A Randomized, Parallel Group Study to Evaluate the Safety, Pharmacokinetics, and Dose Response of Paltusotine Treatment in Subjects With Carcinoid Syndrome
Phase: PHASE2
Conditions: Carcinoid Syndrome, Carcinoid, Carcinoid Tumor, Carcinoid Tumor of Ileum, Carcinoid Tumor of Cecum, Carcinoid Syndrome Diarrhea, Carcinoid Intestine Tumor, Carcinoid Tumor of Liver, Carcinoid Tumor of Pancreas
Sponsor: Crinetics Pharmaceuticals Inc.

Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
Confidential 
1 
 
 
 
Protocol Title: 
A Randomized, Parallel Group Study to Evaluate the Safety, Pharmacokinetics, and Dose 
Response of Paltusotine Treatment in Subjects with Carcinoid Syndrome 
Protocol Number: CRN00808-11 
Compound: Paltusotine 
Study Phase: 2 
Sponsor Name: Crinetics Pharmaceuticals, Inc. 
Legal Registered Address:  6055 Lusk Blvd 
San Diego, CA 92121, USA 
Regulatory Agency Identifier Number(s) 
IND: 154584 
EudraCT: 2022-000762-18 
EU CT Number: 2024-511922-30-00 
Version: 7.0 
Protocol Date: 21 January 2025 
 
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: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
Confidential 
2 
DOCUMENT HISTORY/PROTOCOL AMENDMENT SUMMARY OF 
CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol (Version 1.0) 
20 August 2021 
Protocol Amendment (Version 2.0) 
24 September 2021 
Protocol Amendment (Version 3.0) 
16 December 2021 
Protocol Amendment (Version 3.1) 
29 January 2022 
Protocol Amendment (Version 4.0) 
05 April 2022 
Protocol Amendment (Version 5.0) 
21 March 2023 
Protocol Amendment (Version 6.0) 
20 November 2023 
Protocol Amendment (Version 7.0) 
21 January 2025 

Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
Confidential 
3 
SPONSOR SIGNATURE PAGE 
Sponsor’s Approval 
The protocol has been approved by Crinetics Pharmaceuticals, Inc. (herein, Crinetics or Sponsor) 
Responsible Medical Officer: 
 
 Clinical Research 
Sponsor’s Medical Contact: 
 
See last page for electronic signature manifestation 
 
 
_________________________________________        ________________________ 
                                                           Date 
  
 Clinical Research 
 
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Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
Confidential 
4 
Protocol Number: CRN00808-11 
A Randomized, Parallel Group Study to Evaluate the Safety, Pharmacokinetics, and Dose 
Response of Paltusotine Treatment in Subjects with Carcinoid Syndrome 
Protocol Version: 7.0 
Protocol Date: 21 January 2025 
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: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
Confidential 
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TABLE OF CONTENTS 
DOCUMENT HISTORY/PROTOCOL AMENDMENT SUMMARY OF CHANGES 
TABLE .........................................................................................................................2 
SPONSOR SIGNATURE PAGE ....................................................................................................3 
CRN00808-11 SUMMARY OF CHANGES ................................................................................10 
1. 
PROTOCOL SUMMARY ..........................................................................................17 
1.1. 
Synopsis ......................................................................................................................17 
1.2. 
Schedule of Activities .................................................................................................29 
2. 
INTRODUCTION ......................................................................................................36 
2.1. 
Study Rationale ...........................................................................................................36 
2.2. 
Background .................................................................................................................36 
2.3. 
Benefit/Risk Assessment ............................................................................................37 
2.3.1. 
Safety Risk Assessment ..............................................................................................38 
2.3.2. 
Benefit Assessment .....................................................................................................39 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................40 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................41 
3.1. 
Objectives and Endpoints of the Study .......................................................................41 
4. 
STUDY DESIGN .......................................................................................................45 
4.1. 
Overall Design ............................................................................................................45 
4.1.1. 
Screening ....................................................................................................................45 
4.1.2. 
Randomized Treatment Phase ....................................................................................52 
4.1.2.1. 
Treatment of Breakthrough Carcinoid Syndrome Symptoms During 
Randomized Treatment Phase ....................................................................................52 
4.1.3. 
Open-Label Extension Phase ......................................................................................54 
4.1.4. 
Study Completion and Early Termination ..................................................................55 
4.1.5. 
End of Randomized Treatment Phase and End of Treatment .....................................55 
4.1.6. 
End of Study ...............................................................................................................56 
4.1.7. 
Patient Input into Study Design ..................................................................................56 
4.2. 
Scientific Rationale for Study Design ........................................................................56 
4.3. 
Justification for Dose ..................................................................................................56 
4.4. 
Justification for Duration of Treatment ......................................................................57 
4.5. 
Treatment After End of Trial Participation ................................................................57 
5. 
STUDY POPULATION .............................................................................................58 

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5.1. 
Inclusion Criteria ........................................................................................................58 
5.2. 
Exclusion Criteria .......................................................................................................60 
5.3. 
Screen Failures ............................................................................................................61 
6. 
STUDY INTERVENTION ........................................................................................63 
6.1. 
Study Intervention(s) Administered ...........................................................................63 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................64 
6.3. 
Measures to Minimize Bias: Blinding ........................................................................64 
6.4. 
Study Intervention Compliance ..................................................................................64 
6.5. 
Study Intervention Dose Modification .......................................................................65 
6.5.1. 
Dose Adjustment During the Randomized Treatment Phase .....................................65 
6.5.2. 
During the Open-Label Extension Phase ....................................................................65 
6.6. 
Treatment of Overdose ...............................................................................................65 
6.7. 
Concomitant Therapy .................................................................................................66 
6.7.1. 
Permitted Medications ................................................................................................66 
6.7.2. 
Prohibited Medications ...............................................................................................66 
6.7.3. 
Rescue Medications (Auxiliary Medicinal Products) .................................................67 
7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................68 
7.1. 
Discontinuation of Study Treatment/Participation .....................................................68 
7.1.1. 
Amylase or Lipase Study Drug Stopping Criteria ......................................................69 
7.1.2. 
Cardiac Study Drug Stopping Criteria ........................................................................69 
7.1.3. 
Liver Chemistry Abnormality Monitoring and Study Drug Stopping Criteria ..........70 
7.1.4. 
Neurological Adverse Events .....................................................................................71 
7.2. 
Lost to Follow-up .......................................................................................................71 
7.3. 
Criteria for Study Termination ...................................................................................71 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................72 
8.1. 
Demographics and Baseline Characteristics ...............................................................72 
8.2. 
Subject-reported Assessments ....................................................................................72 
8.2.1. 
Electronic Symptom Diary .........................................................................................72 
8.2.2. 
Global Impressions of Change and Severity ..............................................................73 
8.2.3. 
EQ-5D-5L ...................................................................................................................73 
8.2.4. 
EORTC QLQ-C30 Quality of Life Questionnaire......................................................73 
8.2.5. 
EORTC QLQ-GI.NET21 Quality of Life Questionnaire ...........................................73 

Study code: CRN00808-11 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
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8.2.6. 
FACT-CSI...................................................................................................................73 
8.2.7. 
Treatment Preference Question ..................................................................................73 
8.3. 
Safety Assessments .....................................................................................................74 
8.3.1. 
Physical Examinations ................................................................................................74 
8.3.2. 
Vital Signs ..................................................................................................................74 
8.3.3. 
Electrocardiograms .....................................................................................................74 
8.3.4. 
Continuous Cardiac Monitoring .................................................................................75 
8.3.5. 
Clinical Safety Laboratory Assessments ....................................................................75 
8.3.6. 
Biliary/Gallbladder Ultrasound ..................................................................................75 
8.3.7. 
Ophthalmic Assessments ............................................................................................75 
8.4. 
Adverse Events, Serious Treatment-emergent Adverse Events, and Other 
Safety Reporting .........................................................................................................76 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................76 
8.4.2. 
Method of Detecting Adverse Events .........................................................................77 
8.4.3. 
Follow-up of Adverse Events .....................................................................................77 
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events .............................77 
8.4.5. 
Pregnancy ...................................................................................................................78 
8.5. 
Pharmacokinetics ........................................................................................................78 
8.6. 
Pharmacogenomics .....................................................................................................79 
8.7. 
Biomarkers ..................................................................................................................79 
8.8. 
Imaging and Tumor Surveillance ...............................................................................79 
8.8.1. 
Surveillance of Tumor Growth ...................................................................................79 
8.9. 
Additional Assessments ..............................................................................................80 
8.9.1. 
Subject Interview ........................................................................................................80 
8.9.2. 
Unscheduled Visit .......................................................................................................80 
8.10. 
Collection and Storage of Biological Samples ...........................................................80 
9. 
STATISTICAL CONSIDERATIONS .......................................................................81 
9.1. 
Statistical Hypotheses .................................................................................................81 
9.2. 
Sample Size Determination ........................................................................................81 
9.3. 
Analysis Sets ...............................................................................................................81 
9.4. 
Statistical Analyses .....................................................................................................81 
9.4.1. 
General Considerations ...............................................................................................81 
9.4.2. 
Efficacy Analyses .......................................................................................................82 

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9.4.2.1. 
Analyses ......................................................................................................................82 
9.4.2.2. 
Multiplicity .................................................................................................................85 
9.4.3. 
Safety Analyses ..........................................................................................................86 
9.4.4. 
Protocol Deviations ....................................................................................................86 
9.5. 
Interim Analysis ..........................................................................................................86 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................87 
10.1. 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ..................................................................................................87 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................87 
10.1.2. 
Financial Disclosure ...................................................................................................87 
10.1.3. 
Informed Consent Process ..........................................................................................88 
10.1.4. 
Data Protection ...........................................................................................................88 
10.1.5. 
Safety Monitoring Committee ....................................................................................89 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................89 
10.1.7. 
Data Quality Assurance ..............................................................................................89 
10.1.8. 
COVID-19 Procedures ................................................................................................90 
10.1.9. 
Source Documents ......................................................................................................91 
10.1.10. 
Publication Policy .......................................................................................................91 
10.2. 
APPENDIX 1: CLINICAL LABORATORY TESTS ................................................92 
10.3. 
APPENDIX 2: ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ...............................................93 
10.3.1. 
Definition of Adverse Event .......................................................................................93 
10.3.2. 
Definition of Serious Adverse Event ..........................................................................94 
10.3.3. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event ............95 
10.3.4. 
Reporting of Serious Adverse Events .........................................................................98 
10.4. 
APPENDIX 3: ABBREVIATIONS ...........................................................................99 
11. 
REFERENCES .........................................................................................................101 
 

Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
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LIST OF TABLES 
Table 1: 
Schedule of Activities - Randomized Treatment Phase .............................................29 
Table 2: 
Schedule of Activities - Open-Label Extension Phase ...............................................33 
Table 3: 
Oral Antidiarrheal Agents During the Screening Period ............................................51 
Table 4: 
Use of Short-acting Octreotide During the Screening Period ....................................51 
Table 5: 
Possible Treatment Regimens for Breakthrough Symptoms ......................................52 
Table 6: 
Short-acting Octreotide Rescue Therapy ....................................................................53 
Table 7: 
Dose Adjustments During Randomized Treatment Phase ..........................................53 
Table 8: 
Dose Adjustments during Open-Label Extension Phase ............................................55 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................18 
Figure 2: 
Screening Schematics for Subjects Not Currently Treated with Any SRL 
Therapy .......................................................................................................................46 
Figure 3: 
Screening Schematics for Subjects Using Pretrial Lanreotide or Octreotide 
LAR ............................................................................................................................48 
Figure 4: 
Screening Schematics for Subjects Using Regular Doses of Short-acting 
Octreotide ...................................................................................................................50 
 

Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
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CRN00808-11 SUMMARY OF CHANGES 
Version 6.0 to Version 7.0 
This Summary of Changes includes all changes made from Version 6.0 to Version 7.0  
This amendment is to ensure the protocol is compliant with EU Clinical Trials Regulation (CTR) 
(EU No 536/2014) and includes adverse drug reaction (ADR) updates which align with the 
revised Paltusotine Investigator’s Brochure. 
Underlined text in the table denotes added text; strikethrough text denotes deleted text. 
Section 
Summary of Changes 
Rationale 
Throughout protocol 
 
Revised text for clarity as needed 
 
Revised/updated order of headings, text and/or tables, 
version number, dates, and footnotes as needed 
 
Revised abbreviations and definitions as needed 
Minor corrections for 
clarity or consistency 
Throughout protocol 
 
Updated Sandostatin and Somatuline references  
 
Deleted text referring to “ongoing COVID 19 
pandemic” 
Minor updates to align 
with current version or 
current events 
Responsible Medical 
Officer 
 
 Clinical Research 
Updated study 
information 
Sponsor’s Authorized 
Officer 
Sponsor’s Authorized OfficerMedical Contact: 
 
  
  
 Clinical Research 
 
Updated study 
information 
Principal Investigator 
Signature Page 
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. 
Updated to ensure 
compliance with EU CTR 
(EU No 536/2014). 
Synopsis/Figure 1 
For subjects completing the OLE Phase, EOS Visit will be 
at Week 62. 
Updated to align with 
definition of EOS in 
Section 4.1.6  
Synopsis/Screening 
Antidiarrheal Agents Agent Use During Screening 
(Concomitant Medications) 
Antidiarrheal agents, diphenoxylate and loperamide, are 
considered concomitant medications and may be used 
during screening as recommended by the Investigator.  
Updated to comply with 
Clinical Trial Regulation 
(CTR) EU No 536/2014. 
Synopsis/Screening 
Rescue Medication Use During Screening (Auxiliary 
Medicinal Product) 
Short-acting octreotide is considered a rescue medication 
(ie, auxiliary medicinal product) 
 
 Investigators 
should 
 
 
 
Updated to comply with 
Clinical Trial Regulation 
(CTR) EU No 536/2014. 
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Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
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Section 
Summary of Changes 
Rationale 
Synopsis/Randomized 
Treatment Phase 
Rescue Treatment of Breakthrough Carcinoid Syndrome 
Symptoms 
Antidiarrheal Agent Use During RTP  
Rescue Medication Use During RTP 
Updated to comply with 
Clinical Trial Regulation 
(CTR) EU No 536/2014. 
2.2 Background 
Paltusotine is also under development for the treatment of 
acromegaly, with two Phase 2 trials completed and two 
Phase 3 trials ongoing in 2021. In these Phase 2 studies, 
paltusotine appeared to be well tolerated. The most 
common reported adverse events (AEs) included headache, 
arthralgia, diarrhea, and abdominal pain. No subjects 
discontinued from the Phase 2 studies due to 
AEsAdditionally, the clinical program includes two 
completed Phase 2 studies (CRN00808-02, CRN00808-03) 
and one Phase 2 open-label long-term extension study 
(CRN00808-05) that is still ongoing in participants with 
acromegaly. The RC Phase of two Phase 3 studies 
(CRN00808-08, CRN00808-09) in participants with 
acromegaly have been completed, in addition to an RTP of 
one Phase 2 study (CRN00808-11) in participants with 
carcinoid syndrome. The OLE phases of these studies are 
still ongoing. 
Additional details on the background of Carcinoid 
syndrome, treatment options, and nonclinical and clinical 
data on paltusotine can be found in the current 
Investigator’s Brochure (IB). 
Paltusotine was generally well tolerated across all studies 
in the clinical program with no unexpected safety signals. 
The safety profile of paltusotine includes adverse drug 
reactions (ADRs) of gastrointestinal events (diarrhea, 
abdominal pain, nausea, and abdominal discomfort), sinus 
bradycardia, and cholelithiasis, consistent with other SRL 
treatments. 
Updated to align with 
current Investigator’s 
Brochure 
2.2 Background 
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. 
Updated to comply with 
Clinical Trial Regulation 
(CTR) EU No 536/2014. 

Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
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Section 
Summary of Changes 
Rationale 
2.3.1 Safety Risk 
Assessment 
Table/CRN00808-11 
Study Intervention-
Paltusotine 
Summary of Data/Rationale for Risk: 
Gastrointestinal (eg, diarrhea, abdominal discomfort). 
Additional reported AEs found in IB 
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 arewere generally mild or moderate. 
There were no and did not lead to discontinuations due to 
AEs in completed Phase 2in previous studies. 
Mitigation Strategy: 
Clinical monitoring, symptomatic measures, study drug 
interruption or discontinuation if necessary. Regular safety 
surveillance, including laboratory testing, physical 
examinations, AE monitoring, ECG monitoring, gall 
bladder monitoring, and evaluations for cardiovascular 
safety.protocol-specified study drug stopping rules 
provided in protocol. 
Updated to align with 
current Investigator’s 
Brochure. 
2.3.2 Benefit 
Assessment 
Furthermore,At this mechanism of actiontime, it is 
expected tounknown whether paltusotine will provide 
control of neuroendocrine tumor growth comparable to 
that seen with octreotide LAR or lanreotide. 
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. ADRs of bradycardia, 
gastrointestinal events (diarrhea, abdominal pain, nausea, 
and abdominal discomfort), and cholelithiasis have been 
identified. These AEs are generally mild or moderate and 
can be managed through the appropriate risk mitigation 
measures (eg, clinical monitoring, safety surveillance). 
Updated to align with 
current Investigator’s 
Brochure. 
4.1.1 Screening 
Antidiarrheal agents, diphenoxylate and loperamide, are 
considered concomitant medications and may be used as 
recommended by the Investigator.  
Updated to comply with 
Clinical Trial Regulation 
(CTR) EU No 536/2014. 
4.1.1 Screening 
Short-acting octreotide is considered a rescue medication 
(ie, auxiliary medicinal product) and can be used according 
to Table 4. Investigators should 
 
 
 
Updated to comply with 
Clinical Trial Regulation 
(CTR) EU No 536/2014. 
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Section 
Summary of Changes 
Rationale 
4.1.2.1. Treatment of 
Breakthrough 
Carcinoid Syndrome 
Symptoms During 
Randomized 
Treatment Phase 
4.1.2.1. Rescue Treatment of Breakthrough Carcinoid 
Syndrome Symptoms During Randomized Treatment 
Phase 
Rescue therapy with SA Octreotide is at the discretion of 
the Investigator. Options for rescue therapy are described 
in this section. 
Diphenoxylate or loperamide may be used as needed at the 
discretion of the Investigator for improved symptom 
control at any time during the study except when short-
acting octreotide is being used for rescue therapy. 
Investigators should 
 
 
 
Updated to comply with 
Clinical Trial Regulation 
(CTR) EU No 536/2014. 
4.1.6 End of Study 
Definition 
The EOS is defined as the date of the last visit of the last 
subject in the study.  
Added to define of the 
end of the clinical trial, to 
ensure compliance with 
EU CTR (EU No 
536/2014).  
4.1.7. Patient Input 
into Study Design 
4.1.7 Patient Input into Study Design 
Patient insight was collected over several meetings (June 
2021- June 2022) through a formalized Patient Leadership 
Council made up of 12 individuals living with carcinoid 
syndrome associated with NETs. These patients had a 
range of experiences including treating physician, medical 
treatments, geographic location, and age of diagnosis. In 
these meetings, the following topics were discussed: 
clinical study protocols, 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.  
Added description of 
patient input into study 
design to ensure 
compliance with EU CTR 
(EU No 536/2014). 
4.4. Justification for 
Duration of Treatment 
4.4 Justification for Duration of Treatment 
The study was designed with an 8-week RTP to allow 
sufficient time to demonstrate dose-responsiveness of 40 
vs 80 mg paltusotine. In addition, a 102-week OLE was 
included in the study to assess long-term safety in adults 
with Carcinoid syndrome. 
Added to comply with 
Clinical Trial Regulation 
(CTR) EU No 536/2014. 
4.5. Treatment After 
End of Trial 
Participation 
4.5 Treatment After End of Trial Participation 
After the end of the study, subjects may resume regionally 
licensed Carcinoid syndrome treatment as prescribed by 
their healthcare provider. 
Added to describe the 
arrangements for 
treatment options for 
subjects after their 
participation in the 
clinical trial has ended, to 
ensure compliance with 
EU CTR (EU No 
536/2014). 
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Section 
Summary of Changes 
Rationale 
6.1 Study 
Intervention(s) 
Administered 
Paltusotine is the Investigational Medicinal Product (IMP), 
diphenoxylate atropine and loperamide are concomitant 
medications, and short-acting octreotide is a rescue 
medication (ie, auxiliary medicinal protect [AuxMP]). 
Investigators should 
 
 
  
Added to clarify that 
paltusotine is the IMP for 
this trial and that rescue 
treatments are treated as 
auxiliary medicinal 
products. 
6.1 Study 
Intervention(s) 
Administered Table 
Table updated to add details for diphenyloxylate and 
loperamide. 
Added to clarify that 
diphenyloxylate and 
loperamide are 
considered concomitant 
medications in this study. 
6.2 Preparation/ 
Handling/Storage/ 
Accountability 
At the end of the study (ie, 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. 
Added a description of 
the arrangements for 
tracing, storing, 
destroying and returning 
the IMP and unauthorized 
auxiliary medicinal 
product in accordance 
with Article 51. 
6.7.3. Rescue 
Medications 
(Auxiliary Medicinal 
Products) 
6.7.3 Rescue Medications (Auxiliary Medicinal 
Products) 
Short-acting octreotide is considered a rescue medication 
(ie, auxiliary medicinal product) 
 
 
Added to comply with 
Clinical Trial Regulation 
(CTR) EU No 536/2014. 
8.4.4 Regulatory 
Reporting 
Requirements for 
Serious Adverse 
Events 
 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. 
 Suspected unexpected serious adverse reactions 
(ie, 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. 
Added to clarify the 
process for reporting of 
suspected unexpected 
serious adverse reactions 
by the sponsor to the 
Eudravigilance database. 
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Section 
Summary of Changes 
Rationale 
8.10 Collection and 
Storage of Biological 
Samples 
8.10 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 CTIS submission. 
To describe the 
arrangements to comply 
with the applicable rules 
for the collection, storage 
and future use of 
biological samples from 
clinical trial subjects. 
10.1.4 Data Protection 
Subjects will be assigned a unique identifier by the 
Sponsor. Any subject records or datasets that are 
transferred to the Sponsor will contain the identifier only; 
subject names or any information which would make the 
subject identifiable will not be transferred. 
The subject must be informed that his/her 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 subject who will be required to give 
consent for their data to be used as described in the 
informed consent. 
The subject must be informed that his/her medical records 
may be examined by Clinical Quality Assurance auditors 
or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
 
This trial will be conducted in accordance with the CTR 
EU No 536/2014 and General Data Protection Regulation 
(EU) 2016/679 (GDPR) in addition to the requirements of 
21 CFR 50, local regulations, ICH guidelines, privacy and 
data protection requirements. 
If a subject revokes authorization to collect or use personal 
health data, the Investigator retains the ability to use all 
information collected before the revocation of subject 
authorization. For subjects that have revoked authorization 
to collect or use personal health data, attempts should be 
made to obtain permission to collect at least vital status 
(ie, that the subject is alive) at the end of their scheduled 
study period. 
All parties will comply with all applicable laws, including 
laws regarding the implementation of organizational and 
technical measures to ensure protection of subject data. 
Subjects’ personal data will be stored at the study site in 
encrypted electronic and/or paper form and will be 
password protected or secured in a locked room to ensure 
that only authorized study staff have access. The study site 
will implement appropriate technical and organizational 
measures to ensure that the personal data can be recovered 
in the event of disaster. In the event of a potential personal 
To update the description 
of the arrangements to 
comply with the 
applicable rules on the 
protection of personal 
data, to ensure 
compliance with EU CTR 
(EU No 536/2014). 

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Section 
Summary of Changes 
Rationale 
data breach, the study site will be responsible for 
determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as 
required by law. To protect the rights and freedoms of 
subjects with regard to the processing of personal data, 
subjects will be assigned a single, subject-specific 
numerical code. Any subject records or data sets that are 
transferred to the Sponsor will contain the numerical code; 
subject names will not be transferred. All other identifiable 
data transferred to the Sponsor will be identified by this 
single, subject-specific code. The study site will maintain a 
confidential list of subjects who participated in the study, 
linking each subject’s numerical code to their actual 
identity and medical record ID. In case of data transfer, the 
Sponsor will protect the confidentiality of subjects’ 
personal data consistent with the clinical study agreement 
and applicable privacy laws. Information technology 
systems used to collect, process, and store study-related 
data are secured by technical and organizational security 
measures designed to protect such data against accidental 
or unlawful loss, alteration, or unauthorized disclosure or 
access. The Sponsor maintains standard operating 
procedures on how to respond in the event of unauthorized 
access, use, or disclosure of Sponsor information or 
systems. 
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 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). 
 Study records and source documents must be preserved 
for at least 1525 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. 
Updated to comply with 
Clinical Trial Regulation 
(CTR) EU No 536/2014. 
AuxMP=Auxiliary Medicinal Product, CTR=Clinical Trials Regulation, CFR=Code of Federal Regulations, EOS=End of Study, 
EU=European Union, GCP=Good Clinical Practice, IEC=Independent Ethics Committee, IMP=Investigational Medicinal 
Product, IRB=Institutional Review Board 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title 
A Randomized, Parallel Group Study to Evaluate the Safety, Pharmacokinetics, and Dose 
Response of Paltusotine Treatment in Subjects with Carcinoid Syndrome. 
Rationale 
Carcinoid syndrome usually occurs in intestinal neuroendocrine tumors (NETs) with liver 
metastases, which makes surgical cure very difficult in most patients. Excess serotonin and other 
hormonally active substances (including histamine, tachykinins, kallikrein, and prostaglandins) 
produced by some NETs are responsible for the symptoms collectively referred to as Carcinoid 
syndrome (Vinik, 2018). These symptoms most commonly include cutaneous flushing 
(seen in 85%) and recurrent watery diarrhea and cramping (seen in 75%-85%). Carcinoid 
syndrome is confirmed biochemically with documentation of elevations of serum serotonin or 
the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA). While long-acting somatostatin 
receptor ligand (SRL) therapies are mainstay treatments for Carcinoid syndrome, relief of 
Carcinoid syndrome symptoms at labeled doses is inadequate for many patients. Long-acting 
SRL therapies have also demonstrated efficacy in prolonging progression free- survival in 
patients with nonfunctional, metastatic, well or moderately differentiated enteropancreatic NETs 
(Rinke, 2009; Caplin, 2014; Kunz, 2015; Chan and Kulke, 2016; Oronsky, 2017). Long-acting 
SRL therapies may be associated with significant dose-to-dose exposure variability related to 
injection techniques. For example, nurses at MD Anderson Cancer Center successfully delivered 
only 52% of 328 octreotide long-acting release (LAR) injections to the intramuscular space when 
evaluated by computed tomography (Boyd, 2013). Negative experiences with chronic injections 
of long-acting SRL therapies, particularly octreotide LAR, also have been identified in patients 
with Carcinoid syndrome, including injection site pain or soreness (Adams, 2019). 
A daily oral treatment such as paltusotine may achieve higher drug concentrations in the liver, 
which is the most common source of the vasoactive mediators causing Carcinoid syndrome 
symptoms. Paltusotine, an orally administered nonpeptide somatostatin type 2 receptor (SST2) 
agonist, has the potential to improve treatment outcomes, achieving symptom control while 
eliminating painful injections. 
The purpose of this study is to evaluate the safety, pharmacokinetic (PK), and dose response of 
paltusotine treatment in subjects with Carcinoid syndrome. 
Overall Design 
This is a Phase 2, randomized, open-label, parallel-group, multi-center study. The study includes 
a Screening Period of up to 12 weeks. After completion of Screening, subjects will be randomly 
assigned to 40 mg QD vs. 80 mg once daily (QD) open-label dose groups for 8 weeks, referred to 
as the Randomized Treatment Phase (RTP). A dose up-titration by 40 mg QD is an option based 
on symptomatology once during the first 4 weeks of the Randomized Treatment Phase. 
Following the completion of the Randomized Treatment Phase, subjects may be eligible to enter 
the Open-Label Extension (OLE) Phase of the study in which they will receive paltusotine for 
102 weeks. Subjects who complete the Randomized Treatment Phase, and for whom the 

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Investigator recommends continuation of treatment on paltusotine, may be eligible to participate 
in the OLE Phase. There will be a 4-week follow-up as depicted in Figure 1. The total duration 
of paltusotine treatment is up to 110 weeks or up to 28 months. This is summarized and 
presented in Figure 1. 
Figure 1: 
Study Schema 
 
EOR=End of Randomized Treatment Phase; EOS=End of Study; EOT=End of Treatment; W=week; FU=follow-up; 
LAR=long-acting release; OLE=Open-Label Extension 
Note: The EOS Visit will be 28 days after last dose of study drug.  
a S1, S2 are Screening visits 1 and 2, graph is not proportional to duration; last injection of lanreotide or octreotide 
LAR and the expected visit S2 is not longer than the usual interval between injections for the subject. 
b It is anticipated that subjects will complete the 8 weeks of Randomized Treatment Phase. Subjects who complete 
the Randomized Treatment Phase, and for whom the Investigator recommends continuation of treatment on 
paltusotine, may be eligible to participate in the OLE Phase. 
c If subjects have recurrent carcinoid symptoms that require short-acting octreotide, the dose will be up-titrated once 
by 40 mg QD at the Day 14 or Day 28 visit (Section 4.1). 
d Dose of paltusotine during OLE Phase is determined by Investigator based on the frequency of rescue treatment 
and of study drug tolerability and will start on Day 56 (Section 4.1.3). 
Screening 
The Screening Period will vary from 2 to 12 weeks, depending on when subjects meet the 
qualifying criteria for randomization as described below. 
Subjects will be eligible for Screening if they are: 
 Not currently treated with any SRL therapy for at least 12 weeks prior to Screening, 
and are actively symptomatic (average of ≥4 bowel movements (BM)/day or 
>2 flushing episodes per day in at least 2 days over a period of 2 weeks)  
 
OR 
 Currently symptomatically controlled (average <4 bowel movements [BMs]/day and 
average ≤2 flushing episodes/day over a 2-week period) while treated with lanreotide, 
octreotide LAR, or short-acting octreotide (immediate release octreotide injection or 
oral octreotide) and who are willing to wash out of their medication 
The completion of an electronic Symptom Diary will continue daily throughout Screening 
beginning within 1 day of S1, and through Week 12 of the study (through Randomized 
Treatment Phase and 4 weeks into OLE) and then at selected time periods in the OLE Phase 
(Section 8.2.1). During the Screening Period, data from the diary will be used to assess initial 

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screening symptom frequencies and, for those who wash out of lanreotide or octreotide, to assess 
post-washout symptom frequencies. Stool consistency according to the Bristol scale and 
abdominal pain according to a numeric rating scale (NRS) will also be recorded in the electronic 
Symptom Diary. In addition to determining eligibility for randomization, the Screening Period 
will be used to assess the understanding and compliance of the subject with the electronic 
Symptom Diary. Some endpoints use Baseline defined from the Screening Period which is 
defined as the last 7 days prior to start of randomized treatment. Otherwise, Baseline is defined 
as the last value prior to start of randomized treatment. 
Subjects Not Currently Treated with Any SRL Therapy 
For subjects not currently treated with any SRL therapy, 2 Screening visits (S1 and S2) will be 
scheduled in the Screening Period. After completing the initial eligibility assessment in S1, a 
2-week assessment of untreated symptom frequencies (BMs and flushing episodes) will be 
initiated. At the S1 visit, plasma 5-HIAA levels will be assessed. If the plasma 5-HIAA result is 
≥2× the upper limit of normal (ULN), and the 2-week assessment is complete, demonstrating the 
subject meets symptomatic qualifying criteria (average of ≥4 BM/day OR >2 flushing episodes 
per day in at least 2 days over the period of 2 weeks), the Day 1 randomization visit should be 
scheduled (Figure 2). Subjects not meeting these criteria will be considered screen failures. 
Subjects Controlled Symptomatically Using Pretrial SRLs 
Subjects Using Lanreotide or Octreotide LAR 
For subjects using pretrial lanreotide or octreotide LAR, 2 Screening visits (S1 and S2) will be 
scheduled. Both S1 and S2 are determined based on the subject’s injection schedule, which is 
ascertained prior to trial entry. Subjects will not continue their lanreotide or octreotide LAR after 
the informed consent is given at S1. 
Screening Visit 1 (S1) should be scheduled after the subject’s last dose of pretrial lanreotide or 
octreotide LAR. The second Screening Visit (S2) will occur approximately 2 weeks after S1 
(Figure 3). The interval between S1 and S2 should not be longer than the usual interval between 
injections for the subject. The 2-week interval between S1 and S2 will be used for the assessment 
of the subject’s baseline symptom control. 
At the S2 Visit, the degree of symptom control resulting from pretrial lanreotide or octreotide 
LAR dosing will be assessed. For subjects who are controlled symptomatically using pretrial 
SRLs, adequate symptom control is defined as having an average of <4 BM/day and an average 
of ≤2 flushing episodes/day over a 2-week period. Only subjects with adequate symptom control 
over a 2-week period following S1 will continue into the Screening Period for up to 10 weeks 
after S2. During this time, the subject’s diary will be closely monitored for changes in flushing 
and BMs. 
Subjects may qualify for trial entry as the result of an increase in the occurrence of either BMs or 
of flushing. Eligible subjects will have an increase in symptoms during a 7-day period after S2, 
compared to the period between S1 and S2, of either: 
 An average increase ≥1 BM/day over the average daily BM frequency observed in the 
period between S1 and S2 AND 
 An absolute frequency of ≥3 daily BMs in at least 4 days within the 7-day period 

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OR 
 An increase in daily average flushing episodes AND 
 At least 3 flushing episodes on at least 1 day 
If the subject does not qualify for the Day 1 randomization visit within 10 weeks of S2, the 
subject will be considered a screen failure (Figure 3). 
Subjects Using Short-acting Octreotide 
For subjects using regular doses of short-acting octreotide (immediate release octreotide 
injection or oral octreotide) for the prevention of Carcinoid syndrome symptoms pretrial, 
2 Screening visits (S1 and S2) will be scheduled in the Screening Period. After S1, a 2-week 
assessment of treated symptom frequencies (BMs and flushing episodes) will be initiated. The 
subject should continue pretrial dosing of short-acting octreotide at the most recent pretrial dose 
and administration frequency during this period. Completion of the electronic Symptom Diary 
should begin within 1 day of S1. S2 will occur approximately 2 weeks after S1. 
At the S2 Visit, symptom control from short-acting octreotide will be assessed. Subjects may 
qualify for trial entry as the result of an increase in the occurrence of either BMs or of flushing. 
Eligible subjects will have an increase in symptoms during a 7-day period after S2, compared to 
the period between S1 and S2, of either: 
 An average increase ≥1 BM/day over the average daily BM frequency observed in the 
period between S1 and S2 AND 
 An absolute frequency of ≥3 daily BMs, in at least 4 days of the 7-day period 
OR 
 An increase in daily average flushing episodes AND 
 At least 3 flushing episodes on at least 1 day 
If the subject does not qualify for the Day 1 randomization visit within 10 weeks of S2, the 
subject will be considered a screen failure Figure 3. 
Antidiarrheal Agent Use During Screening (Concomitant Medications) 
Antidiarrheal agents, diphenoxylate or loperamide, are considered concomitant medications and 
may be used during Screening as recommended by the Investigator. Investigator should refer to 
guidelines provided by the Sponsor for recommending antidiarrheal agents to the subjects 
(Table 3). Diphenoxylate or loperamide may be used as needed at the discretion of the 
Investigator for improved symptom control at any time during the study except when 
short-acting octreotide is being used for rescue therapy. 
Rescue Medication Use During Screening (Auxiliary Medicinal Product) 
Short-acting octreotide is considered a rescue medication (ie, auxiliary medicinal product) 
 
 Investigators should 
 
 
 All administrations of short-acting octreotide or 
antidiarrheal medications should be recorded in the electronic Symptom Diary. 
CCI
CCI
CCI
CCI
CCI

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Rescue therapy with SA octreotide is at the discretion of the Investigator. Options for therapy are 
described below. 
If there is a delay in scheduling the Day 1 randomization visit for subjects in Screening who have 
met the symptomatic criteria qualifying them for randomization, subjects may begin short-acting 
octreotide. Subjects also will receive instructions on how to use short-acting octreotide 200 µg 
up to 3 times daily, at the discretion of the Investigator, when symptomatic criteria are met 
(Table 4). Short-acting octreotide must be stopped no later than 12 hours prior to the 
randomization visit. 
Randomized Treatment Phase 
Once all Screening assessments are complete and the subject’s eligibility is verified by the 
Investigator and confirmed by the Medical Monitor via submission of the Medical Monitor 
Eligibility Verification Form, the subject will be randomized to 40 mg QD vs. 80 mg QD for the 
8-week Randomized Treatment Phase. On Day 1 of the Randomized Treatment Phase, the 
Investigator will query the subject to identify the most troublesome target symptom as assessed 
by the subject (BM or flushing). The target symptom will be documented. Subjects will be 
provided on Day 1 with sufficient paltusotine 20 mg tablets for 40 mg QD or 80 mg QD for 
14 days and will return to the site on Day 14. Scheduled study visits will occur on Days 28, 42, 
and 56. An evaluation on Day 56 (referred to as Week 8 in the SOAs) will be made for potential 
enrollment in the OLE Phase. Beginning at W2, visits may be performed at home at the 
discretion of the Investigator, with home health care support as needed. 
Antidiarrheal Agent Use During RTP  
Diphenoxylate or loperamide may be used as needed for improved symptom control at any time 
during the study except when short-acting octreotide is being used for rescue therapy. Possible 
treatment regimens for breakthrough symptoms of Carcinoid syndrome occurring during the 
study are delineated in Table 5. 
Rescue Medication Use During RTP 
On Day 1, all subjects who have not already received instructions on how to use short-acting 
octreotide 200 µg up to 3 times daily, at the direction of the Investigator, will receive instructions 
for rescue therapy when criteria are met (Table 6). Study staff should instruct subjects on the 
criteria for initiating and stopping short-acting octreotide as described in Table 6. Short-acting 
octreotide should not be given for at least 12 hours before biomarker sample collection. 
All administrations of short-acting octreotide or antidiarrheal medications should be recorded in 
the study diary. 
If the subject experiences Carcinoid syndrome symptoms that meet protocol criteria for 
short-acting octreotide rescue, another option to treat the symptoms is to increase the respective 
dose by 40 mg QD based on symptomatology to a maximum dose of 80 or 120 mg QD once 
during the first 28 days. No dose increases are allowed after Day 28 through the remaining 
4 weeks of the Randomized Treatment Phase. Table 7 summarizes the dose adjustments during 
the Randomized Treatment Phase of the study. 

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Open-Label Extension Phase 
Subjects completing the 8 weeks Randomized Treatment Phase may begin the OLE Phase of the 
study if, in the opinion of the Investigator, the subject may benefit from OLE Phase participation. 
For those rolling over into the OLE, the initial OLE dose will be based on frequency of rescue 
treatments and study drug tolerability, as assessed by the Investigator (Table 8). The first dose of 
OLE will be administered at the clinical research site on Week 8 (Day 56) visit. If the subject 
experiences Carcinoid syndrome symptoms that meet protocol criteria for short-acting octreotide 
rescue during the OLE Phase, the dose may be increased by 40 mg QD to a maximum dose of 
120 mg QD (ie, the maximum dose will be reached at 1 study visit for subjects starting at 80 mg 
and at 2 study visits for subjects starting at 40 mg; Table 8). In the event that the worsening of 
Carcinoid syndrome symptoms that meet protocol criteria for short-acting octreotide rescue 
(Section 4.1.3) occurs between the scheduled visits and the Investigator determines it is 
appropriate to increase the subject’s dose before the next scheduled visit, an unscheduled visit 
can be added in order to increase the subject’s dose. The site should perform a triplicate 
echocardiogram (ECG) at 1 to 3 hours postdose and 24-hour continuous cardiac (Holter) 
monitoring 5 to 7 days after the dose increase if the dose is increased to 120 mg. A paltusotine 
predose blood draw for PK, safety labs and postdose PK blood draw at 1 to 3 hours should also 
be done. Subjects not continuing in the OLE study will have their last Randomized Treatment 
Phase dose administered at the Week 8 visit. 
The completion of an electronic Symptom Diary will continue daily throughout Screening 
beginning within 1 day of S1 and through Week 12 of the study (through Randomized Treatment 
Phase and 4 weeks into OLE) and then selected time periods in the OLE Phase (Section 8.2.1). 
Subjects who have previously completed the OLE (when the OLE concluded at Week 58) may 
rejoin the OLE at the same dose they were previously on if they meet the following conditions: 
(1) the Investigator has determined that the subject’s disease is stable, (2) safety assessments, 
including chemistry, hematology, urinalysis, and baseline electrocardiogram, show no significant 
changes compared to previous evaluations, and (3) approval from the Medical Monitor. 
Once these three conditions are met, the subject may reenter the OLE after discontinuation of 
their current SSA therapy, with the timing at the discretion of the Investigator. The subject will 
reenter the OLE at the Week 58 timepoint and follow the Summary of Activities (SOA) as 
described in Table 2. 
Study Completion and Early Termination 
Study completion and early termination (ET) for subjects are each defined separately for the 
Randomized Treatment Phase and the OLE Phase. Completion of Randomized Treatment Phase 
and the OLE Phase of the study requires that subject complete the final visit within each phase 
(End of Study [EOS] Visit for Randomized Treatment Phase and the OLE Phase) (Table 5 and 
Table 6). Subjects discontinuing early from Randomized Treatment Phase or the OLE Phase of 
the study should be treated with standard treatment as recommended by the Investigator and will 
have an ET Visit. 

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End of Randomized Treatment Phase and End of Treatment 
Completion of last scheduled dosing in Randomized Treatment Phase is defined as End of 
Randomized Treatment Phase (EOR) and completion of last scheduled dosing in OLE Phase is 
defined as End of Treatment (EOT). 
End of Study 
An EOS Visit will occur to collect the safety data and other assessments as detailed in the SOAs. 
An EOS Visit will be 28 days after last dose of study drug and is required for subjects who 
completed the study or early terminated. 
Objectives and Endpoints of the Study 
Objectives 
Endpointsa 
Safety 
To evaluate the safety and tolerability of 
paltusotine at 40, 80, and 120 mg QD doses 
Incidence of TEAEs, including serious TEAEs and TEAEs 
leading to discontinuation; change from Baseline to the EOR in 
safety parameters: clinical laboratory tests, physical exam 
findings, vital signs, 12-lead ECG, and 24-hour continuous 
cardiac monitoring (only for subjects on 120 mg dose) 
Pharmacokinetics 
To assess the PK of 40, 80, and 120 mg 
paltusotine  
Steady state trough levels at each dose at EOR 
Exploratory Efficacy for Randomized Treatment Phase 
To derive responder rates for the different 
dose arms 
Proportion of clinical responders by dose during the last week of 
the Randomized Treatment Phase: 
In subjects who meet diarrhea entry criteria only: 
 
Have fewer than 4 mean bowel movements daily 
 
Have a >20% reduction in the mean daily number of bowel 
movements compared with Baseline 
In subjects who meet flushing entry criteria only: 
 
Have a >30% reduction compared with Baseline in the 
mean daily number of flushing episodes. 
In subjects who meet both diarrhea and flushing entry criteria: 
 
Have less than 4 mean bowel movements daily 
 
Have a >20% reduction in the mean daily number of bowel 
movements compared with Baseline 
 
Have any reduction from Baseline in the mean daily 
number of flushing episodes. 
To derive target symptom responder rates for 
subjects in the different dose arms 
Proportion of target symptom responders by dose during the last 
week of the Randomized Treatment Phase: 
 
Subjects with at least 20% decline in the number of target 
symptom episodes compared to Baseline. (Target symptom 
is the symptom [either BM or flushing] that troubled the 
subject the most at Baseline.) 

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Objectives 
Endpointsa 
To evaluate the effect of paltusotine treatment 
on frequency of BMs/day 
Change in mean daily BMs: 
 
From the Baseline Period of Screening to the last week of 
the Randomized Treatment Phase 
To evaluate the effect of paltusotine treatment 
on frequency of flushing episodes/day 
Change in mean daily number of flushing episodes: 
 
From the Baseline Period of Screening to the last week of 
the Randomized Treatment Phase 
To evaluate the effect of paltusotine treatment 
on severity of flushing episodes/day 
Change in worst flushing in last 24 hours (using a 0 to 10 NRS): 
 
From the mean Baseline Period of Screening to the mean in 
the last week of the Randomized Treatment Phase 
 
From the highest score during Baseline Period in Screening 
to the highest score during the last week of the Randomized 
Treatment Phase 
To evaluate the effect of paltusotine treatment 
on the frequency of daily target symptom 
episodes 
Change in mean daily target symptom episodes: 
 
From the Baseline Period of Screening to the last week of 
the Randomized Treatment Phase 
To evaluate the effect of paltusotine treatment 
on biochemical markers of Carcinoid 
syndrome 
Change from Baseline to EOR in: 
 
Plasma 5-HIAA 
 
Plasma pancreastatin 
 
Serum chromogranin A 
 
Serum serotonin 
To evaluate the effect of paltusotine treatment 
on the use of protocol defined rescue with 
short-acting octreotide injections  
Change in use of short-acting octreotide: 
 
Change in the proportion of days on short-acting octreotide 
in Screening, after subject has met entry criteria, to the 
proportion of days on short-acting octreotide of the last 
week of the Randomized Treatment Phase 
 
Change in mean daily dose of octreotide in Screening, after 
subject has met entry criteria to the mean daily dose of 
short-acting octreotide during the last week of the 
Randomized Treatment Phase 
To evaluate the effect of paltusotine treatment 
on incontinence 
Change in the mean daily fecal incontinence episodes (defined 
as accidental passing of bowel movements including solid 
stools, liquid stools, or mucus): 
 
From the Baseline Period of Screening to the last week of 
the Randomized Treatment Phase 
To evaluate the effect of paltusotine treatment 
on abdominal pain severity 
Change in worst abdominal pain in last 24 hours (using a 0 to 
10 NRS): 
 
From the mean Baseline Period of Screening to the mean in 
the last week of the Randomized Treatment Phase 
 
From the highest score during Baseline Period in Screening 
to the highest score during the last week of the Randomized 
Treatment Phase 

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Objectives 
Endpointsa 
To evaluate the effect of paltusotine treatment 
on stool consistency 
Change in “worst” (highest) stool score in last 24 hours 
(Bristol scale): 
 
From the mean Baseline Period of Screening to the mean in 
the last week of the Randomized Treatment Phase 
 
From the highest score during Baseline Period in Screening 
to the highest score during the last week of the Randomized 
Treatment Phase 
To evaluate the effect of paltusotine treatment 
on health-related quality of life 
Change from Baseline to EOR in: 
 
EORTC QLQ-C30 
 
EORTC QLQ-GI.NET21 scores 
 
EQ-5D-5L 
 
FACT-CSI 
To evaluate subject-perceived carcinoid 
symptom severity and change 
 
Change from Baseline to EOR in PGI-S (Patient Global 
Impression of Status) 
 
PGI-C (Patient Global Impression of Change) at EOR 
To evaluate treatment preference 
Change in Treatment preference from Baseline 
(pretrial treatment) to EOR  
To evaluate the effect of paltusotine treatment 
on urgency to defecate 
Change in mean daily urgency episodes (defined as BMs that 
make subjects rush to the bathroom): 
From the Baseline Period of Screening to the last week of the 
Randomized Treatment Phase  
Open-label Extension (OLE) Phase 
To evaluate the safety and tolerability of 
paltusotine 
Incidence of TEAEs, including serious TEAEs and TEAEs 
leading to discontinuation; change from EOR to EOT in safety 
parameters: clinical laboratory tests, physical exam findings, 
vital signs, 12-lead ECG, and ophthalmic assessments 
Pharmacokinetics 
To assess the PK of 40, 80, and 120 mg 
paltusotine  
Steady state trough levels at each dose at EOT 

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Objectives 
Endpointsa 
Exploratory Efficacy for OLE Phase 
To evaluate the effect of paltusotine on tumor 
progression 
Incidence of NET progression at EOT using 6 month interval 
imaging assessment while on paltusotine 
To evaluate the persistence of effect of 
paltusotine 
Proportion of clinical responders during the last week of the 
OLE Phase by dose: 
In subjects who meet diarrhea entry criteria only: 
 
Have less than 4 mean bowel movements daily, and have a 
>20% reduction in the mean daily number of bowel 
movements compared with Baseline 
In subjects who meet flushing entry criteria only: 
 
Have a >30% reduction compared with Baseline in the 
mean daily number of flushing episodes 
In subject who meet both diarrhea and flushing entry criteria: 
Have less than 4 mean bowel movements daily, and have a 
>20% reduction in the mean daily number of bowel movements 
compared with Baseline and have any reduction from Baseline 
in the mean daily number of flushing episodes 
Proportion of target symptom responders during the last week of 
the OLE Phase by dose 
Change in the mean from mean of the last week prior to 
Baseline to the mean of the last week of participation in the 
OLE Phase in daily BM frequency 
Change from the mean of the last week prior to Baseline to the 
mean of the last week of participation in the OLE Phase in daily 
flushing episode frequency 
Change from Baseline to EOT in biomarkers of Carcinoid 
syndrome (listed in Randomized Treatment Phase) 
Mean change from the last week prior to Baseline to the last 
week of participation in the OLE Phase in daily target symptom 
frequency 
Change from Baseline to EOT 
 
EORTC QLQ-C30 
 
EORTC QLQ-GI.NET21 scores 
 
EQ-5D-5L 
 
FACT-CSI 
To evaluate subject-reported carcinoid 
symptom severity and change 
 
PGI-S at EOT 
 
PGI-C at EOT 
To evaluate the effect of paltusotine treatment 
on the use of protocol defined rescue with 
short-acting octreotide injections  
Change in number of days treated with short-acting octreotide: 
 
Change in the days on short-acting octreotide in last week 
prior to Baseline compared to the last week of EOT 
 
Change in mean daily dose of octreotide during the last 
week prior to Baseline to the last week of EOT 

Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
Confidential 
27 
Objectives 
Endpointsa 
To evaluate the effect of paltusotine treatment 
on incontinence 
Change in mean daily fecal incontinence episodes (defined as 
accidental passing of bowel movements including solid stools, 
liquid stools, or mucus): 
 
From the last week prior to Baseline to the last week prior 
to EOT 
To evaluate the effect of paltusotine treatment 
on abdominal pain severity 
Change in worst abdominal pain in the last 24 hours (using a 
0 to 10 NRS): 
 
From the mean in the last week prior to Baseline to the last 
week of OLE 
 
From the highest score during last week prior to Baseline to 
the last week of OLE 
To evaluate the effect of paltusotine treatment 
on urgency to defecate 
Change in mean daily urgency episodes (defined as BMs that 
make subjects rush to the bathroom): 
 
From the last week prior to Baseline to the last week prior 
to EOT 
BM=bowel movement; ECG=electrocardiogram; EORTC QLQ-C30=EORTC Quality of Life questionnaire; EORTC 
QLQ-GI.NET21=EORTC Quality of Life questionnaire in GI NET; EOR=end of randomized Treatment Phase; EOS=End of 
Study; EOT=end of treatment; EQ-5D-5L=EuroQoL-5 Dimensions 5-Level; FACT-CSI=Functional Assessment of Cancer 
Therapy – Carcinoid syndrome Symptom Index; 5-HIAA=5-hydroxyindoleacetic acid; NET=neuroendocrine tumors; 
NRS=numeric rating scale; OLE=Open-Label Extension; PGI-C=Patient Global Impression - Change; PGI-S=Patient Global 
Impression of Severity; PK=pharmacokinetic; QD=once a day; TEAE=treatment-emergent adverse events 
a All endpoint assessments, except biochemical markers of Carcinoid syndrome and safety laboratories to be collected in daily 
electronic diary. 
Number of Subjects 
Approximately 30 subjects (15 subjects/arm) will be enrolled in the study. Subjects taking 
proton-pump inhibitors (PPIs) at Screening may contribute up to 6 subjects enrolled in the study. 
Subjects who screen fail may be reconsidered for enrollment after a new and successful 
Screening Period. 
Duration and Intervention Groups 
Total Duration of the Study 
The study is comprised of a Screening Period up to 12 weeks and 2 treatment phases 
(Randomized Treatment Phase and OLE Phase) with a Safety Follow-up (EOS Visit) 4 weeks 
after the last dose. Subjects who are randomized to participate in the Randomized Treatment 
Phase and continue in the OLE Phase will complete the study in up to 110 weeks or 28 months. 
The study will consist of: 
 Screening Period: 2 to 12 weeks 
 Randomized Treatment Phase: 8 weeks 
 Randomized 1:1 to 40 mg or 80 mg for up to 8 weeks 
 OLE Phase: 102 weeks 
 EOS Visit: 4 weeks post last dose of study drug 

Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
Confidential 
28 
Study Drug 
Paltusotine will be provided as 20 mg tablets, packaged in 36 count, high-density polyethylene 
bottles containing desiccant cannister. During the Randomized Treatment Phase, those assigned 
to 40 mg will take two 20 mg tablets daily and those assigned to 80 mg will take four 20 mg 
tablets daily. Those who require 120 mg will take six 20 mg tablets daily. 
Scientific Rationale for Study Design 
This study consists of a Randomized Treatment Phase followed by an OLE Phase. A randomized 
parallel-group design allows for a rigorous assessment of the safety and efficacy associated with 
each dose. These data will be useful for dose selection in the design of subsequent trials. 
The OLE Phase will provide important long-term safety and efficacy information that will also 
inform later stage trial designs. Standardized dose titration criteria are provided in the protocol 
taking into account reasonable treatment goals and study drug toleration. 
Subject safety will be ensured using protocol defined criteria for treatment discontinuation and 
rescue therapy with short-acting octreotide and antidiarrheal medication. 
Statistical Methods 
Formal sample size calculations were not performed. A total of 30 subjects with Carcinoid 
syndrome is considered suitable to assess the study objectives for PK in subjects with Carcinoid 
syndrome. 
Safety Monitoring Committee 
A Safety Monitoring Committee (SMC), comprising independent subject matter experts, will be 
established to assess the risk versus benefit of the interventions during the trial. The SMC will 
meet at intervals as specified in the SMC charter and may convene for ad hoc meetings if there 
are immediate safety concerns identified during the study. 

CRN00808 
Crinetics Pharmaceuticals, Inc. 
Clinical Protocol CRN00808-11, version 7.0 
Confidential 
29 
1.2. 
Schedule of Activities 
Table 1: 
Schedule of Activities - Randomized Treatment Phase 
STUDY PROCEDURES 
Screening Period 
Randomized Treatment Phase 
ET 
Follow-up 
Week (Day) 
W=week; D=day 
W -12b to D -1 
W1 (D1) 
W2 
(D14) 
W4 
(D28) 
W6 
(D42) 
W8 
(D56) 
- 
28 days 
after last 
dose 
Visit Name 
S1 
S2 
- 
- 
- 
- 
EOR 
ETc 
FU/EOSd 
Window Period (Days)a 
- 
±3 
- 
±2 
±2 
±3 
±3 
- 
±2 
Onsite Visit 
X 
X 
X 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Obtain informed consent 
Xf 
- 
- 
- 
- 
- 
- 
- 
- 
Verify eligibility 
Xg 
X 
- 
- 
- 
- 
- 
- 
- 
Eligibility checklist/ Randomization 
- 
- 
X 
- 
- 
- 
- 
- 
- 
Health history, demographics, Baseline characteristics 
Xg 
- 
- 
- 
- 
- 
- 
- 
- 
Full physical including neurological exam, weight, height 
(height at Screening only) 
X 
- 
X 
- 
- 
- 
X 
X 
- 
Target symptom evaluation 
 
 
X 
 
 
 
 
 
 
Dispense electronic Symptom Diaryh 
Xg 
- 
- 
- 
- 
- 
- 
- 
- 
Subject completes electronic Symptom Diary daily from S1 to 
EORi, 
Xg 
X 
X 
X 
X 
X 
X 
X 
- 
Investigator reviews electronic Symptom Diary 
- 
X 
X 
X 
X 
X 
X 
X 
- 
Symptom-directed and neurological physical exam 
- 
X 
- 
X 
X 
- 
- 
- 
- 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGj 
X 
- 
X 
X 
X 
X 
X 
X 
- 
Continuous cardiac (Holter) monitoring 
- 
X 
- 
Xk 
Xk 
- 
Xk 
- 
- 
Ophthalmic Assessments l 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
 
Biliary/gallbladder ultrasound 
Xm 
- 
- 
- 
- 
- 
- 
- 
- 

CRN00808 
Crinetics Pharmaceuticals, Inc. 
Clinical Protocol CRN00808-11, version 7.0 
Confidential 
30 
STUDY PROCEDURES 
Screening Period 
Randomized Treatment Phase 
ET 
Follow-up 
Week (Day) 
W=week; D=day 
W -12b to D -1 
W1 (D1) 
W2 
(D14) 
W4 
(D28) 
W6 
(D42) 
W8 
(D56) 
- 
28 days 
after last 
dose 
Visit Name 
S1 
S2 
- 
- 
- 
- 
EOR 
ETc 
FU/EOSd 
Window Period (Days)a 
- 
±3 
- 
±2 
±2 
±3 
±3 
- 
±2 
Onsite Visit 
X 
X 
X 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
AE monitoring 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
Review of prior & concomitant therapies 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testn 
X 
- 
X (predose) 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests (hematology, chemistry, urinalysis) 
Xg 
- 
X 
- 
X 
X 
X 
X 
X 
Serology (HIV, Hepatitis B, and Hepatitis C) 
Xg 
- 
- 
- 
- 
- 
- 
- 
- 
Thyroid hormones and HbA1c 
Xg 
- 
X 
- 
X 
- 
X 
X 
- 
SARS-CoV-2 testingo 
Xg 
- 
X 
- 
- 
- 
 
- 
- 
Carcinoid syndrome biomarkers (plasma 5-HIAA and 
pancreastatinp; serum chromogranin A and serotonin) 
Xg 
- 
X 
- 
X 
X 
X 
X 
X 
Genotype blood sample (optional) 
- 
- 
X q 
- 
- 
- 
- 
- 
- 
Paltusotine predose fasting PK 
- 
- 
- 
X 
X 
X 
X 
- 
- 
Paltusotine postdose PKr 
- 
- 
X 
X 
X 
X 
X 
- 
- 
Lanreotide or octreotide PKs 
- 
X 
X 
X 
X 
X 
X 
- 
- 
Study drug administered during visit 
- 
- 
X 
Xt 
Xt 
X 
X 
- 
- 
Dispense study drug  
- 
- 
X 
X 
X 
- 
Xu 
- 
- 
Study drug accountability  
- 
- 
- 
X 
X 
 
X 
X 
- 
EQ-5D-5L EORTC: QLQ-C30, QLQ-GI.NET21 and 
FACT-CSI 
- 
- 
X 
- 
- 
- 
X 
X 
- 
PGI-S  
- 
- 
X 
- 
X 
- 
X 
X 
- 
PGI-C 
- 
- 
- 
- 
X 
- 
X 
X 
- 

CRN00808 
Crinetics Pharmaceuticals, Inc. 
Clinical Protocol CRN00808-11, version 7.0 
Confidential 
31 
STUDY PROCEDURES 
Screening Period 
Randomized Treatment Phase 
ET 
Follow-up 
Week (Day) 
W=week; D=day 
W -12b to D -1 
W1 (D1) 
W2 
(D14) 
W4 
(D28) 
W6 
(D42) 
W8 
(D56) 
- 
28 days 
after last 
dose 
Visit Name 
S1 
S2 
- 
- 
- 
- 
EOR 
ETc 
FU/EOSd 
Window Period (Days)a 
- 
±3 
- 
±2 
±2 
±3 
±3 
- 
±2 
Onsite Visit 
X 
X 
X 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Treatment Preference Question 
- 
- 
- 
- 
- 
- 
X 
X 
- 
Subject Interview 
- 
- 
- 
- 
- 
- 
Xv 
X 
- 
Roll-over to OLE 
- 
- 
- 
- 
- 
- 
X 
- 
- 
5-HIAA=5-hydroxyindoleacetic acid, AE=adverse event, CS=Carcinoid syndrome, D=Day, ECG=electrocardiogram, EORTC QLQ-C30=EORTC Quality of Life questionnaire, 
EORTC QLQ-GI.NET21=EORTC Quality of Life questionnaire in GI.NET, EQ-5D-5L=EuroQoL-5 Dimensions 5-Level, EOR=End of Randomized Treatment Phase, EOS=End 
of Study, ET=Early Termination, FACT-CSI=Functional Assessment of Cancer Therapy – Carcinoid Syndrome Symptom Index, FU=Follow-up, HbA1c=hemoglobin A1c, 
HIV=human immunodeficiency virus, NET=neuroendocrine tumor, OCT=optical coherence tomography, OLE=Open-Label Extension, PCR=polymerase chain reaction, 
PGI-C=Patient Global Impression of Change, PGI-S=Patient Global Impression of Severity, PK=pharmacokinetic, SARS-CoV-2=severe acute respiratory syndrome coronavirus 2, 
S1= Screening Visit 1, S2=Screening Visit 2, W=Week 
a 
All visit dates are projected based on the number of days with Day 1 being the day of randomization which corresponds to Week 1 for the study. The subsequent visit weeks 
in the Schedule of Activities Table 1 (eg, Week 2/Day 14) signify the end of the week. 
b 
For subjects using long-acting lanreotide or octreotide or short-acting octreotide, see washout instructions in Section 4.1.1. 
c 
This visit is for subjects who discontinue early. 
d 
Follow-up/EOS Visit will be 28 days after last dose for those who completed EOR and do not enter OLE Phase, or those who early terminated from the study. 
e 
Beginning at W2, visits may be performed at home at the discretion of the Investigator with home health care support as needed. 
f 
Informed consent can be obtained on a different day prior to any study procedures of S1 visit being performed in the event of scheduling issue with the subject and this 
interval should be no more than 2 weeks approximately. 
g 
Procedure is required to be performed on the first day of S1. 
h 
In rare cases when the electronic Symptom Diary cannot be used, exceptions may be allowed upon discussion with the Sponsor to complete the Symptom Diary on paper. 
i 
The completion of an electronic Symptom Diary will continue throughout Screening beginning within 1 day of S1, Week 1 through Week 12 (throughout Randomized 
Treatment Phase), and selected time periods in the OLE Phase (Section 8.2.1). 
j 
Triplicate ECG to be performed at Screening, 1-3 hours after supervised administration of first dose of study drug, and any subsequent visit where the dose is increased 
(to 80 or 120 mg) (Section 8.3.3). 
k 
The 24-hour continuous cardiac (Holter) monitoring should be performed ~5 to 7 days after the first 120 mg dose. For W8, continuous cardiac (Holter) monitoring should be 
performed if the subject is rolling into the OLE and increasing the dose to 120 mg. 
l 
Visual Acuity, Fundus Photography, OCT, 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. 
m 
In the event of a scheduling issue, biliary/gallbladder ultrasound can be performed at any time during the Screening Period prior to verification and confirmation of subject 
eligibility. 

CRN00808 
Crinetics Pharmaceuticals, Inc. 
Clinical Protocol CRN00808-11, version 7.0 
Confidential 
32 
n 
Female subjects of childbearing potential must have a negative serum pregnancy test at Screening. All pregnancy tests at other visits will be urine pregnancy tests. If the result 
of a urine pregnancy test is positive, then the result will be confirmed with a serum pregnancy test. 
o 
SARS-CoV-2 antigen test to be conducted according to local lab procedures, if required as per local regulations. 
p 
Pancreastatin will not be collected and analyzed for subjects enrolled in EU countries. 
q 
If not collected at W1 (D1) visit, may be collected at W2 (D14) visit. 
r 
Postdose PK is taken between 1 and 3 h postdose which corresponds to the Tmax of paltusotine. 
s 
Octreotide and lanreotide PK sample is to be collected from previously treated subjects only for visit S2 and during Randomized Treatment Phase. 
t 
Dose adjustment is allowed once at either Week 2 or Week 4. See Table 7. 
u 
Only for subjects entering the OLE Phase. 
v 
The Subject Interview will be available to subjects only in certain countries. 

CRN00808 
Crinetics Pharmaceuticals, Inc. 
Clinical Protocol CRN00808-11, version 7.0 
Confidential 
33 
Table 2: 
Schedule of Activities - Open-Label Extension Phase 
STUDY PROCEDURES 
Open-Label Extension Phasea 
Week (Day) 
W=week; D=day 
W8 
(D56) 
W10 
(D70) 
W12 
(D84) 
W24 
(D168) 
W36 
(D252) 
W48 
(D336) 
W58m 
(D406) 
W70 
(D490) 
W82 
(D574) 
W96 
(D672) 
W110 
(D770) 
- 
4 Weeks 
after ET/ 
EOT 
Visit Name 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
EOT 
ETb 
FU/ 
EOSc 
Window (Days) 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
±7 
Onsite Visit 
Xd 
X 
Xd 
Xd 
X 
Xd 
X 
X 
Xd 
Xd 
X 
X 
X 
Full physical including neurological 
exam, weight 
X 
- 
- 
- 
- 
- 
X 
- 
- 
- 
X 
X 
- 
CT or MRI tumor imaging e 
- 
X 
- 
- 
X 
- 
- 
X 
- 
- 
X 
X 
- 
Symptom-directed and neurological 
physical exam 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject completes electronic 
Symptom Diary daily at specified 
periods f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
12-lead ECGg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Continuous cardiac (Holter) 
monitoring 
~5-7 days after the first 120 mg dose 
- 
- 
- 
Ophthalmic assessments h 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
- 
Investigator reviews electronic 
Symptom Diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests (hematology, 
chemistry, urinalysis) 
X 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 

CRN00808 
Crinetics Pharmaceuticals, Inc. 
Clinical Protocol CRN00808-11, version 7.0 
Confidential 
34 
STUDY PROCEDURES 
Open-Label Extension Phasea 
Week (Day) 
W=week; D=day 
W8 
(D56) 
W10 
(D70) 
W12 
(D84) 
W24 
(D168) 
W36 
(D252) 
W48 
(D336) 
W58m 
(D406) 
W70 
(D490) 
W82 
(D574) 
W96 
(D672) 
W110 
(D770) 
- 
4 Weeks 
after ET/ 
EOT 
Visit Name 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
EOT 
ETb 
FU/ 
EOSc 
Window (Days) 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
±7 
Onsite Visit 
Xd 
X 
Xd 
Xd 
X 
Xd 
X 
X 
Xd 
Xd 
X 
X 
X 
Thyroid hormones  
and HbA1c 
- 
- 
- 
- 
X 
- 
X 
- 
X 
- 
X 
X 
- 
Carcinoid syndrome 
biomarkers:(plasma 5-HIAA and 
pancreastatin; serum chromogranin A 
and serotonin) 
X 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Paltusotine pre- and postdose PKj  
X 
- 
- 
X 
- 
- 
X 
X 
- 
- 
X 
- 
- 
Study drug administered during visitk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Lanreotide or octreotide PKl 
- 
- 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Dispense study drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
- 
Study drug accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
EQ-5D-5L, EORTC QLQ-C30, 
QLQ-GI.NET21, and FACT-CSI 
X 
- 
X 
- 
- 
- 
X 
- 
X 
- 
X 
X 
- 
PGI-C 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
PGI-S 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
AE=adverse event, CT=computed tomography, D=Day, ECG=electrocardiogram, EORTC QLQ-C30=EORTC Quality of Life questionnaire, EORTC QLQ-GI.NET21=EORTC 
Quality of Life questionnaire in GI.NET, EQ-5D-5L=EuroQoL-5 Dimensions 5-Level, EOS=End of Study, EOT=End of Treatment, ET=Early Termination, 
FACT-CSI=Functional Assessment of Cancer Therapy – Carcinoid syndrome Symptom Index, FU=Follow-up, HbA1c=hemoglobin A1c, MRI=magnetic resonance imaging, 
NET=neuroendocrine tumor, OLE=Open-Label Extension, PGI-C=Patient Global Impression of Change, PGI-S= Patient Global Impression of Severity, PK=pharmacokinetic, 
W=Week 
a 
All visit dates are projected based on the number of days from D1 and the subsequent visit weeks in the Schedule of Activities Table 2 (eg, Week 10/Day 70) signify the end 
of the week. Data from the Week 8 Visit will be used as Baseline (D1) data in the OLE. 
b 
This visit is for subjects who discontinue early. 

CRN00808 
Crinetics Pharmaceuticals, Inc. 
Clinical Protocol CRN00808-11, version 7.0 
Confidential 
35 
c 
Follow-up/EOS Visit will be 28 days after last dose for subjects completing OLE Phase or terminating early. Subjects are to continue to self-administer study drug until the 
EOT (Week 110), except when subjects are dosed during a study visit, they will receive study intervention directly from the Investigator or designee, under medical 
supervision. 
d 
Visits may be performed at home at the discretion of the Investigator with home health care support as needed. 
e 
Refer to Imaging Section 8.8. While on study drug, CT or MRI scan should be obtained approximately 6 months after the subject’s most recent pretrial scan. The choice of 
CT or MRI scan should be consistent with previous scans. If an assessment is performed within 3 months of ET, there is no need to repeat at ET. 
f 
An electronic Symptom Diary completed daily will be completed from Week 8 through Week 12, and selected time periods in the OLE Phase (Section 8.2.1). 
g 
Triplicate ECG should be performed 1 to 3 hours after supervised administration of study drug, where the dose is increased (to 80 or 120 mg) (Section 8.3.3). 
h 
Visual Acuity, Fundus Photography, OCT, 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. 
i 
All pregnancy tests during this phase will be urine pregnancy tests. If the result of a urine pregnancy test is positive, then the result will be confirmed with a serum pregnancy 
test. 
j 
Predose PK should be a fasting sample. Postdose PK is taken between 1 and 3 h postdose which corresponds to the Tmax of paltusotine. 
k 
In cases of poor tolerability, the Investigator may reduce dose based on his/her assessment. 
l 
Octreotide and lanreotide PK samples are to be collected from previously treated subjects only. 
m 
Subjects who previously completed the OLE (when the OLE was until Week 58) are eligible to reenter OLE. Week 58 visit will be used as the visit time point where the 
subjects reenter the study. The dose level will be at the dose they were at when they previously completed the OLE.  

Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
Confidential 
36 
2. 
INTRODUCTION 
2.1. 
Study Rationale 
Carcinoid syndrome usually occurs in intestinal neuroendocrine tumors (NETs) with liver 
metastases, which makes surgical cure very difficult in most patients. While long-acting 
somatostatin receptor ligand (SRL) therapies are mainstay treatments for Carcinoid syndrome, 
relief of Carcinoid syndrome symptoms at labeled doses is inadequate for many patients. 
Long-acting SRL therapies have also demonstrated efficacy in prolonging progression-free 
survival in patients with nonfunctional, metastatic, well or moderately differentiated 
enteropancreatic NETs (Rinke, 2009; Caplin, 2014; Kunz, 2015; Chan and Kulke, 2016; 
Oronsky, 2017). Long-acting SRL therapies may be associated with significant dose-to-dose 
exposure variability related to injection techniques. For example, nurses at MD Anderson Cancer 
Center successfully delivered only 52% of 328 octreotide long-acting release (LAR) injections to 
the intramuscular space when evaluated by computed tomography (CT) (Boyd, 2013). Negative 
experiences with chronic injections of long-acting SRL therapies, particularly octreotide LAR, 
also have been identified in patients with Carcinoid syndrome, including injection site pain or 
soreness (Adams, 2019). A daily oral treatment such as paltusotine may achieve higher drug 
concentrations in the liver, which is the most common source of the vasoactive mediators 
causing Carcinoid syndrome symptoms. Paltusotine has the potential to improve treatment 
outcomes, achieving symptom control while eliminating painful injections. 
The purpose of this study is to evaluate the safety, pharmacokinetic (PK), and dose response of 
paltusotine treatment in patients with Carcinoid syndrome. 
2.2. 
Background 
Neuroendocrine tumors (NETs) arise from cells of the enteroendocrine system in the 
gastrointestinal tract (approximately 70% of cases), the lung (approximately 25% of cases), and 
more rarely, the pancreas. The estimated 20-year limited duration prevalence of NETs in the 
United States as of 01 January 2014 was 171,321. Approximately 48% of these tumors are 
locally advanced or metastatic at the time of diagnosis (Dasari, 2017). Approximately 10 to 20% 
(Halperin, 2017) of these tumors may present with symptoms of chronic flushing and diarrhea, 
referred to as Carcinoid syndrome. 
Excess serotonin and other hormonally active substances (including histamines, tachykinins, 
kallikreins, and prostaglandins) produced by some NETs are responsible for the symptoms 
collectively referred to as Carcinoid syndrome (Vinik, 2018). These symptoms most commonly 
include cutaneous flushing (seen in 85%) and recurrent watery diarrhea and cramping (seen in 
75%-85%). Carcinoid syndrome is confirmed biochemically with documentation of elevations of 
serum serotonin or the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) in plasma or 
urine. Once biochemical confirmation of Carcinoid syndrome is established, imaging studies are 
conducted to stage the tumor. Multiphasic contrast enhanced CT scanning of the abdomen is 
often used to initiate localization and to assess for the presence of metastatic disease. Abdominal 
magnetic resonance imaging (MRI) is preferred by some because of increased sensitivity for the 
detection of metastatic disease in the liver. Whenever possible, tumor histology, including 
assessment of proliferative indices, is important for diagnostic, prognostic, and treatment 
planning purposes. 

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Carcinoid syndrome is usually caused by well-differentiated NETs, nearly 90% of which express 
somatostatin receptors (SSTRs) (Vinik, 2018) and 80% of patients with Carcinoid syndrome 
respond to octreotide (Kvols, 1986). The dominant target for octreotide is somatostatin type 2 
receptor (SST2). Therefore, SSTR imaging can be useful for localizing NETs not visualized with 
CT or MRI, providing whole body images of tumor burden as well as documenting tumoral 
expression of SSTRs prior to treatment with SRLs. Currently, positron emission tomography 
(PET) tracers for SSTR imaging (eg, 68Ga-Dotatate and 68Ga-Dotatoc, and 64Cu-Dotatate) in 
combination with CT are preferred relative to 111In-pentetreotide imaging because of increased 
spatial resolution and sensitivity for detection of small tumors. 
Paltusotine (formerly CRN00808) is an orally administered nonpeptide SST2 agonist currently 
under development by Crinetics Pharmaceuticals, Inc. for the treatment of Carcinoid syndrome. 
Additionally, the clinical program includes two completed Phase 2 studies 
(CRN00808-02, CRN00808-03) and one Phase 2 open-label long-term extension study 
(CRN00808-05) that is still ongoing in participants with acromegaly. The RC Phase of two 
Phase 3 studies (CRN00808-08, CRN00808-09) in participants with acromegaly have been 
completed, in addition to an RTP of one Phase 2 study (CRN00808-11) in participants with 
carcinoid syndrome. The OLE phases of these studies are still ongoing. 
Paltusotine was generally well tolerated across all studies in the clinical program with no 
unexpected safety signals. The safety profile of paltusotine includes adverse drug reactions 
(ADRs) of gastrointestinal events (diarrhea, abdominal pain, nausea, and abdominal discomfort), 
sinus bradycardia, and cholelithiasis, consistent with other SRL treatments. 
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 AEs of paltusotine may be found in the IB. 

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2.3.1. 
Safety Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
CRN00808-11 Study Intervention – 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 were generally mild or 
moderate and did not lead to discontinuations 
in previous studies. 
Clinical monitoring, 
symptomatic measures, 
study drug interruption if 
necessary. Regular safety 
surveillance, including 
laboratory testing, physical 
examinations, AE 
monitoring, ECG 
monitoring, gall bladder 
monitoring, and evaluations 
for protocol-specified study 
drug stopping rules.  
CRN00808-11 Study Intervention – Short-Acting Octreotidea 
Side effects 
Gallbladder (eg, cholelithiasis, cholecystitis, 
cholangitis, pancreatitis) 
Cardiac function (eg, complete atrioventricular 
block, bradycardia, arrhythmia, conduction 
abnormalities, other electrocardiogram 
changes) 
Gastrointestinal (eg, pancreatitis, diarrhea, 
loose stools, nausea, and abdominal 
discomfort) 
Pregnancy (eg, risk of pregnancy with 
normalization of IGF-1 and growth hormone) 
Glucose metabolism (eg, hypoglycemia, 
hyperglycemia) 
Thyroid function (eg, hypothyroidism, goiter) 
Nutrition (eg, may alter absorption of dietary 
fats, decreased vitamin B12 levels, and 
abnormal Schilling’s Tests) 
Regular safety surveillance, 
including laboratory testing, 
physical examinations, AE 
monitoring, and evaluations 
for cardiovascular safety. 
Study drug stopping rules 
provided in protocol 

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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
CRN00808-11 Study Procedures 
Blood draws 
Pain, bleeding, or infection possible. 
Rationale: Needed for safety evaluation of 
study drug 
Symptomatic measures 
MRI or CT scans 
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: Monitoring NET tumor status 
Standard of care 
symptomatic and 
preventative management 
measures  
Ultrasound 
Ultrasound waves may heat the tissues slightly 
and, in some cases, also can produce small 
pockets of gas in body fluids or tissues. 
Rationale: Needed for monitoring gallbladder 
and biliary ducts 
Symptomatic measures 
Scintigraphy / PET 
scan 
Low dose radiation exposure from these scans. 
Uncommon side effects may include fever, 
flushing, headache, low blood pressure, joint 
pain, nausea, sweating and weakness 
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  
OCT of the macula 
Some subjects may experience some eye 
dryness or fatigue. 
Symptomatic measures 
AE(s)=adverse event(s); CT=computed tomography; IB=Investigator’s Brochure; IGF-1=insulin-like growth 
factor 1; MRI=magnetic resonance imaging; NET=neuroendocrine tumor, OCT=optical coherence tomography. 
a. Source: (Sandostatin LAR 2024) 
2.3.2. 
Benefit Assessment 
Based on nonclinical data, paltusotine is expected to have benefit in the treatment of Carcinoid 
syndrome (see current Investigator’s Brochure). 
Completed Phase 2 studies CRN00808-02 and CRN00808-03 showed evidence for insulin-like 
growth factor 1 (IGF-1) maintenance in acromegaly subjects previously treated with octreotide 
LAR or lanreotide monotherapy 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 octreotide LAR or lanreotide injections. Results from the ongoing 
OLE study CRN00808-05 support the long -term maintenance of effect and safety profile in 
subjects with acromegaly. Because octreotide LAR and lanreotide are approved first line 
treatments for both acromegaly and Carcinoid syndrome and because the pharmacologic effect of 

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paltusotine is similar to that of octreotide LAR and lanreotide, the evidence from clinical studies 
of paltusotine in acromegaly supports the hypothesis that it also will be effective in Carcinoid 
syndrome. At this time, it is unknown whether paltusotine will provide control of neuroendocrine 
tumor growth. 
ADRs of bradycardia, gastrointestinal events (diarrhea, abdominal pain, nausea, and abdominal 
discomfort), and cholelithiasis have been identified. These AEs are generally mild or moderate 
and can be managed through the appropriate risk mitigation measures (eg, clinical monitoring, 
safety surveillance). 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, to monitor for neuroendocrine tumor growth, and manage as clinically appropriate. 
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 subjects 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 
Carcinoid syndrome. 

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3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives and Endpoints of the Study 
Objectives 
Endpointsa 
Safety 
To evaluate the safety and tolerability of 
paltusotine at 40, 80, and 120 mg QD doses 
Incidence of TEAEs, including serious TEAEs and TEAEs 
leading to discontinuation; change from Baseline to the EOR in 
safety parameters: clinical laboratory tests, physical exam 
findings, vital signs, 12-lead ECG, and 24-hour continuous 
cardiac monitoring (only for subjects on 120 mg dose) 
Pharmacokinetics 
To assess the PK of 40, 80, and 120 mg 
paltusotine  
Steady state trough levels at each dose at EOR 
Exploratory Efficacy for Randomized Treatment Phase 
To derive responder rates for the different 
dose arms 
Proportion of clinical responders by dose during the last week of 
the Randomized Treatment Phase: 
In subjects who meet diarrhea entry criteria only: 
 
Have less than 4 mean bowel movements daily 
 
Have a >20% reduction in the mean daily number of bowel 
movements compared with Baseline 
In subjects who meet flushing entry criteria only: 
 
Have a >30% reduction compared with Baseline in the mean 
daily number of flushing episodes. 
 
In subject who meet both diarrhea and flushing entry criteria: 
 
Have less than 4 mean bowel movements daily 
 
Have a >20% reduction in the mean daily number of bowel 
movements compared with Baseline 
 
Have any reduction from Baseline in the mean daily number 
of flushing episodes. 
To derive target symptom responder rates 
for subjects in the different dose arms 
Proportion of target symptom responders by dose during the last 
week of the Randomized Treatment Phase: 
 
Subjects with at least 20% decline in the number of target 
symptom episodes compared to Baseline. (Target symptom is 
the symptom [either BM or flushing] that troubled the subject 
the most at Baseline).  
To evaluate the effect of paltusotine 
treatment on frequency of BMs/day 
Change in mean daily BMs: 
 
From the Baseline Period of Screening to the last week of the 
Randomized Treatment Phase 
To evaluate the effect of paltusotine 
treatment on frequency of flushing 
episodes/day 
Change in mean daily number of flushing episodes: 
 From the Baseline Period of Screening to the last week of the 
Randomized Treatment Phase 

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Objectives 
Endpointsa 
To evaluate the effect of paltusotine 
treatment on the severity of flushing 
episodes/day 
Change in worst flushing in last 24 hours (using a 0 to 10 NRS): 
  From the mean Baseline Period of Screening to the mean in 
the last week of the Randomized Treatment Phase 
  From the highest score during Baseline Period in Screening to 
the highest score during the last week of the Randomized 
Treatment Phase 
To evaluate the effect of paltusotine 
treatment on the frequency of daily target 
symptom episodes 
Change in mean daily target symptom episodes: 
 From the Baseline Period of Screening to the last week of the 
Randomized Treatment Phase 
To evaluate the effect of paltusotine 
treatment on biochemical markers of 
Carcinoid syndrome 
Change from Baseline to EOR in: 
 Plasma 5-HIAA 
 Plasma Pancreastatin 
 Serum Chromogranin A 
 Serum Serotonin 
To evaluate the effect of paltusotine 
treatment on the use of protocol defined 
rescue with short-acting octreotide injections  
Change in use of short-acting octreotide: 
 Change in the proportion of days on short-acting octreotide in 
Screening, after subject has met entry criteria, to the 
proportion of days on short-acting octreotide of the last week 
of the Randomized Treatment Phase 
 Change in mean daily dose of octreotide in Screening, after 
subject has met entry criteria to the mean daily dose of short-
acting octreotide during the last week of the Randomized 
Treatment Phase 
To evaluate the effect of paltusotine 
treatment on incontinence 
Change in the mean daily fecal incontinence episodes (defined as 
accidental passing of bowel movements including solid stools, 
liquid stools, or mucus): 
 From the Baseline Period of Screening to the last week of the 
Randomized Treatment Phase 
To evaluate the effect of paltusotine 
treatment on abdominal pain severity 
Change in worst abdominal pain in last 24 hours (using a 0 to 
10 NRS): 
 From the mean Baseline Period of Screening to the mean in 
the last week of the Randomized Treatment Phase 
 From the highest score during Baseline Period in Screening to 
the highest score during the last week of the Randomized 
Treatment Phase 
To evaluate the effect of paltusotine 
treatment on stool consistency 
Change in “worst” (highest) stool score in last 24 hours 
(Bristol scale): 
 From the mean Baseline Period of Screening to the mean in the 
last week of the Randomized Treatment Phase 
 From the highest score during Baseline Period in Screening to 
the highest score during the last week of the Randomized 
Treatment Phase 

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Objectives 
Endpointsa 
To evaluate the effect of paltusotine 
treatment on health-related quality of life 
Change from Baseline to EOR in: 
 EORTC QLQ-C30 
 EORTC QLQ-GI.NET21 scores 
 EQ-5D-5L 
 FACT-CSI 
To evaluate subject-perceived carcinoid 
symptom severity and change 
 Change from Baseline to EOR in PGI-S (Patient Global 
Impression of Status) 
 PGI-C (Patient Global Impression of Change) at EOR 
To evaluate treatment preference 
Change in treatment preference from Baseline (pretrial treatment) 
to EOR  
To evaluate the effect of paltusotine 
treatment on urgency to defecate 
Change in mean daily urgency episodes (defined as BMs that 
make subjects rush to the bathroom): 
From the Baseline Period of Screening to the last week of the 
Randomized Treatment Phase  
Open-Label Extension (OLE) Phase 
To evaluate the safety and tolerability of 
paltusotine 
Incidence of TEAEs, including serious TEAEs and TEAEs 
leading to discontinuation; change from EOR to EOT in safety 
parameters: clinical laboratory tests, physical exam findings, vital 
signs, 12-lead ECG, and ophthalmic assessments 
Pharmacokinetics 
To assess the PK of 40, 80, and 120 mg 
paltusotine  
Steady state trough levels at each dose at EOT 
Exploratory Efficacy for OLE Phase 
To evaluate the effect of paltusotine on 
tumor progression 
Incidence of NET progression at EOT using 6-month interval 
imaging assessment while on paltusotine 
To evaluate the persistence of effect of 
paltusotine 
Proportion of clinical responders during the last week of the OLE 
Phase by dose: 
In subjects who meet diarrhea entry criteria only: 
 Have less than 4 mean bowel movements daily, and have a 
>20% reduction in the mean daily number of bowel 
movements compared with Baseline 
In subjects who meet flushing entry criteria only: 
 Have a >30% reduction compared with Baseline in the mean 
daily number of flushing episodes 
In subject who meet both diarrhea and flushing entry criteria: 
Have less than 4 mean bowel movements daily, and have a >20% 
reduction in the mean daily number of bowel movements 
compared with Baseline and have any reduction from Baseline in 
the mean daily number of flushing episodes 
Proportion of target symptom responders during the last week of 
the OLE Phase by dose 

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Objectives 
Endpointsa 
Change in the mean from mean of the last week prior to Baseline 
to the mean of the last week of participation in the OLE Phase in 
daily BM frequency 
Change from the mean of the last week prior to Baseline to the 
mean of the last week of participation in the OLE Phase in daily 
flushing episode frequency 
Change from Baseline to EOT in biomarkers of Carcinoid 
syndrome (listed in Randomized Treatment Phase) 
Mean change from the last week prior to Baseline to the last week 
of participation in the OLE Phase in daily target symptom 
frequency. 
Change from Baseline to EOT 
 EORTC QLQ-C30 
 EORTC QLQ-GI.NET21 scores 
 EQ-5D-5L 
 FACT-CSI 
To evaluate subject-perceived carcinoid 
symptom severity and change 
 PGI-S at EOT 
 PGI-C at EOT 
To evaluate the effect of paltusotine 
treatment on the use of protocol defined 
rescue with short-acting octreotide injections  
Change in number of days treated with short-acting octreotide: 
 Change in the days on short-acting octreotide in last week 
prior to Baseline compared to the last week of EOT 
 Change in mean daily dose of octreotide during the last week 
prior to Baseline to the last week of EOT 
To evaluate the effect of paltusotine 
treatment on incontinence 
Change in mean daily fecal incontinence episodes (defined as 
accidental passing of bowel movements including solid stools, 
liquid stools, or mucus): 
 From the last week prior to Baseline to the last week prior to 
EOT 
To evaluate the effect of paltusotine 
treatment on abdominal pain severity 
Change in worst abdominal pain in the last 24 hours (using a 
0 to 10 NRS): 
 From the mean in the last week prior to Baseline to the last 
week of OLE 
 From the highest score during last week prior to Baseline to 
the last week of OLE 
To evaluate the effect of paltusotine 
treatment on urgency to defecate 
Change in mean daily urgency episodes (defined as BMs that 
make subjects rush to the bathroom): 
 From the last week prior to Baseline to the last week prior to 
EOT 
BM=bowel movement; ECG=electrocardiogram; EORTC QLQ-C30=EORTC Quality of Life questionnaire; EORTC 
QLQ-GI.NET21=EORTC Quality of Life questionnaire in GI NET; EOR=end of randomized Treatment Phase; EOS=End of 
Study; EOT=end of treatment; EQ-5D-5L=EuroQoL-5 Dimensions 5-Level; FACT-CSI=Functional Assessment of Cancer 
Therapy – Carcinoid Syndrome Symptom Index; 5-HIAA=5-hydroxyindoleacetic acid; NET=neuroendocrine tumors; 
NRS=numeric rating scale; OLE=Open-Label Extension; PGI-C=Patient Global Impression - Change; PGI-S=Patient Global 
Impression of Severity; PK=pharmacokinetic; QD=once a day; TEAE=treatment-emergent adverse events 
a All endpoint assessments, except biochemical markers of Carcinoid syndrome and safety laboratories to be collected in daily 
electronic diary. 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2, randomized, open-label, parallel-group, multi-center study. The study includes 
a Screening Period of up to 12 weeks. After completion of Screening, subjects will be randomly 
assigned to 40 mg QD vs. 80 mg QD open-label dose groups for 8 weeks, referred to as the 
Randomized Treatment Phase. A dose up-titration by 40 mg QD is an option based on 
symptomatology during the first 4 weeks of the Randomized Treatment Phase. 
Following completion of the Randomized Treatment Phase, subjects may be eligible to enter the 
Open-Label Extension (OLE) Phase of the study in which they will receive paltusotine for 
102 weeks. Subjects who complete the Randomized Treatment Phase, and for whom the 
Investigator recommends continuation of treatment on paltusotine, may be eligible to participate 
in the OLE Phase. There will be a 4-week follow-up as depicted in Figure 1. The total duration 
of paltusotine treatment is up to 110 weeks or up to 28 months. This is summarized and 
presented in Figure 1. 
4.1.1. 
Screening 
The Screening Period will vary from 2 to 12 weeks, depending on when subjects meet the 
qualifying criteria for randomization as described below. 
Subjects will be eligible for Screening if they are: 
 Not currently treated with any SRL therapy for at least 12 weeks prior to Screening 
and are actively symptomatic (average of ≥4 bowel movements (BM)/day or 
>2 flushing episodes per day in at least 2 days over a period of 2 weeks), OR 
 Currently symptomatically controlled (average <4 bowel movements [BMs]/day and 
average ≤2 flushing episodes/day over a 2-week period) while treated with lanreotide, 
octreotide LAR, or short-acting octreotide (immediate release octreotide injection or 
oral octreotide) and who are willing to wash out of their medication. 
The completion of an electronic Symptom Diary will continue daily throughout Screening 
beginning within 1 day of S1, and through Week 12 of the study (through Randomized 
Treatment Phase and 4 weeks into OLE) and then during selected time periods in the OLE Phase 
(Section 8.2.1). During the Screening Period, data from the diary will be used to assess initial 
screening symptom frequencies and, for those who wash out of lanreotide or octreotide, to assess 
post-washout symptom frequencies. Stool consistency according to the Bristol scale and 
abdominal pain according to a numeric rating scale (NRS) will also be recorded in the electronic 
Symptom Diary. In addition to determining eligibility for randomization, the Screening Period 
will be used to assess the understanding and compliance of the subject with the electronic 
Symptom Diary. Some endpoints use Baseline defined from the Screening Period which is 
defined as the last 7 days prior to start of randomized treatment. Otherwise, Baseline is defined 
as the last value prior to start of randomized treatment. 

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Figure 2: 
Screening Schematics for Subjects Not Currently Treated with Any SRL 
Therapy 
 
BMs=bowel movements, 5-HIAA=5-Hydroxyindoleacetic acid, SRL=somatostatin receptor ligand, ULN=upper 
limit of normal 
For subjects not currently treated with any SRL therapy, 2 Screening visits (S1 and S2) will be 
scheduled in the Screening Period. After completing the initial eligibility assessment in S1, a 
2-week assessment of untreated symptom frequencies (BMs and flushing episodes) will be 
initiated. At the S1 visit, plasma 5-HIAA levels will be collected. If the plasma 5-HIAA result is 
≥2× the upper limit of normal (ULN), and the 2-week assessment is complete, demonstrating the 
subject meets symptomatic qualifying criteria (average of ≥4 BM/day OR >2 flushing episodes 
per day in at least 2 days over the period of 2 weeks), the Day 1 randomization visit should be 
scheduled (Figure 2) after completing S2. Subjects not meeting these criteria will be considered 
screen failures. 
For subjects using pretrial lanreotide or octreotide LAR, 2 Screening visits (S1 and S2) will be 
scheduled. Both S1 and S2 are determined based on the subject’s injection schedule, which is 
ascertained prior to trial entry. Subjects will not continue their lanreotide or octreotide LAR after 
the informed consent is given at S1. 
Screening Visit 1 (S1) should be scheduled after the subject’s last dose of pretrial lanreotide or 
octreotide LAR. The second Screening Visit (S2) will occur approximately 2 weeks after S1 
(Figure 3). The interval between S1 and S2 should not be longer than the usual interval between 
injections for the subject. Completion of the Symptom Diary should begin within 1 day of S1. 
The 2-week interval between S1 and S2 will be used for the assessment of the subject’s baseline 
symptom control. 
At the S2 Visit, the degree of symptom control resulting from pretrial lanreotide or octreotide 
LAR dosing will be assessed. For subjects who are controlled symptomatically using pretrial 
SRLs, adequate symptom control is defined as having an average of <4 BM/day and an average 
of ≤2 flushing episodes/day over a 2-week period. Only subjects with adequate symptom control 
over a 2-week period following S1 will continue into the Screening Period for up to 10 weeks 
after S2. During this time, the subject’s diary will be closely monitored for changes in flushing 
and BMs. 
Initial Eligibility 
Assessment
- Assessment of initial 
screening symptom 
frequencies 
- Assessment of the 
understanding and 
compliance of the 
subject with the 
electronic symptom 
diary
- Confirmation of no 
SRL therapy
Assessment of 
Untreated Symptoms
2-week assessment of 
untreated symptom 
frequencies (BMs and 
flushing episodes)
Day 1 Randomization
Visit scheduled if 
plasma 5-HIAA 
≥2×ULN and actively 
symptomatic (average of 
≥4 BM/day OR 
>2 flushing episodes per 
day in at least 2 days 
over the period of 
2 weeks) 

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Subjects may qualify for trial entry as the result of an increase in the occurrence of either BMs or 
of flushing. Eligible subjects will have an increase in symptoms during a 7-day period after S2, 
compared to the period between S1 and S2, of either: 
 An average increase of ≥1 BM/day over the after daily BM frequency observed in the 
period between S1 and S2 AND 
 An absolute frequency of ≥3 daily BMs, in at least 4 days within the 7-day period 
OR 
 An increase in daily average flushing episodes AND 
 At least 3 flushing episodes on at least 1 day 
If the subject does not qualify for the Day 1 randomization visit within 10 weeks of S2, the 
subject will be considered a screen failure (Figure 3). 

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Figure 3: 
Screening Schematics for Subjects Using Pretrial Lanreotide or Octreotide 
LAR 
 
Note: Subject is a screen failure if Day 1 cannot be scheduled within 10 weeks of S2. 
BMs=bowel movements; LAR=long-acting release; S1=Screening Visit 1; S2=Screening Visit 2; ULN=upper limit 
of normal. 

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For subjects using regular doses of short-acting octreotide (immediate release octreotide 
injection or oral octreotide) with or without combined long-acting SRL therapy (lanreotide or 
octreotide LAR) for the prevention of Carcinoid syndrome symptoms pretrial, 2 Screening visits 
(S1 and S2) will be scheduled in the Screening Period. The interval between S1 and S2 should 
not be longer than the usual interval between injections of lanreotide or octreotide LAR for the 
subject. Completion of the Symptom Diary should begin within 1 day of S1. The 2-week interval 
between S1 and S2 will be used for the assessment of the subject’s baseline symptom control. 
After S1, a 2-week assessment of treated symptom frequencies (BMs and flushing episodes) will 
be initiated. The subject should continue pretrial dosing of short-acting octreotide at the most 
recent pretrial dose and administration frequency during this period. Completion of the electronic 
Symptom Diary should begin within 1 day of S1. S2 will occur approximately 2 weeks after S1 
(Figure 4). 
At the S2 Visit, symptom control from regular short-acting octreotide, with or without lanreotide 
or octreotide LAR, will be assessed. Subjects may qualify for trial entry as the result of an 
increase in the occurrence of either BMs or of flushing. Eligible subjects will have an increase in 
symptoms during a 7-day period after S2, compared to the period between S1 and S2, of either: 
 An average increase ≥1 BM/day over the average daily BM frequency observed in the 
period between S1 and S2 AND 
 An absolute frequency of ≥3 daily BMs in at least 4 days of the 7-day period 
OR 
 An increase in daily average flushing episodes AND 
 At least 3 flushing episodes on at least 1 day 
If the subject does not qualify for the Day 1 randomization visit within 10 weeks of S2, the 
subject will be considered a screen failure (Figure 3). 

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Figure 4: 
Screening Schematics for Subjects Using Regular Doses of Short-acting 
Octreotide 
 
Note: Subject is a screen failure if Day 1 cannot be scheduled within 10 weeks of S2. 
BMs=bowel movements; S1=Screening Visit 1; S2=Screening Visit 2. 
The subject should continue 
pretrial dosing of short-acting 
octreotide at the most recent pre-
trial dose and administration 
frequency during a 2-week treated 
symptom assessment period.
Completion of the daily symptom 
diary should begin within 1 day of
S1.
S2 scheduled approximately 2 
weeks after S1
Assessment of symptom control 
from short acting octreotide
Subjects having average <4 
BM/day AND average ≤2 
flushing episodes/day over 
the 2-week period will 
proceed in Screening.
If an increase in symptoms during a 7-day period 
after S2, compared to the period between S1 and 
S2, of either: 
-an increase in the average BM frequency of ≥1 
from the period between S1 and S2 (the daily 
treated average) AND an absolute frequency of ≥3 
daily BM events in at least 4 days of the 7-day 
period; 
OR 
-an increase in daily average flushing episodes 
AND at least 3 flushing episodes on at least 1 day,
subjects proceed to Day 1. Day 1 randomization 
may occur up to 10 weeks after S2.

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Antidiarrheal agents, diphenoxylate and loperamide, are considered concomitant medications 
and may be used as recommended by the Investigator.  
Investigator should refer to guidelines provided by the Sponsor for recommending antidiarrheal 
agents to the subjects during Screening (Table 3). 
Table 3: 
Oral Antidiarrheal Agents During the Screening Period 
Regimen 
Criteria for Initiating 
Dose and Frequency 
Diphenoxylate  
As needed for improved 
symptom control 
5 mg ≤4×daily as needed 
Loperamide 
As needed for improved 
symptom control 
4 mg initiation, 2 mg after each 
loose bowel movement as 
needed; total daily dose ≤16 mg 
Short-acting octreotide is considered a rescue medication (ie, auxiliary medicinal product) and 
can be used according to Table 4. Investigators 
 
 
 
If there is a delay in scheduling the Day 1 randomization visit for subjects in Screening who have 
met the symptomatic criteria qualifying them for randomization, subjects may begin short-acting 
octreotide. Subjects also will receive instructions on how to use short-acting octreotide 200 µg 
up to 3 times daily, at the direction of the Investigator, when symptomatic criteria are met 
(Table 4). Short-acting octreotide must be stopped no later than 12 hours prior to the 
randomization visit. 
Table 4: 
Use of Short-acting Octreotide During the Screening Period 
Pretrial Treatment 
Status 
Required to Start Short-acting 
Octreotide*  
Criteria for Stopping Short-acting 
Octreotide 
Not currently treated 
with any SRL therapy 
≥4 BM/day for 2 consecutive days or if 
flushing frequency is ≥3 flushing 
episodes/day for at least 1 day 
Symptom relief for 24 hours after 
initiation of short-acting octreotide 
SRL treated: 
Octreotide LAR 
Short-acting octreotide 
Lanreotide  
Increased bowel movement frequency with 
≥2 BM/day for 2 consecutive days above the 
Screening daily treated average measured 
between S1-S2 or ≥3 flushing episodes/day 
for at least 1 day 
Symptom relief for 24 hours after 
initiation of short-acting octreotide 
BM=bowel movement; LAR=long-acting release; S1=Screening Visit 1; S2=Screening Visit 2; SRL=somatostatin receptor 
ligand 
*Symptoms requiring treatment are defined as diarrhea or flushing episodes of severe intensity, ie, symptoms which prevent 
normal everyday activities. 
Diphenoxylate or loperamide may be used as needed for improved symptom control at any time 
during the study except when short-acting octreotide is being used for rescue therapy. All 
administrations of short-acting octreotide or antidiarrheal medications should be recorded in the 
study diary. 
CCI
CCI
CCI

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4.1.2. 
Randomized Treatment Phase 
Once all Screening assessments are complete and the subject’s eligibility is verified by the 
Investigator and confirmed by the Medical Monitor via submission of the Medical Monitor 
Eligibility Verification Form, the subject will be randomized to 40 mg QD vs. 80 mg QD for the 
8-week Randomized Treatment Phase. On Day 1 of the Randomized Treatment Phase, the 
Investigator will query the subject to identify the most troublesome target symptom as assessed 
by the subject (BM or flushing). The target symptom will be documented. Subjects will be 
provided on Day 1 with sufficient paltusotine 20 mg tablets for 40 mg QD or 80 mg QD for 
14 days and will return to the site on Day 14. Scheduled study visits will occur on Days 28, 42, 
and 56. A determination on Day 56 (referred to as Week 8 in the SOAs) will be made for 
potential enrollment in the OLE Phase. Beginning at W2, visits may be performed at home at the 
discretion of the Investigator, with home health care support as needed. 
4.1.2.1. 
Treatment of Breakthrough Carcinoid Syndrome Symptoms During 
Randomized Treatment Phase 
Diphenoxylate or loperamide may be used as needed at the discretion of the Investigator for 
improved symptom control at any time during the study except when short-acting octreotide is 
being used for rescue therapy. Investigators should 
 
 
 Possible treatment regimens for breakthrough symptoms of Carcinoid syndrome 
occurring during the study are delineated in Table 5. 
On Day 1, all subjects who have not already received instructions on how to use short-acting 
octreotide 200 µg up to 3 times daily, at the direction of the Investigator, will receive instructions 
for rescue therapy when criteria are met (Table 6). Study staff should instruct subjects on the 
criteria for initiating and stopping short-acting octreotide as described in Table 6. Short-acting 
octreotide should not be given for at least 12 hours before biomarker sample collection. 
All administrations of short-acting octreotide or antidiarrheal medications should be recorded in 
the study diary. 
Table 5: 
Possible Treatment Regimens for Breakthrough Symptoms 
Regimen 
Criteria for Initiating 
Dose/Frequency 
Diphenoxylate  
As needed for improved 
symptom control 
5 mg ≤4×daily as needed 
Loperamide 
As needed for improved 
symptom control 
4 mg initiation, 2 mg after each 
loose BM as needed; total daily 
dose ≤16 mg 
Short-acting octreotide  
Table 6 rescue criteria 
200 µg up to 3×daily until 
criteria for stopping (Table 6) 
are met 
CCI
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Table 6: 
Short-acting Octreotide Rescue Therapy 
Pretrial 
Treatment 
Status 
Criteria for Starting Short-acting Octreotide*  Criteria for Stopping Short-acting 
Octreotide* 
Not currently 
treated with any 
SRL therapy 
After 3 days of starting study drug or a new 
study drug dose, ≥4 BM/day for 2 consecutive 
days or if flushing frequency is ≥3 flushing 
episodes/day for at least 1 day 
Symptom relief for 24 hours after 
initiation of short-acting octreotide 
SRL treated: 
Octreotide LAR, 
Short-acting 
octreotide 
Lanreotide 
After 3 days of starting study drug or a new 
study drug dose, increased bowel movement 
frequency with ≥2 BM/day for 2 consecutive 
days above the Screening daily treated average 
measured between S1-S2 or ≥3 flushing 
episodes/day for at least 1 day 
Symptom relief for 24 hours after 
initiation of short-acting octreotide 
Notes: If the criteria for rescue therapy are met on a second occasion between visits and the subject starts the second course of 
short-acting octreotide, the subject should stay on short-acting octreotide regularly until the next scheduled visit 
BM = bowel movement; LAR = long-acting release; S1 = Screening Visit 1; S2 = Screening Visit 2; SRL=somatostatin receptor 
ligand 
*Symptoms requiring treatment are defined as diarrhea or flushing episodes of severe intensity, ie, symptoms which prevent 
normal everyday activities. 
If the subject experiences Carcinoid syndrome symptoms that meet protocol criteria for 
short-acting octreotide rescue, another option to treat the symptoms is to increase the respective 
dose by 40 mg QD based on symptomatology to a maximum dose of 80 or 120 mg QD once 
during the first 28 days (see Table 7). No dose increases are allowed after Day 28 through the 
remaining 4 weeks of the Randomized Treatment Phase of the study. Table 7 summarizes the 
dose adjustments during the randomized, parallel-group portion of the study. 
Table 7: 
Dose Adjustments During Randomized Treatment Phase 
Carcinoid Symptom Criteria 
Tolerability Criteria 
Dose Adjustment 
On Day 14 or Day 28: no rescue 
treatment initiated or required during 
preceding 7 days 
Acceptable tolerability of 
current dose 
No dose change  
On Day 14 or Day 28: ≥1 rescue 
treatment initiated or required during 
preceding 7 days 
Acceptable tolerability of 
current dose 
40 mg→80 mg or 
80 mg→120 mg*  
Any time during Randomized 
Treatment Phase 
Unacceptable tolerability 
of 80 or 120 mg doses 
80 mg→40 mg or  
120 mg→80 mg 
ECG = electrocardiogram 
Note: Triplicate ECG should be performed at Screening, 1-3 hours after supervised administration of first dose of 
study drug, and any subsequent visit where the dose is increased (to 80 or 120 mg) (Section 8.3.3). Continuous 
cardiac (Holter) monitoring (24 hour) should be performed approximately 5-7 days after the first 120 mg dose. 
*The first dose of paltusotine and the initial dose after the 40 mg increase to 80 mg or 80 mg increase to 120 mg 
should be administered at the clinical research site. 

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4.1.3. 
Open-Label Extension Phase 
Subjects completing the 8 weeks Randomized Treatment Phase may begin the OLE Phase of the 
study if, in the opinion of the Investigator, the subject may benefit from OLE Phase participation. 
For those rolling over into the OLE, the initial OLE dose will be based on the frequency of 
rescue treatments and study drug tolerability, as assessed by the Investigator. The first dose of 
OLE will be administered at the clinical research site on Week 8 (Day 56) visit. If the subject 
experiences Carcinoid syndrome symptoms that meet protocol criteria for short-acting octreotide 
rescue during the OLE Phase (Table 6 Section 4.1.2.1), the dose may be increased by 40 mg QD 
to a maximum dose of 120 mg QD (ie, the maximum dose will be reached at 1 study visit for 
subjects starting at 80 mg and at 2 study visits for subjects starting at 40 mg; Table 8). In the 
event that the worsening of Carcinoid syndrome symptoms that meet protocol criteria for short-
acting octreotide rescue (Table 6 Section 4.1.2.1), occurs between the scheduled visits and the 
Investigator determines it is appropriate to increase the subject’s dose before the next scheduled 
visit, an unscheduled visit can be added in order to increase the subject’s dose. Subjects in the 
OLE Phase who are uptitrated to the 80 mg or 120 mg dose will need to swallow the first dose 
under the supervision in the research center. Triplicate ECGs will be performed 1 to 3 hours after 
supervised administration of study drug where the dose is increased (to 80 or 120 mg). 24-hour 
continuous cardiac (Holter) monitoring should be performed 5 to 7 days after the first 120 mg 
dose. For W8, continuous cardiac (Holter) monitoring should be performed if the subject is 
rolling into the OLE and increasing the dose to 120 mg. A paltusotine predose blood draw for 
PK, safety labs and postdose PK blood draw at 1 to 3 hours should also be done. If the subject is 
on 120 mg of paltusotine and meets rescue criteria, they should be discontinued from the study 
for lack of efficacy (Section 7.1). 
Subjects not continuing in the OLE study will have their last Randomized Treatment Phase dose 
administered at the Week 8 visit. 
Subjects who have previously completed the OLE (when the OLE concluded at Week 58) may 
rejoin the OLE at the same dose they were previously on if they meet the following conditions: 
(1) the Investigator has determined that the subject’s disease is stable, (2) safety assessments, 
including chemistry, hematology, urinalysis, and baseline electrocardiogram, show no significant 
changes compared to previous evaluations, and (3) approval from the Medical Monitor. 
Once these three conditions are met, the subject may reenter the OLE after discontinuation of 
their current SSA therapy, with the timing at the discretion of the Investigator. The subject will 
reenter the OLE at the Week 58 timepoint and follow the SOA as described in Table 2.  

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Table 8: 
Dose Adjustments during Open-Label Extension Phase 
Carcinoid Symptom Criteria 
Tolerability Criteria 
Dose Adjustment 
On Day 56: no rescue treatments 
initiated or required during 
preceding week 
After Day 56: <2 rescue treatments 
initiated or required during 
scheduled visit interval 
Acceptable tolerability of current 
dose 
No dose change 
On Day 56: ≥1 rescue treatment 
initiated or required during 
preceding week 
After Day 56: ≥2 rescue 
treatments** initiated or required 
during scheduled visit interval 
Acceptable tolerability of 40 mg 
Acceptable tolerability of 80 mg 
40 mg→80 mg* 
80 mg→120 mg* 
At any time 
Unacceptable tolerability of 80 or 
120 mg doses 
80 mg→40 mg or  
120 mg→80 mg 
Note: Triplicate ECG should be performed 1-3 hours after supervised administration of study drug where the dose is 
increased (to 80 or 120 mg) (Section 8.3.3). Continuous cardiac (Holter) monitoring (24 hour) should be performed 
5-7 days after the first 120 mg dose. 
*The initial dose after the 40 mg increase to 80 mg or 80 mg increase to 120 mg should be administered at the 
clinical research site. Subjects starting the Open-Label Extension Phase at 40 mg who increased to 80 mg may have 
an additional dose increase to 120 mg. 
**Second rescue treatment occurs after having met stopping criteria for initial short-acting octreotide rescue 
(Table 6). 
The completion of an electronic Symptom Diary will continue daily throughout Screening 
beginning within 1 day of S1, and through Week 12 of the study (through Randomized 
Treatment Phase and 4 weeks into OLE) and then selected time periods in the OLE Phase 
(Section 8.2.1). 
4.1.4. 
Study Completion and Early Termination 
Study completion and early termination (ET) for subjects are each defined separately for the 
Randomized Treatment Phase and the OLE Phase. Completion of Randomized Treatment Phase 
and the OLE Phase of the study requires that subject complete the final visit within each phase 
(End of Study [EOS] Visit for Randomized Treatment Phase and the OLE Phase) (Refer to 
Table 1 and Table 2). Subjects discontinuing early from Randomized Treatment Phase or the 
OLE Phase of the study should be treated with standard treatment as recommended by the 
Investigator and will have an ET Visit. 
4.1.5. 
End of Randomized Treatment Phase and End of Treatment 
End of Randomized Treatment Phase (EOR) is defined as completion of last scheduled dosing in 
Randomized Treatment Phase.  
End of Treatment (EOT) is defined as completion of last scheduled dosing in OLE Phase.  

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4.1.6. 
End of Study 
End of Study (EOS) is defined as the date of the last visit of the last subject in the study. 
An EOS Visit will occur to collect the safety data and other assessments as detailed in the SOAs 
(Section 1.2). 
An EOS Visit will be 28 days after last dose of study drug and is required for subjects who 
completed the study or early terminated. 
4.1.7. 
Patient Input into Study Design 
Patient insight was collected over several meetings (June 2021- June 2022) through a formalized 
Patient Leadership Council made up of 12 individuals living with carcinoid syndrome associated 
with NETs. These patients had a range of experiences including treating physician, medical 
treatments, geographic location, and age of diagnosis. In these meetings, the following topics 
were discussed: clinical study protocols, 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 
This study consists of a Randomized Treatment Phase followed by an OLE Phase. A randomized 
parallel-group design allows for a rigorous assessment of the safety and efficacy associated with 
each dose. These data will be useful for study design and dose selection in subsequent trials. 
The OLE will provide important long-term safety and efficacy information that will also inform 
later stage trial designs. Standardized dose adjustment criteria are provided in the protocol taking 
into account reasonable treatment goals and study drug toleration. 
Subject safety will be ensured using protocol defined criteria for study drug discontinuation and 
rescue therapy with short-acting octreotide subcutaneous injections and antidiarrheal medication. 
4.3. 
Justification for Dose 
The duration of treatment and dose range to be explored in CRN00808-11 is based on dose 
response and safety information from paltusotine healthy volunteer and acromegaly trials as well 
as clinical information pertaining to approved octreotide LAR and lanreotide for treatment of 
Carcinoid syndrome. 
Dose and exposure-response analyses of completed Phase 2 acromegaly trial data with 
paltusotine have shown that the appropriate starting dose of paltusotine is 40 mg because it 
results in similar IGF-1 suppressive activity as long-acting SRL therapies; exposure-response 
modeling suggests this dose maintains trough effective concentration (EC)80 in most subjects. 
The starting dose of approved long-acting SRL therapies for Carcinoid syndrome is the same or 
higher as the starting dose for acromegaly (Sandostatin LAR 2024; Somatuline Depot 2024); 
therefore, the starting dose of paltusotine for this Phase 2 trial CRN00808-11 in Carcinoid 
syndrome will be 40 mg (same dose as for acromegaly subjects), with higher doses also being 
examined in this trial. The Sponsor expects 40 mg to be a well-tolerated starting dose for 
subjects who enroll CRN00808-11 as this dose has been well tolerated in studies in subjects with 

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acromegaly. Although subjects naïve to long-acting SRL therapies are also eligible, the Sponsor 
expects these to be a small proportion of subjects enrolled. Further, current clinical practice 
generally excludes initiation of treatment with short-acting octreotide before starting treatment 
with octreotide LAR (Strosberg, 2020), indicating that a “run-in” period with lower SRL doses is 
not necessary for subjects who are initiating treatment with SRL therapies. 
As of 31 August 2021, doses up to 80 mg have been studied in healthy volunteers and up to 
40 mg have been studied in subjects with acromegaly. The Sponsor proposes to explore 
paltusotine doses up to 120 mg for this exploratory trial in Carcinoid syndrome subjects. While 
this is higher than the 40 to 60 mg dose range expected to result in IGF-1 suppression in 
acromegaly subjects, Carcinoid syndrome subjects may require higher doses than acromegaly 
subjects due to malabsorption syndromes commonly associated with Carcinoid syndrome or its 
treatment (Naraev, 2019). In addition, the pharmacokinetics (clearance and volume of 
distribution) of paltusotine may be different in Carcinoid syndrome subjects compared to 
acromegalics because of differences in liver and body composition which effect metabolic 
activity. 
Current clinical recommendations for treating Carcinoid syndrome symptoms include starting 
with long-acting SRL therapies at maximum approved doses detailed in the respective 
Prescribing Information (octreotide LAR 30 mg every 4 weeks and lanreotide 120 mg every 
4 weeks) and escalation up to 2 times this for refractory patients (Strosberg, 2020). Given this 
current practice and that paltusotine 60 mg QD is anticipated to be the maximum dose for the 
treatment of acromegaly, this study will evaluate a maximum dose of 120 mg QD in Carcinoid 
syndrome subjects to ensure a clinically relevant dose range for this condition is evaluated. 
4.4. 
Justification for Duration of Treatment 
The study was designed with an 8-week RTP to allow sufficient time to demonstrate 
dose-responsiveness of 40 vs 80 mg paltusotine. In addition, a 102-week OLE was included in 
the study to assess long-term safety in adults with Carcinoid syndrome. 
4.5. 
Treatment After End of Trial Participation 
After the end of the study, subjects may resume regionally licensed Carcinoid syndrome 
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. 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 prior to performing any Day 1 
study procedures. Up to 6 subjects taking proton-pump inhibitors (PPIs) at Screening may enroll 
in the study. 
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, 
including at least 70% compliance with electronic Symptom Diary for the 2-week 
period prior to the S2 Visit and prior to the Day 1 visit.  
Demographics and Medical History 
3. 
Male or female subjects ≥18 years of age, at the time of Screening. 
4. 
Documented Carcinoid syndrome requiring medical therapy. Eligible subjects fall 
into one of the following categories: 
 Not currently treated with SRL agonists for at least 12 weeks prior to 
Screening, and actively symptomatic (average of ≥4 BM/day or >2 flushing 
episodes per day in at least 2 days over a period of 2 weeks). This can include 
treatment-naïve subjects. 
 Subjects currently treated with lanreotide, octreotide LAR, or short-acting 
octreotide (subcutaneous or oral) who are currently symptomatically 
controlled (average <4 BM/day and average ≤2 flushing episodes/day over a 
2-week period) and willing to wash out of their medication. The subject must 
demonstrate symptomatic worsening after washout. These subjects must have 
at least one historical instance of an elevated 5-HIAA or serotonin level. 
5. 
Evaluable documentation of locally advanced or metastatic histopathologically 
confirmed well-differentiated NET. Tumors must be Grade 1 or Grade 2 (Ki-67 
index ≤20%, or a mitotic count of ≤20 mitoses per 10 high-power fields, if the Ki-67 
index is not available) per the World Health Organization neuroendocrine neoplasm 
classification (Rindi and Inzani, 2020). Grade 3 tumors are not eligible. 
 
HPF = high-power fields; NEN = neuroendocrine neoplasms; NET = neuroendocrine tumor 

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6. 
No significant disease progression* as assessed by the Investigator within the last 
6 months before initiation of study drug dosing. 
*Pretrial imaging with MRI or CT, the most recent of which should be no more than 
approximately 3 months prior to Screening, should be available and compared to a previous 
imaging study to assess disease stability for established subjects on SRL maintenance 
therapy, while clinical symptoms and/or biomarker assessments should be used to assess 
disease stability for newly diagnosed subjects naïve to SRLs.  
7. 
Historical documentation of positive SSTR tumor status by PET or somatostatin 
receptor scintigraphy.* 
*If subject does not have historical documentation, this can be done during Screening. 
Screening and Testing Evaluations 
8. 
Plasma 5-HIAA ≥2× ULN during Screening for subjects not currently treated with 
any SRL therapy who are not washing out of SRLs. 
Lifestyle Restrictions 
9. 
Females who engage in heterosexual intercourse must be of nonchildbearing 
potential, defined as either surgically sterile (ie, hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy), OR be postmenopausal with at least 
1 year of amenorrhea, OR must agree to use a highly effective method of 
contraception from the beginning of Screening to the last study visit. 
 Acceptable highly effective methods of contraception include: 
 Combined estrogen-progestin oral hormonal contraception associated 
with consistent inhibition of ovulation 
 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) 
In addition to these methods of contraception, the male partner should use a condom from 
the beginning of Screening to the last study visit. 
10. 
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 [ie, 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.  
Diarrhea attributed to any condition(s) other than Carcinoid syndrome (including but 
not limited to fat malabsorption, bile acid malabsorption, short bowel syndrome, 
pancreatic exocrine insufficiency, infections, VIPoma, Zollinger-Ellison syndrome). 
Exception to this are subjects with prior cholecystectomy or small bowel resections, 
provided diarrhea is controlled prior to washout or if not currently treated with any 
SRL therapy. 
2.  
Uncontrolled/severe diarrhea associated with significant volume contraction, 
dehydration, or hypotension. 
3.  
Requires second line treatments (eg, telotristat) for control of Carcinoid syndrome 
symptoms in the opinion of the Investigator 
4.  
Treatment with specific NET tumor therapy <4 weeks before Screening (such as 
everolimus or sunitinib) or hepatic embolization, radiotherapy, peptide receptor 
radionuclide therapy (PRRT), and/or tumor debulking <12 weeks before Screening. 
5.  
Karnofsky performance status <60%. 
6.  
Major surgery within 8 weeks before Screening. 
7.  
History of another primary malignancy <3years prior to the date of first dose of study 
treatment unless at least one of the following criteria are met: 
 Adequately treated basal or squamous cell carcinoma of the skin 
 Cancer of the breast or cervix in situ 
 Previously treated malignancy, if all treatment for that malignancy was 
completed at least 3 years prior to first dose of study treatment, and no current 
evidence of disease. 
 
Concurrent malignancy determined to be clinically stable and not requiring 
treatment. 
8.  
Life expectancy <12 months from Screening. 
9.  
Diabetes mellitus treated with insulin for less than 6 weeks prior to the study entry. 
10.  
Poorly controlled diabetes mellitus defined as having a hemoglobin A1c (HbA1c) 
≥8.5% (ie, ≥69.5 mmol/mol) or estimated HbA1c based on fructosamine if HbA1c is 
not evaluable (eg, due to hemoglobinopathy). 
11.  
History of unstable angina or acute myocardial infarction within the 12 weeks 
preceding the Screening Visit or other clinically significant cardiac disease (including 
clinically significant carcinoid heart disease) at the time of Screening as judged by the 
Investigator. 
12.  
Known history of, or current alcohol or drug abuse, within the last year. 
13.  
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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14.  
Current use of medications that are strong inducers of cytochrome P450 3A4 
(CYP3A4) (including but not limited to carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, St. John’s wort) within 2 weeks prior to Screening because they 
may reduce systemic exposure to paltusotine. 
Current use of medications that are sensitive substrates of CYP3A4 with a narrow 
therapeutic index (including but not limited to tolvaptan, lomitapide, pimozide, 
dronedarone, dasatinib, sirolimus) as paltusotine may increase exposure of these 
medications. 
15.  
Unable to administer short-acting octreotide (octreotide acetate injection), or prior 
nonresponse documented with somatostatin agonists. 
16.  
Known allergy or hypersensitivity to any of the test materials or related compounds. 
Screening Tests and Evaluations 
17.  
Active COVID-19 confirmed or suspected based on SARS-CoV-2 testing and clinical 
symptoms. 
18.  
QT interval corrected using Fridericia’s formula (QTcF) >480 msec (or QTcF 
>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.). 
Other Criteria 
19.  
Clinically significant concomitant disease that is not a result of primary disease under 
study, including but not limited to cardiovascular disease, estimated glomerular 
filtration rate <30 mL/min/1.73 m2, cirrhosis, baseline AST and/or ALT >2× ULN, 
and/or total bilirubin >1.5× ULN. (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.) 
5.3. 
Screen Failures 
Subjects who fail to meet the eligibility criteria at any point during the Screening Period are 
defined as screen failures. The reason for each screening failure will be recorded. Refer to 
Section 4.1.1. 
Subjects who fail screening assessments based on findings the Investigator believes are 
temporary and not reflective of the usual state of the subject (eg, HbA1c of ≥8.5% 
[69.5 mmol/mol] when the subject is usually well below this value, or clinical symptoms) can be 
considered for retesting of assessments that are considered atypical for subject’s usual status. 
These cases should be discussed with the Medical Monitor. 
In the event of rescreening, it may be determined that certain laboratory assessments conducted 
during the initial Screening Phase may not need to be repeated for individual subjects. The 
decision will be made on a case-by-case basis in discussion with the Medical Monitor. 
Subjects who are screen failures because they did not meet clinical and/or biomarker criteria as 
specified in Section 4.1.1 cannot be rescreened. 

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If there is <70% compliance with completion of the electronic Symptom Diary between S1 and 
S2, the subject is a screen failure; however, the subject can rescreen if other eligibility 
requirements are met; this is allowed (one more attempt only). Site staff should reeducate the 
subject on the compliance with completion of the electronic Symptom Diary and document the 
retraining in the source documents. 

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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s) or marketed product(s) 
intended to be administered to a study subject according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
Study drug will be swallowed, with at least 8 ounces (237 mL) of water, after fasting at least 
6 hours. No food, drink (except for water), or other medications will be allowed for at least 
1 hour after study drug administration, including at the time of study drug administration. The 
first dose of the OLE Phase will be administered during the Week 8 visit for those continuing 
into the OLE Phase. 
Paltusotine is the Investigational Medicinal Product (IMP), diphenoxylate atropine and 
loperamide are concomitant medications, and short-acting octreotide is a rescue medication 
(ie, auxiliary medicinal protect [AuxMP]). Investigators should 
 
 
Intervention 
Name 
Paltusotine 
Short-acting 
octreotide  
Diphenoxylate 
atropine 
Loperamide 
Type  
Experimental drug 
(IMP) 
Rescue medication 
(AuxMP) 
Concomitant 
medication 
Concomitant 
medication 
Dose 
Formulation 
Tablet 
Solution in vial or 
prefilled syringe 
Tablet 
Tablet 
Unit Dose 
Strength 
20 mg 
Details provided in 
Pharmacy Manual 
Details provided in 
Pharmacy Manual 
Details provided in 
Pharmacy Manual 
Dosage Levels 
40 mg (two 20 mg 
tablets), 80 mg 
(four 20 mg 
tablets), or 120 mg 
(six 20 mg tablets) 
once daily. See 
Section 6.5. 
200 μg, up to 
3×daily at the 
direction of the 
Investigator  
5 mg up to 4×daily as 
needed 
4 mg initiation, 2 mg 
after each loose bowel 
movement as needed; 
total daily dose 
≤16 mg 
Controlled 
Room 
Temperature 
15-25°C (59-77°F) 
Details provided in 
Pharmacy Manual 
Details provided in 
Pharmacy Manual 
Details provided in 
Pharmacy Manual 
Route of 
Administration 
Oral 
Subcutaneous 
Injection 
Oral 
Oral 
Sourcing 
Provided centrally 
by the Sponsor 
Sourced by 
institution and 
reimbursed by 
Sponsor or sourced 
centrally and 
supplied by Sponsor  
Sourced by institution 
and reimbursed by 
Sponsor  
Sourced by institution 
and reimbursed by 
Sponsor  
Packaging and 
Labeling 
Paltusotine will be 
provided in bottles 
and labeled as 
required 
(Section 6.2).  
Details provided in 
Pharmacy Manual 
Details provided in 
Pharmacy Manual 
Details provided in 
Pharmacy Manual 
AuxMP=auxiliary medicinal product, IMP=investigational medicinal product 
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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 intervention (ie, they will be responsible for the receipt and accountability 
of the study intervention). 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 for the study 
intervention(s). Study staff at the study site will take all steps to maintain adequate records and 
will ensure that the study intervention 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-patient shipments of study drug will be allowed in 
exceptional cases (ie, where subjects would not be able to attend onsite visits and would risk 
continued access to study drug). Study intervention will be provided by the Sponsor and are to be 
dispensed only in accordance with the protocol. Study intervention must not be dispensed to any 
person not enrolled in the study. 
Paltusotine will be packaged in 36-count, high-density polyethylene bottles containing desiccant 
cannister. 
Accurate inventory and accountability records of the study intervention will be kept by the 
appointed team member. Study intervention accountability must be performed for all delivered 
dispensing unit number. Returned study intervention (partly used or unused including empty 
packaging material) must be stored separately from nonallocated study intervention. 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. If the Investigator, the site staff, or the site monitor suspect that the study 
intervention is defective or potentially defective, Crinetics Pharmaceuticals or designee should 
be contacted immediately. Full details concerning study intervention handling eg, allocation, 
accountability, tracking, and recording will be provided in the Pharmacy Manual. 
At the end of the study (ie, 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. 
6.3. 
Measures to Minimize Bias: Blinding 
Not applicable. 
6.4. 
Study Intervention Compliance 
When subjects are dosed during a study visit, they will receive study intervention directly from 
the Investigator or designee, under medical supervision. The date and time of each dose 

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administered in the clinic will be recorded in the source documents. Subjects in the OLE Phase 
who are up-titrated to the 120 mg dose will need to swallow the first dose under the supervision 
in the research center. 
When subjects self-administer study intervention at home, compliance will be assessed at each 
visit. Compliance will be assessed by either direct questioning and/or counting returned 
tablets/vials 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 intervention dispensed to and administered by each subject 
must be maintained and reconciled with study intervention and compliance records. Study 
intervention 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 interventions 
(including paltusotine tablets and short-acting octreotide) at each study visit during the 
Randomized Treatment Phase. All returned study interventions should be stored, inventoried, 
reconciled, and returned according to applicable local regulations and study procedures. 
6.5. 
Study Intervention Dose Modification 
See Section 6.5.1 and Section 6.5.2 for the dose titration/adjustment in this study. 
6.5.1. 
Dose Adjustment During the Randomized Treatment Phase 
In the Randomized Treatment Phase, the subject will be randomized to 40 mg QD vs. 80 mg QD 
for the 8 week parallel-group phase. It is anticipated that subjects will complete the 8 weeks 
parallel dose without changing the dose of paltusotine assigned at randomization. However, if 
the subject experiences Carcinoid syndrome symptoms that meet protocol criteria for 
short-acting octreotide rescue, the dose may be increased once to a maximum dose of 120 mg 
QD during the first 28 days as tolerated. No dose increases are allowed after Day 28 through the 
remaining 4 weeks of the parallel-group phase of the study. The details are outlined in Table 7. 
6.5.2. 
During the Open-Label Extension Phase 
Subjects completing the 8 weeks Randomized Treatment Phase may begin the OLE Phase of the 
study if, in the opinion of the Investigator, the subject may benefit from OLE Phase participation. 
The initial OLE dose will be chosen by the Investigator based on criteria of carcinoid symptom 
control and of tolerability and will start on Day 56 (Table 8). 
6.6. 
Treatment of Overdose 
There are no clinical data available on effects associated with overdose of the study drug. No 
documented incidents of overdose have occurred with paltusotine to date. Preclinical animal 
studies indicate bradycardia or hypertension may result from overdose. Signs, symptoms, or the 
clinical sequelae of a suspected overdose of study drug should be reported as an AE/serious 
adverse event (SAE). Overdose in the absence of clinical sequelae will be reported as a protocol 
deviation unless it is an intentional overdose taken with possible suicidal/self-harming intent. 

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Such overdoses should be reported regardless of sequelae. 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. 
Octreotide acetate injection given in intravenous boluses of 1 mg (1,000 µg) to healthy 
volunteers did not result in serious ill effects, nor did doses of 30 mg (30,000 μg) given 
intravenously over 20 minutes and 120 mg (120,000 μg) given intravenously over 8 hours to 
research subjects (Sandostatin LAR 2024). If overdose occurs, the healthcare provider should be 
contacted for symptomatic management as indicated. 
6.7. 
Concomitant Therapy 
6.7.1. 
Permitted Medications 
Concomitant medications allowed in this study are those permitted medications used during 
Screening to control existing medical conditions and/or those used during the study, if medically 
needed, including antidiarrheal medications (such as diphenoxylate, loperamide).  
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 record the drug, 
the dose, start and stop dates, indication, route, and frequency. The Investigator is responsible for 
ensuring the new medication is not prohibited by the protocol and to contact the Medical 
Monitor for any questions or discussions. 
6.7.2. 
Prohibited Medications 
Any questions regarding prohibited medications should be discussed with the Medical Monitor 
or appropriate designee. Prohibited medications will not be allowed from start of the Screening 
Period and for the study duration and includes: 
 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). 
 Current use of medications that are sensitive substrates of CYP3A4 with a narrow 
therapeutic index (including but not limited to tolvaptan, lomitapide, pimozide, 
dronedarone, dasatinib, sirolimus) as paltusotine may increase exposure of these 
medications. 
 Any standard drug for treatment of Carcinoid syndrome that is not used as a rescue 
medication during the Randomized Treatment Phase and OLE Phase. 
 Any other investigational drug, unless approved by the Medical Monitor (eg, COVID-19 
therapies). 
 Randomized subjects who are not on PPIs on Day 1 should not start taking PPIs during 
the Randomized Treatment Phase. 
 Treatment with NET specific therapy (eg, everolimus, sunitinib, PRRT therapy, hepatic 
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The Medical Monitor will review the subjects’ medications prior to randomization to assess for 
potential clinically relevant interactions with paltusotine and to confirm eligibility. 
6.7.3. 
Rescue Medications (Auxiliary Medicinal Products) 
Short-acting octreotide is considered a rescue medication (ie, auxiliary medicinal product) 
 
  
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7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment/Participation 
If the subject is eligible and in the opinion of the Investigator there may be benefit, subjects 
completing the Randomized Treatment Phase may begin the OLE Phase of the study. If the 
subject withdraws consent or, in the opinion of the Investigator, should be permanently 
discontinued from the study during the Randomized Treatment Phase (and would therefore, not 
be eligible for enrollment in the OLE), an ET Visit should be completed as specified in the SOAs 
(Section 1.2 and Section 4.1.4) and the subject should return to standard Carcinoid syndrome 
treatment as prescribed by the Investigator. 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. In addition, the Investigator will report the subject’s withdrawal to the 
responsible Medical Monitor within 24 hours. 
Subjects will be withdrawn from the OLE Phase of the study if NET progression according to 
local standards is evident on scheduled or unscheduled imaging studies. 
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, in consultation with 
the Medical Monitor; 
3. Unacceptable tolerability of the lowest study drug dose (40 mg per day) in the opinion of 
the Investigator; 
4. Other clinically significant potentially drug-related abnormalities (eg, newly developed or 
worsening hyperglycemia, hypersensitivity, symptomatic cholelithiasis, or pancreatitis); 
5. Investigator’s decision (ie, 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); 
6. Need for administration of a prohibited concomitant medication; 
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 noncompliance 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 fulfil study requirements and procedures; 
11. Death. 

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7.1.1. 
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 2-fold and exceed 3× ULN. Testing should be repeated within 1 week and 
if the amylase or lipase elevation persists, study drug should be held. The Medical Monitor and 
Investigator will determine together the appropriateness of continued study participation. 
7.1.2. 
Cardiac Study Drug Stopping Criteria 
If a clinically significant finding is identified (including, but not limited to changes from 
Baseline 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, eg, evidence 
for new arrhythmia, significant chest discomfort/pain, presyncope or syncope. 
Discontinuation of study drug is required when a subject meets 1 of the clinically significant 
cardiac symptoms or findings as outlined below: 
 Ventricular tachycardia; 
 Based on the average of triplicate ECGs, QTcF >500 msec (or QTcF >530 msec in 
subjects with a bundle branch block) repeated on a second set of electrocardiograms 
(ECGs) at least 2 hours apart and confirmed by a stat central ECG reading; 
 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. 

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7.1.3. 
Liver Chemistry Abnormality Monitoring and Study Drug Stopping Criteria 
Closely monitoring for abnormalities of liver tests and discontinuation for evidence of liver 
injury will be performed according to the following process: 
 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: 
o ALT or AST >3× ULN (for subjects with ALT and AST <ULN at Baseline); 
o ALT or AST >3× ULN and >2× Baseline (for subjects with ALT or AST >ULN 
at Baseline); 
o Total bilirubin (TB) >2× ULN (for subjects with TB <ULN at Baseline); 
o TB >2× ULN and >2× Baseline (for subjects with TB >ULN at Baseline); 
o Alkaline phosphatase (ALP) >3× ULN (for subjects with ALP <ULN at 
Baseline); 
o 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, TB and INR) to confirm the 
abnormalities and to determine if they are increasing or decreasing. There also should be 
inquiry made about symptoms. 
If the above-listed liver test abnormalities (and/or related symptoms) persist or worsen, 
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 discontinued. 
 Close Observation of Any Subject with Detected Liver Test Abnormalities 
Close observation includes: 
o 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; 
o Obtaining a more detailed history of symptoms and prior or concurrent diseases; 
o Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets; 
o Assessment for acute viral hepatitis (including types A, B, C, D, and E as 
appropriate); autoimmune or alcoholic hepatitis; nonalcoholic steatohepatitis; 
hypoxic/ischemic hepatopathy; and biliary tract disease; 
o Obtaining a history of exposure to environmental chemical agents; 

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o Obtaining additional tests to evaluate liver function, as appropriate 
(eg, international normalized ratio); 
o Considering gastroenterology or hepatology consultations. 
Discontinuation of study drug for abnormal liver tests is required when a subject (with ALT and 
AST <ULN at Baseline) 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%). 
7.1.4. 
Neurological Adverse Events 
If a subject develops severe neurologic treatment-related AEs (including but not limited to 
seizures, worsening of tremors, decreased activity [eg, lethargy]) the study drug should be 
discontinued, and neurology consultation obtained. The Medical Monitor and Investigator will 
determine the appropriateness of any further study drug dosing if clinically appropriate 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 (ie, 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 (eg, 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 intervention; 
 Results from ongoing safety monitoring; 
 Other medical or ethical reasons. 
Regulatory Authorities also have the right to terminate the study for any reason. 
In the event the study is terminated, Investigators and the Institutional Review Boards (IRBs) or 
Independent Ethics Committee (IECs) will be notified as soon as possible. 

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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 
history of Carcinoid syndrome, medical history, and concomitant medications. Target symptom 
will be evaluated at Baseline on Day 1. 
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) Electronic Symptom 
Diary, (2) Patient Global Impression of Severity (PGI-S), (3) Patient Global Impression of 
Change (PGI-C), (4) EuroQoL 5 Dimensions 5 Level (EQ-5D-5L), (5) EORTC QLQ-C30 
Quality of Life Questionnaire, (6) EORTC QLQ-GI.NET21 Quality of Life Questionnaire, 
(7) Functional Assessment of Cancer Therapy – Carcinoid Syndrome Symptom Index 
(FACT-CSI) (Shaunfield, 2021), and (8) Treatment Preference Question. 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). Exceptions may be allowed upon discussion 
with the Sponsor to complete the Symptom Diary on paper. 
8.2.1. 
Electronic Symptom Diary 
Subjects will be asked to complete the electronic Symptom Diary, a brief Symptom Diary, daily 
at home beginning after the initial Screening and continuing throughout Screening beginning 
within 1 day of S1, Week 1 through Week 12 (throughout Randomized Treatment Phase and 
beginning of the OLE Phase), then for the rest of the OLE Phase, it should be completed daily 
approximately 2 weeks before the Week 24, 36, 48, 58, 70, 82, 96, and 110 visits (or simply 
during Week 23-24, Week 35-36, Week 47-48, Week 57-58, Week 69-70, Week 81-82, 
Week 95-96, and Week 109-110).  
This electronic Symptom Diary will be used to assess the understanding and compliance of the 
subject and to measure the Baseline symptom frequencies of BMs and flushing frequency and 
severity, episodes of fecal urgency and incontinence, abdominal pain severity, and stool 
consistency. The Baseline symptoms of stool consistency will be evaluated according to Bristol 
scale and abdominal pain according to an NRS. To determine subject eligibility, screening data 
will be reviewed prior to study drug dosing (Section 5.1). 
Subjects will be instructed to complete the diary at about the same time, every evening during 
the periods specified above. Site staff will review subject compliance with self-reported 
electronic Symptom Diary completion as outlined in the Study Reference Guide. 
At least 5 days of diary data per 7-day period are required for the qualifying assessments for 
eligibility to be made. 
Subjects will be asked to record use of all breakthrough symptom treatments in the daily 
electronic Symptom Diary. 
In rare cases when the electronic Symptom Diary cannot be used, a paper diary may be used 
upon consultation with the Sponsor. 

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8.2.2. 
Global Impressions of Change and Severity 
The PGI-S assesses the subject’s perception of overall disease severity using a 4-point verbal 
rating scale (no symptoms, mild symptoms, moderate symptoms, and severe symptoms). 
The PGI-C assesses the subject’s perception of change in disease severity using a 7-point verbal 
rating scale (much better, moderately better, a little better, no change, a little worse, moderately 
worse, and much worse). 
8.2.3. 
EQ-5D-5L 
The EQ-5D-5L (5 severity levels EQ-5D), developed by the European Quality of Life 
(EuroQoL), is a standardized instrument to be completed by the subject for use as a measure of 
health outcomes applicable to a wide range of health conditions. It comprises 5 dimensions of 
health: mobility, ability to self-care, ability to undertake usual activities, pain and discomfort, 
and anxiety and depression. Based on qualitative and quantitative studies conducted by the 
EuroQoL Group, there are 5 options (levels) under each domain: ‘no problems’, ‘slight 
problems’, ‘moderate problems’, ‘severe problems’, and ‘unable to/extreme problems’. The 
responses to all 5 dimensions can be converted to a single summary index, utility (range: 0 to 1), 
by using value sets. Higher index values represent better health states. 
8.2.4. 
EORTC QLQ-C30 Quality of Life Questionnaire 
EORTC QLQ-C30 quality of life questionnaire will be used to assess health-related quality of 
life in subjects with cancer. The questionnaire entails 28 questions to assess health-related 
quality of life, each question can be answered on a 1 to 4 scale. Lower scores indicate a better 
quality of life. There are 2 additional questions, 1 to rate subjects’ ‘overall health in the past 
week’ and 1 to rate the subjects’ ‘overall quality of life in the past week’. Each of these 
2 questions can be answered on a 1 to 7 scale. Higher scores indicate a better quality of life. 
8.2.5. 
EORTC QLQ-GI.NET21 Quality of Life Questionnaire 
EORTC QLQ-GI.NET21 quality of life questionnaire will be used to follow up with symptoms 
in subjects with neuroendocrine carcinoids. There will be around 21 questions divided into the 
category of ‘during the past week’ and ‘during the past 4 weeks’, which will be used to follow up 
with symptoms in subjects. Each of the questions can be answered on a 1 to 4 scale. Lower 
scores indicate a better quality of life. 
8.2.6. 
FACT-CSI 
The FACT-CSI is a 24-item instrument that can be scored as a single, multidimensional 
symptom index, consisting of the following domains: disease-related physical symptoms, 
disease-related emotional symptoms, treatment side effects, and functional well-being. Subjects 
select a response to each statement on a 5-point Likert scale ranging from 0 (Not at all) to 
4 (Very much). Lower total score indicates a better quality of life (Shaunfield, 2021). 
8.2.7. 
Treatment Preference Question 
The Treatment Preference Question is a single question regarding the subject’s preferred 
treatment form, ie, previously used injections, oral study drug, or no preference. 

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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 (including but not limited to assessments of alertness and orientation with 
respect to person, place and time, and involuntary movements such as tremor) and, where 
appropriate, other body systems. Symptom-related physical examinations should also include 
neurologic assessments as above (with weight measurement as appropriate). 
Physical examination including weight measurement will be done at specified time points in 
SOA. Height measurement will be done at Screening only. 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 all visits including home visits. 
Blood pressure (resting) should be measured with calibrated digital equipment in the supine 
position after resting quietly for 5 minutes. 
Vital sign measurements will be repeated if clinically indicated 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, TV, etc). Triplicate ECG should be performed at Screening, 1 to 3 hours after 
supervised administration of the first dose of study drug, and any subsequent visit where the dose 
is increased to 80 or 120 mg. 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 and can include use of 
the central reading results when provided. The Investigator’s assessment will be recorded in the 
eCRF. Potentially significant outlier values should be confirmed after review by the central ECG 
reader. Any ECG measurement determined to be clinically significant (occurring after signing 

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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 7.1.2 for cardiac withdrawal criteria and any additional ECG readings that may 
be necessary. 
8.3.4. 
Continuous Cardiac Monitoring 
Outpatient 24-hour continuous cardiac (Holter) monitoring and recording will be conducted as 
specified in the SOAs (Section 1.2). An adequate continuous cardiac monitor recording should 
be confirmed by the central reader as soon as possible after completion, so that a repeat 
continuous cardiac monitor recording may be performed, if necessary. 
8.3.5. 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and the SOAs 
(Section 1.2) 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. 
After sampling, blood collection tubes will be labeled and handled per the local institutional 
procedures. 
All results (except 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. 
8.3.6. 
Biliary/Gallbladder Ultrasound 
Biliary/gallbladder ultrasound will be performed for subjects who have not had a prior 
cholecystectomy, according to the study site procedures for the evaluation of presence or absence 
of lithiasis or sludge or other significant biliary abnormalities. The results will be recorded. 
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. Participants in Screening at the 
time of amendment approval are to have initial ophthalmic testing prior to randomization and 
study drug dosing. 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 (central 24 degrees, for instance, a Humphrey 24-2 Sita Fast) 

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 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 Ophthalmic Central Reader. 
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 
conditions occurring after the moment of signing the ICF or a worsening of a medical condition 
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 treatment-emergent adverse events (TEAEs). 
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. 
AEs related to the study drug that are ongoing at early termination and at the EOS Visit 
(Week 114) for subjects continuing in the OLE Phase and at the EOS Visit (28 days after the last 
dose) for subjects not continuing in the OLE Phase will be followed for outcome information 
until resolution or stabilization. Nonserious AEs will not be followed past database lock. 
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 
AEs will be recorded from 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 
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8.4.2. 
Method of Detecting Adverse Events 
Care will be taken not to introduce bias when screening for AEs. Open-ended and nonleading 
verbal questioning of the subject is the preferred method to inquire about AE or 
TEAE occurrences. 
8.4.3. 
Follow-up of Adverse Events 
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: 
 it has resolved; 
 laboratory abnormalities have returned to normal; 
OR 
 steady state of the symptoms has been achieved. 
If none of the above-mentioned 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 the study drug 
(equivalent to EOS) and the status must be reported in the eCRF and this will end the follow-up 
process of 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 Serious Adverse Events 
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 within 24 hours of occurrence or when the Investigator becomes aware 
of the event. A properly completed SAE reporting form should be sent via email. 
 
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. 
Serious AE 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 
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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 (ie, 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. 
Serious AEs 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. 
Detailed information is given in Appendix 3. 
8.4.5. 
Pregnancy 
Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening. All pregnancy tests at other visits as specified in the SOAs will be urine pregnancy 
tests. If the result of a urine pregnancy test is positive, then the result will be confirmed with a 
serum pregnancy test. Pregnancy tests may 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 emailing a 
completed Pregnancy Report to the Sponsor’s pharmacovigilance Group within 24 hours of 
knowledge of the pregnancy to 
 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 Report. If the outcome of the pregnancy meets the criteria for immediate 
classification as a SAE (eg, 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 emailing a completed SAE form to the 
Sponsor’s pharmacovigilance Group within 24 hours of knowledge of the event to 
 
8.5. 
Pharmacokinetics 
During the Randomized Treatment Phase, and OLE Phase of the study, plasma samples will be 
collected for measurement of plasma concentration of study drug as specified in the SOAs. 
Instructions for the collection and handling 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. 
Plasma samples for lanreotide and octreotide will be collected for previously treated subjects 
only as per the SOAs (Section 1.2). 
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8.6. 
Pharmacogenomics 
On Day 1, optional blood will be drawn for genotyping for the determination of the 
 
 
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in the Laboratory Manual. 
8.7. 
Biomarkers 
Blood will be drawn at the time points on the SOAs to measure plasma 5-HIAA and 
pancreastatin; and serum chromogranin A and serotonin. Pancreastatin will not be collected and 
analyzed for subjects enrolled in EU countries. 
Note: Short-acting octreotide should not be used for at least 12 hours before biomarker sample 
collection. 
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in the Laboratory Manual. 
8.8. 
Imaging and Tumor Surveillance 
Imaging for surveillance of tumor progression will be performed using the same modality as 
previously used in each subject (MRI or CT scan). 
8.8.1. 
Surveillance of Tumor Growth 
The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and 
Medical Management of Midgut Neuroendocrine Tumors recommends initiating radiographic 
surveillance at six-months intervals (Strosberg, 2017). Subjects should have pretrial imaging 
assessment available within 3 months of Screening. After enrollment in the study, subjects 
should have an appropriate tumor surveillance imaging assessment (CT or MRI based on that 
which was used pretrial). Imaging assessments at Week 10, Week 36, Week 70, Week 110, and 
ET are included in Table 2 but can be adjusted to conform to the six-month interval 
recommendation for radiographic surveillance, based on the timing of pretrial imaging 
assessment and Screening duration. 
If the Investigator has any clinical suspicion of tumor progression at any time during the study, at 
a time a surveillance scan is not already scheduled, unscheduled imaging or other appropriate 
testing may be performed. Clinical evidence for tumor progression could include but are not 
limited to any of the following: new or worsening pain or discomfort, new physical examination 
findings such as new or enlarged palpable abdominal masses, hepatomegaly, or jaundice or new 
elevations in liver function tests, or any NET biomarker. The Investigator should obtain imaging 
or other assessments that are appropriate for the clinical finding. 
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8.9. 
Additional Assessments 
8.9.1. 
Subject Interview 
Subjects may have the opportunity to participate in a qualitative interview conducted at the end 
of their participation in the Randomized Treatment Phase. The interview will only be available to 
subjects in certain countries and those applicable countries have the option explicitly stated in the 
consent form to confirm their agreement to participate in the interview. The interview will 
collect information in the subject’s words regarding their own perceptions of their experiences 
with Carcinoid syndrome both before and during the clinical trial. Specifically, interview 
subjects will be asked to describe their Carcinoid syndrome symptoms and impacts before the 
clinical trial and their expectations of treatment prior to entering the study. Subjects will then be 
asked to describe how, if at all, their Carcinoid syndrome symptoms and impacts changed during 
the clinical trial, and to describe the meaningfulness of any changes experienced. The subject 
interviews will be performed via telephone and will be audio recorded and transcribed. 
8.9.2. 
Unscheduled Visit 
In the event that the worsening of Carcinoid syndrome symptoms that meet protocol criteria for 
short-acting octreotide rescue (Section 4.1.3) occurs between the scheduled visits, and the 
Investigator determines it is appropriate to increase the subject’s dose before the next scheduled 
visit, an unscheduled visit can be added in order to increase the subject’s dose. The site should 
perform a triplicate ECG at 1 to 3 hours postdose and 24-hour continuous cardiac (Holter) 
monitoring 5 to 7 days after the dose increase if the dose is increased to 120 mg. A paltusotine 
predose blood draw for PK, safety labs and postdose PK blood draw at 1 to 3 hours should also 
be done. 
8.10. 
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 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No formal hypothesis testing is planned for this study. 
9.2. 
Sample Size Determination 
Formal sample size calculations were not performed due to the exploratory nature of the study 
design. A total of 30 subjects with Carcinoid syndrome is considered adequate to assess the study 
objectives for PK in subjects with Carcinoid syndromes. Subjects taking PPIs at Screening may 
contribute up to 6 subjects enrolled in the study. 
9.3. 
Analysis Sets 
The following analysis sets will be evaluated and used for presentation and analysis of the data in 
this study: 
Safety Set (SS): 
The SS includes all treated subjects. This set will be used for all safety and exploratory efficacy 
analyses. 
Pharmacokinetic Set (PKS): 
The PKS includes all subjects who have received any amount of study drug and have evaluable 
PK data. This set will be used for the PK analyses. 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to database lock of Randomized 
Treatment Phase. It will include a more technical and detailed description of the statistical 
analyses described in this section. This section is a summary of the planned statistical analyses of 
the most important safety, efficacy, and key exploratory endpoints. 
There will be 2 database locks, one for the Randomized Treatment Phase and the other for the 
OLE Phase of the study. 
9.4.1. 
General Considerations 
For continuous variables, the number of subjects (N), mean, median, interquartile range, standard 
deviation, minimum and maximum values will be presented. For discrete variables, the N and 
percent will be presented. These summaries will be presented for all endpoints by visit and dose 
group. Change from Baseline and change from EOR to each subsequent visit will also be 
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9.4.2. 
Efficacy Analyses 
9.4.2.1. 
Analyses 
Pharmacokinetic Analysis: 
Summary of steady state trough levels at each dose will be presented showing the N, mean, 
median, interquartile range, geometric mean, standard deviation, minimum and maximum values 
at EOR. The 95% confidence interval (CI) will be presented for the mean and geometric mean. 
All steady state trough levels as well as other PK analyses will be performed on the PK set. 
Exploratory Analyses: 
 
 
 
 
Randomized Treatment Phase Exploratory Endpoints are as follows: 
 Proportion of clinical responders by dose during the last week of the Randomized 
Treatment Phase. Subjects with missing data at the EOR will be considered 
nonresponders. 
In subjects who meet diarrhea entry criteria only: 
 Have less than 4 mean bowel movements (BMs) daily 
 Have a >20% reduction in the mean daily number of BMs compared with 
Baseline 
In subjects who meet flushing entry criteria only: 
 Have a >30% reduction compared with Baseline in the mean daily number of 
flushing episodes. 
In subjects who meet both diarrhea and flushing entry criteria: 
 Have less than 4 mean BMs daily 
 Have a >20% reduction in the mean daily number of BMs compared with 
Baseline 
 Have any reduction from Baseline in the mean daily number of flushing episodes 
 Proportion of target symptom responders by dose during the last week of the 
Randomized Treatment Phase: 
 Subjects who met the target symptom (BM or flushing) response criteria. Target 
symptom is the symptom [either BM or flushing] that troubled the subject the 
most at Baseline. 
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 Change in mean daily BMs from Baseline Period of Screening to last week of 
Randomized Treatment Phase. The change for missing data will be set to 0. 
 Change in mean daily number of flushing episodes from Baseline Period of Screening 
to the last week of Randomized Treatment Phase. The change for missing data will be 
set to 0. 
 Change in worst flushing in last 24 hours (using a 0 to 10 NRS). The change score 
will be set to 0 if missing: 
 From the mean Baseline Period of Screening to the mean in the last week of the 
Randomized Treatment Phase 
 From the highest score during Baseline Period in Screening to the highest score 
during the last week of the Randomized Treatment Phase 
 Change in mean daily target symptom episodes from the Baseline Period of Screening 
to the last week of the Randomized Treatment Phase. The change for missing data 
will be set to 0. 
 Change from Baseline to EOR in biomarkers: 
 Plasma 5-HIAA 
 Plasma pancreastatin 
 Serum chromogranin A 
 Serum serotonin 
Missing values of biomarkers at the end of the EOR will be left missing. 
 Change in the use of short-acting octreotide: 
 Change in proportion of days on short-acting octreotide in the Screening Period, 
after subject has met entry criteria, to the proportion of days on short-acting 
octreotide of the last week of Randomized Treatment Phase 
 Change in mean daily dose of short-acting octreotide in the Screening Period, 
after subject has met entry criteria, to the mean daily dose of short-acting 
octreotide during the last week of Randomized Treatment Phase 
 Change in mean daily fecal incontinence episodes (defined as accidental passing of 
BMs including solid stools, liquid stools, or mucus) from Baseline Period of 
Screening to the last week of the Randomized Treatment Phase 
 Change in worst abdominal pain in the last 24 hours (using a 0 to 10 NRS). The 
change score will be set to 0 if missing: 
 From the mean Baseline Period of Screening to the mean in the last week of 
Randomized Treatment Phase 
 From the highest score during Baseline Period in Screening to the highest score 
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 Change in “worst” (highest) stool score in the last 24 hours (Bristol scale). The 
change score will set to 0 for missing values: 
 From the mean Baseline Period in Screening to the mean in the last week of the 
Randomized Treatment Phase 
 From the highest score during the Baseline Period in Screening to the highest 
score during the last week of the Randomized Treatment Phase 
 Change in health-related quality of life from Baseline to EOR for: 
 EORTC QLQ-C30 
 EORTC QLQ-GI.NET21 scores 
 EOR in EQ-5D-5L 
 FACT-CSI 
 Patient global impressions of symptom severity and change: 
 Change from Baseline to EOR in PGI-S 
 PGI-C at EOR 
 Change in treatment preference from Baseline (pretrial treatment) to EOR 
 Change in mean daily urgency episodes (defined as BMs that make subjects rush to 
the bathroom) from the Baseline Period of Screening to last week of Randomized 
Treatment Phase 
Open-Label Extension Phase Exploratory Endpoints are as follows: 
 Incidence of NET progressive disease at EOT using 6-month interval imaging 
assessment while on paltusotine 
 Proportion of clinical responders during the last week of the OLE Phase by dose 
In subjects who meet diarrhea entry criteria only: 
 Have less than 4 mean BMs daily, and have a >20% reduction in the mean daily 
number of BMs compared with Baseline 
In subjects who meet flushing entry criteria only: 
 Have a >30% reduction compared with Baseline in the mean daily number of 
flushing episodes 
In subject who meet both diarrhea and flushing entry criteria: 
 Have less than 4 mean BMs daily, and have a >20% reduction in the mean daily 
number of BMs compared with Baseline and have any reduction from Baseline in 
the mean daily number of flushing episodes 
 Proportion of target symptom responders during the last week of the OLE Phase by 
dose 
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 Change from mean of the last week prior to Baseline to the mean of the last week of 
participation in the OLE Phase in daily BM frequency 
 Change from the mean of the last week prior to Baseline to the mean of the last week 
of participation in the OLE Phase in daily flushing episode frequency 
 Change from Baseline to EOT in biomarkers of Carcinoid syndrome (listed in 
Randomized Treatment Phase) 
 Mean change from the last week prior to Baseline to the last week of participation in 
the OLE Phase in daily target symptom frequency 
 Change in health-related quality of life from Baseline to EOT for: 
 EORTC QLQ-C30 
 EORTC QLQ-GI.NET21 scores 
 EOR in EQ-5D-5L 
 FACT-CSI 
 PGI-S 
 Change in number of days treated with short-acting octreotide: 
 Change in the days on short-acting octreotide in last week prior to Baseline 
compared to the last week of EOT 
 Change in mean daily dose of octreotide during the last week prior to Baseline to 
the last week of EOT 
 Change in mean daily fecal incontinence episodes (defined as accidental passing of 
BMs including solid stools, liquid stools, or mucus) from the last week prior to 
Baseline to last week prior to EOT 
 Change in worst abdominal pain in the last 24 hours (using a 0 to 10 NRS) 
 From the mean in the last week prior to Baseline to last week of OLE 
 From the highest score during the last week prior to Baseline to last week of OLE 
 Change in mean daily urgency episodes (defined as BMs that make subjects rush to 
the bathroom) from the last week prior to Baseline to the last week prior to EOT 
9.4.2.2. 
Multiplicity 
There will be no adjustment for type 1 error, as all analyses are exploratory. 

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9.4.3. 
Safety Analyses 
Analysis of safety endpoints in the Randomized Treatment Phase and OLE will be based on the 
Safety Set (SS). For all endpoints that are defined as a mean over a 7- day period, the endpoint 
will be missing if 3 or more of the 7 days have missing data. 
The safety endpoints consist of the safety and tolerability of the 3 doses of paltusotine (40 mg, 
80 mg, and 120 mg) based on the incidence of TEAEs, including serious TEAEs and TEAEs 
leading to discontinuation; change in safety parameters: clinical laboratory tests, physical exam 
findings, vital signs, 12-lead ECG, 24-hour continuous cardiac (Holter) monitoring tracing 
analysis (only for subjects on 120 mg dose), and ophthalmic assessments. 
Summaries will be presented by dose level and study phase (Randomized Treatment Phase, and 
OLE Phase) for the SS. 
Vital signs, select clinical laboratory results (see Section 10.2 Appendix 2), and ECG data will be 
summarized descriptively by visit. Their change scores from Baseline will also be derived and 
summarized by visit. 
9.4.4. 
Protocol Deviations 
Protocol deviations are defined as any failure to comply with the study protocol as approved by 
the IRB/IEC, whether planned or unplanned. 
Protocol deviations will be handled in accordance with the procedures established for the study. 
9.5. 
Interim Analysis 
No formal interim futility analysis is planned. 

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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 Code of Federal Regulation, in compliance with ICH Good Clinical Practice 
(GCP) guidelines, and per all applicable local regulatory guidelines. 
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/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 IRB/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 IRB/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 if there is a safety concern upon discussion 
with the Investigator and the physician. 
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 one 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 subject 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 International 
Council for Harmonization (ICH) guidelines. 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 
This trial will be conducted in accordance with the CTR EU No 536/2014 and General Data 
Protection Regulation (EU) 2016/679 (GDPR) in addition to the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements. 
If a subject revokes authorization to collect or use personal health data, the Investigator retains 
the ability to use all information collected before the revocation of subject authorization. For 
subjects that have revoked authorization to collect or use personal health data, attempts should be 
made to obtain permission to collect at least vital status (ie, that the subject is alive) at the end of 
their scheduled study period. 
All parties will comply with all applicable laws, including laws regarding the implementation of 
organizational and technical measures to ensure protection of subject data. Subjects’ personal 
data will be stored at the study site in encrypted electronic and/or paper form and will be 
password protected or secured in a locked room to ensure that only authorized study staff have 
access. The study site will implement appropriate technical and organizational measures to 
ensure that the personal data can be recovered in the event of disaster. In the event of a potential 
personal data breach, the study site will be responsible for determining whether a personal data 
breach has in fact occurred and, if so, providing breach notifications as required by law. To 
protect the rights and freedoms of subjects with regard to the processing of personal data, 
subjects will be assigned a single, subject-specific numerical code. Any subject records or data 
sets that are transferred to the Sponsor will contain the numerical code; subject names will not be 
transferred. All other identifiable data transferred to the Sponsor will be identified by this single, 
subject-specific code. The study site will maintain a confidential list of subjects who participated 
in the study, linking each subject’s numerical code to their actual identity and medical record ID. 
In case of data transfer, the Sponsor will protect the confidentiality of subjects’ personal data 
consistent with the clinical study agreement and applicable privacy laws. Information technology 
systems used to collect, process, and store study-related data are secured by technical and 
organizational security measures designed to protect such data against accidental or unlawful 
loss, alteration, or unauthorized disclosure or access. The Sponsor maintains standard operating 
procedures on how to respond in the event of unauthorized access, use, or disclosure of Sponsor 
information or systems. 

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10.1.5. 
Safety Monitoring Committee 
An unblinded SMC comprising independent subject matter experts will be established to assess 
the risk versus benefit of the interventions during the trial. The SMC will meet at intervals as 
specified in the SMC charter and may convene for ad hoc meetings if there are immediate safety 
concerns identified during the study. 
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 IRB/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 
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. 
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 (eg, 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. 

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 Quality tolerance limits (QTLs) will be predefined in the Study Management Plan to 
identify systematic issues that can impact subject safety and/or reliability of study 
results. These predefined parameters will be monitored during the study and 
important deviations from the QTLs and remedial actions taken will be summarized 
in the clinical study report. 
 Monitoring details describing strategy (eg, 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 onsite 
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 
(eg, 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. 
10.1.8. 
COVID-19 Procedures 
The following preventive and protective safety measures will follow local government guidance, 
and subjects, monitors, and research staff can safely complete study procedures according to the 
protocol: 
 SARS-CoV-2 testing will be carried out at Screening and as mentioned in SOA 
(refer to Section 1.2). 
 Site staff to inform study subjects of changes to the study conduct, prior to change 
implementation. Verbal consent approved for use and in such cases, the consent 
process and subject consent must be documented in the study records. 
 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. 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. 
 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. 
 During the OLE Phase, subjects will be supplied with a 3-month supply of study drug 
to guarantee continuous treatment. If COVID-19 related inability to conduct visits at 
sites continues beyond 3 months, all subjects will be resupplied with an additional 

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supply of study drug, to allow continued treatment. If local regulations allow, study 
drug will be shipped directly to a subject’s home. In such cases, subjects must first 
provide informed consent (verbal or written) to share their personal contact 
information (eg, name, address, and phone number) with the courier service. This 
consent will be documented as described above. 
 Onsite Monitoring Visits by study monitors will be canceled until it is safe for 
monitors to return to the study site and resume their regular monitoring activities, 
including complete drug accountability. If necessary (eg, for SAEs), review of data 
will be performed remotely with consideration made to minimize site staff burden. 
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 start 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, onsite 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/IEC 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 site local laboratory. 
 Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5. 
 Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
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 
Alanine 
aminotransferase 
Glucose 
 
 
Thyroid 
Hormones and 
HbA1c 
Free T4, and TSH 
HbA1c 
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 
Serology  
HIV antibody, hepatitis B surface antigen, and hepatitis C virus antibody 
SARS-CoV-2 
testing 
By nasopharyngeal or salivary sampling 
*These lab safety parameters are intended for site evaluation only and will not be transferred to the Sponsor. 
HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; HIV = human immunodeficiency virus; LDL = low density 
lipoprotein; OLE = open-label extension; RBC = red blood cell; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 
2; T4 = thyroxine; TSH = thyroid stimulating hormone; WBC = white blood cell. 
Notes: Investigators must document their review of each laboratory safety report. 
Fasting blood samples (unless otherwise indicated) should be collected after fasting at least 6 hours. No fasting blood samples are 
required for S1 visit. 

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10.3. 
APPENDIX 3: ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES 
FOR RECORDING, EVALUATING, FOLLOW-UP, AND 
REPORTING 
10.3.1. 
Definition of Adverse Event 
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 (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from Baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator. 
 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 preexisting 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. 
 Medical or surgical procedure (eg, 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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 

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10.3.2. 
Definition of Serious Adverse Event 
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 preexisting condition that did not worsen 
from Baseline is not considered an SAE. 
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 (eg, 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 
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. 

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10.3.3. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 The Investigator will then record all relevant AE/ SAE information in the EDC 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 until 4 weeks after the last dose 
must be reported on SAE reporting form (Section 10.3.4) within 24 hours of 
occurrence or when the Investigator becomes aware of the event whether or not related 
to the study drug. 
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. 
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. 
Breakthrough symptoms requiring treatment are defined as diarrhea or flushing episodes of 
severe intensity, ie, symptoms which prevent normal everyday activities.  

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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 
study drug, 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 (eg, as in bone marrow 
depression, fixed drug eruptions, or tardive dyskinesia); or (4) it follows a known pattern of 
response to the IMP. 
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 reexposure to the IMP (if rechallenge occurs); and (4) it 
follows a known pattern of response to the IMP. 

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 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. 
 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. 

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Unknown - There is an inability to access the subject or the subject’s records to determine 
the outcome (ie, 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 Serious Adverse Events 
SAE Reporting to pharmacovigilance unit 
 The primary mechanism for reporting a SAE to the pharmacovigilance unit will be 
done using the SAE report 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. 
 Completed SAE reporting forms should be sent via email to: mailto:
 
PPD

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10.4. 
APPENDIX 4: ABBREVIATIONS 
Abbreviation 
Definition 
ADR 
Adverse drug reaction 
AcroQoL 
Acromegaly Quality of Life Questionnaire 
AE 
Adverse event 
BM 
Bowel movement 
COVID-19 
Coronavirus Disease 2019 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTR 
Clinical Trials Regulation 
CYP3A4 
Cytochrome P450 3A4 
EC 
Effective concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOR 
End of Randomized Treatment Phase 
EORTC QLQ-C30 
EORTC Quality of Life questionnaire 
EORTC QLQ-GI.NET21 
EORTC Quality of Life questionnaire in GI NET 
EOS 
End of study 
EOT 
End of treatment 
EQ-5D-5L 
EuroQoL 5 Dimensions 5 Level 
ET 
Early termination 
EuroQoL 
European Quality of Life 
FACT-CSI 
Functional Assessment of Cancer Therapy – Carcinoid Syndrome Symptom 
Index 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HbA1c 
Hemoglobin A1c 
HIV 
Human immunodeficiency virus 
5-HIAA 
5-Hydroxyindolacetic acid  
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IGF-1 
Insulin-like growth factor 1 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
LAR 
Long-acting release 
MRI 
Magnetic resonance imaging 

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Abbreviation 
Definition 
N 
Number of subjects 
NET 
Neuroendocrine tumor 
NRS 
Numeric rating scale 
OCT 
optical coherence tomography 
OLE 
Open-label extension 
PET 
Positron emission tomography 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic Set 
PPIs 
Proton-pump inhibitors 
QD 
Once a day 
QTcF 
QT interval corrected using Fridericia’s formula 
QTL 
Quality tolerance limit 
RBC 
Red blood cell 
RTP 
Randomized Treatment Phase 
SA 
Short-acting 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2  
Severe Acute Respiratory Syndrome Coronavirus 2 
SC 
Subcutaneous 
S1 
Screening Visit 1 
S2 
Screening Visit 2 
SSA 
somatostatin analog 
SMC 
Safety Monitoring Committee 
SOAs 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SRL 
Somatostatin receptor ligand 
SS 
Safety Set 
SSTR 
Somatostatin receptor 
SST2 
Somatostatin type 2 receptor 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to achieve maximum plasma concentration 
ULN 
Upper limit of normal 

Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
Confidential 
101 
11. 
REFERENCES 
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Study code: CRN00808-11 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 7.0 
Confidential 
102 
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CRN00808-11 Protocol 21 Jan 2025 v7.0
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