A Randomized, Controlled, Multi-Center Study to Evaluate the Safety and Efficacy of Paltusotine in Subjects With Acromegaly Treated With Long-acting Somatostatin Receptor Ligands (PATHFNDR-1)
Phase: PHASE3
Conditions: Acromegaly
Sponsor: Crinetics Pharmaceuticals Inc.

Official Title: 
A Randomized, Controlled, Multi-Center Study to Evaluate the Safety and 
Efficacy of Paltusotine in Subjects with Acromegaly Treated with Long-acting 
Somatostatin Receptor Ligands 
NCT Number: 
NCT04837040 
Document Date: 
Clinical Study Protocol  Version 5.0  06 December 2024 
 

Study code: CRN00808-09
Clinical Study Protocol
Study Sponsor: Crinetics Pharmaceuticals, Inc.
Version 5.0
Confidential
1
A Randomized, Controlled, Multi-Center Study to Evaluate the Safety and 
Efficacy of Paltusotine in Subjects With Acromegaly Treated With 
Long-Acting Somatostatin Receptor Ligands
Study Name: PATHFNDR-1: Paltusotine Acromegaly Therapy Featuring a Non-Invasive Daily 
Regimen
Protocol Number: CRN00808-09
Compound: Paltusotine
Study Phase: 3
Sponsor Name: Crinetics Pharmaceuticals, Inc.
Legal Registered Address: 6055 Lusk Blvd, San Diego, CA 92121
Regulatory Agency Identifier Number(s):
IND: 137912
EudraCT: 2020-005431-70
EU CT Number: 2024-511925-71-00
NCT: 04837040
Version 5.0 - Approval Date: 06 December 2024
Statement of Confidentiality 
The information contained in this document is considered privileged and confidential and is the 
property of Crinetics Pharmaceuticals, Inc. It is provided to you in confidence in accordance with 
the terms of your confidentiality agreement with Crinetics Pharmaceuticals, Inc. The recipient 
agrees that no information contained herein will be published or disclosed without the written 
approval of Crinetics Pharmaceuticals, Inc. This document may be disclosed to applicable 
Institutional Review Boards, or other duly authorized regulatory agency representatives as 
applicable, under the condition that confidentiality is maintained.

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
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DOCUMENT HISTORY/PROTOCOL AMENDMENT SUMMARY OF 
CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Version 5.0  
06 December 2024 
Version 4.0 
21 November 2023 
Version 3.0 
14 September 2021 
Version 2.0 
24 February 2021 
Original Protocol (Version 1.0) 
18 December 2020 
  

Study code: CRN00808-09 
Clinical Study Protocol 
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Version 5.0 
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SPONSOR SIGNATURE PAGE 
Sponsor’s Approval 
The protocol has been approved by Crinetics Pharmaceuticals, Inc. (herein, Crinetics or 
Sponsor). 
Responsible Medical Officer: 
Sponsor’s Medical Contact: 
See last page for electronic signature manifestation 
 
 
 
 
Date 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
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INVESTIGATOR’S AGREEMENT 
A Randomized, Controlled, Multi-Center Study to Evaluate the Safety and Efficacy of 
Paltusotine in Subjects with Acromegaly Treated with Long-acting Somatostatin Receptor 
Ligands 
Protocol Number: CRN00808-09 
Protocol Version: 5.0 
Protocol Date: 06 December 2024 
I have read and I understand this protocol. I will conduct this protocol as outlined herein and will 
make all reasonable efforts to complete the study within the designated time.  
I agree to conduct this trial in accordance with the Declaration of Helsinki, the International 
Council for Harmonization (ICH), Guideline for Good Clinical Practice (GCP), applicable local 
legislation including the EU Clinical Trials Regulation (CTR) (EU No 536/2014) and all 
applicable regulatory requirements. 
I will provide copies of the protocol and access to all information furnished by Crinetics 
Pharmaceuticals, Inc. to study personnel under my supervision. I will discuss material with them 
to ensure that they are fully informed about the study. 
I understand that the study may be terminated, or enrollment suspended at any time, by Crinetics 
Pharmaceuticals, Inc., with or without cause, or by me, if it becomes necessary to do so in the 
best interests of the study subjects. 
Site name:  
 
Site address:  
 
Phone number:  
 
Principal Investigator:  
Name and title (printed):  
 
Signature:  
 
Date:  
 

Study code: CRN00808-09 
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TABLE OF CONTENTS 
DOCUMENT HISTORY/PROTOCOL AMENDMENT SUMMARY OF CHANGES 
TABLE .........................................................................................................................2 
SPONSOR SIGNATURE PAGE ....................................................................................................3 
INVESTIGATOR’S AGREEMENT ...............................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
1. 
PROTOCOL SUMMARY ..........................................................................................10 
1.1. 
Synopsis ......................................................................................................................10 
1.2. 
Schedule of Activities: Randomized, Controlled Phase .............................................19 
1.3. 
Schedule of Activities: Open-label Extension Phase ..................................................25 
2. 
INTRODUCTION ......................................................................................................29 
2.1. 
Study Rationale ...........................................................................................................29 
2.2. 
Background .................................................................................................................30 
2.3. 
Benefit/Risk Assessment ............................................................................................30 
2.3.1. 
Risk Assessment .........................................................................................................31 
2.3.2. 
Benefit Assessment .....................................................................................................32 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................32 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................33 
3.1. 
Objectives and Endpoints for the Controlled Part of the Study..................................33 
3.2. 
Objective and Endpoints for the Open-label Extension .............................................34 
4. 
STUDY DESIGN .......................................................................................................35 
4.1. 
Overall Design ............................................................................................................35 
4.1.1. 
Screening ....................................................................................................................35 
4.1.2. 
Treatment Period (Randomized, Controlled Phase) ...................................................35 
4.1.3. 
Open-label Extension Phase .......................................................................................36 
4.1.4. 
End of Study ...............................................................................................................36 
4.1.5. 
Patient Input into Study Design ..................................................................................36 
4.2. 
Scientific Rationale for Study Design ........................................................................36 
4.3. 
Justification for Dose and Treatment Duration ..........................................................37 
4.4. 
End of Study Definition ..............................................................................................37 
4.5. 
Treatment After End of Trial Participation ................................................................37 
5. 
STUDY POPULATION .............................................................................................38 
5.1. 
Inclusion Criteria ........................................................................................................38 

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5.2. 
Exclusion Criteria .......................................................................................................40 
5.3. 
Lifestyle Considerations .............................................................................................42 
5.3.1. 
Contraception ..............................................................................................................42 
5.4. 
Screen Failures ............................................................................................................43 
6. 
STUDY DRUG AND CONCOMITANT THERAPY ...............................................44 
6.1. 
Study Drugs Administered .........................................................................................44 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................45 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................46 
6.4. 
Study Drug Compliance .............................................................................................47 
6.5. 
Dose Modification ......................................................................................................47 
6.5.1. 
During the RC Phase ..................................................................................................47 
6.5.2. 
During the OLE ..........................................................................................................48 
6.6. 
Treatment of Overdose ...............................................................................................48 
6.7. 
Concomitant Therapy .................................................................................................48 
6.7.1. 
Permitted Medicine .....................................................................................................48 
6.7.2. 
Prohibited Medicine ....................................................................................................49 
6.8. 
Auxiliary Medicinal Products .....................................................................................49 
6.8.1. 
RC Phase Rescue Medication (Auxiliary Medicinal Products) ..................................49 
6.8.2. 
OLE Phase Adjunctive Treatments (Auxiliary Medicinal Products) .........................50 
7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................51 
7.1. 
Discontinuation of Study Treatment/Participation .....................................................51 
7.1.1. 
Liver Chemistry Abnormality Monitoring and Study Drug Stopping Criteria ..........52 
7.1.2. 
Amylase or Lipase Study Drug Stopping Criteria ......................................................53 
7.1.3. 
Cardiac Study Drug Stopping Criteria ........................................................................53 
7.2. 
Lost to Follow up ........................................................................................................54 
7.3. 
Criteria for Study Termination ...................................................................................54 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................55 
8.1. 
Demographics and Baseline Characteristics ...............................................................55 
8.2. 
Subject-reported Assessments ....................................................................................55 
8.2.1. 
Acromegaly Symptoms Diary ....................................................................................55 
8.2.2. 
..............................................................55 
8.2.3. 
..............................................................55 

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8.2.4. 
...................................................56 
8.2.5. 
...................................................56 
8.3. 
Safety Assessments .....................................................................................................56 
8.3.1. 
Physical Examinations ................................................................................................56 
8.3.2. 
Vital Signs ..................................................................................................................56 
8.3.3. 
Electrocardiograms .....................................................................................................57 
8.3.4. 
Clinical Safety Laboratory Assessments ....................................................................57 
8.3.5. 
Biliary/Gallbladder Ultrasound ..................................................................................57 
8.3.6. 
Magnetic Resonance Imaging .....................................................................................58 
8.3.7. 
Ophthalmic Assessments ............................................................................................58 
8.4. 
Adverse Events, Serious Treatment-emergent Adverse Events, and Other 
Safety Reporting .........................................................................................................58 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................59 
8.4.2. 
Method of Detecting AEs ...........................................................................................59 
8.4.3. 
Follow-up of AEs .......................................................................................................59 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................60 
8.4.5. 
Pregnancy ...................................................................................................................61 
8.5. 
Pharmacokinetics ........................................................................................................61 
8.6. 
Genetics ......................................................................................................................61 
8.7. 
Biomarkers ..................................................................................................................61 
8.8. 
Immunogenicity Assessments ....................................................................................62 
8.9. 
Collection and Storage of Biological Samples ...........................................................62 
9. 
STATISTICAL CONSIDERATIONS .......................................................................63 
9.1. 
Statistical Hypotheses .................................................................................................63 
9.2. 
Sample Size Determination ........................................................................................63 
9.3. 
Analysis Sets ...............................................................................................................63 
9.4. 
Statistical Analyses .....................................................................................................64 
9.4.1. 
General Considerations ...............................................................................................64 
9.4.2. 
Efficacy Analyses .......................................................................................................64 
9.4.2.1. 
Analyses ......................................................................................................................64 
9.4.2.2. 
Open-Label Extension ................................................................................................65 
9.4.2.3. 
Multiplicity .................................................................................................................66 
9.4.3. 
Safety Analyses ..........................................................................................................66 

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9.4.4. 
Protocol Deviations ....................................................................................................66 
9.5. 
Interim Analysis ..........................................................................................................66 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................67 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................67 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................67 
10.1.2. 
Financial Disclosure ...................................................................................................67 
10.1.3. 
Informed Consent Process ..........................................................................................68 
10.1.4. 
Data Protection ...........................................................................................................68 
10.1.5. 
Data Monitoring Committee .......................................................................................70 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................70 
10.1.7. 
Data Quality Assurance ..............................................................................................70 
10.1.8. 
COVID-19 Procedures ................................................................................................72 
10.1.9. 
Source Documents ......................................................................................................73 
10.1.10. 
Publication Policy .......................................................................................................73 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................74 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................75 
10.3.1. 
Definition of AE .........................................................................................................75 
10.3.2. 
Definition of SAE .......................................................................................................76 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................77 
10.3.4. 
Reporting of SAEs ......................................................................................................80 
10.4. 
Appendix 4: Abbreviations .........................................................................................81 
11. 
REFERENCES ...........................................................................................................84 
  

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LIST OF TABLES 
Table 1: 
Objectives and Endpoints for the Controlled Part of the Study..................................13 
Table 2: 
Objective and Endpoints for the Open-label Extension .............................................14 
Table 3: 
Risk Assessment Table ...............................................................................................31 
Table 4: 
Study Interventions .....................................................................................................44 
Table 5: 
Protocol-Required Safety Laboratory Tests ...............................................................74 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................11 
Figure 2: 
Dose Titration Options ...............................................................................................16 
  

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Randomized, Controlled, Multi-Center Study, to Evaluate the Safety and 
Efficacy of Paltusotine in Subjects with Acromegaly Treated with Long-acting Somatostatin 
Receptor Ligands 
Rationale 
Therapy for acromegaly is targeted at decreasing growth hormone (GH) and insulin-like growth 
factor-1 (IGF-1) levels, ameliorating patients' symptoms and decreasing any local compressive 
effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, 
radiotherapy, and medical therapies, such as somatostatin receptor ligands, dopamine agonists, 
and the GH receptor antagonist pegvisomant.  
When surgery, which is the usual first-line treatment, fails to correct GH/IGF-1 hypersecretion, 
medical treatment can be used. Somatostatin receptor ligands (SRLs) are, at present, the most 
widely used drugs to control acromegaly. Octreotide has been approved as an immediate-release 
injectable solution by the FDA since 1988 and in the United Kingdom since 1989. Octreotide is 
available under the brand name Sandostatin® by Novartis or as a generic form sold by several 
different suppliers. Octreotide long-acting formulation is marketed under the brand name 
Sandostatin LAR® by Novartis. It is administered as monthly deep intragluteal intramuscular 
injection. Lanreotide long-acting formulation is marketed under the brand name Somatuline® 
Depot in the United States by Ipsen. It is administered every 4 weeks (or 6 to 8 weeks at the 
higher dose).  
Paltusotine is a nonpeptide orally bioavailable somatostatin receptor 2 (SST2) agonist that is 
administered once per day. In Phase 2 studies, daily oral administration of paltusotine has been 
shown to maintain GH and IGF-1 levels in subjects with acromegaly that were previously on 
octreotide long-acting release (LAR) or lanreotide depot monotherapy. An orally bioavailable 
somatostatin agonist should reduce acromegaly patient burden by eliminating the pain and 
complications (e.g., subcutaneous, or intramuscular nodules) of injections and the cost and 
inconvenience of the health care provider office visits required for those injections. Additionally, 
it may allow physicians to determine an optimized dosing regimen more quickly compared with 
existing therapies. To our knowledge, paltusotine is the first nonpeptide oral somatostatin agonist 
being evaluated for the treatment of acromegaly. 
This study is a Phase 3, randomized, placebo-controlled trial. This is a standard design in this 
disease and, by avoiding potential bias in assessing clinical efficacy and safety, will allow the 
comparison between paltusotine versus placebo. IGF-1 levels as well as acromegaly-related 
symptoms will be monitored regularly throughout the study and criteria for rescue therapy have 
been defined to ensure subject safety. 
The proposed titration design aims to maintain subjects in their baseline biochemical status and 
optimize their dose while minimizing the period in which their IGF-1 is above baseline. Subjects 
will be switched from a stable regimen of octreotide/lanreotide to 40 mg paltusotine and their 
dose titrated up to 60 mg based on biochemical status and tolerability. Down-titration will be 
allowed based on tolerability. It is expected that by the end of titration period (Week 24) the 
concentrations of residual pre-trial octreotide or lanreotide will be too low to contribute to 

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efficacy. Finally, the dose-titration design reflects how the drug is likely to be used in clinical 
practice. Rescue criteria are in place to ensure safety for those who require resumption of 
standard acromegaly treatment, in those randomized to paltusotine or placebo. 
Overall Design 
This is a randomized, placebo-controlled, multi-center study. The study includes a Screening 
Period of up to 12 weeks. After the Screening Period, subjects will be randomly assigned in a 
1:1 ratio to receive either paltusotine or placebo. At the end of the Treatment Period, subjects 
who, in the opinion of the Investigator, may benefit from treatment with paltusotine, may be 
enrolled in a long-term open-label extension (OLE) for up to 200 weeks. During the OLE, all 
subjects will receive paltusotine. An End of Study (EOS) Visit will occur approximately 4 weeks 
after the last dose of study drug. 
Figure 1: 
Study Schema 
 
Average IGF-1 = Average of all (up to 3) study assessments taken during Screening. 
EOR=End of Treatment (randomized, controlled phase), EOS=End of Study, IGF-1=insulin-like growth factor-1, 
LA SRL=long-acting somatostatin receptor ligand (octreotide/lanreotide only), OLE=open-label extension, 
ULN=upper limit of normal 
Screening 
The Screening Period consists of 2 to 3 visits over 4 to 12 weeks. Administration of the last 
pre-randomization long-acting SRL (octreotide/lanreotide) injections should be performed before 
or during Screening to maintain the dosing interval between octreotide/lanreotide and the first 
dose of the study drug, i.e., the first dose of study drug will be administered when the next dose 
of lanreotide/octreotide would have been due.  
IGF-1 values must be confirmed by the average of at least 2 central laboratory tests during the 
Screening Period. If a third IGF-1 measurement is needed per the Investigator, the Medical 
Monitor should be consulted and the average of the 3 measurements must meet the IGF-1 criteria 
for eligibility. 
The last octreotide or lanreotide injection will be given during the Screening Period.  
The octreotide/lanreotide injection can be administered any time during the Screening Period 
provided 1) Day 1 aligns with the approximate scheduled date of the subject’s next 
octreotide/lanreotide injection (±3 days), and 2) the Screening Period does not exceed 12 weeks.  
The octreotide/lanreotide injection is the key temporal event during Screening. Day 1 (start of 
treatment) must be 4 weeks (±3 days) or 6 weeks (±3 days) after the last dose of 
octreotide/lanreotide if a subject is administered his/her octreotide/lanreotide every 4 weeks or 

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6 weeks, respectively. Additionally, if a subject is administering his/her lanreotide every 
8 weeks, Day 1 (start of treatment) must be 8 weeks (±3 days) after the last dose of lanreotide. 
Treatment Period (Randomized, Controlled Phase)  
Once all Screening assessments are completed, the subject’s eligibility is verified by the 
Investigator and confirmed by the Medical Monitor via submission of the Medical Monitor 
Eligibility Verification Form. Subjects meeting all eligibility criteria and an average Screening 
IGF-1 ≤1.0×ULN will be randomized (1:1) to either paltusotine (n=26) or placebo (n=26) 
(Figure 1).  
The Treatment Period will be approximately 36 weeks.  
Subjects will not be administered octreotide/lanreotide on Day 1. Instead, subjects will receive 
their first dose of study drug on site (paltusotine or placebo). 
It is anticipated that the study drug dose will be stable, and titration completed prior to or at 
Week 24, with no dose titrations/adjustments after Week 24. Up-titration after Week 24 should 
not occur; subjects who require dose up-titration after Week 24 will be considered non-
responders. Down-titration will be allowed based on tolerability. 
Rescue criteria are in place for those who require standard acromegaly treatment in those 
randomized to paltusotine or placebo. If rescue therapy is required during the Randomized 
Controlled (RC) phase, subjects will discontinue paltusotine or placebo, initiate rescue therapy 
and should continue the visits and surveillance in the study for the remainder of the 36-week 
RC phase (see Section 6.8.1 for Rescue Criteria). Subjects who discontinue treatment for any 
reason prior to End of Randomized Control Phase (EOR), including those undergoing rescue 
procedures, will be considered non-responders. Only rescue therapy with approved SRLs 
(octreotide LAR or lanreotide depot monotherapy) will be permitted during the study. A 
Follow-up Visit, approximately 4 weeks after the last dose of study drug, will occur at Week 40 
for subjects who do not enter the OLE. 
If the subject withdraws consent or, in the opinion of the Investigator, should be permanently 
discontinued from the study, the Early Termination (ET) Visit should be completed as specified 
in the Schedules of Activities (SOAs) and the subject should return to standard acromegaly 
treatment as prescribed by the Investigator. 
Open-label Extension Phase 
Subjects who complete the 36-week RC phase or who meet rescue criteria and complete the 
36-week RC phase with rescue medication can continue participation in the OLE phase if the 
subject is willing to participate and, in the opinion of the Investigator, the subject may benefit 
from continued participation and treatment with paltusotine. The OLE Treatment Period is 
200 weeks. Data from the EOR visit of the RC phase will be used as baseline of the OLE, unless 
otherwise specified. 
End of Study 
An EOS Visit, approximately 4 weeks after the last dose of study drug, will occur at Week 240 
to collect final safety data and other assessments as detailed in the SOAs. 

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Table 1: 
Objectives and Endpoints for the Controlled Part of the Study 
Objectives 
Endpoints 
Primary  
To evaluate the effect of paltusotine versus 
placebo on IGF-1 response 
Proportion of subjects who maintain biochemical 
response in IGF-1 (≤1.0×the upper limit of normal 
[ULN]) at the End of the Randomized Control 
Phase (EOR) 
Secondary  
To evaluate the effect of paltusotine versus 
placebo on IGF-1 level 
Change from baseline in IGF-1, in units of ULN, 
to EOR 
To evaluate the effect of paltusotine versus 
placebo on GH response 
Proportion of subjects with GH <1.0 ng/mL at 
Week 34, out of those who had GH <1.0 ng/mL at 
baseline 
To evaluate the effect of paltusotine versus 
placebo on acromegaly symptoms 
Change from baseline in Total Acromegaly 
Symptoms Diary (ASD) score to EOR 
Exploratory  
To evaluate the effect of paltusotine versus 
placebo on GH level 
Change from baseline to Week 34 in GH 
To evaluate the effect of paltusotine versus 
placebo on the need for rescue therapy 
Proportion of subjects who receive rescue therapy 
To evaluate the effect of paltusotine versus 
placebo on IGF-1 response 
Proportion of subjects who achieve IGF-1 
<1.3×ULN at EOR 
To evaluate the effect of paltusotine versus 
placebo on GH response 
Proportion of subjects with GH <2.5 ng/mL at 
Week 34 
To evaluate the effect of paltusotine versus 
placebo on tumor volume 
Change from baseline in residual tumor volume at 
EOR 
To evaluate loss of biochemical control 
Time from randomization to the first IGF-1 
>1.0×ULN for 2 consecutive visits 
Time from randomization to the first IGF-1 
≥1.3×ULN for 2 consecutive visits 
Safety  
To evaluate the safety and tolerability of 
paltusotine versus placebo in subjects with 
acromegaly 
Incidence of treatment-emergent adverse events 
(TEAEs), including serious adverse events 
(SAEs) and TEAEs that lead to discontinuation  
Change in safety parameters: clinical laboratory 
tests (hematology, serum chemistry, lipid panel, 
and hormones), vital signs, and 12-lead 
electrocardiogram (ECG) parameters 
Incidence of clinically significant changes in 
abdominal (gallbladder) ultrasound compared 
with baseline 

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Table 2: 
Objective and Endpoints for the Open-label Extension 
Objective 
Endpoints 
To evaluate the long-term safety and efficacy of 
paltusotine 
Safety endpoints:  
Incidence of TEAEs, including serious adverse 
events (SAEs) and TEAEs leading to 
discontinuation of study drug 
Change in quantitative safety parameters: clinical 
laboratory tests, lipid panel, hormones, vital signs, 
and 12-lead ECG parameters 
Ophthalmic assessments 
The same efficacy endpoints that are in the main 
study but at subsequent timepoints with the 
following additional efficacy endpoint: 
Proportion of subjects who receive permitted 
adjunctive standard acromegaly treatment 
Number of Subjects 
The total sample size is 52 subjects (26 in the paltusotine arm, 26 in the placebo arm). 
Refer to Section 9.2 for more information about determination of sample size. 
Duration and Intervention Groups  
Total Duration of the Study 
The study comprises 2 phases: an RC phase and long-term OLE phase. Subjects who participate 
in both phases will complete approximately 240 weeks (approximately 4 ½ years) of treatment 
and observation. The study will consist of:  
 Screening Period: Up to 12 weeks; Week -12 through Day -1 (There are 2 to 3 visits 
during the Screening Period) 
 RC phase: 36 weeks 
 Treatment Period: Day 1 through Week 36 with up to 11 planned visits; the end of 
Week 36 is the last planned visit of the RC phase and is defined as EOR  
 Week 1 through Week 24 will be the dose titration Period 
 OLE: 200 weeks 
 1 visit approximately every 12 weeks 
 Eligible subjects who complete the RC phase may enter the OLE and continue or 
initiate treatment with paltusotine until end of treatment (EOT); the end of 
200 weeks of the OLE phase is the planned EOT 
 EOS: Defined as the day final study data are collected and should occur 4 weeks 
after the last dose of study drug; the end of the Week 240/EOS is the last planned 
visit of the study (Follow-up Visit), but EOS could occur at Week 40 for subjects 
who do not enter the OLE 

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 Subjects who withdraw consent or are permanently discontinued from the study 
before Week 240 are to complete an ET Visit, as specified in the SOAs, unless the 
subject completes the RC phase and concludes study participation at Week 40 in 
which assessments specified at EOS are to be completed. 
Study Drug 
Paltusotine will be provided as 
tablets. Matching placebo tablets will be identical in 
appearance to paltusotine and will be administered orally according to the randomization 
scheme, on an identical schedule to those receiving paltusotine. Paltusotine and matching 
placebo tablets will each be packed in 
 Drug labels will comply with the legal requirements of each country and will be 
printed in local language.  
Scientific Rationale for Study Design 
A prospective randomized, placebo-controlled trial is the gold standard methodology to define 
the safety and efficacy profile of an experimental drug. Placebo controlled trials have been 
successfully conducted and are feasible in rare orphan diseases, including acromegaly. Protocol 
safeguards are in place to ensure subjects who experience worsening of symptoms associated 
with rise in IGF-1 receive rescue injections of standard therapy, to ensure that they can safely 
complete the trial (Section 6.8.1). 
Dose Adjustment During the RC Phase 
The starting daily dose will be 40 mg (
 tablets of active paltusotine or matching 
placebo) once daily (QD) for oral self-administration. The dose of study drug can be titrated up 
to 60 mg QD. Dose levels may increase from 40 mg 
 tablets) to 60 mg 
 
tablets) based on IGF-1 response.  
It is anticipated that the study drug dose will be stable, and titration completed prior to or at 
Week 24, with no dose titrations/adjustments after Week 24. Up-titration after Week 24 should 
not occur; subjects who require dose up-titration after Week 24 will be considered non-
responders. Down-titration will be allowed based on tolerability.  
Protocol specified dose adjustments are summarized in Figure 2. 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
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16 
Figure 2: 
Dose Titration Options 
Dose Titration/Adjustment 
IGF-1 Criteria 
Tolerability Criteria 
40 mg→60 mg 
Subject’s most recent IGF-1 
results on 40 mg is >0.9×ULN 
Increase allowed due to acceptable 
tolerability on 40 mg 
40 mg→20 mg 
-- 
Dose reduction required due to 
unacceptable tolerability on 40 mg 
20 mg→40 mg 
Subject’s most recent IGF-1 
results on 20 mg is >0.9×ULN 
Tolerability is acceptable on 
20 mg 
60 mg→40 mg 
-- 
Dose reduction required due to 
unacceptable tolerability on 60 mg 
If the Investigator determines that a dose titration/adjustment after Week 24 is required, the Investigator should contact the 
Medical Monitor to ensure that a consistent approach to dose titration/adjustment is applied across the study. 
IGF-1=insulin-like growth factor-1; ULN=upper limit of normal 
Dose up-titration will be based on 2 criteria: 
 Acceptable tolerability at the current dose, as evaluated by the Investigator, 
AND 
 The subject’s most recent IGF-1 result is >0.9×ULN  
If needed, an unscheduled dose titration Visit may be performed. The study drug dose may be 
decreased at any time during the study if study drug toleration is unacceptable in the judgment of 
the Investigator. A dose reduction based on tolerability may be necessary for subjects who are 
taking P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) inhibitors (see 
Section 6.7.1). In general, a TEAE of severe intensity for which there is a reasonable possibility 
it is caused by (related to) study drug would be expected to result in study drug dose reduction. If 
tolerance improves following a dose reduction, the Investigator may increase the dose in 
 
increments, if needed, based on protocol-specified dose titration criteria to a maximum of 60 mg 
(
 tablets). See Section 10.3.1 for the definition of a TEAE and Section 10.3.3 for 
definitions of intensity and causality. When, in the Investigator’s judgment, the study medication 
is not tolerated, the study medication may be held for up to a total of 14 days per year, but no 
more than 7 consecutive days per year during the study, followed by resumption of the study 
medication at the same or reduced dose as appropriate. 
During the RC phase, planned study visits are to occur approximately every 4 weeks; however, 
unscheduled visits may be required for more frequent monitoring, dose titration, and to assess 
rescue criteria. 
RC Phase Rescue Medication (Auxiliary Medicinal Products) 
During the RC phase, acromegaly treatments other than study drug are prohibited, unless the 
subject meets the rescue criteria described as follows: 
 Significant worsening of 1 or more acromegaly symptoms or the development of a 
new acromegaly symptom, at the highest dose (60 mg) for at least 2 weeks, as 
assessed by the Investigator. Symptoms should be attributed to uncontrolled 
acromegaly in the opinion of the Investigator and could include, but are not limited 
to, the following: headache, arthralgia, fatigue, hyperhidrosis, or soft tissue swelling. 
(“Significant worsening” in the opinion of the Investigator may be defined as 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
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17 
symptoms requiring a substantial increase in level of clinical care [e.g., significant 
intervention needed to avert hospitalization or clinically notable increase in frequency 
or intensity of subject contact required] or substantial clinical deterioration [e.g., 
worsening from a mild to severe AE or the onset of an SAE would meet these 
criteria]). 
AND 
 IGF-1 value ≥1.3×ULN at the highest dose (60 mg) measured at 2 successive planned 
visits or at an unscheduled visit if an earlier result is needed (as evaluated by the 
Investigator). 
If rescue therapy is required during the RC phase, subjects will discontinue paltusotine or 
placebo, initiate rescue therapy, and should continue the visits and surveillance in the study for 
the remainder of the 36-week RC phase (see Section 6.8.1 for Rescue Criteria). Only rescue 
therapy with approved SRLs (octreotide LAR or lanreotide depot monotherapy [auxiliary 
medicinal products (AuxMPs)]) will be permitted during the study. Rescue therapy should be 
used according to approved marketing authorization or standard clinical practice.  
Investigators should contact the Medical Monitor about any subjects who do not meet criteria for 
rescue, but for whom the Investigator recommends discontinuation of study drug and initiation of 
standard acromegaly medication, to discuss the possibility of continuation in the RC phase on 
rescue therapy with approved SRLs and eligibility for OLE on a case-by-case basis.  
Dosage and Dose Adjustment During the Open-label Extension 
The starting daily dose regimen for all subjects who participate in the OLE will be paltusotine 
40 mg QD, dispensed in an open-label manner, i.e., subjects will be given bottles of paltusotine 
containing 
 tablets and instructed to take 2 tablets daily until their next visit.  
Dose escalation in the OLE may occur once the first IGF-1 result is available. At that time, the 
Investigator can determine whether the dose can be up-titrated to 60 mg.  
Open-label Extension Adjunctive Treatments (Auxiliary Medicinal Products) 
If there is evidence of paltusotine efficacy and at 6 months, subjects have not reached therapeutic 
target goals, adjunctive treatment may be initiated if clinically appropriate beginning at Week 60. 
If these criteria are met, non-SRL acromegaly treatments, such as oral cabergoline or GH 
receptor antagonist pegvisomant are permitted and may be initiated as an adjunct when a subject 
has experienced at least 2 consecutive elevated IGF-1 (≥1.3×ULN) measurements at the highest 
paltusotine dose level (60 mg), or otherwise not at the subject’s therapeutic target in the 
judgement of the Investigator. 
 The adjunctive medications cabergoline and pegvisomant are considered AuxMPs. 
Use of any adjunctive medications should be discussed with the Medical Monitor and 
should be used according to approved marketing authorization or standard practice. 
Adjunct medications are not provided by the Sponsor. 
 If it is determined that adjunctive medication is required, then use of cabergoline 
would be the expected first-line adjunct, as clinically appropriate. If after an adequate 
period of assessment, study medication combined with a cabergoline does not achieve 
therapeutic targets, then pegvisomant may be added as a second-line adjunct, if 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
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18 
clinically appropriate (Katznelson, 2014). In this situation, the Investigator should 
assess if there was evidence of an IGF-1 lowering response from the cabergoline. If 
so, the pegvisomant may be added to the paltusotine + cabergoline drug combination. 
If there was no evidence of a therapeutic response to combined paltusotine + 
cabergoline, the cabergoline should be stopped and pegvisomant added to paltusotine 
therapy. 
 Short- and long-acting somatostatin receptor agonists (other than paltusotine) remain 
prohibited and are not permitted during the study (subjects will be discontinued from 
the study if these are needed and an ET Visit will be scheduled prior to resuming 
these treatments). 
Statistical Methods 
The primary endpoint assumes that IGF-1 ≤1×ULN rates for paltusotine versus placebo are 70% 
and 20%, respectively. Based on a 2-sample Fisher’s Exact test at a 2-sided alpha=0.05 level of 
significance, a total sample size of 52 subjects (26 in the paltusotine arm, 26 in the placebo arm) 
will provide 93.6% power to achieve superiority of paltusotine over placebo. 
The estimates used for the power are based on Phase 2 data with paltusotine as well as the 
observed placebo response in similarly designed clinical study of oral octreotide (Chiasma Inc.; 
Optimal Study; EudraCT: 2017-000737-31). In the Phase 2 paltusotine acromegaly studies, the 
drop-out (discontinuation) rates were approximately 10%. These study discontinuation rates are 
accounted for in the estimates of overall non-response seen in a in similarly designed clinical 
study of oral octreotide (Chiasma Inc.; Optimal Study; EudraCT: 2017-000737-31) where 68% 
of the placebo group either dropped out or were on rescue medications defining them as a non-
responder.  
Data Monitoring Committee 
An unblinded Data Monitoring Committee (DMC), comprising independent subject matter 
experts, will be established to assess the risk versus benefit of the interventions during the trial. 
The DMC will meet at intervals as specified in the DMC charter and may convene for ad hoc 
meetings if there are immediate safety concerns identified during the study. In the event an 
interim futility analysis is undertaken when 50% of subjects have completed the Treatment 
Period of the RC phase, the DMC will be responsible for evaluating those data.  
  

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 5.0 
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19 
1.2. 
Schedule of Activities: Randomized, Controlled Phase 
STUDY 
PROCEDURES 
SCREENING 
PERIOD 
TREATMENT PERIOD (36 Weeks) 
ET 
DT* 
F/U 
REFs 
W -12 to D -1 
S1, S2, or S3  
(as needed) 
D1 
TITRATION PERIOD 
STABLE DOSE 
DAY/WEEK 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W34 
W36 
EOR 
W40 
WINDOW (DAYS) 
- 
- 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±3 
- 
- 
±3 
- 
Visit to be in-clinic 
X 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
- 
X 
X 
X 
X 
- 
Visit to be in-clinic or 
subject’s home/suitable 
alternate location  
 
X 
X 
- 
X 
X 
- 
X 
X 
- 
X 
X 
X 
- 
- 
- 
- 
- 
Obtain informed consent  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 10.1.3 
Register subject in 
IWRS 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 6.3  
Verify eligibility  
X 
X 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 5.1  
Section 5.2  
Randomization 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 6.3  
Demographics and Baseline Characteristics 
Health history, 
demographics, baseline 
characteristics 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 8.1 
Pre-trial acromegaly 
symptoms  
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 8.1 
Safety Assessments 
Full physical exam, 
weight, ring size (height 
at screening only) 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
Section 8.3.1 
Symptom-directed 
physical exam 
- 
- 
- 
- 
X 
X 
- 
X 
X 
- 
X 
X 
X 
- 
- 
 
X 
Section 8.3.1 
Vital signs  
X 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Section 8.3.2 
12-lead ECG (triplicate) 
X 
- 
- 
X 
X 
- 
X 
- 
X 
- 
X 
- 
- 
X 
X 
- 
X 
Section 8.3.3 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 5.0 
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20 
STUDY 
PROCEDURES 
SCREENING 
PERIOD 
TREATMENT PERIOD (36 Weeks) 
ET 
DT* 
F/U 
REFs 
W -12 to D -1 
S1, S2, or S3  
(as needed) 
D1 
TITRATION PERIOD 
STABLE DOSE 
DAY/WEEK 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W34 
W36 
EOR 
W40 
WINDOW (DAYS) 
- 
- 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±3 
- 
- 
±3 
- 
Visit to be in-clinic 
X 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
- 
X 
X 
X 
X 
- 
Visit to be in-clinic or 
subject’s home/suitable 
alternate location  
 
X 
X 
- 
X 
X 
- 
X 
X 
- 
X 
X 
X 
- 
- 
- 
- 
- 
Biliary/gallbladder 
ultrasound  
Ultrasound may be done at 
any Screening visit, but 
results MUST be available 
to determine eligibility 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.5  
Pituitary MRI 
MRI may be done at any 
Screening visit, but results 
MUST be available to 
determine eligibility 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.6 
AE monitoring  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X 
Section 8.4 
Appendix 3  
Prior & concomitant 
therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X 
Section 6.7  
Laboratory Tests 
Monthly pregnancy test  
X 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
X 
- 
X 
Section 8.4.5  
Appendix 2 
Clinical laboratory tests 
(hematology, chemistry, 
urinalysis) 
X 
- 
- 
X 
X 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
- 
X 
Section 8.3.4 
Appendix 2 
HbA1c 
X 
- 
- 
X 
- 
X 
- 
- 
- 
X 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.4  
Lipid panel (fasting) 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.4 
Appendix 2 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 5.0 
Confidential 
21 
STUDY 
PROCEDURES 
SCREENING 
PERIOD 
TREATMENT PERIOD (36 Weeks) 
ET 
DT* 
F/U 
REFs 
W -12 to D -1 
S1, S2, or S3  
(as needed) 
D1 
TITRATION PERIOD 
STABLE DOSE 
DAY/WEEK 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W34 
W36 
EOR 
W40 
WINDOW (DAYS) 
- 
- 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±3 
- 
- 
±3 
- 
Visit to be in-clinic 
X 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
- 
X 
X 
X 
X 
- 
Visit to be in-clinic or 
subject’s home/suitable 
alternate location  
 
X 
X 
- 
X 
X 
- 
X 
X 
- 
X 
X 
X 
- 
- 
- 
- 
- 
Serology (HIV, 
Hepatitis B and 
Hepatitis C) 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 8.3.4 
Appendix 2 
TSH and Free T4  
X 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.4 
Appendix 2 
Screening fasting 
Integrated GH 
5 samples collected at least 
30 minutes apart drawn 
within a 3-hour period  
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 8.3.4 
Appendix 2 
Screening IGF-1  
X 
X 
X** 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 8.3.4 
Appendix 2 
Genotype blood sample 
(optional) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.6  
Pre-dose fasting PK 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
Section 8.5  
PK  
(any time) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Section 8.5 
Pre-dose fasting IGF-1 
(W40 can be done any time) 
- 
- 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
X 
X 
- 
X 
Section 8.3.4  
Appendix 2 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 5.0 
Confidential 
22 
STUDY 
PROCEDURES 
SCREENING 
PERIOD 
TREATMENT PERIOD (36 Weeks) 
ET 
DT* 
F/U 
REFs 
W -12 to D -1 
S1, S2, or S3  
(as needed) 
D1 
TITRATION PERIOD 
STABLE DOSE 
DAY/WEEK 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W34 
W36 
EOR 
W40 
WINDOW (DAYS) 
- 
- 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±3 
- 
- 
±3 
- 
Visit to be in-clinic 
X 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
- 
X 
X 
X 
X 
- 
Visit to be in-clinic or 
subject’s home/suitable 
alternate location  
 
X 
X 
- 
X 
X 
- 
X 
X 
- 
X 
X 
X 
- 
- 
- 
- 
- 
Fasting Integrated GH 
5 samples collected at least 
30 minutes apart within a 
3-hour period. At W34, 
collection should be started 
approximately 1-2 hours 
after study drug dose 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
(Post-
dose) 
- 
X 
- 
- 
Section 8.3.4 
Appendix 2 
Post dose PK, GH, and 
IGF-1  
One sample between 1 and 
8 hours post-dose 
- 
- 
- 
- 
X 
- 
X 
- 
X 
- 
X 
- 
- 
- 
- 
- 
- 
Section 8.3.4 
Appendix 2 
Drug Administration 
Screening octreotide/ 
lanreotide injection 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 6  
Study drug 
administration during 
visit 
(W36 study drug 
administration (paltusotine 
40 mg) for subjects 
continuing into the OLE 
only) 
- 
- 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
X 
- 
- 
- 
Section 6.1 
Dispense study drug  
(via IWRS) 
(W36 dispensation for 
subjects continuing into 
OLE only) 
- 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
X* 
- 
Section 6.1 
Study drug compliance 
- 
- 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
- 
Section 6.4 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 5.0 
Confidential 
23 
STUDY 
PROCEDURES 
SCREENING 
PERIOD 
TREATMENT PERIOD (36 Weeks) 
ET 
DT* 
F/U 
REFs 
W -12 to D -1 
S1, S2, or S3  
(as needed) 
D1 
TITRATION PERIOD 
STABLE DOSE 
DAY/WEEK 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W34 
W36 
EOR 
W40 
WINDOW (DAYS) 
- 
- 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±4 
±3 
- 
- 
±3 
- 
Visit to be in-clinic 
X 
- 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
- 
X 
X 
X 
X 
- 
Visit to be in-clinic or 
subject’s home/suitable 
alternate location  
 
X 
X 
- 
X 
X 
- 
X 
X 
- 
X 
X 
X 
- 
- 
- 
- 
- 
Study drug 
accountability  
- 
- 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
X 
X* 
- 
Section 6.4  
Subject-reported Assessments 
ASD  
ASD should be completed 
by the subject daily at home 
beginning at least 
approximately 2 weeks 
prior to study drug dosing 
for the duration of the RC 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Section 8.2.1  
  
- 
- 
- 
X 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
X 
- 
- 
Section 8.2.2 
Section 8.2.3  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Section 8.2.4 
  
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.2.4 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
- 
- 
Section 8.2.5  
Notes:  
To the extent practical, conduct all study assessments at the same time of day, unless otherwise specified. The screening MRI and/or ultrasound do not need to be performed on the 
same day as the screening study visit (SV1) but must be performed within the screening window. The pituitary MRI and biliary/gallbladder ultrasound may be performed within 
± 2 weeks of the Week 36/EOR visit. 
The Screening Period consists of 2 to 3 visits over 4 to 12 weeks. Subjects administer their pre-trial octreotide (every 4 weeks)/lanreotide (every 4, 6, or 8 weeks) according to their 
pre-trial routine dosing interval. The date and dose level of the most recent octreotide/lanreotide prior to consent will be recorded as prior medication, to the extent reasonable.  
*A DT Visit may occur as an unscheduled visit when an in-person dose adjustment visit is necessary. In cases of poor tolerability, the Investigator may reduce dose based on 
his/her assessment during a telemedicine (phone, video) evaluation. 
**IGF 1 values must be confirmed by the average of at least 2 central laboratory tests during the Screening Period. If a third IGF 1 measurement is needed per the Investigator, the 
Medical Monitor should be consulted and the average of the 3 measurements must meet the criteria for eligibility. A third screening visit should be completed only if a third IGF-1 
sample is needed. 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 5.0 
Confidential 
24 
Fasting integrated GH will be collected during screening, Week 34, and ET only. Integrated GH consists of 5 samples collected at least 30 minutes apart within a 3-hour period. 
Integrated GH should be measured after at least a 4 hour fast and the subjects should remain fasting during the 3 hours of GH sampling. The integrated GH sampling at Week 34 
should be started approximately 1-2 hours after last study drug dose. 
At other visits (W4, W12, W20, W28), single samples for GH will be collected. 
Female subjects of childbearing potential must have a negative serum pregnancy test at Screening. All other pregnancy tests will be urine tests. Pregnancy tests may be obtained at 
any time during the study as an unscheduled test if clinically appropriate. 
Fasting blood samples (unless otherwise indicated) should be collected after an overnight fast of at least 6 hours. 
The last dose of study drug for the RC phase will be self-administered the day prior to the W36/EOR visit. The first dose of the OLE phase will be administered during the 
W36/EOR visit for subjects continuing into the OLE. 
Follow-up Visit is to occur approximately 4 weeks after the last dose of study drug for subjects who do not enter the OLE (Week 40). 
The last octreotide/lanreotide injection during Screening does not need to occur on the same day as the other S2 assessments. The date of Day 1 should align within ±3 days of the 
routine dosing interval following the last octreotide/lanreotide injection.  
Unscheduled visits for octreotide/lanreotide injections may be necessary for subjects who meet criteria for rescue therapy. 
 AE=adverse event, ASD=Acromegaly Symptoms Diary, D=day, DT=dose titration, ECG=electrocardiogram, 
 
 EOR=End of Treatment (randomized, controlled phase), ET=Early Termination Visit, F/U=follow-up, GH=growth hormone, HbA1c=hemoglobin A1c, 
HIV=human immunodeficiency virus, IGF-1=insulin-like growth factor-1, IWRS=interactive web response system, MRI=magnetic resonance imaging, OLE=open-label 
extension, 
 PK=pharmacokinetic, REFs=references, S=Screening, TSH=thyroid-
stimulating hormone, W=Week 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 5.0 
Confidential 
25 
1.3. 
Schedule of Activities: Open-label Extension Phase 
STUDY PROCEDURES  
INITIAL OLE PERIOD 
2-YEAR EXTENSION 
EOS 
Refs 
WEEK 
EOR 
W36 
W39 
W48 
W60 
W72 
W84 
W96 
W108 
W120 
W132/ 
W156/ 
W180/ 
W204/ 
W228/ 
W144/ 
W168 
W192/ 
W216/ 
-W236 
EOT/ 
ET 
DTa 
W240 
 
WINDOW (DAYS) 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
- 
±7 
 
Visit to be in-clinic 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
Visit to be in-clinic or 
subject’s home/suitable 
alternate location 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
- 
- 
- 
 
Verify eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
Section 5.2 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical exam, weight, 
ring size  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Section 8.3.1 
Symptom directed physical 
exam 
- 
- 
- 
X 
- 
X 
- 
X 
- 
X 
- 
- 
- 
X 
Section 8.3.1 
Vital signs  
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Section 8.3.2 
12-lead ECG (triplicate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Section 8.3.3 
Biliary/gallbladder ultrasound  
X 
 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
 
 
Section 8.3.5  
Pituitary MRI 
X 
- 
- 
- 
- 
X 
- 
- 
- 
Xc 
 
- 
X 
- 
- 
Section 8.3.6 
Ophthalmic Assessments 
 
 
 
 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
 
 
Section 8.3.7  
AE monitoring  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X 
Section 8.4 
Appendix 3  
Concomitant therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X 
Section 6.7 
Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monthly pregnancy teste  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Section 8.3.4  
Appendix 2 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 5.0 
Confidential 
26 
STUDY PROCEDURES  
INITIAL OLE PERIOD 
2-YEAR EXTENSION 
EOS 
Refs 
WEEK 
EOR 
W36 
W39 
W48 
W60 
W72 
W84 
W96 
W108 
W120 
W132/ 
W156/ 
W180/ 
W204/ 
W228/ 
W144/ 
W168 
W192/ 
W216/ 
-W236 
EOT/ 
ET 
DTa 
W240 
 
WINDOW (DAYS) 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
- 
±7 
 
Visit to be in-clinic 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
X 
X 
 
Visit to be in-clinic or 
subject’s home/suitable 
alternate location 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
- 
- 
- 
 
Clinical laboratory tests 
(hematology, chemistry, 
urinalysis) and HbA1c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Section 8.3.4  
Appendix 2 
Fasting lipid panel  
X 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
X 
- 
- 
Section 8.3.4 
Appendix 2 
TSH and Free T4  
X 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
X 
- 
- 
Section 8.3.4 
Appendix 2 
PK 
(any time) 
X 
- 
- 
X 
- 
- 
- 
- 
- 
Xf 
- 
X 
- 
- 
Section 8.5  
Pre-dose fasting IGF-1 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 8.3.4 
Appendix 2 
GH and IGF-1 
(any time) 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Section 8.3.4 
Appendix 2 
Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study drug 
(via IWRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X* 
- 
Section 6.1 
Study drug administration 
during visit 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 6.1 
Study drug compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X* 
- 
Section 6.4 
Study drug accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
- 
Section 6.4 

Study code: CRN00808-09 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 5.0 
Confidential 
27 
STUDY PROCEDURES  
INITIAL OLE PERIOD 
2-YEAR EXTENSION 
EOS 
Refs 
WEEK 
EOR 
W36 
W39 
W48 
W60 
W72 
W84 
W96 
W108 
W120 
W132/ 
W156/ 
W180/ 
W204/ 
W228/ 
W144/ 
W168 
W192/ 
W216/ 
-W236 
EOT/ 
ET 
DTa 
W240 
 
WINDOW (DAYS) 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
- 
±7 
 
Visit to be in-clinic 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
X 
X 
 
Visit to be in-clinic or 
subject’s home/suitable 
alternate location 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
- 
- 
- 
 
Subject-reported Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASD and 
 
Sparse periodic administrations at 
home or at study visits 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Section 8.2.1 
Section 8.2.4  
  
X 
 
 
 
 
X 
 
 
 
Xg 
 
X 
 
 
Section 8.2.2 
Section 8.2.3  
X 
- 
- 
- 
- 
- 
- 
- 
- 
Xg 
- 
X 
- 
- 
Section 8.2.4 
 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Xg 
- 
- 
- 
- 
Section 8.2.5  
Notes:  
To the extent practical, conduct all study assessments at the same time of day, unless otherwise specified. 
The pituitary MRIs and biliary/gallbladder ultrasounds do not need to be performed on the same day as the study visit. They may be performed within ± 2 weeks of the study visit. 
EOS/Follow-up Visit is to occur approximately 4 weeks after the last dose of study drug for subjects (Week 240). 
Data from the EOR Visit in the RC Phase will be used as baseline (D1) data in the OLE. 
Fasting blood samples (unless otherwise indicated) should be collected after an overnight fast of at least 6 hours. 
The first dose of the OLE phase will be administered during the W36/EOR visit. 
a A DT Visit may occur as an unscheduled visit when an in-person dose adjustment visit is necessary. In cases of poor tolerability, the Investigator may reduce dose based on 
his/her assessment during a telemedicine (phone, video) evaluation.  
b Biliary/gallbladder ultrasounds are required at Week 132 and Week 236/ET visits but may be performed at any time if clinically indicated in the opinion of the Investigator. 
c Pituitary MRI performed at Week 132 and Week 180 only. 
d Visual Acuity, Fundus Photography, Optical Coherence Tomography, Visual Fields. Initial ophthalmic testing should be performed as soon as practical and then at approximately 
6- month intervals, preferably associated with scheduled visits whenever possible, through study completion. If the most recent ophthalmic assessment is performed within 3 
months of ET, there is no need to repeat at ET. 
e Urinary pregnancy tests will be performed monthly for women of childbearing potential, and may be obtained at any time during the study as an unscheduled test if clinically 
appropriate. 
f PK sample collections at Week 132, Week 180 and Week 228 only. 
g 
, and 
at Week 132, Week 156, Week 180. and Week 204 only. 
 at Week 132 only. 

Study code: CRN00808-09 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 5.0 
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28 
 AE=adverse event, ASD=Acromegaly Symptoms Diary, D=Day, DT=Dose Titration, 
 
EOR=End of Treatment (RC phase), EOS=End of Study, EOT=End of Treatment, ET=Early Termination Visit, GH=growth hormone, HbA1c=hemoglobin A1c, IGF-1=insulin-
like growth factor-1, IWRS=interactive web response system, MRI=magnetic resonance imaging, OLE=open-label extension, 
 
, PK=pharmacokinetic, RC=randomized, controlled phase, REFs=references, TSH=thyroid-stimulating hormone; W=week 

Study code: CRN00808-09 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
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29 
2. 
INTRODUCTION 
2.1. 
Study Rationale 
Therapy for acromegaly is targeted at decreasing growth hormone (GH) and insulin-like growth 
factor-1 (IGF-1) levels, ameliorating patients' symptoms and decreasing any local compressive 
effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, 
radiotherapy, and medical therapies such as somatostatin receptor ligands, dopamine agonists, 
and the GH receptor antagonist pegvisomant.  
When surgery, which is the usual first-line treatment, fails to correct GH/IGF-1 hypersecretion, 
medical treatment can be used. Somatostatin receptor ligands (SRL) are, at present, the most 
widely used drugs to control acromegaly. Octreotide has been approved as an immediate-release 
injectable solution by the Food and Drug Administration since 1988 and in United Kingdom in 
1989. Octreotide is available under the brand name Sandostatin® by Novartis or as a generic 
form sold by several different suppliers. Octreotide long-acting formulation is marketed under 
the brand name Sandostatin LAR® by Novartis. It is administered as monthly deep intragluteal 
intramuscular injection. Lanreotide long-acting formulation is marketed under the brand name 
Somatuline® Depot in the United States by Ipsen. It is administered every 4 weeks (or 6 to 
8 weeks at the higher dose).  
Paltusotine is a nonpeptide orally bioavailable somatostatin receptor 2 (SST2) agonist that is 
administered once per day. In Phase 2 studies, daily oral administration of paltusotine has been 
shown to maintain GH and IGF-1 levels in subjects with acromegaly that were previously on 
octreotide LAR or lanreotide depot monotherapy. An orally bioavailable somatostatin agonist 
should reduce acromegaly patient burden by eliminating the pain and complications (e.g., 
subcutaneous, or intramuscular nodules) of injections and the cost and inconvenience of the 
health care provider office visits required for those injections. Additionally, it may allow 
physicians to determine an optimized dosing regimen more quickly compared with existing 
therapies. To our knowledge, paltusotine is the first nonpeptide oral somatostatin agonist being 
evaluated for the treatment of acromegaly. 
This study is a Phase 3 randomized, placebo-controlled trial. This is a standard design in this 
disease and, by avoiding potential bias in assessing clinical efficacy and safety, will allow the 
comparison between paltusotine versus placebo. IGF-1 levels as well as acromegaly-related 
symptoms will be monitored regularly throughout the study and criteria for rescue therapy have 
been defined to ensure subject safety. 
The proposed titration design aims to maintain subjects in their baseline biochemical status and 
optimize their dose while minimizing the period in which their IGF-1 is above baseline. Subjects 
will be switched from a stable regimen of octreotide/lanreotide to 40 mg paltusotine and their 
dose titrated up to 60 mg based on biochemical status and tolerability. Down-titration will be 
allowed based on tolerability. It is expected that by the end of titration period (Week 24) the 
concentrations of residual pre-trial octreotide or lanreotide will be too low to contribute to 
efficacy. Finally, the dose-titration design reflects how the drug is likely to be used in clinical 
practice. 

Study code: CRN00808-09 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
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2.2. 
Background 
Acromegaly is typically caused by a GH secreting tumor (adenoma) in the pituitary. Excess GH 
secretion results in excess secretion of IGF-1 from the liver, which causes bone overgrowth, 
organ enlargement, and changes in glucose and lipid metabolism. The symptoms of acromegaly 
include abnormal growth of hands and feet and changes in shape of the bones that result in 
alteration of facial features. Overgrowth of bone and cartilage and thickening of tissue leads to 
arthritis, carpal tunnel syndrome, joint aches, enlargement of lips, nose, and tongue, deepening of 
voice due to enlarged vocal cords, sleep apnea due to obstruction of airways, and enlargement of 
heart, liver, and other organs. Additional symptoms include thick, coarse, oily skin, skin tags, 
excessive sweating and skin odor, fatigue and weakness, headaches, impaired vision, goiter, 
decreased libido, menstrual abnormalities in women, and erectile dysfunction in men (Melmed 
and Kleinberg, 2016; Carroll and Jenkins, 2016; NIDDK diseases online health information).  
The major goals of treatment are to normalize serum GH and IGF-1, relieve pressure of the 
growing tumors, treat hormonal deficiencies, and normalize pituitary function. Surgical removal 
of pituitary adenoma, if possible, is the first option and often results in rapid symptom 
improvement. Parenterally administered SRLs are the most commonly employed primary 
pharmacological treatment options for patients that are not candidates for surgical removal of the 
tumor or when surgery is only partially successful or unsuccessful in achieving treatment goals 
(Melmed and Kleinberg, 2016; Carroll and Jenkins, 2016; NIDDK diseases online health 
information). Parenteral SRLs require large bore needles for monthly injections which often need 
to be administered by health care providers. Additionally, because these injections are depot 
preparations, dose optimization is prolonged, leading to delays in biochemical and symptomatic 
control of the disease. These agents, when used as monotherapy, achieve IGF-1 normalization in 
approximately 20 to 40% of patients.  
Paltusotine is a nonpeptide orally bioavailable SST2 agonist that is administered once daily (QD) 
under development for the treatment of acromegaly. Phase 1 clinical data suggest that QD 
paltusotine administration for up to 10 days can result in IGF-1 lowering in healthy volunteers. 
Phase 2 studies in subjects with acromegaly have shown subjects can successfully switch from 
long-acting octreotide or lanreotide therapy to QD oral paltusotine for a 13-week treatment 
period while maintaining IGF-1 levels, and that paltusotine appears to be well tolerated.  
The purpose of this current study is to evaluate the safety and efficacy of paltusotine in 
acromegaly subjects who are currently treated with either long-acting octreotide or lanreotide 
monotherapy. 
Additional details on the background of acromegaly, treatment options, and nonclinical and 
clinical data on paltusotine can be found in the current Investigator’s Brochure (IB). 
This study will be conducted in compliance with the protocol, the International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and with applicable local 
legislation including the Clinical Trial Regulation (CTR) EU No 536/2014. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of paltusotine may be found in the current version of the IB. 

Study code: CRN00808-09 
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31 
2.3.1. 
Risk Assessment 
Table 3: 
Risk Assessment Table 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk  
Mitigation Strategy 
Study Drug - Paltusotine 
Side effects 
Diarrhea, abdominal pain, nausea, 
abdominal discomfort, bradycardia 
(including sinus bradycardia and 
bradycardia), and cholelithiasis 
have been identified as ADRs 
associated with paltusotine. 
Rationale: these AEs are generally 
mild or moderate and did not lead 
to discontinuations. 
Clinical monitoring, symptomatic 
measures, study drug interruption if 
necessary. Regular safety 
surveillance, including laboratory 
testing, physical examinations, AE 
monitoring, ECG monitoring, and 
gall bladder monitoring, and 
evaluations for protocol specified 
study drug stopping rules per 
protocol. 
Study Procedures 
Participation in a placebo-
controlled trial evaluating an 
experimental agent 
Rise in GH/IGF-1 and worsening in 
acromegaly symptoms 
Clinical monitoring including 
frequent assessment of symptoms, 
AEs, safety laboratories, GH/IGF-1 
monitoring, and protocol defined 
rescue criteria 
Blood draws 
Pain, bleeding infection possible. 
Rationale: Needed for safety 
evaluation of study drug 
Symptomatic measures 
Pituitary magnetic resonance 
imaging scans (MRI)  
Claustrophobia, dizziness, mild 
nausea, numbness, tingling, muscle 
twitches, tiny flashing lights in field 
of vision, or momentary imbalance 
after leaving the magnet.  
Possible use of intravenous contrast 
with associated risk of renal injury 
(in people with severe kidney 
disease) or hypersensitivity reaction 
Rationale: Needed for monitoring 
of residual pituitary tumor volume 
Standard of care symptomatic and 
preventative management measures  
Biliary/gallbladder ultrasound 
Ultrasound waves may heat the 
tissues slightly and, in some cases, 
it can also produce small pockets of 
gas in body fluids or tissues. 
Rationale: Needed for monitoring 
gallbladder and biliary ducts 
Symptomatic measures 
Distance-corrected visual acuity 
testing 
Visual field testing 
There are no known risks or 
complications associated with these 
tests 
None needed 
Fundus photography 
Optical coherence tomography of 
the macula  
Some participants may experience 
some eye dryness or fatigue 
Symptomatic measures 
AE=adverse event; ADR=adverse drug reaction; ECG=electrocardiogram; GH/IGF-1=growth hormone/insulin-like 
growth factor 1 

Study code: CRN00808-09 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
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32 
2.3.2. 
Benefit Assessment 
On the basis of nonclinical data, paltusotine is expected to have benefit in the treatment of 
acromegaly.  
Completed Phase 2 studies CRN00808-02 and CRN00808-03 showed evidence for IGF-1 
maintenance in acromegaly subjects previously treated with long-acting injected octreotide or 
lanreotide who were switched to paltusotine oral monotherapy for a period of 13 weeks. Overall, 
IGF-1 levels after the switch to paltusotine were similar to those at baseline during treatment 
with long-acting injections. 
The overall safety profile of paltusotine appears to be consistent with those reported for other 
SRLs and common AEs observed with paltusotine are likely related to this mechanism of action. 
In addition to protocol specified safety surveillance, Investigators in clinical trials for paltusotine 
are advised to monitor subjects based on the known side effect profile of SRLs and manage as 
clinically appropriate. 
The ongoing COVID-19 pandemic has not presented a substantial new risk to the acromegaly 
subjects participating in the Phase 2 trials evaluating the safety and efficacy of paltusotine 
(CRN00808-02, CRN00808-03, and CRN00808-05). This protocol (Section 10.1.8) has 
incorporated flexibility in the need for in-person visits at study sites while safeguarding the 
health and well-being of trial participants and minimizing risk to trial and study data integrity. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Based on the available information, the known and potential risks of treatment with paltusotine 
are considered acceptable in relation to the potential benefits of treatment in subjects with 
acromegaly. 

Study code: CRN00808-09 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
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33 
3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives and Endpoints for the Controlled Part of the Study 
Objectives 
Endpoints 
Primary  
To evaluate the effect of paltusotine versus 
placebo on IGF-1 response 
Proportion of subjects who maintain biochemical 
response in IGF-1 (≤1.0×the upper limit of normal 
[ULN]) at the End of the Randomized Control 
Phase (EOR) 
Secondary  
To evaluate the effect of paltusotine versus 
placebo on IGF-1 level 
Change from baseline in IGF-1, in units of ULN, 
to EOR 
To evaluate the effect of paltusotine versus 
placebo on GH response 
Proportion of subjects with GH <1.0 ng/mL at 
Week 34, out of those who had GH <1.0 ng/mL at 
baseline 
To evaluate the effect of paltusotine versus 
placebo on acromegaly symptoms 
Change from baseline in Total Acromegaly 
Symptoms Diary (ASD) score to EOR 
Exploratory  
To evaluate the effect of paltusotine versus 
placebo on GH level 
Change from baseline to Week 34 in GH 
To evaluate the effect of paltusotine versus 
placebo on the need for rescue therapy 
Proportion of subjects who receive rescue therapy 
To evaluate the effect of paltusotine versus 
placebo on IGF-1 response 
Proportion of subjects who achieve IGF-1 
<1.3×ULN at EOR 
To evaluate the effect of paltusotine versus 
placebo on GH response 
Proportion of subjects with GH <2.5 ng/mL at 
Week 34 
To evaluate the effect of paltusotine versus 
placebo on tumor volume 
Change from baseline in residual tumor volume at 
EOR 
To evaluate loss of biochemical control 
Time from randomization to the first IGF-1 
>1.0×ULN for 2 consecutive visits 
Time from randomization to the first IGF-1 
≥1.3×ULN for 2 consecutive visits 

Study code: CRN00808-09 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
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Objectives 
Endpoints 
Safety  
To evaluate the safety and tolerability of 
paltusotine versus placebo in subjects with 
acromegaly 
Incidence of treatment-emergent adverse events 
(TEAEs), including serious adverse events 
(SAEs) and TEAEs that lead to discontinuation  
Change in safety parameters: clinical laboratory 
tests (hematology, serum chemistry, lipid panel, 
and hormones), vital signs, and 12-lead 
electrocardiogram (ECG) parameters 
Incidence of clinically significant changes in 
abdominal (gallbladder) ultrasound compared 
with baseline 
3.2. 
Objective and Endpoints for the Open-label Extension  
Objective 
Endpoints 
To evaluate the long-term safety and efficacy of 
paltusotine 
Safety endpoints:  
 
Incidence of TEAEs, including serious 
adverse events (SAEs) and TEAEs 
leading to discontinuation of study drug 
 
Change in quantitative safety parameters: 
clinical laboratory tests, lipid panel, 
hormones, vital signs, and 12-lead ECG 
parameters 
 
Ophthalmic assessments 
The same efficacy endpoints that are in the main 
study but at subsequent timepoints with the 
following additional efficacy endpoint: 
Proportion of subjects who receive permitted 
adjunctive standard acromegaly treatment 

Study code: CRN00808-09 
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Version 5.0 
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35 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, placebo-controlled, multi-center study. The study includes a Screening 
Period of up to 12 weeks. After the Screening Period, subjects will be enrolled in parallel in a 
36-week Treatment Period. Subjects will be randomly assigned in a 1:1 ratio to receive either 
paltusotine or placebo. At the end of the Treatment Period, subjects, who in the opinion of the 
Investigator, may benefit from treatment with paltusotine, may be enrolled in a long-term, open-
label extension (OLE) for up to 200 weeks. During the OLE, all subjects will receive paltusotine.  
Subjects who meet rescue criteria in the RC Phase will have treatment with paltusotine or 
placebo discontinued and will be considered non-responders, but they should be encouraged to 
continue in the study on rescue therapy for assessment and observation. These subjects can 
participate in the OLE phase if they meet all eligibility requirements including willingness to 
participate, and in the opinion of the Investigator, the subject may benefit from continued 
participation and treatment with paltusotine. See Figure 1 for the study schema. 
4.1.1. 
Screening 
The Screening Period consists of 2 to 3 visits over 4 to 12 weeks. Administration of the last 
pre-randomization long-acting SRL (octreotide/lanreotide) injections should be performed during 
Screening to maintain the dosing interval between octreotide/lanreotide and the first dose of the 
study drug, i.e., the first dose of study drug will be administered when the next dose of 
lanreotide/octreotide would have been due.  
The octreotide/lanreotide injection can be administered any time during the Screening Period 
provided 1) Day 1 aligns with the approximate scheduled date of the subject’s next 
octreotide/lanreotide injection (±3 days), and 2) the Screening Period does not exceed 12 weeks.  
The octreotide/lanreotide injection is the key temporal event during Screening. Day 1 (start of 
treatment) must be 4 weeks (±3 days) or 6 weeks (±3 days) after the last dose of 
octreotide/lanreotide if a subject is administered his/her octreotide/lanreotide every 4 weeks or 
6 weeks, respectively. Additionally, if a subject is administering his/her lanreotide every 
8 weeks, Day 1 (start of treatment) must be 8 weeks (±3 days) after the last dose of lanreotide. 
IGF-1 values must be confirmed by the average of at least 2 central laboratory tests during the 
Screening Period. If a third IGF-1 measurement is needed per the Investigator, the Medical 
Monitor should be consulted and the average of the 3 measurements must meet the IGF-1 criteria 
for eligibility. 
4.1.2. 
Treatment Period (Randomized, Controlled Phase)  
Once all Screening assessments are completed, the subject’s eligibility is verified by the 
Investigator and confirmed by the Medical Monitor via submission of the Medical Monitor 
Eligibility Verification Form. Subjects meeting all eligibility criteria and an average Screening 
IGF-1 ≤1.0×ULN will be randomized (1:1) to either paltusotine (n=26) or placebo (n=26) 
(Figure 1). 
The Treatment Period will be approximately 36 weeks.  

Study code: CRN00808-09 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
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36 
Subjects will not be administered octreotide/lanreotide on Day 1. Instead, subjects will receive 
their first dose of study drug on site (paltusotine or placebo). 
It is anticipated that the study drug dose will be stable, and titration completed prior to or at 
Week 24, with no dose titrations/adjustments after Week 24. Up-titration after Week 24 should 
not occur; subjects who require dose up-titration after Week 24 will be considered non-
responders. Down-titration will be allowed based on tolerability. See Figure 2 for the dose 
titration schema.  
If rescue therapy is required during the RC phase, subjects will discontinue paltusotine or 
placebo, initiate rescue therapy, and should continue the visits and surveillance in the study for 
the remainder of the 36-week RC phase (see Section 6.8.1 for Rescue Criteria). Only rescue 
therapy with approved SRLs (octreotide LAR or lanreotide depot monotherapy) will be 
permitted during the study. A Follow-up Visit will occur approximately 4 weeks after the last 
dose of study drug at Week 40, for subjects who do not enter the OLE. 
If the subject withdraws consent or, in the opinion of the Investigator, should be permanently 
discontinued from the study, the Early Termination (ET) Visit should be completed as specified 
in the Schedules of Activities (SOAs) and the subject should return to standard acromegaly 
treatment as prescribed by the Investigator. 
4.1.3. 
Open-label Extension Phase 
Subjects who complete the 36-week RC phase or who meet rescue criteria and complete the 
36-week RC phase with rescue medication can continue participation in the OLE phase if the 
subject is willing to participate and, in the opinion of the Investigator, the subject may benefit 
from continued participation and treatment with paltusotine. The OLE Treatment Period is 
200 weeks. Data from the EOR visit of the RC phase will be used as baseline of the OLE, unless 
otherwise specified. 
4.1.4. 
End of Study 
An End of Study (EOS) Visit, approximately 4 weeks after the last dose of study drug, will occur 
at Week 240 to collect final safety data and other assessments as detailed in the SOAs.  
4.1.5. 
Patient Input into Study Design 
Patient insight was collected over several meetings (November 2019-August 2020) through a 
formalized Patient Leadership Council made up of 12 individuals living with acromegaly. These 
patients had a range of experiences including treating physician, medication treatments, 
geographic location, and age of diagnosis. In these meetings, the following topics were 
discussed: treatment naïve and maintenance treatment study protocols, use of placebo, rescue 
therapy, frequency of visits, daily diary execution, study recruitment tactics, and participants’ 
preferred method of learning about potential studies. Results of these discussions were shared 
with the internal paltusotine study team and incorporated into study design where possible.  
4.2. 
Scientific Rationale for Study Design 
A prospective randomized, placebo-controlled trial is the gold standard methodology to define 
the safety and efficacy profile of an experimental drug. Placebo controlled trials have been 

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successfully conducted and are feasible in rare orphan diseases, including acromegaly. Protocol 
safeguards are in place to ensure subjects who experience worsening of symptoms associated 
with acromegaly receive rescue injections of standard therapy, to ensure that they can safely 
complete the trial (see Section 6.8.1). 
4.3. 
Justification for Dose and Treatment Duration 
The dose rationale and the proposed titration is designed to achieve the goal of maintaining 
subjects in a controlled state and optimizing their dose while minimizing the duration of being 
biochemically uncontrolled (i.e., elevated IGF-1) and experiencing the return of symptoms. 
Subjects will be switched from labeled stable regimen of octreotide/lanreotide to 40 mg 
paltusotine and titrated up to 60 mg based on biochemical control or down to 20 mg if 40 mg is 
not tolerable. Based on dose and exposure analysis of data from completed studies 
CRN00808-02 and CRN00808-03, the 40 mg dose is expected to be an effective dose for 
majority of the subjects. The systemic exposures associated with the lower 20 mg dose are 
expected to be sub-therapeutic in the majority of the subjects, but this lower dose is available for 
the few subjects who do not tolerate the 40 mg dose. A higher 60 mg dose is available for those 
subjects who may not derive a full benefit from the 40 mg dose. The safety of these doses has 
been evaluated in healthy volunteers and found to be similar to that of lower doses and other 
somatostatin receptor ligands. The dose-titration design reflects how the drug is likely to be used 
in clinical practice and provides a simple mechanism to switch subjects from parenteral therapy 
to oral therapy. 
Treatment duration was extended up to 240 weeks (approximately 4 ½ years), to allow 
participants, who in the opinion of the Investigator, are benefiting from treatment with 
paltusotine, to continue treatment. 
Data from an ongoing Phase 2 OLE clinical study (CRN00808-05) show that paltusotine lowered 
and maintained IGF-1 and GH at levels comparable to prior injected SRLs for up to 103 weeks. 
Additionally, RC Phase results from this placebo controlled pivotal study (CRN00808-09) show 
that paltusotine 40 or 60 mg QD provides sustained efficacy in terms of maintenance of disease 
control for up to 36 weeks in participants with acromegaly, who switched from being controlled 
on standard of care injectable SRLs. The durability of this clinical meaningful treatment effect 
was maintained in the OLE with participants continuing to experience clinical benefits. 
Paltusotine was well tolerated, with no unexpected safety findings with long-term treatment.  
4.4. 
End of Study Definition 
The EOS is defined as the date of the last visit of the last subject in the study. 
4.5. 
Treatment After End of Trial Participation 
After the end of the trial, participants may resume regionally licensed acromegaly treatment as 
prescribed by their healthcare provider. 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
1.  
Willing and able to provide written informed consent prior to any study-related 
procedures. 
2.  
Willing and able to comply with the study procedures as specified in the protocol 
and comply with the study treatment administration. 
Demographics and Medical History 
3.  
Adults ≥18 years of age with medically stable, confirmed-active acromegaly and on 
an approved, stable monotherapy dose of long-acting octreotide or lanreotide, for at 
least 12 weeks prior to Screening*. Continuous treatment with octreotide or 
lanreotide must be at least 24 weeks prior to Screening.  
*The following prior treatment regimens are allowed for inclusion into this study: 
long-acting octreotide: 10, 20, 30, 40 mg every 4 weeks or long-acting lanreotide: 
60, 90, 120 mg every 4 weeks or 120 mg every 6 or 8 weeks.  
4.  
Previous diagnosis of acromegaly confirmed by the Investigator and approved by the 
Medical Monitor. This requires evaluable documentation of a pituitary tumor 
diagnosed by pituitary imaging or histopathologic confirmation of a pituitary 
adenoma at least 24 weeks prior to Screening. 
For subjects who have had pituitary surgery, there must be documentation of IGF-1 
concentration ≥1.3×ULN at least 12 weeks after last pituitary surgery. The surgery 
must have been performed ≥24 weeks prior to Screening. Subjects who have not had 
pituitary surgery must have documentation of IGF-1 concentration ≥1.3×ULN 
performed ≥24 weeks prior to Screening.  
Screening and Testing Evaluations 
5.  
Screening average IGF-1 levels of ≤1.0×ULN.  
The upper limit for eligibility is mean IGF-1 of 1.04 (rounded to 2 decimal places) 
and will be based on 2 or 3 separate measurements in consultation with the Medical 
Monitor. 
6.  
Willing and able to undergo biliary/gallbladder ultrasound procedure and pituitary 
MRI during Screening and during the study. 
7.  
If currently using thyroid hormone therapy, the subject should be adequately treated 
based on clinical status and free thyroxine concentration measured during Screening 
and on a stable dose of thyroid hormone for at least 8 weeks prior to Screening. 

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Lifestyle Restrictions 
8.  
Females who engage in heterosexual intercourse must be of non-childbearing 
potential, defined as either surgically sterile (i.e., hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy), OR be postmenopausal with at least 
1 year of amenorrhea, OR must agree to use either a highly effective or a clinically 
acceptable method of contraception from the beginning of Screening until at least 
30 days after the last dose of study drug. 
 Acceptable highly effective methods of contraception include: 
 Non-cyclic, stable dose (monophasic) combined estrogen-progestin 
oral hormonal contraception associated with consistent inhibition of 
ovulation. Oral contraceptives containing estrogens should be in 
stable use for at least 12 weeks prior to Screening.  
 Desogestrel-based progestin-only contraception associated with 
consistent inhibition of ovulation; this includes oral, injectable, and 
implantable methods 
 Intravaginal and transdermal hormone delivery methods  
 Intrauterine device (with or without hormone elution) 
 Bilateral tubal occlusion or ligation (must be documented) 
 Vasectomized partner (must be documented) or 
 Sexual abstinence (only when it is the usual and preferred lifestyle of 
the subject) 
 Clinically acceptable methods of birth control include: 
 Male or female condom with or without spermicide; 
 Norethindrone-based progestin-only oral contraceptives; or 
 Cap, diaphragm, or sponge with spermicide.  
 Withdrawal method (“coitus interruptus”) is not permitted.  
9.  
If the subject is male, the subject should agree to use a condom when sexually active 
with a female partner of childbearing potential from Screening until at least 30 days 
after the last dose of study drug (or be surgically sterile [i.e., vasectomy with 
documentation]; or remain abstinent [when this is in line with the preferred and 
usual lifestyle]. Male subjects should also agree to not donate sperm for the duration 
of the study and until at least 30 days after the last dose of study drug. 
  

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5.2. 
Exclusion Criteria  
Medical History and Medications 
1.  
Treatment-naïve or treatment-withdrawn acromegaly subjects. 
2.  
History of pituitary radiation therapy.  
3.  
Subjects with adrenal insufficiency, diabetes insipidus, or central hypogonadism 
who are not receiving adequate hormone replacement therapy at the time of 
Screening, as determined by the Investigator. 
4.  
High risk pituitary tumor pattern as defined by: 
 Compression of the optic chiasm or invasion of adjacent brain structures 
(other than sphenoid sinus or cavernous sinus)  
 History of tumor growth within 1 year after surgery or radiation (unless it 
occurred during a period of medical therapy interruption) 
 Anticipated requirement for neurosurgical intervention or radiation 
therapy within the time course of the study. 
 Pituitary carcinoma currently or at any time in the past. 
5.  
History of major surgery/surgical therapy for any cause within 4 weeks prior to 
Screening. 
6.  
Diabetes mellitus treated with insulin for less than 6 weeks prior to the study entry, 
or with change in total daily insulin dose by >15% within 6 weeks prior to 
Screening. 
7.  
History of unstable angina or acute myocardial infarction within the 12 weeks 
preceding the screening visit or other clinically significant cardiac disease at the 
time of screening as judged by the Investigator. 
8.  
Known history of hepatitis B or human immunodeficiency virus, or active 
hepatitis C infection 
9.  
Known history of, or current alcohol or drug abuse, within the last year. 
10.  
Active malignant disease within the last 5 years with exception of basal and 
squamous cell carcinoma of the skin with complete local excision and resected 
carcinoma in situ of cervix. 
11.  
Concomitant mental condition rendering him/her unable to understand the nature, 
scope, and possible consequences of the study, and/or evidence of poor compliance 
with medical instructions. 

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12.  
Use of the following medications as outlined:  
 Pasireotide LAR (within 24 weeks prior to Screening), 
 Pegvisomant (within 12 weeks before Screening),  
 Dopamine agonists (within 12 weeks before Screening), or  
 Short-acting somatostatin analogs (SA-SSAs) within last 12 weeks 
before the first dose of study drug. 
Note: Withdrawal of these medications should be part of the subject’s medical care 
plan prior to Screening; entry into the study should not be the sole reason for 
withdrawal of a prior medication. 
13.  
Current use of oral estrogen replacement therapy for <12 weeks prior to Screening. 
14.  
Current use of medications that are strong inducers of cytochrome (CYP)3A4 within 
2 weeks prior to Screening (refer to Section 6.7.2 Prohibited Medicine). 
15.  
Known allergy or hypersensitivity to any of the test materials or related compounds. 
Screening Tests and Evaluations 
16.  
Active COVID-19 confirmed or suspected based on clinical symptoms. 
17.  
Symptomatic cholelithiasis. 
18.  
Clinically significant concomitant disease including but not limited to cardiovascular 
disease, moderate or severe renal insufficiency (estimated glomerular filtration rate 
<30 mL/min/1.73 m2), or significant liver disease (including cirrhosis). 
19.  
Clinically significant abnormal findings during the Screening Period or any other 
medical condition(s) or laboratory findings that, in the opinion of the Investigator, 
might jeopardize the subject’s safety or ability to complete the study. 
20.  
Systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg 
during Screening. If the initial measurement is out of range, it may be repeated 
2 more times after 15 minutes and the last assessment should be used to determine 
subject’s eligibility. 
21.  
Resting (at least 10 minutes) palpated pulse rate <45 bpm or >105 bpm during 
Screening. If either of these criteria is met, the assessment should be repeated 
2 more times and the last assessment should be used to determine the subject’s 
eligibility. 
22.  
QT interval corrected using Fridericia’s formula (QTcF) >480 msec (or corrected 
QT [QTc] interval >500 msec in the presence of complete bundle branch block) or 
PR interval >240 msec during Screening based on a central reading of an average of 
3 ECGs each separated in time by approximately 1 minute after the subject has 
rested quietly in the supine position for at least 10 minutes without significant 
stimulation (noise, television, etc.).  
23.  
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3×ULN 
and/or total bilirubin >1.5×ULN during Screening. Subjects with previously 
diagnosed Gilbert’s syndrome not accompanied by other hepatobiliary disorders and 
associated with total bilirubin <3.5 mg/dL (<51.3 µmol/L) will be permitted. 

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24.  
Poorly controlled diabetes mellitus defined as having a hemoglobin A1c (HbA1c) 
≥8.5% (≥ 69 mmol/mol), or estimated HbA1c based on fructosamine if HbA1c is not 
evaluable (e.g., due to hemoglobinopathies). 
25.  
Female subjects who are pregnant or lactating. Subjects must have a negative 
pregnancy test during Screening and prior to the first dose of study drug. 
26.  
Not applicable; exclusion criterion removed in protocol version 3.0. 
Other 
27.  
An employee or immediate family member of an employee of Crinetics. 
28.  
Participation in any previous clinical study with paltusotine. 
29.  
Subjects who have received an investigational drug (either approved or not 
approved) in any prior clinical study within 30 days or 5 half-lives (whichever is 
longer) prior to Screening. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Contraception 
Females who engage in heterosexual intercourse must be of non-childbearing potential, defined 
as either surgically sterile (i.e., hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy), OR be postmenopausal with at least 1 year of amenorrhea, OR must agree to use 
either a highly effective or a clinically acceptable method of contraception from the beginning of 
Screening until at least 30 days after the last dose of study drug. 
 Acceptable highly effective methods of contraception include: 
 Non-cyclic, stable dose (monophasic) combined estrogen-progestin oral hormonal 
contraception associated with consistent inhibition of ovulation. Oral 
contraceptives containing estrogens should be in stable use for at least 12 weeks 
prior to Screening.  
 Desogestrel-based progestin-only contraception associated with consistent 
inhibition of ovulation; this includes oral, injectable, and implantable methods 
 Intravaginal and transdermal hormone delivery methods  
 Intrauterine device (with or without hormone elution) 
 Bilateral tubal occlusion (must be documented) 
 Vasectomized partner (must be documented) or 
 Sexual abstinence (only when it is the usual and preferred lifestyle of the subject) 
 Clinically acceptable methods of birth control include: 
 Male or female condom with or without spermicide; 
 Norethindrone-based progestin-only oral contraceptives; or 
 Cap, diaphragm, or sponge with spermicide.  

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 Withdrawal method (“coitus interruptus”) is not permitted.  
If the subject is male, the subject should agree to use a condom when sexually active with a 
female partner of childbearing potential from Screening until at least 30 days after the last dose 
of study drug (or be surgically sterile [i.e., vasectomy with documentation]; or remain abstinent 
[when this is in line with the preferred and usual lifestyle]. Male subjects should also agree to not 
donate sperm for the duration of the study and until at least 30 days after the last dose of study 
drug. 
5.4. 
Screen Failures 
Subjects who fail to meet the eligibility criteria at any point during the Screening Period are 
defined as screening failures. The reason for each screening failure will be recorded.  
Subjects who have failed screening based on findings which the Investigator believes are 
temporary and not reflective of the usual state of the subject (e.g., HbA1c of ≥8.5% 
[69 mmol/mol] when the subject is usually well below this value) can be considered for 
re-screening. These cases should be discussed with the Medical Monitor. 

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6. 
STUDY DRUG AND CONCOMITANT THERAPY 
Study drug is defined as any investigational drug or placebo intended to be administered to a 
study subject according to the study protocol. 
6.1. 
Study Drugs Administered 
Paltusotine will be provided as 
 tablets in
 Matching 
placebo tablets will be identical in appearance to paltusotine tablets and will be administered 
orally according to the randomization scheme, on an identical schedule to those receiving 
paltusotine. Paltusotine and matching placebo tablets will each be packed in 
 containing desiccant. Drug labels will comply with the legal 
requirements of each country and will be printed in local language.  
The starting daily dose will be paltusotine 40 mg (or matching placebo) QD for oral 
self-administration. Study drug will be swallowed in the morning, with at least 8 ounces 
(237 mL) of water, after an overnight fast of at least 6 hours. No food or drink (except for water) 
will be allowed for at least 1 hour after drug administration, including time for study drug 
administration. The last dose of study drug for the RC phase will be self-administered the day 
prior to the W36/EOR visit. The first dose of the OLE phase will be administered during the 
W36/EOR visit for those continuing into the OLE. 
Table 4: 
Study Interventions 
ARM Name 
Paltusotine Arm  
Placebo Arm  
Intervention Name 
Paltusotine 
Placebo 
Type  
Drug 
Drug (placebo) 
Dose Formulation 
Tablet 
Tablet 
Unit Dose Strength(s) 
Placebo for 
 tablet 
Dosage Level(s) 
Starting dose is 
 tablets 
daily. The dose can be titrated up to 
tablets daily. Dose levels 
may be decreased to
 tablet 
daily. 
Starting dose is 
 tablets 
daily. The dose can be titrated up to 
tablets daily. Dose levels 
may be decreased to 
 tablet 
daily. 
Route of 
Administration 
Oral 
Oral 
Use 
Experimental 
Placebo  
IMP and AuxMP 
IMP  
IMP  
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 

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ARM Name 
Paltusotine Arm  
Placebo Arm  
Packaging and 
Labeling 
Sponsor will package and label the 
study drug. Drug labels will comply 
with the legal requirements of each 
country and will be printed in the 
local language. The labels will 
supply no information about the 
subjects. Each bottle or pack will 
have a unique Dispensing Unit 
Number (DUN) for drug 
accountability purposes and 
traceability. The storage conditions 
for study drug will be described on 
the study drug label. 
Sponsor will package and label the 
study drug. Drug labels will comply 
with the legal requirements of each 
country and will be printed in the 
local language. The labels will 
supply no information about the 
subjects. Each bottle or pack will 
have a unique DUN for drug 
accountability purposes and 
traceability. The storage conditions 
for study drug will be described on 
the study drug label. 
IMP=investigational medicinal product, AuxMP=auxiliary medicinal product 
Note: AuxMPs are described in Section 6.8. 
6.2. 
Preparation/Handling/Storage/Accountability 
The appointed team members will be identified at each center whose role in the study will be 
handling of the study drugs (i.e., they will be responsible for the receipt and accountability of the 
study drug). Furthermore, other tasks can be delegated to them in a clear manner by the 
Investigator and that will be documented and completed in the Study Staff Signature and 
Delegation Log. 
The Investigator must ensure the availability of proper storage conditions. Study staff at the 
study site will take all steps to maintain adequate records and will ensure that the study drug is 
stored as specified on the medication labels, in a strictly controlled, secure area, at appropriate 
temperature and in accordance with the protocol and any applicable regulatory requirements. 
Direct-to-subject shipments of study drug will be allowed in exceptional cases (i.e., where 
subjects would not be able to attend on-site visits and would risk continued access to study drug). 
Study drug will be provided by the Sponsor and are to be dispensed only in accordance with the 
protocol. Study drug must not be dispensed to any person not enrolled in the study. 
An accurate inventory and accountability records of the study drug will be kept by the appointed 
team member. Drug accountability must be performed for all delivered DUNs. Returned study 
drug (partly used or unused including empty packaging material) must be stored separately from 
non-allocated study drug. The storage temperature should be monitored by recording the actual, 
minimum, and maximum temperatures using a calibrated thermometer or thermocouple, or by 
continuous recording using a qualified temperature monitoring system. The temperature should 
be evaluated and documented at least on working days on a temperature log. This log must be 
included in the Investigator Site File upon study termination. 
The appointed study staff must contact the site monitor in case of temperature deviations outside 
the acceptable range. 
Paltusotine tablets and matching placebo tablets will each be packed in 
. Bottles of tablets should be stored at the study site at 
 

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Paltusotine and matching placebo will be provided by the Sponsor and the logistics of supply 
would be managed by the Sponsor/appropriate designee. 
All study drugs should be stored and inventoried according to applicable state and federal 
regulations and study procedures. 
At the end of the study (i.e., close-out visit) and following reconciliation and documentation by 
the site monitor, all study drugs and related materials will be either returned to the Sponsor or a 
designee or destroyed locally following the review and approval of the site’s destruction 
procedures. 
The study drugs (sufficient to last until the next planned visit) will be dispensed by the appointed 
study staff to the subjects at relevant study visits. 
Subjects will be instructed to store the study drug 
 in the 
original packaging and out of reach of children. The storage conditions will be carefully 
described to the subjects. 
If the Investigator, the site staff, or the site monitor suspect that the study drug is defective or 
potentially defective, Crinetics Pharmaceuticals or designee should be contacted immediately. 
Full details concerning study drug handling e.g., allocation, accountability, tracking, and 
recording will be provided in a Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Subjects will be randomized to study treatment, using an interactive, automated system which 
has been validated for the intended use under the International Society of Pharmaceutical 
Engineers Good Automated Manufacturing Practice guidelines, 21 CFR 11 (FDA regulation for 
Electronic Records and Electronic Signatures) and the International Council for Harmonization 
(ICH) Guidance E6 for Industry on GCP.  
Randomization will be performed using a fixed-block randomization scheme. The randomization 
scheme will be generated prior to the initiation of the study by an independent 
statistician/programmer who will not be a member of the study team; all Investigators and the 
study team will not be aware of the block size of the randomization scheme. Randomization will 
be stratified by IGF-1 level (<0.86×ULN, ≥0.86×ULN) and prior treatment (lanreotide or 
octreotide).  
Study drug will be dispensed at the study visits summarized in the SOAs.  
Returned study drug should not be re-dispensed to the subjects. 
The Interactive Voice Response System/Interactive Web Response System will be programmed 
with blind-breaking instructions. In case of an emergency, the Investigator has the sole 
responsibility for determining if unblinding of a subject’s intervention assignment is warranted. 
Subject safety must always be the first consideration in making such a determination. If the 
Investigator decides that unblinding is warranted, the Investigator should make every effort to 
contact the Medical Monitor prior to unblinding a subject’s intervention assignment unless this 
could delay emergency treatment of the subject. If a subject’s intervention assignment is 
unblinded, the Medical Monitor must be notified within 24 hours after breaking the blind. The 
date and reason that the blind was broken must be recorded in the source documentation. 

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Sponsor safety staff or designee may unblind the intervention assignment for any subject with an 
SAE. If the SAE requires that an expedited regulatory report be sent to 1 or more regulatory 
agencies, a copy of the report, identifying the subject’s intervention assignment, may be sent to 
Investigators in accordance with local regulations and/or Sponsor policy. 
6.4. 
Study Drug Compliance 
Subject randomization, study drug allocation, and dose titration must be performed in the 
interactive, automated system. 
When subjects are dosed during a study visit, they will receive study drug directly from the 
Investigator or designee, under medical supervision. The date and time of each dose 
administered during the visit will be recorded in the source documents. 
When subjects self-administer study drug at home, compliance will be assessed at each visit. 
Compliance will be assessed by either direct questioning and/or counting returned tablets during 
the site visits and documented in the source documents and relevant forms. Deviations from the 
prescribed dosage regimen should be recorded. 
A record of the quantity of study drug dispensed to and administered by each subject must be 
maintained and reconciled with study drug and compliance records. Study drug start and stop 
dates, including dates for study drug delays, drug interruptions and/or dose reductions, will also 
be recorded. 
Further details are provided in the Pharmacy Manual and relevant monitoring plan.  
Subjects will be instructed to return all used and unused study drugs at each study visit during 
the Treatment Period. All returned study drug and study drug materials should be stored, 
inventoried, reconciled, and returned according to applicable local regulations and study 
procedures. 
6.5. 
Dose Modification 
See Figure 2 for the dose titration schema. 
6.5.1. 
During the RC Phase 
The dose of study drug can be titrated up to 60 mg QD. Dose levels may increase from 40 mg 
tablets) to 60 mg (
tablets) based on IGF-1 response. It is anticipated that the 
study drug dose will be stable and titration completed prior to or at Week 24, with no dose 
titrations/adjustments after Week 24. Up-titration after Week 24 should not occur; subjects who 
require dose up-titration after Week 24 will be considered non-responders. Down-titration will 
be allowed based on tolerability.  
Dose up-titration will be based on 2 criteria: 
 Acceptable tolerability at the current dose, as evaluated by the Investigator, 
AND 
 The subject’s most recent IGF-1 result is >0.9×ULN  

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If needed, an unscheduled dose titration Visit may be performed. The study drug dose may be 
decreased at any time during the study if study drug toleration is unacceptable in the judgment of 
the Investigator. A dose reduction based on tolerability may be necessary for subjects who are 
taking P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) inhibitors (see 
Section 6.7.1). In general, a TEAE of severe intensity for which there is a reasonable possibility 
it is caused by (related to) study drug would be expected to result in study drug dose reduction. If 
tolerance improves following a dose reduction, the Investigator may increase the dose in 
 
increments, if needed, based on protocol specified dose titration criteria to a maximum of 60 mg 
 tablets). See Section 10.3.1 for the definition of a TEAE and Section 10.3.3 for 
definitions of intensity and causality. When, in the Investigator’s judgment the study medication 
is not tolerated, the study medication may be interrupted for up to a total of 14 days per year, but 
no more than 7 consecutive days per year, during the study followed by resumption of the study 
medication at the same or reduced dose as appropriate. 
During the RC phase, planned study visits are to occur approximately every 4 weeks; however, 
unscheduled visits may be required for more frequent monitoring, dose titration, and to assess 
rescue criteria. 
6.5.2. 
During the OLE 
The starting daily dose regimen for all subjects who participate in the OLE will be paltusotine 
40 mg QD, dispensed in an open-label manner. The first dose of the OLE phase will be 
administered at the W36/EOR visit. Subjects will be given bottles of paltusotine containing 
 tablets and instructed to take 2 tablets daily until their next visit.  
Dose escalation in the OLE will generally occur once the first IGF-1 result is available. At that 
time, the Investigator can determine whether the dose can be up-titrated to 60 mg.  
The study medication may be held for up to a total of 14 days, but no more than 7 consecutive 
days per year in the OLE. If the study drug has to be stopped for longer due to appropriate 
medical care for the subject, the medical monitor should be contacted. 
6.6. 
Treatment of Overdose 
There are no clinical data available on effects associated with overdose. No documented 
incidents of overdose have occurred with paltusotine to date. Preclinical animal studies indicate 
bradycardia or hypertension may result from overdose. The recommended treatment of overdose 
with paltusotine would include supportive and symptomatic measures employed in the 
management of overdose with a drug with potential cardiovascular events. 
6.7. 
Concomitant Therapy 
6.7.1. 
Permitted Medicine 
Concomitant medications allowed in this study are those non-prohibited medications used during 
Screening to control existing medical conditions and/or those initiated during the study if 
medically needed. All concomitant medications will be recorded in the subject’s electronic case 
report form (eCRF). If a new medication should become necessary for any reason during the 
course of the study, the subject is required to inform the Investigator immediately, who will 
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is responsible for ensuring the new medication is not prohibited by the protocol and to contact 
the Medical Monitor for any questions. 
Caution should be used when co-administering permitted concomitant medications that have the 
potential to interact with drug metabolizing enzymes or drug transporters shared with or affected 
by paltusotine (see IB and Paltusotine Guidance on Concomitant Medications reference 
document for Investigators). In addition, caution should be used with concomitant medications 
that have been associated with QT prolongation/Torsades de Pointes or may be associated with 
significant heart rate slowing. For a regularly updated list of drugs with known and possible risk 
for Torsade des Pointes, refer to www.crediblemeds.org. 
6.7.2. 
Prohibited Medicine 
Any questions regarding prohibited medications should be discussed with the Medical Monitor 
or appropriate designee. Prohibited medications include: 
 Oral estrogen, except for monophasic estrogen-progestin oral contraception; 
 Strong inducers of the drug metabolizing enzyme CYP3A4, including but not limited to: 
apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s 
wort (because these medicines may decrease the concentration of paltusotine in the 
systemic circulation); 
 Any standard acromegaly drug that is not used as a rescue medication during the RC 
phase of the study or an allowed adjunctive medication in the OLE; 
 Any other investigational drug, unless approved by the Medical Monitor (e.g., 
COVID-19 therapies). 
6.8. 
Auxiliary Medicinal Products  
6.8.1. 
RC Phase Rescue Medication (Auxiliary Medicinal Products) 
During the RC phase, acromegaly treatments other than study drug are prohibited, unless the 
subject meets criteria for rescue therapy as described below. 
Criteria for rescue with approved SRLs (injected long-acting octreotide or lanreotide [auxiliary 
medicinal products (AuxMPs)]) consist of the following: 
 Significant worsening of 1 or more acromegaly symptoms or the development of a 
new acromegaly symptom, at the highest dose (60 mg) for at least 2 weeks, as 
assessed by the Investigator. Symptoms should be attributed to uncontrolled 
acromegaly in the opinion of the Investigator and could include, but are not limited 
to, the following: headache, arthralgia, fatigue, hyperhidrosis, or soft tissue swelling. 
(“Significant worsening” in the opinion of the Investigator may be defined as 
symptoms requiring a substantial increase in level of clinical care [e.g., significant 
intervention needed to avert hospitalization or clinically notable increase in frequency 
or intensity of subject contact required] or substantial clinical deterioration [e.g., 
worsening from a mild to severe AE or the onset of an SAE would meet these 
criteria]). 
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 IGF-1 value ≥1.3×ULN at the highest dose (60 mg) measured at 2 successive planned 
visits or at an unscheduled visit if an earlier result is needed (as evaluated by the 
Investigator). 
It is anticipated that the study drug dose will be stable, and titration completed prior to or at 
Week 24, with no dose titrations/adjustments after Week 24. Up-titration after Week 24 should 
not occur; subjects who require dose up-titration after Week 24 will be considered non-
responders. If rescue therapy is required during the RC phase, subjects will discontinue 
paltusotine or placebo, initiate rescue therapy, and should continue the visits and surveillance in 
the study for the remainder of the 36-week RC phase. Rescue therapy should be used according 
to approved marketing authorization or standard clinical practice. 
Once rescue therapy is administered during the RC Phase, the subject will be considered as non-
responder.   
6.8.2. 
OLE Phase Adjunctive Treatments (Auxiliary Medicinal Products) 
If there is evidence of paltusotine efficacy and at 6 months, subjects have not reached therapeutic 
target goals, adjunctive treatment may be initiated if clinically appropriate beginning at Week 60. 
If these criteria are met, non-SRL acromegaly treatments, such as cabergoline or GH receptor 
antagonist pegvisomant are permitted and may be initiated as an adjunct when a subject has 
experienced at least 2 consecutive elevated IGF-1 (≥1.3×ULN) measurements at the highest 
paltusotine dose level (60 mg), or otherwise not at the subject’s therapeutic target in the 
judgement of the Investigator. 
 Use of any adjunctive medications should be discussed with the Medical Monitor and 
should be used according to approved marketing authorizations or standard practice. 
Adjunct medications are not provided by the Sponsor. 
 If it is determined that adjunctive medication is required, then use of cabergoline 
would be the expected first-line adjunct, as clinically appropriate. If after an adequate 
period of assessment, study medication combined with cabergoline does not achieve 
therapeutic targets, then pegvisomant may be added as a second-line adjunct, if 
clinically appropriate (Katznelson, 2014). In this situation, the Investigator should 
assess if there was evidence of an IGF-1 lowering response from cabergoline. If so, 
the pegvisomant may be added to the paltusotine + cabergoline drug combination. If 
there was no evidence of a therapeutic response to combined paltusotine + 
cabergoline, the cabergoline should be stopped and pegvisomant added to paltusotine 
therapy. 
 Short- and long-acting somatostatin receptor agonists (other than paltusotine) remain 
prohibited and are not permitted during the study (subjects will be discontinued from 
the study if these are needed and an ET Visit will be scheduled prior to resuming 
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7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment/Participation 
All subjects will be informed that they have the right to withdraw from the study at any time, for 
any reason, without prejudice, and without having to justify their reasons or decisions. 
Additionally, the Investigator may discontinue a subject’s participation at any time if he/she 
considers that to be in the subject’s best interest or if the Investigator determines that continuing 
participation would result in a significant safety risk for that subject. A discontinuation of 
treatment occurs when an enrolled subject discontinues participation in the study, regardless of 
the circumstances, prior to completion of the study. However, every effort should be made to 
observe subjects who have been enrolled until the scheduled end of their observation without 
study discontinuation, even if they discontinue early from the study drug treatment, if clinically 
appropriate. A subject who discontinues from study drug early by meeting protocol criteria for 
rescue with approved SRLs and completes the 36-week RC phase may be eligible for 
participation in the OLE portion of the study. Subjects who do not meet criteria for rescue, but 
for whom the Investigator recommends discontinuation of study drug and resumption of 
approved SRLs should be discussed with the Medical Monitor. Such cases will be considered for 
continuation in the RC phase on approved SRLs and eligibility for the OLE on a case-by-case 
basis.  
If a subject discontinues the study early, the Investigator should schedule an ET visit, particularly 
to ensure collection of AE follow-up data (if applicable) and to collect samples for laboratory 
evaluations. This visit should be documented as appropriate. The Investigator will record the 
reason for the study discontinuation and provide or arrange for appropriate follow-up and ensure 
return to standard acromegaly treatment for such subjects. In addition, the Investigator will 
report the subject’s withdrawal to the responsible Medical Monitor within 24 hours. In case of 
occurrence of adverse reactions the Investigator will ensure that adequate follow-up measures are 
in place to monitor the outcome of the adverse reaction itself. 
Reasons for a subject to discontinue the study treatment and/or participation in this clinical study 
include, but are not limited to:  
1. Withdrawal of informed consent by the subject; 
2. Occurrence of AEs for which study treatment and/or study participation discontinuation 
is desired by the subject or considered necessary by the Investigator or the Medical 
Monitor; 
3. Unacceptable tolerability of the lowest study drug dose (
 per day) in the opinion of 
the Investigator; 
4. Other clinically significant potentially drug-related abnormalities (e.g., newly developed 
or worsening hypoglycemia, hyperglycemia, hypersensitivity, symptomatic cholelithiasis, 
or pancreatitis); 
5. Investigator’s decision (i.e., if in the Investigator’s opinion it is not in the best medical 
interest for the subject to continue participation in the study for reasons other than AEs); 
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7. Any other protocol deviation that may result in a significant risk to the subject’s safety or 
protocol deviations that will interfere with assessment of the efficacy endpoints of this 
study, including subject’s non-compliance with the study procedures/study protocol;  
8. Pregnancy; 
9. Lost to follow-up (the subject stopped coming for visits, and study personnel are unable 
to contact the subject); 
10. Inability to fulfill study requirements and procedures; 
11. Death. 
12. After 6 months of treatment during the OLE phase, cabergoline and pegvisomant may be 
used as adjuncts to maximal dose paltusotine as clinically appropriate. Subjects who need 
to resume standard injected SRLs because paltusotine or paltusotine in combination with 
allowed adjuncts do not achieve adequate control of acromegaly will be discontinued 
from the study (see Section 6.8.2). 
7.1.1. 
Liver Chemistry Abnormality Monitoring and Study Drug Stopping Criteria 
Closely monitoring abnormalities of liver tests and discontinuation for evidence of liver injury 
will be performed according to the following process (DHHS DILI 2009): 
 Detection of Liver Test Abnormalities 
All subjects will have a serum chemistry panel as per the SOAs. Confirmation of 
detected liver test abnormalities is required for any subject with 1 or more of the 
following: 
 ALT or AST >3×ULN (for subjects with ALT and AST <ULN at baseline); 
 ALT or AST >3×ULN and >2×Baseline (for subjects with ALT or AST >ULN at 
Baseline); 
 Total bilirubin (TB) >2×ULN (for subjects with TB <ULN at baseline); 
 TB >2×ULN and >2×Baseline (for subjects with TB >ULN at baseline); 
 Alkaline phosphatase (ALP) >3×ULN (for subjects with ALP <ULN at baseline); 
 ALP >3×ULN and >2×Baseline (for subjects with ALP >ULN at baseline). 
 Confirmation of Detected Liver Test Abnormalities 
If any of the above-listed liver test abnormalities are detected, they should be 
followed by repeat testing within 48 to 72 hours (of ALT, AST, ALP, and TB) to 
confirm the abnormalities and to determine if they are increasing or decreasing. There 
also should be inquiries made about symptoms. 
If the above-listed liver test abnormalities (and/or related symptoms) persist or 
worsen, it is appropriate to initiate close observation to determine whether the 
abnormalities are improving or worsening over time. (See Close Observation 
recommendations below.) If close monitoring is not possible, the drug should be 
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 Close Observation of Any Subject with Detected Liver Test Abnormalities. 
Close observation includes: 
 Repeating ALT, AST, ALP, and TB tests 2 to 3 times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the study 
drug has been discontinued and the subject is asymptomatic; 
 Obtaining a more detailed history of symptoms and prior or concurrent diseases; 
 Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets;  
 Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; non-alcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary 
tract disease.  
 Obtaining a history of exposure to environmental chemical agents; 
 Obtaining additional tests to evaluate liver function, as appropriate 
(e.g., international normalized ratio); 
 Considering gastroenterology or hepatology consultations.  
Discontinuation of study drug for abnormal liver tests is required when a subject meets 1 of the 
conditions outlined below: 
 ALT or AST >8×ULN; 
 ALT or AST >5×ULN for more than 2 weeks; 
 ALT or AST >3×ULN and TB >2×ULN or INR >1.5; 
 ALT or AST >3×ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
7.1.2. 
Amylase or Lipase Study Drug Stopping Criteria 
The Medical Monitor should be contacted promptly if amylase or lipase levels increase from 
baseline by more than two-fold and exceed 3×ULN. Testing should be repeated within 1 week 
and if the amylase or lipase elevation persists, study drug should be stopped. The Medical 
Monitor and Investigator will determine together the appropriateness of continued study 
participation.  
7.1.3. 
Cardiac Study Drug Stopping Criteria 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
[average of triplicate ECGs] in QTcF after enrollment), the Investigator or qualified designee 
will determine if the subject can continue in the study and if any change in subject management 
is needed. Any new clinically relevant finding should be reported as an AE. 
Cardiology consultation should be obtained within 7 days for new clinically important symptoms 
or findings judged by the Investigator to be reasonably likely to be of cardiac origin, e.g., 
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Discontinuation of study drug is required when a subject meets 1 of the clinically significant 
cardiac symptoms or findings as outlined below: 
 Based on the average of triplicate ECGs, QTcF >500 msec (or QTc >530 msec in 
subjects with a bundle branch block) repeated on a second set of ECGs at least 
2 hours apart and confirmed by a stat central ECG reading;  
 Any ventricular tachyarrhythmia associated with symptoms of hemodynamic 
response; 
 Sustained ventricular tachycardia (lasting >30 seconds) irrespective of symptoms; 
 Torsades de pointes; 
 Cardiac arrest; 
 Pause >5 seconds; 
 Type 2 second degree block or third degree atrioventricular block; 
 New occurrence of clinically significant, symptomatic bradycardia; 
 Based on the average of triplicate ECGs, an increase in QTcF >60 msec with an 
absolute QTcF <500 msec repeated on a second set of ECGs at least 2 hours apart and 
confirmed by a stat central ECG reading; 
 Any supraventricular tachyarrhythmia associated with symptoms of hemodynamic 
response. 
The Medical Monitor and Investigator will determine the appropriateness of any further study 
drug dosing after stabilization of any of the above events. 
7.2. 
Lost to Follow up 
If a subject fails to attend scheduled assessments, the Investigator must determine the reasons 
and the circumstances as completely and accurately as possible.  
For subjects who are lost to follow-up (i.e., subjects whose status is unclear because they fail to 
appear for the study visits without stating an intention to withdraw), the Investigator should 
document in the source documents all steps taken to contact the subject (e.g., dates of telephone 
calls, registered letters, etc.). 
7.3. 
Criteria for Study Termination 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such reasons 
may include, but not limited to, the following: 
 Inefficacy of the study medication; 
 Results from ongoing safety monitoring; 
 Other medical or ethical reasons. 
Regulatory Authorities/Institutional Review Boards/Independent Ethics Committees (IRBs/IECs) 
also have the right to terminate the study for any reason.  
In the event the study is terminated, the IRBs/IECs and Competent Authorities will be notified of 
the relevant decision. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Demographics and Baseline Characteristics 
Demographics will include age, sex, ethnicity, and race. Baseline characteristics will include 
acromegaly history, medical history, and concomitant medications.  
Pre-trial acromegaly symptoms including assessment of the most bothersome symptom will be 
recorded. 
8.2. 
Subject-reported Assessments 
Planned time points for all subject-reported assessments are provided in the SOAs. When these 
assessments are done at the same visit, the order will be as follows: (1) Acromegaly Symptoms 
Diary, 
 These assessments will be 
completed using an electronic device (either through an application on the subject’s electronic 
device or by a device provided by the Sponsor). 
8.2.1. 
Acromegaly Symptoms Diary 
Subjects will be asked to complete the ASD, a brief symptom diary, daily at home beginning at 
least approximately 2 weeks prior to study drug dosing for the duration of the randomized 
controlled phase. Sparse periodic administrations at home or at study visits will be performed 
during the OLE. The ASD should be completed at approximately the same time of day, as 
consistently as possible. Site staff will review subject compliance with ASD completion at each 
study visit. Responses to the ASD will not be reconciled with AE data.  
The ASD consists of 9 items (headache pain; joint pain; sweating; fatigue; weakness in legs; 
swelling; numbness or tingling; difficulty sleeping; and a question on short-term memory), each 
ranked in intensity from 0-10. The total ASD score will be computed by adding the individual 
symptom intensities for headache pain; joint pain; sweating; fatigue; weakness in legs; swelling; 
and numbness or tingling, therefore total ASD score can range from 0-70. All individual item 
scores, including difficulty sleeping and the question on short-term memory will be collected and 
analyzed in individual item scoring. 
8.2.2. 
8.2.3. 

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8.2.4. 
 
8.2.5. 
 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SOAs. 
8.3.1. 
Physical Examinations 
A complete physical examination includes assessment of head (external), eyes, ears, nose and 
throat, lungs, cardiovascular system, abdomen, musculoskeletal system, skin, lymph nodes, 
central nervous system, ring size, and, where appropriate, other body systems. Symptom-related 
physical examinations (with weight measurement as appropriate) will also be performed. 
Physical examination will include height measurement at Screening and weight measurement at 
certain study visits. The study site must use calibrated equipment with subjects required to 
remove their shoes and heavy objects from their clothing prior to height and weight 
measurement, respectively. 
Any confirmed clinically significant physical examination abnormalities occurring after the 
moment of signing informed consent form (ICF) are to be recorded as AEs. 
8.3.2. 
Vital Signs 
Vital signs (blood pressure at rest, pulse rate, respiratory rate, and oral (or equivalent) body 
temperature) will be assessed as per standard practice at relevant study visits. When possible, 
vital signs should be performed while fasting after the study drug dosing. 
Blood pressure (resting) should be measured with calibrated digital equipment after resting 
quietly for 5 minutes.  

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Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Blood pressure and pulse rate measurements will be repeated at the Investigator’s 
discretion. Any confirmed clinically significant vital sign measurements occurring before signing 
the ICF are to be designated as medical history. 
8.3.3. 
Electrocardiograms 
A standard 12-lead ECG will be performed in triplicate (approximately 1 minute apart) after the 
subject has rested quietly in the supine position for at least 10 minutes without significant 
stimulation (noise, television, etc.). When possible, the ECGs should be performed while fasting 
after the study drug dosing. The ECG parameters that will be assessed include a summary of 
findings as well as measurement of the heart rate, QT, QTcF, and PR intervals, and QRS 
duration based on the ECG machine readings.  
All ECG assessments will be initially assessed by the Investigator for any findings that require 
immediate medical attention and will also be read by an ECG central reader. The clinical 
significance of any ECG findings will be determined by the Investigator, including after the 
central reading result is available. Only the Investigator’s assessment will be recorded in the 
eCRF. Any potentially significant outlier values should be confirmed by the central ECG reader. 
Any ECG measurement determined to be clinically significant (occurring after signing the ICF) 
will be noted as an AE on the appropriate eCRF page(s). Such abnormalities will be monitored 
until the end of the study or until resolution if considered related to the study drug. 
Refer to Section 7.1.3 for cardiac withdrawal criteria and any additional QTc readings that may 
be necessary. 
8.3.4. 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and to the SOAs for the 
timing and frequency. 
All analyses must be done with the minimally required blood amount and the number of needle 
insertions should be minimized during the blood collection.  
Laboratory management and shipping details are described in a Laboratory Manual.  
After sampling, blood collection tubes will be labelled and handled as defined in the Laboratory 
Manual. 
All results (except pharmacokinetics [PK] and genotyping) will be reported to the Investigator 
after completion of analyses. 
All laboratory reports received must be reviewed, assessed for clinical significance, signed, and 
dated by the Investigator or delegated sub-Investigator. A legible copy of all reports must be 
filed in a subject medical record (source document) for that visit. Any laboratory test result 
(occurring after the moment of signing ICF) considered by the Investigator to be clinically 
significant will be recorded as an AE and will be managed as described in Section 8.4. 
8.3.5. 
Biliary/Gallbladder Ultrasound 
Biliary/gallbladder ultrasound will be performed according to the study site procedures for the 
evaluation of presence or absence of lithiasis or sludge or other significant biliary abnormalities. 

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The ultrasounds can be performed at any time if clinically indicated in the opinion of the 
Investigator. An ultrasound is required for all subjects, including those that have had surgical 
removal of the gallbladder (cholecystectomy). The ultrasound does not need to be performed on 
the same day as the study visit. Ultrasounds may be performed within ± 2 weeks of the study 
visit. The results will be recorded.  
8.3.6. 
Magnetic Resonance Imaging 
Pituitary MRI should be performed locally and does not need to be performed on the same day as 
the study visit. MRIs may be performed within ± 2 weeks of the study visit. Tomography is not 
permitted as a replacement for MRI. Image acquisition standards will be provided and must be 
followed to allow proper evaluation of tumor volume. All MRI assessments will be assessed by 
the Investigator for any findings that require immediate medical attention and will also be read 
by an MRI central radiologist. The clinical significance of any MRI findings will be determined 
by the Investigator, including after the central reading result is available. However, only MRI 
results provided by the local report will be recorded in the eCRF. Management of subjects prior 
to and during the MRI should follow standard local procedures. 
8.3.7. 
Ophthalmic Assessments 
Ophthalmic assessments will be conducted on all subjects. Initial ophthalmic testing should be 
performed as soon as practical and then at 6-month intervals, preferably associated with 
scheduled visits whenever possible, through study completion. If the most recent ophthalmic 
assessment is performed within 3 months of ET, there is no need to repeat at ET. Assessments 
will be performed at a local facility with appropriate testing equipment and qualified personnel. 
The following assessments will be conducted: 
 Corrected distance visual acuity evaluation  
 Threshold visual fields (
)  
 Fundus photography of the macula (single photograph centered on macula in each 
eye) and 
 Optical coherence tomography of the macula  
Detailed specifications for acceptable instrumentation, data acquisition, data collection, and test 
results distribution processes will be provided to the investigative sites in separate ophthalmic 
assessment guidance documents. 
Visual acuity and threshold visual field results and images for fundus photography of the macula 
and optical coherence tomography of the macula will be transferred from the local testing facility 
to the designated data processing portal accessible by the 
 
8.4. 
Adverse Events, Serious Treatment-emergent Adverse Events, and 
Other Safety Reporting 
The definitions of AEs and SAEs can be found in Appendix 3. 
All medical conditions present prior to the study entry will be documented. However, medical 
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present prior to the study entry are to be recorded as AEs. All AEs occurring after the study drug 
administration has started will be considered as TEAEs. 
Investigators will be asked to assess whether each reported AE is a symptom of acromegaly. If 
AEs are attributed to acromegaly, they will be reported as AEs of special interest. 
The Investigator or qualified designee is obliged to interview a subject at every visit and 
clarify/discuss with him/her any abnormality that may indicate any potential AE/TEAE. 
Subjects should be informed that they do not have to wait for scheduled visits to report 
AEs/TEAEs. 
Adverse events related to the study drug that are ongoing at the end of the study will be followed 
for outcome information until resolution or stabilization. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Adverse events will be recorded from after the moment of signing ICF, up to 4 weeks after the 
last dose of the study drug. 
All SAEs will be recorded and reported to the Sponsor or designee immediately (and under no 
circumstance should this exceed 24 hours) of knowledge of the event, as indicated in 
Appendix 3. The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of it being available. 
Investigators are not obligated to actively seek information on TEAEs or SAEs after conclusion 
of the study participation. However, if the Investigator learns of any SAE, including a death, at 
any time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
8.4.2. 
Method of Detecting AEs  
Care will be taken not to introduce bias when screening for AEs. Open-ended and non-leading 
verbal questioning of the subject is the preferred method to inquire about AE or 
TEAE occurrences. 
8.4.3. 
Follow-up of AEs  
After the initial AE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. 
Any AE that occurs in the course of a clinical study must be monitored and followed up until 
either: 
 it has resolved, 
 laboratory abnormalities have returned to normal, OR 
 steady state of the symptoms has been achieved. 

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If none of these alternatives apply, then the subject must be asked about the evolution of the AE 
at the follow-up visit 4 weeks after the last dose of study drug. The status must be reported in the 
Case Report Form (CRF), and this ends the follow-up process for this AE. 
It is the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
Further information on follow-up procedures is provided in Appendix 3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to both expedited 
and periodic safety reporting to the regulatory authority, IRB/IEC, and Investigators. 
Any SAE occurring after the ICF has been signed and up until 4 weeks after the last dose of 
study drug must be reported to the designated Pharmacovigilance group.  
Any such SAE due to any cause, whether or not related to the study drug, must be reported on 
the SAE reporting form immediately (and under no circumstances should this exceed 24 hours of 
occurrence) or when the Investigator becomes aware of the event. A properly completed SAE 
reporting form should be sent via email.  
Pharmacovigilance Group e-mail: 
The event must also be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed by detailed descriptions, including clear and anonymized photocopies of hospital case 
reports, consultant reports, autopsy reports, and other documents when requested and applicable. 
SAE reports must be provided whether or not the Investigator considers the event to be related to 
the study drug. 
Appropriate measures should be taken to treat the SAE, and the response should be recorded. 
Clinical, laboratory, and diagnostic measures should be employed as needed in order to 
determine the etiology of the problem. The Investigator must report all available additional 
follow-up information to the Pharmacovigilance Group within 24 hours. All SAEs will be 
followed until the Investigator and Sponsor agree the event is satisfactorily resolved. 
Suspected unexpected serious adverse reactions (SUSARs, i.e., unexpected SAEs considered 
drug related as assessed by the Investigator/Sponsor/authorized person) will qualify for 
expedited reporting and cross reporting to the IRB/IEC, Competent Authorities, and participating 
Investigators by Crinetics Pharmaceuticals, Inc. In the EU, Crinetics Pharmaceuticals, Inc. will 
act in compliance with the CTR EU No 536/2014.  
SAEs occurring after the study termination must be reported only if considered study drug-
related per Investigator judgment.  
Any SAE that is not resolved by the end of the study or upon discontinuation of the subject’s 
participation in the study is to be followed until its resolution or stabilization. 

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8.4.5. 
Pregnancy 
Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening. All other pregnancy tests will be urine tests. If the result of a urine test is positive the 
result will be confirmed with a serum pregnancy test. Urinary pregnancy tests will be performed 
monthly at Screening, during RC phase, and during OLE phase when the duration between the 
visits is longer than 4 weeks. Pregnancy tests may also be obtained at any time during the study 
as an unscheduled test if clinically appropriate. Subjects must discontinue study drug 
immediately in the event of pregnancy in a female subject. Any pregnancy will be reported by 
telephone (optional) and by emailing a completed Pregnancy Exposure Report form to the 
Sponsor’s Pharmacovigilance Group within 24 hours of knowledge of the pregnancy at 
. The pregnancy will not be processed as a SAE. However, the Investigator 
will follow-up with the subject or female partner of the male subject (after obtaining informed 
consent, as appropriate) until completion of the pregnancy and must determine the outcome of 
the pregnancy in the shortest possible time. The Investigator should notify the Sponsor’s 
Pharmacovigilance Group of the pregnancy outcome by submitting a follow-up Pregnancy 
Exposure Report form. If the outcome of the pregnancy meets the criteria for immediate 
classification as a SAE (e.g., spontaneous or therapeutic abortion [any congenital anomaly 
detected in an aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator will report the event by telephone (optional) and by e-mailing a 
completed SAE Report form to the Sponsor’s Pharmacovigilance Group within 24 hours of 
knowledge of the event. 
8.5. 
Pharmacokinetics 
Plasma samples will be collected for measurement of plasma concentration of study drug as 
specified in the SOAs.  
To minimize patient burden, only sparse PK samples are to be collected at various study visits. 
Plasma paltusotine concentrations and elapsed time from the last paltusotine dose taken will be 
listed. A summary of concentrations by paltusotine dose for each timepoint will be presented. 
In addition, PK concentration data from this study will be pooled with data from other 
paltusotine studies for the planned population PK analysis to assess relevant intrinsic and 
extrinsic factors on paltusotine PK dispositions. 
Instructions for the collection, handling, and storage of biological samples will be provided by 
the Sponsor in the Laboratory Manual. The actual date and time (24-hour clock time) of 
collection of each sample will be recorded. The actual date and time of last dose of study drug 
prior to each sample collection will also be recorded. 
8.6. 
Genetics 
On Day 1, blood may be drawn for genotyping for the determination of the 
genotype. This is optional for subjects and consent will be 
obtained before the blood sample is collected. 
8.7. 
Biomarkers 
Blood will be drawn at the time points on the SOAs to measure IGF-1 and GH. 

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8.8. 
Immunogenicity Assessments 
Antidrug antibodies are not evaluated in this study.  
8.9. 
Collection and Storage of Biological Samples 
The Sponsor will comply with the applicable rules for the collection, storage, and future use of 
biological samples from clinical trial subjects. The Sponsor will comply with national 
requirements including those set in the CTR (EU) No 536/2014, Article 7.1 (h).  
A description of the arrangements to comply with CTR (EU) No 536/2014, Article 7.1 (h) is 
provided in the form ‘Compliance with Member State applicable rules for the collection, storage 
and future use of human biological samples (Article 7.1h)’ submitted as a Part 2 document of 
this trials Clinical Trials Information System (CTIS) submission. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary hypothesis:  
 
Ho: πplacebo = πPaltusotine 
 
Ha: πplacebo ≠ πPaltusotine 
Where πplacebo is the proportion of subjects at EOR with IGF-1 ≤1×ULN while on placebo and 
πPaltusotine is the proportion of subjects at EOR with IGF-1 ≤1×ULN while on paltusotine. 
9.2. 
Sample Size Determination 
The primary endpoint assumes that IGF-1 ≤1×ULN rates for paltusotine versus placebo are 70% 
and 20%, respectively. Based on a 2-sample Fisher’s Exact test at a 2-sided alpha=0.05 level of 
significance, a total sample size of 52 subjects (26 in the paltusotine arm, 26 in the placebo arm) 
will provide 93.6% power to achieve superiority of paltusotine over placebo. 
The estimates used for the power are based on Phase 2 data with paltusotine as well as the 
observed placebo response in similarly designed clinical study of oral octreotide (Chiasma Inc.; 
Optimal Study; EudraCT: 2017-000737-31). In the Phase 2 paltusotine acromegaly studies, the 
drop-out (discontinuation) rates were approximately 10%. These study discontinuation rates are 
accounted for in the estimates of overall non-response seen in a in similarly designed clinical 
study of oral octreotide (Chiasma Inc.; Optimal Study; EudraCT: 2017-000737-31) where 68% 
of the placebo group either dropped out or were on rescue medications defining them as a non-
responder. 
9.3. 
Analysis Sets 
The following analysis sets will be evaluated and used for presentation and analysis of the data in 
this study:  
 The Full Analysis Set (FAS) is defined from the intention-to-treat principle and will 
include all randomized subjects. The FAS will be the primary analysis set used for 
efficacy analyses. Treatment assignment will be based on the randomized treatment. 
 The Per Protocol (PPS) Analysis Set is defined as all randomized dosed subjects 
assigned to the treatment received, with no major protocol violations that would 
affect efficacy, and at least 75% treatment compliance based on tablet counts. This 
PPS will be used as a sensitivity analysis for the primary endpoint. 
 The Safety Analysis Set (SS) will include all subjects who received study drug with 
treatment assignment based on the treatment received. If a subject receives any 
amount of paltusotine then the subject will be assigned to the paltusotine group. The 
SS will be the primary analysis set used for safety analyses.  
Analysis Sets for Open-Label Extension 
 The OLE SS will include all subjects who received any amount of paltusotine in the 
OLE.  

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9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to the interim analysis (if undertaken), 
and it will include a more technical and detailed description of the statistical analyses described 
in this section. The SAP will also provide additional information about procedures for 
accounting for missing, unused, data, and will explain how to record and report any deviation 
from the original statistical plan. This section is a summary of the planned statistical analyses of 
the most important endpoints including primary and key secondary endpoints. 
There will be 2 formal database locks of all data, 1 at the end of the EOR and the other at the end 
of the OLE.  
9.4.1. 
General Considerations 
All continuous endpoints will be summarized showing the N, mean, median, standard deviation 
(SD), minimum and maximum values. Discrete endpoints will be presented showing the N and 
percentage. 
9.4.2. 
Efficacy Analyses 
9.4.2.1. 
Analyses  
The primary efficacy analyses will test for superiority in IGF-1 response rates at EOR between 
placebo and paltusotine, at a 2-sided alpha level of 0.05, an Exact Logistic Regression with 
covariates of baseline IGF-1 groups (<0.86×ULN, ≥0.86×ULN) and baseline prior treatment 
groups lanreotide, octreotide) in the FAS. Response is defined as an IGF-1 level ≤1.0×ULN 
(rounded to 2 significant figures based on the average of last 2 measurements at Week 34 and 
Week 36 (EOR). If only one measurement is available at Weeks 34 and 36, then just this one 
measurement will be used to define response. Nonresponse is defined as an IGF-1 level 
>1.0×ULN based on the average of the last 2 measurements or with IGF-1 missing at both 
Week 34 and Week 36. Subjects who discontinue treatment for any reason prior to EOR, receive 
prohibited standard acromegaly treatment, or titrate up in dose after Week 24 will be considered 
non-responders. The following sensitivity analyses will be performed on the primary endpoint: 
 Multiple imputations will be used to impute missing values. The same analysis will be 
performed as described above. Additional details defined in the SAP. 
 A completers analysis will be performed to include only FAS subjects who complete a 
minimum of 34 weeks of treatment. The same analysis will be performed as described 
above.  
 The primary endpoint analysis where subjects are not considered non-responders for 
titrating up in dose after Week 24. 
 All primary endpoint analyses will be performed on the PPS in addition to the FAS which 
will be the primary analysis set.  
Secondary endpoints in order of clinical importance along with their corresponding analyses are 
as follows: 
 Change from baseline in IGF-1 will be analyzed using a rank analysis of covariance 
(ANCOVA) model including fixed effects for treatment group with the ranked IGF-1 

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baseline group and baseline prior treatment group included as a covariate for the FAS. 
The Hodges-Lehman estimate of the median treatment difference with associated 95% 
confidence interval (CI) will also be presented. Baseline IGF-1 will be defined as the 
average of the measurements taken on Day 1 of first dose of study drug and the last 
IGF-1 value measured just prior to this day. EOR will be defined as the average of the 
last 2 assessments at Week 34 and Week 36 (EOR) for subjects who complete 36 weeks 
of treatment. If IGF-1 values are not available for both of these visits, then only the one 
available IGF-1 values will be used to define EOR. If IGF-1 is missing at both of these 
visits, subjects discontinue treatment, receive prohibited standard acromegaly treatment, 
or titrate up in dose after Week 24 then they will be assigned a rank based on the reason 
for missing data. Subjects will be ranked as follows, ordered from worst to best:  
1. Subjects who died prior to EOR where time to death is used to rank earlier deaths 
worse than later deaths; 
2. Subjects who are missing EOR and vital status is unknown at EOR; 
3. Subjects who are missing EOR because the subject physically cannot perform the 
test, due to physical incapacity, hospitalization, or other reason; 
4. Subjects who are missing EOR, known to be alive, took a prohibited standard 
acromegaly treatment where time to start of the prohibited treatment is used to rank 
earlier worse than later; 
5. Completed subject’s values will be ranked from worst (largest change) to best 
(smallest change). 
 Growth hormone maintenance of response will be analyzed for the FAS using the same 
methodology as the primary endpoint. Response is defined as GH <1 ng/mL at Week 34, 
in the subgroup of subjects with GH <1 ng/mL at baseline. Non-response is defined as 
GH ≥1 ng/mL or missing at Week 34. Subjects who discontinue treatment for any reason 
prior to EOR, take prohibited standard acromegaly treatment, or titrate up in dose after 
Week 24 will be considered non-responders.  
 Change from baseline in Total ASD score will be analyzed for the FAS using the same 
methodology specified for the change from Baseline in IGF-1. 
Exploratory endpoints will include nominal p-values with descriptive statistics. Continuous 
endpoints will be analyzed using parametric or non-parametric methods as applicable (to be 
defined in the SAP) and summarized with the number of non-missing observations, mean, SD, 
median, minimum, and maximum. Binary endpoints will be analyzed using the same 
methodology as specified for the primary endpoint and summarized using the number and 
percentage of subjects for each category. Where applicable, 95% CIs will also be calculated. 
Time to event endpoints will be analyzed using Kaplan-Meier methods with a Cox regression 
model hazard ratio to evaluate the magnitude of effect. 
9.4.2.2. 
Open-Label Extension 
The endpoints and analyses for the OLE will be defined in the SAP.  

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9.4.2.3. 
Multiplicity 
All hypothesis testing will be performed using the gatekeeping test strategy based on a fixed 
sequential method. The primary and secondary efficacy analyses will have an overall 2-sided 
level of significance at an alpha of 0.05. The secondary endpoints will be tested in the order they 
are listed in Section 9.4.2.1. The hypothesis testing of secondary endpoints will be conducted 
only if the primary efficacy endpoint comparison is statistically significant at the pre-defined 
alpha level of 0.05. If this comparison is not statistically significant, then the comparison of 
secondary efficacy endpoints will be considered nominal, descriptive, and exploratory.  
9.4.3. 
Safety Analyses 
The subject incidence of TEAEs, SAEs, and TEAEs leading to discontinuation will be 
summarized overall by system organ class and preferred term, and similarly by dose level. 
TEAEs will also be summarized by those on paltusotine monotherapy and paltusotine plus 
adjunctive therapy. 
Vital signs, clinical laboratory results (including lipid panel and thyroid hormone levels), and 
ECG data will be summarized descriptively. Subject level listings for all safety endpoints 
(including ophthalmic assessments) will be provided. 
9.4.4. 
Protocol Deviations 
Protocol deviations are defined as any variation from the protocol, including enrollment of a 
subject who did not meet all inclusion and exclusion criteria and failure to perform the 
assessments and procedures within the required time frame. Protocol deviations will be 
categorized as major or minor based on Sponsor review. 
The Sponsor or designee will be responsible for producing the final protocol deviation file, in 
collaboration with the data monitoring group as applicable. This file will be finalized prior to 
database lock. 
9.5. 
Interim Analysis 
An interim futility analysis may be conducted for the primary analysis of the primary endpoint 
when 50% of subjects have completed or withdrawn from the Treatment Period of the RC phase.  
If patient recruitment completes rapidly, there could arise a situation in which the results of the 
interim analysis cannot be made available in time to have a meaningful impact prior to study 
completion. This is a scenario in which the Sponsor may not perform the interim analysis. The 
limited conditional power calculation for potential interim assessment of futility will be 
evaluated by the unblinded Data Monitoring Committee (DMC). If conditional power is less than 
30% then the DMC will recommend that the study stop for futility. Otherwise, the DMC will 
recommend that the study continue as planned. No hypothesis testing will be performed for this 
analysis. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 54, 56, and 312 of 
Title 21 of the CFR, in compliance with GCP guidelines, and per all applicable local regulatory 
guidelines and Directive of the European Parliament, guidelines set out in Volume 10 of the 
publications "The rules governing medicinal products in the European Union” and other 
applicable European Medicines Agency regulations. 
Declaration of Helsinki and amendments can be accessed via the website of the World Medical 
Association at https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-
principles-for-medical-research-involving-human-subjects/. 
Conduct of the study must be approved by an appropriately constituted IRB or IEC. Approval is 
required for the Clinical Study Protocol, IB, protocol amendments, ICFs, and subject information 
sheets.  
Amendments to the Clinical Study Protocol that entail corrections of typographical errors, 
clarifications of confusing wording, changes in study personnel, and minor modifications that 
have no impact on the safety of subjects or the conduct of the study will be classified as 
administrative amendments and will be submitted to the IRB/IEC and Regulatory Authorities for 
information only. The Sponsor (or designee) will ensure that acknowledgement is received and 
filed. Amendments that are classed as substantial amendments must be submitted to the 
appropriate Regulatory Authorities and the IRBs/IECs for approval. 
Should protocol deviations that affect subject safety occur, the Sponsor must be informed as 
soon as possible. Important protocol deviations will be included in the Clinical Study Report 
(CSR). Reporting of protocol deviations to IRBs/IECs will be performed in accordance with 
applicable Regulatory Authority mandates and IRB/IEC policies. 
All subjects must meet all eligibility criteria in order to participate in the study. Protocol waivers 
for eligibility will not be granted by the Sponsor under any circumstances. If during the course of 
a subject’s post-enrollment participation in the trial it is discovered that the subject did not meet 
all eligibility criteria, the subject will be discontinued. 
10.1.2. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 

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10.1.3. 
Informed Consent Process 
For each study subject, written informed consent will be obtained prior to any protocol-related 
activities. An ICF must be signed and dated personally by the subject and by the Investigator 
and/or the study team member designated by the Investigator to conduct the informed consent 
procedure. 
As part of this procedure, the Investigator or 1 of his/her associates must explain orally and in 
writing the nature, duration, and purpose of the study, and the action of the drug in such a 
manner that the study is aware of the potential risks, inconveniences, or adverse effects that may 
occur. The subject should be informed that he/she may withdraw from the study at any time, and 
the subject will receive all information that is required by local regulations and ICH guidelines. 
The subject must provide free and willing consent to enroll in the study. (Note that the Sponsor 
does not consider persons who are housed in an institution under a court or official order capable 
of providing free and willing consent.) The Investigator will provide the Sponsor or its 
representative with a copy of the IRB/IEC approved ICF prior to the start of the study. 
10.1.4. 
Data Protection 
The Sponsor, as Data Controller, ensures that all processing activities involving personal data 
performed in the scope of this Study are compliant with, but not limited to, the requirements set 
by EU General Data Protection Regulation (GDPR 2016/679), its subsequent amendments and 
any additional national laws on Data Protection, recommendations, and guidelines as applicable. 
To maintain participant privacy, data capture tools, study drug accountability records, study 
reports, and communications will identify participants by their unique identifier (assigned 
participant number) generated and assigned by the electronic data capture (EDC) system. Any 
participant records or datasets that are transferred to the Sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable will not be 
transferred. 
The participant will be informed both verbally and in written form (ICF) that their personal 
study-related data will be used by the Sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who may be required to give consent 
for their data to be used as described in the ICF, including use of their data that may require a 
separate consent. The participant will also be informed that his/her medical records may be 
examined by Clinical Quality Assurance auditors, Monitors or other authorized personnel 
appointed by the Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
To comply with the applicable rules on the protection of personal data, specifically regarding the 
implementation of the organizational and technical arrangements aiming to avoid unauthorized 
access, disclosure, dissemination, alteration or loss of information and processed personal 
data, the Sponsor has implemented and maintains the following measures: 
 restriction and monitoring of physical access to the offices and information processing 
facilities to employees, personnel and approved visitors; 
 ensuring appropriate and restricted user access relevant to the function and type of 
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 implementing the pseudonymisation and encryption of personal data, as appropriate; 
 implementing the ability to ensure the ongoing confidentiality, integrity, availability and 
resilience of processing systems and services; 
 implementing network, application, and database security by means of firewalls and 
antivirus/anti-malware; ensuring detection of malware purposed for unauthorized 
deletion, blocking, copying of information, disabling security measures and response to 
such attacks; 
 means to restore the availability and access to personal information in a timely manner in 
the event of a physical or technical incident; 
 logging of security events/incidents in information systems; 
 implementing procedures that cover reporting, analysis, monitoring and resolution of 
security incidents; 
 ensuring that information systems, computers and software involved in the performance 
of the services provided in the Study are backed up; 
 a process for regularly testing, assessing and evaluating the effectiveness of technical and 
organizational measures for ensuring the security of the processing; 
 implementing procedures to capture within a reasonable time any personal data breaches; 
 implementing procedures and practices for the destruction of paper documents containing 
personal data; 
 implementing business continuity procedures ensuring continued provision of services 
through operational interruption 
All locations, personnel and information systems that are used to perform services for the Study 
will be covered. The Sponsor will ensure the technical and organizational security measures 
described above are regularly reviewed and updated considering any evolution of technological 
developments. 
The Sponsor may apply additional specific statutory requirements, where applicable in national 
laws, and will implement the necessary security measures even if they are not expressly listed 
above. 
In addition to the already mentioned technical and organizational measures, the Sponsor by 
means of internal measures and imposed standard contractual clauses to the selected contractors, 
service providers, vendors, or sub-contractors (collectively, “Representatives”), ensures the 
confidentiality of records and personal data of subjects. 
With exception of activities in the scope of on-site monitoring, the name of the patient will 
neither be asked for, nor recorded by Sponsor. An identification number will be allocated to each 
patient registered in the Study. This number will identify the patient and will be included on all 
CRFs and corresponding material and data associated with the patient. 
Monitors acting on behalf of Sponsor will have access to fully identifiable information only in 
the scope of the on-site monitoring visits, and only for mandatory source data verification, 
including ICH-GCP obligations, applicable to the conduct of the Study. Staff involved in the 

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performance of this task are bound by any additional stricter confidentiality clauses imposed 
upon them, as compared to other staff members. 
The Sponsor has implemented a functional process for reporting of any data breach occurring 
at Crinetics’ or its Representatives’ facilities and premises. Investigators must promptly report to 
the Sponsor's Data Protection Officer (DPO) any suspected data breaches relevant to personal 
study-related data the Sponsor holds about the participants. If there is a suspected breach related 
to data that the Sponsor holds, the Sponsor’s DPO will be responsible for investigating suspected 
data breaches and notifying authorities, where appropriate. In case of the occurrence of any data 
breach, the Sponsor will immediately apply relevant measures to mitigate the risks to data 
subjects as appropriate in relation to the specific context of the data breach, considering its 
source, underlying intentions, possibilities of recovery etc. Any data breach presenting risks to 
the rights and freedoms of data subjects will be reported to the relevant supervisory data 
protection authority within 72 hours of the Sponsor becoming aware of the data breach. In 
addition, in case of a high-risk data breach, subjects will be informed by the Sponsor. 
Investigators must promptly report to the Sponsor's DPO any participant request to know what 
personal study-related data the Sponsor holds about the participant. 
10.1.5. 
Data Monitoring Committee 
An unblinded DMC comprising independent subject matter experts will be established to 
evaluate the underlying disease and to assess the risk versus benefit of the interventions during 
the trial. The DMC will meet at intervals as specified in the DMC charter and may convene for 
ad hoc meetings if there are immediate safety concerns identified during the study. In the event 
an interim futility analysis is undertaken when 50% of subjects have completed the Treatment 
Period of the RC phase, the DMC will be responsible for evaluating those data.  
10.1.6. 
Dissemination of Clinical Study Data 
Once the study is completed and the CSR written, appropriate information will be provided for 
the clincialtrials.gov or clinicaltrialsregister.eu websites as required. All IRBs/IECs will receive 
appropriate documentation with study results. 
10.1.7. 
Data Quality Assurance 
The study will be conducted according to GCP (as outlined by ICH topic E6, step 5 guidelines) 
and in compliance with applicable local legislation including the EU CTR (EU No 536/2014). 
The contract research organization maintains a quality assurance system with written Standard 
Operating Procedures (SOPs) to ensure that clinical trials are conducted, and data are generated, 
documented, and reported in compliance with the Clinical Study Protocol, GCP, and applicable 
regulatory requirements. 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study. However, responsibility for the accuracy, completeness, and reliability of the study 
data presented to the Sponsor lies with the Investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the Clinical Study Protocol, SOP, GCP, and all 
applicable local regulatory requirements including the EU CTR (EU No 536/2014). Audits will 

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be independent of and separate from the routine monitoring and quality control functions. 
Quality assurance procedures will be performed at the study sites and during data management to 
assure that safety and efficacy data are adequate and well documented.  
Investigators/Institution will permit trial related audits, IRB/IEC review, and regulatory 
inspections, providing direct access to source data/documents. 
Study records and source documents must be preserved for at least 25 years after the completion 
or discontinuation of/withdrawal from the study or 2 years after the last approval of a marketing 
application in an ICH region or as per local requirements, whichever is the longer time period. 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information. The Investigator shall ensure 
that study subjects authorize the use and disclosure of protected health information in accordance 
with Directive 95/46/EC: Directive on the protection of individuals with regard to the processing 
of personal data and on the free movement of such data and in a form satisfactory to the Sponsor. 
 All subject data relating to the study will be recorded on printed or eCRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
 Electronic CRF completion guidance will be provided to Investigators. 
 The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
 Quality tolerance limits (QTLs) will be pre-defined in the Study Management Plan to 
identify systematic issues that can impact subject safety and/or reliability of study 
results. These pre-defined parameters will be monitored during the study and 
important deviations from the QTLs and remedial actions taken will be summarized 
in the CSR. 
 Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
 The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
 The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
 Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for the specified period of time after study 
completion as applicable per local and national regulations or institutional policies 
retention period require. No records may be destroyed during the retention period 
without the written approval of the Sponsor. No records may be transferred to another 
location or party without written notification to the Sponsor. 

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10.1.8. 
COVID-19 Procedures 
Investigators and clinical sites are expected to follow their country, local, and site requirements 
and guidance with respect to COVID-19 monitoring and detection procedures. Only approved 
and/or registered diagnostic tests (per local country requirements) should be used for the 
detection of COVID-19.  
The following preventive and protective safety measures will be in effect until local governments 
lift COVID-19 pandemic restrictions and subjects, monitors, and research staff can safely 
complete study procedures according to the protocol: 
 Site staff to inform study subjects of changes to the study conduct prior to 
implementation and obtain written consent prior to implementation. In regions where 
permitted, verbal consent approved for use and in such cases, the consent process and 
patient consent must be documented in the study records, including follow-up written 
consent.  
 In-clinic visits may be missed for COVID-19 related reasons at the discretion of the 
Investigator. Missed visits/procedures will be classified as protocol deviations due to 
COVID-19 and will be documented. The impact of deviations will be discussed in the 
final CSR. Subjects will not be discontinued from the study due to missed visits or 
procedures as a result of COVID-19. In order to minimize missed visits, home health 
care nursing may be used if available per country regulations. Note that not all 
countries allow home visits. In such countries, all visits must take place at the clinic 
site. 
 Site staff to contact each subject by phone at least once monthly, in place of projected 
in-clinic study visits, to assess their status, safety and compliance. These phone calls 
will be captured as Unscheduled Visits due to COVID-19.  
 Study subjects will be supplied with an adequate supply of study drug to guarantee 
continuous treatment. If COVID-19 related inability to conduct visits at sites, all 
subjects will be re-supplied with an additional supply of study drug, to allow 
continued treatment. If local regulations allow, study drug will be shipped directly to 
a subject’s home. Detailed instructions will be provided in the Guideline to 
Investigators for IMP Shipment from Site to Subject’s Home. In such cases, subjects 
must first provide informed consent (verbal or written as permitted/required by 
regional requirements) to share their personal contact information (e.g., name, 
address, and phone number) with the courier service. This consent will be 
documented as described above. 
 On-site Monitoring Visits by study monitors will be cancelled until it is safe for 
monitors to return to the study site and resume their regular monitoring activities, 
including complete drug accountability. If necessary (e.g., for SAEs) and permitted 
by country regulations, review of data will be performed remotely with consideration 
made to minimize site staff burden. All country and local laws, regulations, and 
guidance must be followed with respect to handling and processes of remote source 
data. 

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10.1.9. 
Source Documents 
The study will be monitored to ensure that it is conducted and documented properly according to 
the Clinical Study Protocol, GCP, and all applicable regulatory requirements. 
Before the study begins at a site initiation visit or at an Investigator’s meeting, a Sponsor 
representative will review the protocol and the eCRF with the Investigators and their staff. 
During the study, on-site monitoring visits will be made at appropriate times. Site monitors will 
visit the site regularly to check the completeness of subject records, the accuracy of entries on 
the eCRF, the adherence to the Clinical Study Protocol and to GCP, the progress of enrollment, 
the completeness of the IRB records and the Investigator Site File, and to ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the site monitor during these visits. 
The Investigator must give the site monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Full verification for the presence of informed consent, 
adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording of data 
that will be used for all primary and safety variables will be checked. Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the subjects will be 
disclosed. 
10.1.10. 
Publication Policy 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the Institution and the Sponsor or their designee. With respect to such rights, 
the Sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by Investigators and others performing the clinical study 
described in this Clinical Study Protocol, subject to the terms of any such agreement. To 
facilitate such ownership, Investigators will be required to assign all such inventions directly to 
the Sponsor as will be set forth in the clinical study agreement. 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
 The tests detailed in below will be performed by the central laboratory. 
 Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5 of the protocol. 
 Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
Table 5: 
Protocol-Required Safety Laboratory Tests 
Laboratory 
Tests 
Parameters 
Hematology 
Hemoglobin  
RBC Indices: 
Mean corpuscular volume 
Mean corpuscular 
hemoglobin 
Mean corpuscular 
hemoglobin concentration 
WBC count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Hematocrit  
RBC count 
Platelet count 
Clinical 
Chemistry 
Total protein 
Sodium 
Phosphate 
Aspartate 
aminotransferase 
Blood urea nitrogen 
Potassium 
Magnesium 
Alkaline phosphatase 
Creatinine 
Chloride 
Albumin 
Amylase 
Uric acid 
Calcium 
Total, direct, and 
indirect bilirubin 
Lipase 
Fasting lipid panel: total cholesterol, LDL, 
HDL, and triglycerides 
Alanine 
aminotransferase 
Glucose 
Thyroid 
Hormones and 
HbA1c 
Free T4, and TSH 
HbA1c 
IGF-1 and GH 
IGF-1 and growth hormone* 
Pregnancy testing 
Serum and urine human chorionic gonadotropin pregnancy test (as needed for women of 
childbearing potential) 
Routine 
Urinalysis 
Specific gravity and appearance 
White blood cells, protein, bilirubin, nitrites, ketones, blood, and pH, by dipstick 
Other Screening 
Tests 
Serology (HIV antibody, hepatitis B surface antigen, and hepatitis C virus antibody) 
Notes: 
Investigators must document their review of each laboratory safety report.  
*Fasting integrated GH consists of 5 samples collected at least 30 minutes apart over 3 hours. Integrated GH should 
be measured after at least a 4-hour fast and the subjects should remain fasting during the 3 hours of GH sampling. 
The integrated GH sampling at Week 34 should be started approximately 1-2 hours after study drug dose. 
Fasting blood samples (unless otherwise indicated) should be collected after an overnight fast of at least 6 hours. 
Subjects receiving pegvisomant as an adjunctive medication during the OLE portion of the study will not have 
growth hormone results analyzed while receiving this agent. 
GH=growth hormone; HDL=high-density lipoprotein; HIV=human immunodeficiency virus, IGF-1=insulin-like 
growth factor-1; LDL=low-density lipoprotein OLE=open-label extension; RBC=red blood cell; TSH=thyroid-
stimulating hormone; WBC=white blood cell 

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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with study participation, whether or not considered related to the study 
intervention. 
 NOTE: A TEAE is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated in either intensity or 
frequency) that is temporally associated with the use of study drug. 
  
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (i.e., not 
related to progression of underlying disease). 
 New conditions initially detected or diagnosed after study drug administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected interaction between a 
concomitant medication and study drug. 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
drug or a concomitant medication. Overdose in the absence of clinical sequelae will 
not be reported as an AE/SAE unless it is an intentional overdose taken with 
possible suicidal/self-harming intent. Such overdoses should be reported regardless 
of sequelae. 
  
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe or increased in frequency 
than expected for the subject’s condition. 

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 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
A SAE is defined as any serious event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the subject has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 

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f. 
Significant Medical Event: 
 Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the subject or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
 Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions or 
development of intervention dependency or intervention abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
 The Investigator will then record all relevant AE/ SAE information in the eCRF 
and on appropriate forms for the reporting of SAEs. 
 It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to the pharmacovigilance unit in lieu of completion of the required form. 
 There may be instances when copies of medical records for certain cases are 
requested by the pharmacovigilance unit. In this case, all subject identifiers, with 
the exception of the subject number, will be redacted on the copies of the medical 
records before submission. 
 The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
 Any SAE occurring after the ICF has been signed and up until 4 weeks after the 
last dose must be reported on SAE reporting form (see Section 10.3.4). 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:  
 Mild: An event that is easily tolerated by the subject, causing minimal discomfort, 
and not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with a SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of a SAE, NOT when it is rated as severe. 
  

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Assessment of Causality 
 The Investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
 The Investigator will use clinical judgment to determine the relationship using the 
following descriptors: not related, unlikely related, possibly related, probably 
related, and definitely related.  
NOT RELATED: This category applies to those AEs that are clearly and incontrovertibly 
due to extraneous causes (disease, environment, etc.). 
UNLIKELY: This category applies to those AEs that are judged to be unrelated to the IMP, 
but for which no extraneous cause may be found. An AE may be considered unlikely to be 
related to the IMP if or when it meets 2 of the following criteria: (1) it does not follow a 
reasonable temporal sequence from administration of the IMP; (2) it could readily have been 
produced by the subject’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the subject; (3) it does not follow a known pattern of response to the 
IMP; or (4) it does not reappear or worsen when the IMP is re‐administered. 
POSSIBLY: This category applies to those AEs for which a connection with the IMP 
administration appears unlikely but cannot be ruled out with certainty. An AE may be 
considered possibly related if or when it meets 2 of the following criteria: (1) it follows a 
reasonable temporal sequence from administration of IMP; (2) it could not readily have 
been produced by the subject’s clinical state, environmental or toxic factors, or other modes 
of therapy administered to the subject; or (3) it follows a known pattern of response to the 
IMP. 
PROBABLY: This category applies to those AEs that the investigator feels with a high 
degree of certainty are related to the IMP. An AE may be considered probably related if or 
when it meets 3 of the following criteria: (1) it follows a reasonable temporal sequence from 
administration of the IMP; (2) it could not be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental or toxic factors, or other modes 
of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose. There are exceptions when an AE does not disappear upon 
discontinuation of the IMP, yet drug-relatedness clearly exists (e.g., as in bone marrow 
depression, fixed drug eruptions, or tardive dyskinesia); or (4) it follows a known pattern of 
response to the IMP. 

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DEFINITELY: This category applies to those AEs that the investigator feels are 
incontrovertibly related to the IMP. An AE may be assigned an attribution of definitely 
related if or when it meets all of the following criteria: (1) it follows a reasonable temporal 
sequence from administration of the IMP; (2) it could not be reasonably explained by the 
known characteristics of the subject’s clinical state, environmental or toxic factors, or other 
modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose and recurs with re-exposure to the IMP (if re-challenge occurs); and (4) it 
follows a known pattern of response to the IMP. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study drug 
administration will be considered and investigated. 
 The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
 For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which a SAE has occurred, and the Investigator has 
minimal information to include in the initial report to the pharmacovigilance unit. 
However, it is very important that the Investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the 
pharmacovigilance unit. 
 The Investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. Possibly, probably, or definitely related will be recorded as 
related for regulatory reporting purposes. 
  
Follow-up of AEs and SAEs 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
pharmacovigilance unit to elucidate the nature and/or causality of the AE or SAE 
as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
 New or updated information will be recorded in the originally submitted 
documents. 

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 Adverse event outcomes will be recorded as 1 of the following: 
Recovered/Resolved, Recovering/Resolving, Not Recovered/Not 
Resolved/Ongoing, Recovered/Resolved with sequelae, Fatal, Unknown. 
Recovered/Resolved - One of the possible results of an adverse event outcome that 
indicates that the event has improved or recuperated. The subject recovered from the AE. 
Record the AE stop date. 
Recovering/Resolving - One of the possible results of an adverse event outcome that 
indicates that the event is improving. No AE stop date should be recorded. 
Not recovered/Not resolved/Ongoing - One of the possible results of an adverse event 
outcome that indicates that the event has not improved or recuperated. No AE stop date 
should be recorded. 
Recovered/Resolved with sequelae - One of the possible results of an adverse event 
outcome where the subject recuperated but retained pathological conditions resulting from 
the prior disease or injury. Record the AE stop date. The AE stop date will represent the 
date the AE stabilized with no change in event outcome anticipated. 
Fatal - The AE directly caused death. Record the date of death as the AE stop date. 
Unknown - There is an inability to access the subject or the subject’s records to determine 
the outcome (i.e., subject withdraws consent or is lost to follow-up). No AE stop date should 
be recorded. 
 The Investigator will submit any updated SAE data to the pharmacovigilance unit 
within 24 hours of receipt of the information. 
10.3.4. 
Reporting of SAEs 
SAE Reporting to the pharmacovigilance unit via SAE Reporting Form 
 The primary mechanism for reporting a SAE to the pharmacovigilance unit will be 
an SAE reporting form. Any such SAE due to any cause, whether or not related to 
the study drug, must be reported on the SAE reporting form immediately (and 
under no circumstances should this exceed 24 hours) of occurrence or when the 
Investigator becomes aware of the event. 
The SAE reporting form should be sent within 24 hours of knowledge of the event to: 
 
 If a site receives updated data on a previously reported SAE, then the site must 
report this follow-up information on the SAE reporting form and send to the 
pharmacovigilance group via 
  

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10.4. 
Appendix 4: Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ASD 
Acromegaly Symptoms Diary 
AST 
Aspartate aminotransferase 
AuxMP 
auxiliary medicinal product 
BCRP 
breast cancer resistance protein 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CSR 
Clinical Study Report 
CTIS 
Clinical Trials Information System 
CTR 
Clinical Trials Regulation 
CYP 
Cytochrome 
DPO 
Data Protection Officer 
DMC 
Data Monitoring Committee 
DT 
Dose titration 
DUN 
Dispensing unit number 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
electronic data capture 
EOR 
End of the Randomized Control Phase 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GH 
Growth hormone 
HbA1c 
Hemoglobin A1c 

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Abbreviation 
Definition 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like growth factor-1 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
LAR 
Long-acting release 
LDL 
Low-density lipoprotein 
MRI 
Magnetic resonance imaging 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Disease 
OLE 
Open-label extension 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
QD 
Once daily 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected using Fridericia’s formula 
QTL 
Quality tolerance limits 
RBC 
Red blood cell 
RC Phase 
Randomized, controlled phase 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SA-SSA 
Short-acting somatostatin analog 
SD 
Standard deviation 
SOAs 
Schedules of Activities 
SOP 
Standard Operating Procedure 
SRL 
Somatostatin receptor ligand 

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Abbreviation 
Definition 
SS 
Safety Set 
SST2 
Somatostatin receptor 2 
SUSAR 
Suspected unexpected serious adverse reactions 
TB 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
 
 
ULN 
Upper limit of normal 
W 
Week 
WBC 
White blood cell 
  

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11. 
REFERENCES 
Carroll PV and Jenkins PJ. Acromegaly. In: De Groot LJ, Chrousos G, Dungan K, et al, eds. 
Endotext. https://www.ncbi.nlm.nih.gov/books/NBK279097. Last updated Sep 2022. 
Katznelson L, Laws Jr ER, Melmed S. et al. Acromegaly: an endocrine society clinical practice 
guideline. J Clin Endocrinol Metab. 2014 Nov;99(11):3933-51. doi: 10.1210/jc.2014-2700. 
Melmed S and Kleinberg D. Pituitary masses and tumors. Chapter 9. pages 232-299. In: Melmed 
S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 13th 
Edition. Elsevier Inc. Copyright 2016. 
NIDDK diseases online health information. Acromegaly. https://www.niddk.nih.gov/health-
information/endocrine-diseases/acromegaly. Last accessed Nov 15, 2023. 
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). 
Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation. July 2009. 

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