complete Period 2 will be 
eligible to enter Period 3. Outpatient dosing with CLTX-305 
(encaleret) will be determined from review of individual dose-
response data from Periods 1 and/or 2 based on identifying 
well-tolerated BID doses with preliminary evidence for 
efficacy. During the initial outpatient period (Period 3), 
participants will undergo additional individualized dose 
titration as necessary in response to safety data and the results 
of key efficacy measures. Participants who complete Period 3 
(up to Week 24) and who elect to continue in the LTE will 
receive CLTX-305 (encaleret) for additional period of time, 
up to 25 months (approximately 2 years) or until they 
transition to the CLTX-305-302/CALIBRATE Phase 3 LTE, 
whichever occurs first.” 
 
Figure A Study Overview Schematic 
Changed “Long Term Extension” box “Duration” from “24 
months” to “Up to 24 months or until transition to Phase 3” 
  
Changed paragraphs: 
Long-term Extension (LTE) - Outpatient dosing with 
CLTX-305 (encaleret) will continue for approximately 25 
months (approximately 2 years) after completion of the Week 
24 visit in Period 3. Participants completing Period 3 will 
continue to receive clinical supplies of CLTX-305 (encaleret) 
at the same BID dose based on their tolerance and response to 
BID dosing during CLTX-305 (encaleret) dosing in Period 3. 
Participants will not take calcitriol but may take calcium 
supplementation as needed to achieve a minimum daily intake 

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of 1000 mg. Participants may receive oral calcium 
supplements as directed by the investigative site if they are 
not able to achieve a minimum of 1000 mg per day of dietary 
calcium intake. A final follow-up safety visit in the LTE will 
occur 30 ± 7 days after the last dose of CLTX-305 (encaleret) 
is taken as part of this protocol.  
 
If at the end of the LTE (duration of about 25 months, or 
approximately 2 years) prescription encaleret is not available, 
participants will be placed back on the conventional therapy 
after the follow-up assessments are completed (see Section 
1.3, Table D). 
To: 
“Long-term Extension (LTE) - Outpatient dosing with 
CLTX-305 (encaleret) will continue for an additional period 
of time, up to 25 months (approximately 2 years), or until they 
transition to the CLTX-305-302/CALIBRATE Phase 3 LTE, 
whichever comes first, after completion of the Week 24 visit 
in Period 3. Participants completing Period 3 will continue to 
receive clinical supplies of CLTX-305 (encaleret) at the same 
BID dose based on their tolerance and response to BID dosing 
during CLTX-305 (encaleret) dosing in Period 3. Participants 
will not take calcitriol but may take calcium supplementation 
as needed to achieve a minimum daily intake of 1000 mg. 
Participants may receive oral calcium supplements as directed 
by the investigative site if they are not able to achieve a 
minimum of 1000 mg per day of dietary calcium intake. A 
final follow-up safety visit in the LTE will occur 30 ± 7 days 
after the last dose of CLTX-305 (encaleret) is taken as part of 
this protocol. 
 

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Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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At any point during the LTE, and before transition to the 
CLTX-305-302/CALIBRATE Phase 3 LTE, participants can 
choose to stop participation and be placed back on the 
conventional therapy. Follow-up assessments should be 
completed per Schedule of Assessment (see Section 1.3 
Table D) and clinical supply of CLTX-305 (encaleret) should 
be returned to the investigative site.” 
4.3 Justification for Dose 
Changed paragraphs: 
“Participants who complete Period 3 (completing up to 25 
weeks) may enter LTE of this study and receive CLTX-305 
(encaleret) doses for an additional of approximately 25 
months (approximately 2 years). The LTE is designed to 
obtain additional safety data and to continue to provide 
enrolled participants with CLTX-305 (encaleret). Participants 
who elect to continue in LTE will receive CLTX-305 
(encaleret) for an additional period of approximately 25 
months (approximately 2 years) or until they have access to 
CLTX-305 (encaleret) via prescription, whichever occurs 
first.  
  
If at the end of the LTE (duration of about 25 months, or 
approximately 2 years) prescription encaleret is not available, 
participants will be placed back on the conventional therapy 
after the follow-up assessments are completed (see Section 1.3 
Table D).” 
To: 
“The LTE is designed to obtain additional safety data for 
CLTX-305 (encaleret). Participants who elect to continue in 
LTE will receive CLTX-305 (encaleret) for an additional 
period of time, up to 25 months (approximately 2 years) or 
until they transition to the CLTX-305-302/CALIBRATE 
Phase 3 LTE, whichever occurs first. Participants who transfer 
Capture the transition planning to 
the CLTX-305-
302/CALIBRATE Phase 3 Long-
term extension 

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Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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to the CLTX-305-302/CALIBRATE Phase 3 LTE will 
continue encaleret dosing at their prescribed dose until 
enrolled into the CLTX-305-302/CALIBRATE Phase 3 LTE.  
 
At any point during the LTE, and before transition to the 
CLTX-305-302/CALIBRATE Phase 3 LTE, participants can 
choose to stop participation and be placed back on the 
conventional. Follow-up assessments are to be completed per 
Schedule of Assessments (see Section 1.3 Table D) and 
clinical supply of CLTX-305 (encaleret) should be returned to 
the investigative site.” 
6 Study Intervention 
6.1.8 Dose Modifications 
Corrected third paragraph first sentence from: 
“For participants who develop clinical laboratory assessments 
unrelated to the dosing algorithm parameters (e.g., corrected 
calcium) indicating that further conduct of per protocol 
clinical assessments/procedures may put the participant at risk 
may have their CLTX-305 (encaleret) dosing interrupted at 
the discretion of the principal investigator.” 
To: 
“For participants who develop clinical laboratory 
abnormalities unrelated to the dosing algorithm parameters 
(e.g., corrected calcium) indicating that further conduct of per 
protocol clinical assessments/procedures may put the 
participant at risk may have their CLTX-305 (encaleret) 
dosing interrupted at the discretion of the principal 
investigator and should be captured as adverse events.” 
Correction of incorrect word 
(“laboratory assessment” to 
“laboratory abnormalities”; 
clarification to capture 
abnormalities as adverse events 
6.2.2 Formulation, 
Appearance, Packaging, and 
Labeling 
Updated first paragraph to: 
“The CLTX-305 (encaleret) will be provided as white film-
coated tablets containing the active ingredient CLTX-305 
(encaleret) provided in 5, 10, 30 and 60 mg doses.” 
Included 5mg tablet size 

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Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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6.5 Concomitant Therapy 
Added paragraph: 
“Participants being treated with nirmatrelvir/ritonavir for 
COVID-19 may decrease the encaleret dosing to once daily 
during the 5-day treatment course given that ritonavir is a 
strong CYP3A4 inhibitor. Participants may take calcium 
supplementation as needed if they experience symptoms of 
hypocalcemia during this time. After completion of the 5-day 
nirmatrelvir/ritonavir treatment course, participants may 
resume twice daily encaleret.” 
Clarify how to manage CLTX-
305 dosing when 
nirmatrelvir/ritonavir may be 
used for COVID-19 treatment in 
participants. 
7 Study Intervention 
Discontinuation and 
Participant 
Discontinuation/Withdrawal 
7.1 Discontinuation of Study 
Intervention 
Added “Participant transitions to the CLTX-305-
302/CALIBRATE Phase 3 LTE” to list of reasons 
Capture the transition planning to 
the CLTX-305-
302/CALIBRATE Phase 3 Long-
term extension 
7.2 Participant 
Discontinuation/Withdrawl 
from the Study 
Added paragraph: 
“Participants who transfer to the CLTX-305-
302/CALIBRATE Phase 3 LTE will continue encaleret dosing 
at their prescribed dose until enrolled into the CLTX-305-
302/CALIBRATE Phase 3 LTE. When a participant 
transitions to CLTX-305-302/CALIBRATE, participant will 
be asked to return to the NIH CC to complete the ET/EoT 
visit assessments, return the unused CLTX-305 (encaleret), 
and complete the screening assessments for the CLTX-305-
302/CALIBRATE Phase 3 study. Follow-up labs will not be 
needed.” 
 
Changed paragraph: 
“All participants who received CLTX-305 (encaleret) and 
terminate early from the study, regardless of cause, should 
undergo a 30-day (± 7 days) follow-up telephone call after the 
last dose of CLTX-305 (encaleret). The reason for early 
Capture the transition planning to 
the CLTX-305-
302/CALIBRATE Phase 3 Long-
term extension 

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Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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termination from the study will be reflected in the CRF. If a 
participant terminates early from the study because of an AE, 
the PI/study staff must record the AE as the reason for 
discontinuation.” 
To: 
“All participants who received CLTX-305 (encaleret) and 
terminate early from the study, regardless of cause, with 
exception of transition to the CLTX-305-302/CALIBRATE 
Phase 3 LTE, should undergo follow-up procedures according 
to Section 1.3 Table D SOA. The reason for early termination 
from the study will be reflected in the CRF. If a participant 
terminates early from the study because of an AE, the PI/study 
staff must record the AE as the reason for discontinuation.” 
 
8 Study Assessments and 
Procedures 
8.2.2 Period 2 (BID Dosing) 
– Cohorts 1 and 2 
Updated seventh paragraph to: 
“The first 7 participants who have completed CLTX-305-201 
Period 2 and entered into Period 3 have had a wide range of 
CLTX-305 (encaleret) dose requirements from 10 mg once 
daily to 180 mg BID suggesting that CLTX-305 (encaleret) 
dosing is highly individualized. As a result, all remaining 
participants in Period 2 will receive an initial CLTX-305 
(encaleret) 90 mg BID dose for at least 3-4 doses for 
evaluation of safety, tolerability and the ability to modulate 
cCa levels. The CLTX-305 (encaleret) dose will be up- or 
down-titrated as needed to maintain cCa levels below 10 
mg/dL and blood phosphorus levels above the lower limit of 
normal. Dosing will be adjusted in 5, 10, 30, or 60 mg 
increments based on the available CLTX-305 (encaleret) 
tablet strengths. A frequent sampling test day with additional 
serial blood and urine sampling to assess 24-hour PK/PD 
profiles will be performed on Day 5. For details on the PK/PD 
Included 5mg tablet size 

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timepoints during frequent sampling on Day 5 see Section 
1.3.1 specifically  Table J and Table K.” 
Updated ninth paragraph to: 
“Cohort 2 – Cohort 2 will commence after Cohort 1 has 
completed Period 1 and the PD dose responses and safety 
have been reviewed. Participants will receive an initial CLTX-
305 (encaleret) 90 mg BID dose for at least 3-4 doses for 
evaluation of safety, tolerability and the ability to modulate 
cCa levels. The CLTX-305 (encaleret) dose will be up- or 
down-titrated as needed to maintain cCa levels below 10 
mg/dL and blood phosphorus levels above the lower limit of 
normal. Dosing will be adjusted in 5, 10, 30, or 60 mg 
increments based on the available CLTX-305 (encaleret) 
tablet strengths. The total blood volume collected during 
Period 2 for Cohort 2 participants will be less than the blood 
volume limits per participant as per NIH Guidelines for Blood 
Draw Limits for Research Purposes (M95-9, June 2009). 
These volumes include the cumulative potential collection 
over an 8-week period: screening visit labs, -10-14 day labs, 
Day -1 safety labs, Period 2 inpatient week, and 4 weeks of 
outpatient labs in Period 3.” 
8.2.4 Long-term Extension 
(LTE) 
Changed second paragraph, last sentence from: 
“Participants who elect to continue in LTE will receive 
CLTX-305 (encaleret) for an additional period of 
approximately 25 months (approximately 2 years) or until 
they have access to CLTX-305 (encaleret) via prescription, 
whichever occurs first.” 
To: 
“Participants who elect to continue in LTE will receive 
CLTX-305 (encaleret) for an additional period of time, up to 
25 months (approximately 2 years) or until they transition to 
Capture the transition planning to 
the CLTX-305-
302/CALIBRATE Phase 3 Long-
term extension 

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Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
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Rationale 
the CLTX-305-302/CALIBRATE Phase 3 LTE, whichever 
occurs first.” 
 
Deleted paragraph: 
“If at the end of the LTE (duration of about 25 months, or 
approximately 2 years) prescription encaleret is not available, 
participants will be placed back on the conventional therapy 
after the follow-up assessments are completed (see Section 1.3 
Table D).” 
And replaced with: 
“At any point during the LTE, and before transition to the 
CLTX-305-302/CALIBRATE Phase 3 LTE, participants can 
choose to stop participation and be placed back on the 
conventional therapy. Follow-up assessments are to be 
completed (see Section 1.3 Table D) and clinical supply of 
CLTX-305 (encaleret) needs to be returned to the 
investigative site.” 
8.2.5 Follow-up and Early 
Termination 
Added paragraphs: 
“Participants who transfer to the CLTX-305-
302/CALIBRATE Phase 3 LTE will continue encaleret dosing 
at their prescribed dose until enrolled into the CLTX-305-
302/CALIBRATE Phase 3 LTE. When a participant 
transitions to CLTX-305-302/CALIBRATE, participant will 
be asked to return to the NIH CC to complete the ET/EoT 
visit assessments, return the unused CLTX-305 (encaleret), 
and complete the screening assessments for the CLTX-305-
302/CALIBRATE Phase 3 study. Follow-up labs will not be 
needed. 
 
Transition to CLTX-305-302/CALIBRATE Phase 3 Long 
Term Extension 
 
Capture the transition planning to 
the CLTX-305-
302/CALIBRATE Phase 3 Long-
term extension 

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Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
Changes  
Rationale 
Participants from CLTX-305-201 who meet the study 
screening eligibility criteria of the CLTX-305-
302/CALIBRATE Phase 3 study will enroll directly into the 
CLTX-305-302/CALIBRATE Phase 3 LTE. If assessments 
for 25-OH Vitamin D, eGFR, 12-lead resting ECG, viral 
hepatits panel and HIV have been completed either at the NIH 
CC or via outpatient lab within the 3 months prior to 
transitioning into the CLTX-305-302/CALIBRATE LTE, they 
do not need to be repeated for eligibility purposes. Other 
assessments performed during the CLTX-305-201 ET/EoT 
visit will be acceptable for assessment of CLTX-305-
302/CALIBRATE eligibility criteria.  
 
If a participant discontinued encaleret during the CLTX-305-
201 LTE for family planning purposes, the participant may 
enroll directly into the CLTX-305-302/CALIBRATE Phase 3 
LTE once family planning is complete if he/she meets the 
study eligibility criteria per the CLTX-305-302/CALIBRATE 
protocol and the CLTX-305-302/CALIBRATE Encaleret 
Resumption Criteria. Participants will resume encaleret as 
described in the CLTX-305-302/CALIBRATE protocol. 
 
Assessments in the CLTX-305-302/CALIBRATE Phase 3 
LTE will be conducted approximately every 3 months as 
described in CLTX-305-302/CALIBRATE protocol’s 
Schedule of Assessments. Participants who transfer to the 
CLTX-305-302/CALIBRATE LTE will receive encaleret for 
an additional period of approximately 48 months or until 
participant has access to commercial encaleret, or the Sponsor 
decides to end the study, whichever occurs first.” 
10 Regulatory and 
Operational Considerations 
Added paragraphs: 
For studies conducted at NIH 
CC, HMID (Health Information 

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10.1 Informed Consent 
Process 
 
The informed consent document will be provided as a 
physical or electronic document to the participant or consent 
designee as applicable for review prior to consenting. A 
designated study investigator will carefully explain the 
procedures and tests involved in this study, and the associated 
risks, discomfort and benefits. In order to minimize potential 
coercion, as much time as is needed to review the document 
will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask 
questions of any designated study investigator. A signed 
informed consent document will be obtained prior to any 
research activities taking place. 
The initial consent process as well as re-consent, when 
required, may take place in person or remotely (e.g., via 
telephone or other NIH approved remote platforms used in 
compliance with policy, including HRPP Policy 303) per 
discretion of the designated study investigator and with the 
agreement of the participant/consent designee(s). Whether in 
person or remote, the privacy of the subject will be 
maintained. Consenting investigators (and participant/consent 
designee, when in person) will be located in a private area 
(e.g., clinic consult room). When consent is conducted 
remotely, the participant/consent designee will be informed of 
the private nature of the discussion and will be encouraged to 
relocate to a more private setting if needed. If the consent 
process is occurring remotely, participants and investigators 
will view individual copies of the approved consent document 
on screens at their respective locations; the same screen may 
be used when both the investigator and the participant are co-
located but this is not required.  
Management Division) wants all 
CC protocols to include the 
current iMED language as all 
consent forms are to be 
transitioned to the iMED system. 

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Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Note: When required, the witness signature will be obtained 
similarly as described for the investigator and participant 
below. 
Consent will be documented with required signatures on the 
physical document (which includes the printout of an 
electronic document sent to the participant) or on the 
electronic document. The process for documenting signatures 
on an electronic document is described below. 
For electronic consent:  
The study team will confirm with the subject that they are 
comfortable using the electronic consenting before proceeding 
with obtaining consent. If not, other methods will be utilized. 
When an electronic document with a digital signature is used 
for the documentation of consent, this study will use the 
iMedConsent™ platform which is 21 CFR, Part 11 compliant 
to obtain the required signatures. During the consent process, 
subjects/LARs and investigators will view the same approved 
consent document simultaneously in their respective 
locations.  The identity of the subject will be determined by 
verifying a government issued identification card via the 
telehealth platform, prior to obtaining the signature.  
iMED consent will capture electronic signatures via the 
methods listed below: 
• Using a smartphone: participants will be registering 
their signatures using their finger. Participants will 
receive a secure link that leads them to secure “web 

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Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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pages” that will capture their electronic signatures 
using their finger. 
• Using a computer/tablet/laptop: participants will be 
registering their signatures using a computer mouse or 
their finger/stylus (for touch/stylus enabled tablets and 
computer screens). Participants will receive a secure 
link that leads them to secure “web pages” that will 
capture their electronic signatures using the 
aforementioned methods. 
Once the completed consent has been saved, it will post to 
CRIS within a few minutes. All consents completed in 
iMedConsent™ will post to both the Documents tab and the 
Consents tab in CRIS.  If the research participant has a 
FollowMyHealth™ account a copy of the completed consent 
will be posted to their account within two business days. The 
study team will provide the research participant with a printed 
copy of the signed document.  
10.4 Future Use of Stored 
Specimens and Data 
Changed paragraph: 
“All stored samples are coded and do not have personal 
identifiers. The codes for identifiers are contained in a 
participant code log that is maintained in secure research files 
at the NIH. Samples received for PK analysis by Calcilytix/or 
designee from participants consented to this protocol, will be 
destroyed after use. Additional research samples collected for 
FGF23 and mid-molecule PTH may be stored at the NIH for 
use in future studies, with the participants’ consent.” 
To: 
“All stored samples are coded and do not have personal 
identifiers. The codes for identifiers are contained in a 
participant code log that is maintained in secure research files 
Clarifying sample usage for 
future use at NIH 

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Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
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Section No./Title 
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Rationale 
at the NIH. Samples received for PK analysis by Calcilytix/or 
designee from participants consented to this protocol, may be 
destroyed or unused samples sent back to the NIH for 
additional research purposes. Additional research samples 
collected for FGF23 and mid-molecule PTH may be stored at 
the NIH for use in future studies, with the participants’ 
consent.participants’ consent.” 
10.8.3 LTE Electronic Data 
Capture 
Added new section 10.8.3 LTE Electronic Data Capture 
Capture the transition planning to 
the CLTX-305-
302/CALIBRATE Phase 3 Long-
term extension 
Section No./Title 
Amendment 9: 25 April 2023 
Rationale 
1 PROTOCOL SUMMARY 
1.3 Schedule of Activities 
(SOA) 
Table D Long-term 
Extension Schedule of 
Activities 
Footnote 13 changed from: 
“When participant transitions to CLTX-305-
302/CALIBRATE, participant will be asked to return to the 
NIH CC to complete the ET/EoT visit assessments, return the 
unused CLTX-305 (encaleret), and complete the screening 
assessments for the CLTX-305-302/CALIBRATE Phase 3 
study. Follow-up labs will not be needed.” 
To: 
“When participant transitions to CLTX-305-
302/CALIBRATE, participant will be asked to return to the 
NIH CC to return the unused CLTX-305 (encaleret), and 
complete any remaining eligibility assessments for the CLTX-
305-302/CALIBRATE Phase 3 study.”   
Reduction of assessment and 
testing required to transfer to 
Phase 3 study 
4.1 Overall Design 
Long-term Extension (LTE): First paragraph, last sentence 
changed from: 
“A final follow-up safety visit in the LTE will occur 30 ± 7 
days after the last dose of CLTX-305 (encaleret) is taken as 
part of this protocol.” 
Clarify final follow-up safety 
visit for participants not 
transitioning to the Phase 3 
study. 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
Page 143 
 
Confidential 
 
Section No./Title 
Changes  
Rationale 
To: 
“A final follow-up safety visit in the LTE will occur 30 ± 7 
days after the last dose of CLTX-305 (encaleret) is taken as 
part of this protocol for participants who withdraw from the 
study or CLTX-305 (encaleret) before transitioning to the 
CLTX-305-302/CALIBRATE LTE.” 
7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
Changed third paragraph from: 
“Participants who transfer to the CLTX-305-
302/CALIBRATE Phase 3 LTE will continue encaleret dosing 
at their prescribed dose until enrolled into the CLTX-305-
302/CALIBRATE Phase 3 LTE. When a participant 
transitions to CLTX-305-302/CALIBRATE, participant will 
be asked to return to the NIH CC to complete the ET/EoT 
visit assessments, return the unused CLTX-305 (encaleret), 
and complete the screening assessments for the CLTX-305-
302/CALIBRATE Phase 3 study. Follow-up labs will not be 
needed.” 
To: 
“Participants who transfer to the CLTX-305-
302/CALIBRATE Phase 3 LTE will continue encaleret dosing 
at their prescribed dose until enrolled into the CLTX-305-
302/CALIBRATE Phase 3 LTE. When a participant 
transitions to CLTX-305-302/CALIBRATE, participant will 
be asked to return to the NIH CC to return the unused CLTX-
305 (encaleret), and complete any remaining eligibility 
assessments for the CLTX-305-302/CALIBRATE Phase 3 
study.” 
Reduction of assessment and 
testing required to transfer to 
Phase 3 study in order to 
minimize duplicative testing for 
participants 
8.2.5 Follow-up and Early 
Termination 
Changed fourth paragraph from: 
“Participants who transfer to the CLTX-305-
302/CALIBRATE Phase 3 LTE will continue encaleret dosing 
at their prescribed dose until enrolled into the CLTX-305-
302/CALIBRATE Phase 3 LTE. When a participant 
Reduction of assessment and 
testing required to transfer to 
Phase 3 study in order to 
minimize duplicative testing for 
participants 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
Page 144 
 
Confidential 
 
Section No./Title 
Changes  
Rationale 
transitions to CLTX-305-302/CALIBRATE, participant will 
be asked to return to the NIH CC to complete the ET/EoT 
visit assessments, return the unused CLTX-305 (encaleret), 
and complete the screening assessments for the CLTX-305-
302/CALIBRATE Phase 3 study. Follow-up labs will not be 
needed.” 
To: 
“Participants who transfer to the CLTX-305-
302/CALIBRATE Phase 3 LTE will continue encaleret dosing 
at their prescribed dose until enrolled into the CLTX-305-
302/CALIBRATE Phase 3 LTE. When a participant 
transitions to CLTX-305-302/CALIBRATE, participant will 
be asked to return to the NIH CC to return the unused CLTX-
305 (encaleret), and complete any remaining eligibility 
assessments for the CLTX-305-302/CALIBRATE Phase 3 
study.” 
8.2.5 Follow-up and Early 
Termination 
Transition to CLTX-305-302/CALIBRATE Phase 3 Long 
Term Extension: Change first paragraph from: 
“Participants from CLTX-305-201 who meet the study 
screening eligibility criteria of the CLTX-305-
302/CALIBRATE Phase 3 study will enroll directly into the 
CLTX-305-302/CALIBRATE Phase 3 LTE. If assessments 
for 25-OH Vitamin D, eGFR, 12-lead resting ECG, viral 
hepatits panel and HIV have been completed either at the NIH 
CC or via outpatient lab within the 3 months prior to 
transitioning into the CLTX-305-302/CALIBRATE LTE, they 
do not need to be repeated for eligibility purposes. Other 
assessments performed during the CLTX-305-201 ET/EoT 
visit will be acceptable for assessment of CLTX-305-
302/CALIBRATE eligibility criteria.” 
To: 
Reduction of assessment and 
testing required to transfer to 
Phase 3 study in order to 
minimize duplicative testing for 
participants 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
Page 145 
 
Confidential 
 
Section No./Title 
Changes  
Rationale 
“Participants from CLTX-305-201 who meet the study 
screening eligibility criteria of the CLTX-305-
302/CALIBRATE Phase 3 study will enroll directly into the 
CLTX-305-302/CALIBRATE Phase 3 LTE. If assessments 
for 25-OH Vitamin D, eGFR, 12-lead resting ECG, viral 
hepatits panel and HIV have been completed either at the NIH 
CC or via outpatient lab within the 3 months prior to 
transitioning into the CLTX-305-302/CALIBRATE LTE, they 
do not need to be repeated for eligibility purposes. Other 
assessments performed during the final CLTX-305-201 
ET/EoT study visit will be acceptable for assessment of 
CLTX-305-302/CALIBRATE eligibility criteria. Blood β-
HCG pregnancy test can be performed at the NIH CC on the 
day of transition to CLTX-305-302/CALIBRATE Phase 3 
LTE, and an aliquot will also be sent to the central lab for the 
CLTX-305-302/CALIBRATE Phase 3 LTE.” 
8.4.5 Dual-energy X-Ray 
Absorptiometry (DXA) 
Changed first paragraph from: 
“Bone densitometry of the spine, hip, distal radius, and total 
body will be performed by DXA at Screening during Periods 
1 and 2, at Week 24 during Period 3, and at Month 12 and 
Month 24 during the LTE (see Schedule of Activities tables in 
Section 1.3).” 
To: 
“Bone densitometry of the spine, hip, distal radius, and total 
body will be performed by DXA at Screening during Periods 
1 and 2, at Week 24 during Period 3, and at Month 12 and 
Month 24 during the LTE (see Schedule of Activities tables in 
Section 1.3). If the Month 24 visit aligns with the transition to 
the CLTX-305-302/CALIBRATE Phase 3 LTE, then the 
DXA will be performed once as part of the CLTX-305-
302/CALIBRATE Phase 3 LTE.” 
Reduction of assessment and 
testing required to transfer to 
Phase 3 study 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
Page 146 
 
Confidential 
 
Section No./Title 
Changes  
Rationale 
8.4.6 Renal Ultrasound 
Changed the paragraph from: 
“Renal ultrasound will be performed at Screening during 
Periods 1 and 2, at Week 24 during Period 3, and at Month 12 
and Month 24 during LTE (see Schedule of Activities tables 
in Section 1.3).” 
To: 
“Renal ultrasound will be performed at Screening during 
Periods 1 and 2, at Week 24 during Period 3, and at Month 12 
and Month 24 during LTE (see Schedule of Activities tables 
in Section 1.3). If the Month 24 visit aligns with the transition 
to the CLTX-305-302/CALIBRATE Phase 3 LTE, then the 
renal ultrasound will be performed once as part of the CLTX-
305-302/CALIBRATE Phase 3 LTE.” 
Reduction of assessment and 
testing required to transfer to 
Phase 3 study 
8.5.6 Backup Contact 
Changed from 
 to 
 
Change in personnel at Calcilytix 
Section No./Title 
Amendment 10: 18 May 2023 
Rationale 
Throughout the document 
Corrected formatting errors and made minor updates to 
enhance readability   
Fix formatting errors and minor 
updates for clarity 
Sponsor’s Agreement Page 
Changed Sponsor Approver from 
 to  
  
Administrative change 
1 PROTOCOL SUMMARY 
1.1 Synopsis 
Corrected the Primary Endpoints, Period 3 duration to 24 
weeks 
Typographical error 
1 PROTOCOL SUMMARY 
1.3 Schedule of Activities 
(SOA) 
Table D: Long-term 
Extension SOA: Footnote #9 
 
 
 
Added footnote #9, “Blood β-HCG pregnancy test can be 
performed at the NIH CC on the day of transition to CLTX-
305-302/CALIBRATE Phase 3 LTE, and an aliquot will also 
be sent to the central lab for the CLTX-305-302/CALIBRATE 
Phase 3 LTE”  
 
Updated subsequent footnote numbers to reflect the change 
 
To align with Section 8.2.5 

CLTX-305 
 
 
Calcilytix Therapeutics, Inc. 
Protocol: CLTX-305-201- Amendment 10: 18 May 2023 NIH 20-D-0122                                              
Page 147 
 
Confidential 
 
Section No./Title 
Changes  
Rationale 
1 PROTOCOL SUMMARY 
1.3 Schedule of Activities 
(SOA) 
Table D: Long-term 
Extension SOA: Footnote 
#14 
7.2 Participant 
Discontinuation/ Withdrawal 
from the Study 
8.2.5 Follow-up and Early 
Termination  
Revised text in Table D footnote #14, Section 4.1, Section 7.2  
and Section 8.2.5 to add “Phase 3 LTE” 
 
 
For clarity and consistency only 
1 PROTOCOL SUMMARY 
1.3 Schedule of Activities 
(SOA) 
Table D: Long-term 
Extension SOA: Footnote 
#15  
Added footnote #15: “If the Month 24 visit aligns with the 
transition to the CLTX-305-302/CALIBRATE Phase 3 LTE, 
then the renal ultrasound and DXA scan will be performed 
once as part of the CLTX-305-302/CALIBRATE Phase 3 
LTE” 
To align with Section 8.4.5 and 
Section 8.4.6.