A Randomized, Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Paltusotine in Subjects With Non-pharmacologically Treated Acromegaly (PATHFNDR-2)
Phase: PHASE3
Conditions: Acromegaly
Sponsor: Crinetics Pharmaceuticals Inc.

Official Title: 
A Randomized, Controlled, Multicenter Study to Evaluate the Safety and 
Efficacy of Paltusotine in Subjects with Nonpharmacologically Treated 
Acromegaly 
NCT Number: 
NCT05192382 
Document Date: 
Clinical Study Protocol Version 5.0 20 December 2024 
 

Study code: CRN00808-08
Clinical Study Protocol
Study Sponsor: Crinetics Pharmaceuticals, Inc.
Version 5.0
Confidential
1
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A RANDOMIZED, CONTROLLED, MULTICENTER STUDY TO EVALUATE THE 
SAFETY AND EFFICACY OF PALTUSOTINE IN SUBJECTS WITH 
NON-PHARMACOLOGICALLY TREATED ACROMEGALY 
Study Name: PATHFNDR-2: Paltusotine Acromegaly Therapy Featuring a Non-Invasive Daily 
Regimen
Protocol Number: CRN00808-08
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Regulatory Agency Identifier Number(s)
IND: 137912
EudraCT: 2021-001703-32
EU CT Number: 2024-511924-15-00
NCT: 05192382
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Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
2 
DOCUMENT HISTORY 
Document 
Date 
Version 5.0 
20 December 2024 
Version 4.0 
22 November 2023 
Version 3.0 
08 July 2022 
Version 2.0 
26 September 2021 
Original Protocol (Version 1.0) 
05 May 2021 
  

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
3 
SPONSOR SIGNATURE PAGE 
Sponsor’s Approval 
The protocol has been approved by Crinetics Pharmaceuticals, Inc. (herein, Crinetics or 
Sponsor). 
Responsible Medical Officer: 
Sponsor’s Medical Contact: 
 
See last page for electronic signature manifestation 
 
 
 
 
 
Date 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
4 
Protocol Number: CRN00808-08 
A Randomized, Controlled, Multicenter Study to Evaluate the Safety and Efficacy of 
Paltusotine in Subjects with Non-pharmacologically Treated Acromegaly  
Protocol Version: 5.0 
Protocol Date: 20 December 2024 
I have read and I understand this protocol. I will conduct this protocol as outlined herein and will 
make all reasonable efforts to complete the study within the designated time.  
I agree to conduct this trial in accordance with the Declaration of Helsinki, the International 
Council for Harmonization (ICH), Guideline for Good Clinical Practice (GCP), applicable local 
legislation including the EU Clinical Trials Regulation (CTR) (EU No 536/2014) and all 
applicable regulatory requirements. 
I will provide copies of the protocol and access to all information furnished by Crinetics 
Pharmaceuticals, Inc. to study personnel under my supervision. I will discuss material with them 
to ensure that they are fully informed about the study. 
I understand that the study may be terminated, or enrollment suspended at any time, by Crinetics 
Pharmaceuticals, Inc., with or without cause, or by me, if it becomes necessary to do so in the 
best interests of the study subjects. 
Site name:  
 
Site address:  
 
Phone number:  
 
Principal Investigator:  
Name and title (printed):  
 
Signature:  
 
Date:  
 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
5 
TABLE OF CONTENTS 
A RANDOMIZED, CONTROLLED, MULTICENTER STUDY TO EVALUATE THE 
SAFETY AND EFFICACY OF PALTUSOTINE IN SUBJECTS WITH 
NON-PHARMACOLOGICALLY TREATED ACROMEGALY ..............................1 
CRN00808-08 SUMMARY OF CHANGES .................................................................................10 
1. 
PROTOCOL SUMMARY ..........................................................................................22 
1.1. 
Synopsis ......................................................................................................................22 
1.2. 
Schedule of Activities: Screening Period for Medically Naïve or Previously 
Treated Groups (No treatment within previous 4 months) .........................................32 
1.3. 
Schedule of Activities: Screening Period for Subjects Washing out of 
Short-acting Octreotide or Lanreotide (SC or oral) ....................................................34 
1.4. 
Schedule of Activities: Screening Period for Subjects Washing out of Long-
acting Octreotide or Lanreotide ..................................................................................36 
1.5. 
Schedule of Activities: Randomized, Controlled Phase .............................................38 
1.6. 
Schedule of Activities: Open-Label Extension Phase ................................................41 
2. 
INTRODUCTION ......................................................................................................44 
2.1. 
Study Rationale ...........................................................................................................44 
2.2. 
Background .................................................................................................................44 
2.3. 
Benefit/Risk Assessment ............................................................................................45 
2.3.1. 
Risk Assessment .........................................................................................................45 
2.3.2. 
Benefit Assessment .....................................................................................................46 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................47 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................48 
3.1. 
Objectives and Endpoints for the Controlled Part of the Study..................................48 
3.2. 
Objectives and Endpoints for the Open-Label Extension ...........................................49 
4. 
STUDY DESIGN .......................................................................................................51 
4.1. 
Overall Design ............................................................................................................51 
4.1.1. 
Screening ....................................................................................................................51 
4.1.2. 
Treatment Period (Randomized, Controlled Phase) ...................................................52 
4.1.3. 
Open-Label Extension Phase ......................................................................................53 
4.1.4. 
End of Study ...............................................................................................................53 
4.1.5. 
Patient Input into Study Design ..................................................................................53 
4.2. 
Scientific Rationale for Study Design ........................................................................53 
4.3. 
Justification for Dose and Treatment Duration ..........................................................53 

Study code: CRN00808-08 
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4.4. 
End of Study Definition ..............................................................................................54 
4.5. 
Treatment After End of Trial Participation ................................................................54 
5. 
STUDY POPULATION .............................................................................................55 
5.1. 
Inclusion Criteria ........................................................................................................55 
5.2. 
Exclusion Criteria .......................................................................................................57 
5.3. 
Lifestyle Considerations .............................................................................................60 
5.3.1. 
Contraception ..............................................................................................................60 
5.4. 
Screen Failures ............................................................................................................60 
5.5. 
Open-Label Extension Participation ...........................................................................61 
6. 
STUDY DRUG AND CONCOMITANT THERAPY ................................................62 
6.1. 
Study Drugs Administered ..........................................................................................62 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................63 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................64 
6.4. 
Study Drug Compliance .............................................................................................65 
6.5. 
Dose Modification ......................................................................................................65 
6.5.1. 
During the RC Phase ..................................................................................................65 
6.5.2. 
During the OLE ..........................................................................................................66 
6.6. 
Treatment of Overdose ...............................................................................................66 
6.7. 
Concomitant Therapy .................................................................................................66 
6.7.1. 
Permitted Medicine .....................................................................................................66 
6.7.2. 
Prohibited Medicine ....................................................................................................67 
6.7.3. 
RC Phase Rescue Procedure – Auxiliary Medicinal Products ....................................67 
6.7.4. 
OLE Phase Adjunctive Treatments – Auxiliary Medicinal Products .........................68 
7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL....................................................................70 
7.1. 
Discontinuation of Study Treatment/Participation .....................................................70 
7.1.1. 
Liver Chemistry Abnormality Monitoring and Study Drug Stopping Criteria ...........71 
7.1.2. 
Amylase or Lipase Study Drug Stopping Criteria ......................................................72 
7.1.3. 
Cardiac Study Drug Stopping Criteria ........................................................................73 
7.2. 
Lost to Follow up ........................................................................................................73 
7.3. 
Criteria for Study Termination ....................................................................................73 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................75 
8.1. 
Demographics and Baseline Characteristics ...............................................................75 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
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8.2. 
Subject-reported Assessments ....................................................................................75 
8.2.1. 
Acromegaly Symptoms Diary ....................................................................................75 
...............................................................75 
..................................................................................................................76 
 .....................................................76 
..........................................................................76 
8.3. 
Safety Assessments .....................................................................................................76 
8.3.1. 
Physical Examinations ................................................................................................76 
8.3.2. 
Vital Signs ...................................................................................................................76 
8.3.3. 
Electrocardiograms .....................................................................................................77 
8.3.4. 
Clinical Safety Laboratory Assessments ....................................................................77 
8.3.5. 
Biliary/Gallbladder Ultrasound ..................................................................................78 
8.3.6. 
Magnetic Resonance Imaging .....................................................................................78 
8.3.7. 
Ophthalmic Assessments ............................................................................................78 
8.4. 
Adverse Events and Serious Adverse Events Reporting ............................................78 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................79 
8.4.2. 
Method of Detecting AEs ...........................................................................................79 
8.4.3. 
Follow-up of AEs ........................................................................................................79 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................80 
8.4.5. 
Pregnancy ...................................................................................................................81 
8.5. 
Pharmacokinetics ........................................................................................................81 
8.6. 
Pharmacogenomics .....................................................................................................81 
8.7. 
Biomarkers ..................................................................................................................82 
8.8. 
Immunogenicity Assessments .....................................................................................82 
8.9. 
Collection and Storage of Biological Samples ...........................................................82 
9. 
STATISTICAL CONSIDERATIONS .........................................................................83 
9.1. 
Statistical Hypotheses .................................................................................................83 
9.2. 
Sample Size Determination ........................................................................................83 
9.3. 
Analysis Sets ...............................................................................................................84 
9.4. 
Statistical Analyses .....................................................................................................85 
9.4.1. 
General Considerations ...............................................................................................85 
9.4.2. 
Efficacy Analyses .......................................................................................................85 
9.4.2.1. 
Primary Endpoint ........................................................................................................85 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
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9.4.2.2. 
Key Secondary Endpoint: ...........................................................................................86 
9.4.2.3. 
Open Label Extension .................................................................................................87 
9.4.2.4. 
Multiplicity .................................................................................................................87 
9.4.3. 
Safety Analyses ...........................................................................................................87 
9.4.4. 
Protocol Deviations ....................................................................................................87 
9.5. 
Interim Analysis ..........................................................................................................88 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................89 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .....................89 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................89 
10.1.2. 
Financial Disclosure ...................................................................................................89 
10.1.3. 
Informed Consent Process ..........................................................................................90 
10.1.4. 
Data Protection ...........................................................................................................90 
10.1.5. 
Data Monitoring Committee .......................................................................................92 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................92 
10.1.7. 
Data Quality Assurance ..............................................................................................92 
10.1.8. 
COVID-19 Procedures ................................................................................................94 
10.1.9. 
Source Documents ......................................................................................................95 
10.1.10. 
Publication Policy .......................................................................................................95 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................96 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................97 
10.3.1. 
Definition of AE .........................................................................................................97 
10.3.2. 
Definition of SAE .......................................................................................................98 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................99 
10.3.4. 
Reporting of SAEs ....................................................................................................103 
10.4. 
Appendix 4: Abbreviations .......................................................................................104 
11. 
REFERENCES .........................................................................................................107 
 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
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LIST OF TABLES 
Table 1: 
Objectives and Endpoints for the Controlled Part of the Study..................................25 
Table 2: 
Objectives and Endpoints for the Open-label Extension ............................................26 
Table 3: 
Dose Titration Options ................................................................................................28 
Table 4: 
Risk Assessment Table ................................................................................................45 
Table 5: 
Study Interventions .....................................................................................................62 
Table 6: 
Protocol-Required Safety Laboratory Tests ................................................................96 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................23 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
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CRN00808-08 SUMMARY OF CHANGES 
Version 4.0 to Version 5.0 
This Summary of Changes includes changes made from Version 4.0 to Version 5.0.  
Underlined text in the table denotes added text; strikethrough denotes deleted text. 
The primary reasons for this protocol amendment are as follows: 
 Harmonize this version of the protocol with the EU Clinical Trials Regulation (CTR) 
(EU No 536/2014). 
 Update Benefit-Risk Assessment section with side effects identified as adverse drug 
reactions (ADRs) and associated mitigation strategy in accordance with the 
paltusotine Investigator’s Brochure (IB) Ed 9.0. 
 Administrative updates to document information. 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
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11 
Section(s) 
Description of Change 
Change Rationale 
Throughout protocol 
Corrected typographical, grammar, spelling, formatting, and definitions of 
abbreviations at first use 
Updated administrative information (eg, document version and dates, company 
address, signatory), tables of contents 
Updated intra-document section number references/links as needed 
Clarification 
Cover page 
EU CT Number: 2024-511924-15-00 
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 
Principal Investigator 
agreement 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 comply with 
Clinical Trial Regulation 
EU No 536/2014 
Responsible Medical Officer 
Responsible Medical Officer: 
Updated study information 
Sponsor’s Medical Contact 
Sponsor’s Authorized OfficerMedical Contact: 
Updated study information 
Site and Principal Investigator 
acknowledgment 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 
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
12 
Section(s) 
Description of Change 
Change Rationale 
Regulation (CTR) (EU No 536/2014) and all applicable regulatory 
requirements. 
Summary of Changes,  
all bullets, 
table replace (not shown) 
 
To extend the open label extension period by 2 years. 
 
Implement ophthalmic monitoring in response to a Health Authority 
request to collect additional data to facilitate evaluation of the 
clinical relevance of a phototoxicity study in rodents (see 
Investigator’s Brochure). 
 
Harmonize this version of the protocol with Protocol the EU 
Clinical Trials Regulation (CTR) (EU No 536/2014).Clarification 
Letter (France) #1, dated 26 September 2022; Protocol Clarification 
Letter #1, dated 23 June 2023; and Protocol Clarification Letter #2, 
dated 02 August 2023. 
 
Update Benefit-Risk Assessment section with side effects identified 
as adverse drug reactions (ADRs) and associated mitigation strategy 
in accordance with the paltusotine Investigator’s Brochure (IB) 
Ed 9.0. 
 
Administrative updates to document information 
Updated text for new 
protocol version 
Synopsis, 
Overall Design, 
paragraph 3 (added last 
sentence) 
An End of Study (EOS) Visit will occur approximately 4 weeks after the last 
dose of study drug. 
Text clarification-aligns 
with 1.6 Schedule of 
Activities: Open-Label 
Extension Phase 
Synopsis, 
End of Study, 
paragraph 1 
An End of Study (EOS) Visit will occur, approximately 4 weeks after the last 
dose of study drug, at Week 228 to collect final safety data and other 
assessments as detailed in the SOA. 
Text clarification-aligns 
with 1.6 Schedule of 
Activities: Open-Label 
Extension Phase 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
13 
Section(s) 
Description of Change 
Change Rationale 
Synopsis, 
RC Phase Rescue Criteria 
(Auxiliary Medicinal 
Products),  
paragraph 3 (added) 
RC Phase Rescue Criteria (Auxiliary Medicinal Products) 
Octreotide LAR or lanreotide depot monotherapy are considered auxiliary 
medicinal products. Rescue therapy should be used according to approved 
marketing authorization or standard clinical practice. 
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 
Synopsis, 
Open-Label Extension 
Adjunctive Treatments 
(Auxiliary Medicinal 
Products), 
bullet 1 
Open-Label Extension Adjunctive Treatments (Auxiliary Medicinal 
Products) 
The adjunctive medications bromocriptine/cabergoline and pegvisomant are 
considered auxiliary medicinal products. Use of any adjunctive medications 
should be discussed with the Medical Monitor and should be used according to 
approved labelsmarketing authorization or standard practice. Adjunct 
medications are not provided by the Sponsor. 
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 
Table 4 Risk Assessment 
Table, 
Side effects,  
Summary of Data/Rationale 
for Risk 
Gastrointestinal (GI) side effects (eg, diarrhea, abdominal discomfort). 
Additional reported adverse events (AEs) found in IB. Side effects or lack of 
drug efficacy could result from interactions with concomitant medications. 
Diarrhea, abdominal pain, nausea, abdominal discomfort, bradycardia (including 
sinus bradycardia and bradycardia), and cholelithiasis have been identified as 
ADRs associated with paltusotine. 
Rationale: These AEs are generally mild or moderate. No discontinuations due 
and did not lead to AEs in Phase 2 studiesdiscontinuation. 
Updated to align with 
Paltusotine IB, Ed 9.0 
Table 4 Risk Assessment 
Table, 
Side effects,  
Mitigation Strategy 
Clinical monitoring, symptomatic measures, study drug interruption if 
necessary. Regular safety surveillance, including laboratory testing, physical 
examinations, AE monitoring, pituitary tumor, and gall bladder monitoring, and 
evaluations for study drug interruption and stopping rules specified per protocol. 
Updated to align with 
Paltusotine IB, Ed 9.0 
4.1.4 End of Study 
An End of Study (EOS) Visit will occur approximately 4 weeks after the last 
dose of study drug, at Week 228 to collect final safety data and other 
Text clarification-aligns 
with 1.6 Schedule of 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
14 
Section(s) 
Description of Change 
Change Rationale 
assessments as detailed in the SOAs. The EOS is defined as the date of the last 
visit of the last subject in the study. 
Activities: Open-Label 
Extension Phase 
Added new Section: 
4.1.5 Patient Input into Study 
Design 
4.1.5 Patient Input into Study Design 
Patient insight was collected over several meetings (November 2019-August 
2020) through a formalized Patient Leadership Council made up of 12 
individuals living with acromegaly. These patients had a range of experiences 
including treating physician, medication treatments, geographic location, and 
age of diagnosis. In these meetings, the following topics were discussed: 
treatment naïve and maintenance treatment study protocols, use of placebo, 
rescue therapy, frequency of visits, daily diary execution, study recruitment 
tactics, and participants’ preferred method of learning about potential studies. 
Results of these discussions were shared with the internal paltusotine study team 
and incorporated into study design where possible. 
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 
4.3 Justification for Dose and 
Treatment Duration, 
paragraph 2 (added) 
4.3Justification for Dose and Treatment Duration 
Treatment duration is extended up to 228 weeks (approximately 4 1/3 years) to 
allow participants who in the opinion of the Investigator are benefiting from 
treatment with paltusotine, to continue treatment. 
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 
paragraph 3 (added) 
Data from an ongoing Phase 2 open-label extension (OLE) clinical study 
(CRN00808-05) show that paltusotine lowered and maintained IGF-1 and GH at 
levels comparable to prior injected somatostatin receptor ligands (SRLs) for up 
to 103 weeks. Additionally, RC Phase results from a placebo controlled pivotal 
study (CRN00808-09) show that paltusotine 40 or 60 mg once daily (QD) 
provides sustained efficacy in terms of maintenance of disease control for up to 
36 weeks in participants with acromegaly, who switched from being controlled 
on standard of care injectable SRLs. The durability of this clinical meaningful 
treatment effect was maintained in the OLE with participants continuing to 
experience clinical benefits. 
 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
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Section(s) 
Description of Change 
Change Rationale 
paragraph 4 (added) 
Paltusotine was well tolerated, with no unexpected safety findings with long-
term treatment. 
 
Added new Section: 
Section 4.5 Treatment After 
End of Trial Participation 
4.5. Treatment After End of Trial Participation 
After the end of the trial participants may resume regionally licensed 
acromegaly treatment as prescribed by their healthcare provider. 
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 
6.7.3. RC Phase Rescue 
Procedure – Auxiliary 
Medicinal Products, 
paragraph 3 (added last 
sentence), 
6.7.3 RC Phase Rescue Procedure – Auxiliary Medicinal Products 
Rescue therapy should be used according to approved marketing authorization 
or standard clinical practice. 
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 
paragraph 4 (added) 
Long-acting octreotide or lanreotide depot monotherapy are considered auxiliary 
medicinal products (AxMPs). 
 
6.7.4 OLE Phase Adjunctive 
Treatments – Auxiliary 
Medicinal Products, 
bullet 1 
6.7.4 OLE Phase Adjunctive Treatments  – Auxiliary Medicinal Products 
Use of any adjunctive medications should be discussed with the Medical 
Monitor and should be used according to approved labelsmarketing 
authorizations or standard practice. Adjunct medications are not provided by the 
Sponsor. 
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 
paragraph 2 (added) 
Adjunctive treatments such as cabergoline and pegvisomant are considered 
auxiliary medicinal products. 
 
8.4.4 Regulatory Reporting 
Requirements for SAEs, 
paragraph 3 
Any such SAE due to any cause, whether or not related to the study drug, must 
be reported on the Crinetics SAE reporting formReport Form immediately (and 
under no circumstances should this exceed 24 hours of occurrence) or when the 
Investigator becomes aware of the event. A properly completed Crinetics SAE 
reporting formReport Form should be sent via email. 
Specify current form title 

Study code: CRN00808-08 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
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Section(s) 
Description of Change 
Change Rationale 
8.4.5 Pregnancy 
Female subjects of childbearing potential must have a negative serum pregnancy 
test at Screening Visit S1. All other pregnancy tests will be urine tests. If the 
result of a urine test is positive the result will be confirmed with a serum 
pregnancy test. Urinary pregnancy tests will be performed monthly at Screening, 
during the RC phase, and during the OLE phase when the duration between the 
visits is longer than 4 weeks. Pregnancy tests may also be obtained at any time 
during the study as an unscheduled test if clinically appropriate. Subjects must 
discontinue study drug immediately in the event of pregnancy in a female 
subject. Any pregnancy will be reported by telephone (optional) and by emailing 
a completed Crinetics Pregnancy Exposure  Report Form to the Sponsor’s 
Pharmacovigilance Group at 
within 24 hours of knowledge 
of the pregnancy. The pregnancy will not be processed as a SAE. However, the 
Investigator will follow-up with the subject or female partner of the male subject 
(after obtaining informed consent, as appropriate) until completion of the 
pregnancy and must determine the outcome of the pregnancy in the shortest 
possible time. The Investigator should notify the Sponsor’s Pharmacovigilance 
Group of the pregnancy outcome by submitting a follow-up Pregnancy 
Exposure Report Form. If the outcome of the pregnancy meets the criteria for 
immediate classification as a SAE (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 
telephone (optional) and by e-mailing a completed SAE formReport Form to the 
Sponsor’s Pharmacovigilance Group within 24 hours of knowledge of the event. 
Specify current form title 
and include email for 
submission 
Added new Section: 
Section 8.9 Collection and 
Storage of Biological Samples 
8.9 Collection and Storage of Biological Samples 
The Sponsor will comply with the applicable rules for the collection, storage, 
and future use of biological samples from clinical trial subjects. The Sponsor 
will comply with national requirements including those set in the CTR (EU) No 
536/2014, Article 7.1 (h).  
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 

Study code: CRN00808-08 
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Version 5.0  
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Section(s) 
Description of Change 
Change Rationale 
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. 
10.1.4 Data Protection 
SubjectsThe Sponsor, as Data Controller, ensures that all processing activities 
involving personal data performed in the scope of this Study are compliant with, 
but not limited to, the requirements set by EU General Data Protection 
Regulation (GDPR 679/2016), its subsequent amendments and any additional 
national laws on Data Protection, recommendations, and guidelines as 
applicable. 
To maintain participant privacy, data capture tools, study drug accountability 
records, study reports, and communications will be assigned aidentify 
participants by their unique identifier by the Sponsor.(assigned participant 
number) generated and assigned by the electronic data capture (EDC) system. 
Any subjectparticipant records or datasets that are transferred to the Sponsor 
will contain the identifier only; subjectparticipant names or any information 
which would make the subjectparticipant identifiable will not be transferred. 
The subject mustparticipant will be informed that his/herboth verbally and in 
written form (ICF) that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the subjectparticipant who willmay be required to give 
consent for their data to be used as described in the informedICF, including use 
of their data that may require a separate consent. The subject mustparticipant 
will also be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors, Monitors or other authorized personnel appointed 
by the Sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
Updated to comply with 
Clinical Trial Regulation 
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Section(s) 
Description of Change 
Change Rationale 
To comply with the applicable rules on the protection of personal data, 
specifically regarding the implementation of the organizational and technical 
arrangements aiming to avoid unauthorized access, disclosure, dissemination, 
alteration or loss of information and processed personal data, the Sponsor 
has implemented and maintains the following measures: 
 restriction and monitoring of physical access to the offices and information 
processing facilities to employees, personnel and approved visitors; 
 ensuring appropriate and restricted user access relevant to the function and 
type of activity performed in relation to the clinical trial; 
 implementing the pseudonymisation and encryption of personal data, as 
appropriate; 
 implementing the ability to ensure the ongoing confidentiality, integrity, 
availability and resilience of processing systems and services; 
 implementing network, application, and database security by means of 
firewalls and antivirus/anti-malware; ensuring detection of malware 
purposed for unauthorized deletion, blocking, copying of information, 
disabling security measures and response to such attacks; 
 means to restore the availability and access to personal information in a 
timely manner in the event of a physical or technical incident; 
 logging of security events/incidents in information systems; 
 implementing procedures that cover reporting, analysis, monitoring and 
resolution of security incidents; 
 ensuring that information systems, computers and software involved in the 
performance of the services provided in the Study are backed up; 
 a process for regularly testing, assessing and evaluating the effectiveness of 
technical and organizational measures for ensuring the security of the 
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Section(s) 
Description of Change 
Change Rationale 
 implementing procedures to capture within a reasonable time any personal 
data breaches; 
 implementing procedures and practices for the destruction of paper 
documents containing personal data; 
 implementing business continuity procedures ensuring continued provision 
of services through operational interruption 
All locations, personnel and information systems that are used to perform 
services for the Study will be covered. The Sponsor will ensure the technical 
and organizational security measures described above are regularly reviewed 
and updated considering any evolution of technological developments. 
The Sponsor may apply additional specific statutory requirements, where 
applicable in national laws, and will implement the necessary security measures 
even if they are not expressly listed above. 
In addition to the already mentioned technical and organizational measures, the 
Sponsor by means of internal measures and imposed standard contractual 
clauses to the selected contractors, service providers, vendors, or sub-contractors 
(collectively, “Representatives”), ensures the confidentiality of records and 
personal data of subjects. 
With exception of activities in the scope of on-site monitoring, the name of the 
patient will neither be asked for, nor recorded by Sponsor. An identification 
number will be allocated to each patient registered in the Study. This number 
will identify the patient and will be included on all case report forms and 
corresponding material and data associated with the patient. 
Monitors acting on behalf of Sponsor will have access to fully identifiable 
information only in the scope of the on-site monitoring visits, and only for 
mandatory source data verification, including ICH-GCP obligations, applicable 
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Section(s) 
Description of Change 
Change Rationale 
bound by any additional stricter confidentiality clauses imposed upon them, as 
compared to other staff members. 
The Sponsor has implemented a functional process for reporting of any data 
breach occurring at Crinetics’ or its Representatives’ facilities and 
premises. Investigators must promptly report to the Sponsor's Data Protection 
Officer (DPO) any suspected data breaches relevant to personal study-related 
data the Sponsor holds about the participants. If there is a suspected breach 
related to data that the Sponsor holds, the Sponsor’s DPO will be responsible for 
investigating suspected data breaches and notifying authorities, where 
appropriate. In case of the occurrence of any data breach, the Sponsor will 
immediately apply relevant measures to mitigate the risks to data subjects as 
appropriate in relation to the specific context of the data breach, considering its 
source, underlying intentions, possibilities of recovery etc. Any data breach 
presenting risks to the rights and freedoms of data subjects will be reported to 
the relevant supervisory data protection authority within 72 hours of the Sponsor 
becoming aware of the data breach. In addition, in case of a high-risk data 
breach, subjects will be informed by the Sponsor. 
Investigators must promptly report to the Sponsor's DPO any participant request 
to know what personal study-related data the Sponsor holds about the 
participant. 
10.1.7 Data Quality 
Assurance,  
paragraph 1 
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). 
Updated to comply with 
Clinical Trial Regulation 
EU No 536/2014 
paragraph 3 
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). 
 

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Section(s) 
Description of Change 
Change Rationale 
paragraph 6 
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 informationtheir personal data 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. 
 
10.3.3 Recording and Follow-
Up of AE and/or SAE, 
bullet 6 
Any SAE occurring after the ICF has been signed and up until 4 weeks after the 
last dose must be reported on the Crinetics SAE reporting formReport Form (see 
Section 10.3.4). 
Specify current form title 
10.3.4 Reporting of SAEs 
The primary mechanism for reporting a SAE to the pharmacovigilance unit will 
be via the SAE reporting formReport Form. Any such SAE due to any cause, 
whether or not related to the study drug, must be reported on the Crinetics SAE 
reporting formReport Form immediately (and under no circumstances should 
this exceed 24 hours of occurrence) or when the Investigator becomes aware of 
the event. 
The Crinetics SAE reporting formReport Form should be sent within 24 hours 
of knowledge of the event to: 
. mailto:If a site receives 
updated data on a previously reported SAE, then the site can report the follow-
up information on the Crinetics SAE reporting formReport Form and send to the 
pharmacovigilance group via 
 
Specify current form title 
  

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Randomized, Controlled, Multicenter Study to Evaluate the Safety and 
Efficacy of Paltusotine in Subjects with Non-pharmacologically Treated Acromegaly  
Rationale 
Therapy for acromegaly is targeted at decreasing growth hormone (GH) and insulin-like growth 
factor-1 (IGF-1) levels, ameliorating patients' symptoms and decreasing any local compressive 
effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, 
radiotherapy, and medical therapies, such as somatostatin receptor ligands (SRL), dopamine 
agonists, and the GH receptor antagonist pegvisomant.  
When surgery, which is the usual first-line treatment, fails to correct GH/IGF-1 hypersecretion, 
medical treatment can be used. Somatostatin receptor ligands octreotide long-acting release 
(LAR) and lanreotide depot are, at present, the most widely used drugs to control acromegaly.  
Paltusotine is a nonpeptide orally bioavailable somatostatin receptor 2 (SST2) agonist that is 
administered once per day. In Phase 2 studies, daily oral administration of paltusotine has been 
shown to maintain GH and IGF-1 levels in subjects with acromegaly that were previously on 
octreotide LAR or lanreotide depot monotherapy. An orally bioavailable somatostatin agonist 
should reduce acromegaly patient burden by eliminating the pain and complications 
(eg, subcutaneous, or intramuscular nodules) of injections and the cost and inconvenience of the 
health care provider office visits required for those injections. Additionally, it may allow 
physicians to determine an optimized dosing regimen more quickly compared with existing 
therapies. To our knowledge, paltusotine is the first nonpeptide oral somatostatin agonist being 
evaluated for the treatment of acromegaly. 
Overall Design 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study where 
subjects with nonpharmacologically treated acromegaly will be randomly allocated to receive 
either paltusotine or placebo. Three groups of subjects will be enrolled: (1) subjects with no prior 
medical therapy, (2) subjects who last received medical therapy at least 4 months prior to 
Screening, and (3) subjects who are controlled on medical therapy for at least 3 months but agree 
to washout prior to beginning study treatment. Groups 1 and 2 constitute Stratum 1 and Group 3 
constitutes Stratum 2. The study population will be stratified to ensure equivalent active 
treatment versus placebo allocations in each stratum.  
Approximately 76 subjects will be enrolled. This sample size was generated based on the 
assumption that there will be an equal number of subjects in each stratum. If this assumption is 
violated, there could be a reduction in statistical power. Therefore, when 
 of the projected 
76 subjects (approximately 
) are randomized, enrollment into the strata will be assessed. 
If there are less than 
 subjects in Group 3 (subjects who washout of octreotide or lanreotide 
during the screening period) at that time, the sample size may be increased (see Section 9.2).  

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The Screening Period for this study may be approximately 2 to 4, 8, or 12 to 16 weeks, 
depending on prior treatment. After the Screening Period, subjects will be enrolled in a 24-week 
Randomized Controlled (RC) phase and randomly assigned in a 1:1 ratio to receive paltusotine 
or matching placebo, stratified by prior treatment (medically naïve or previously treated versus 
washout). Rescue criteria are in place for those who require standard acromegaly treatment 
during the RC Phase. At the End of the Randomized Control Phase (EOR), subjects who, in the 
opinion of the Investigator, could benefit from treatment with paltusotine, may be enrolled in a 
long-term open-label extension (OLE) study, during which they will receive paltusotine for up to 
200 weeks. An End of Study (EOS) Visit will occur approximately 4 weeks after the last dose of 
study drug. 
Figure 1: 
Study Schema 
 
EOR=End of Treatment (randomized, controlled phase), EOS=End of Study, IGF-1=insulin-like growth factor-1, 
OLE=open-label extension, ULN=upper limit of normal 
Screening 
Subjects ≥18 years of age at the time of Screening who fall into 1 of the following 3 groups are 
eligible to participate in the study. 
 Medically naïve group (Group 1): Those who have not been previously treated with 
acromegaly medications (including long-acting somatostatin receptor ligands 
[LA-SRLs]) who at Screening have IGF-1 ≥1.3×the upper limit of normal (ULN) 
confirmed by the central laboratory test at S1. Group 1 subjects must have had at least 
1 pituitary surgery 3 months or more prior to Screening. 
 Previously Treated group (no treatment within previous 4 months) (Group 2): 
Subjects who have last been treated with acromegaly medications at least 4 months 
prior to Screening and who have IGF-1 ≥1.3×ULN confirmed by the central 
laboratory test at S1.  
 Washout group (Group 3): Subjects at Screening who are receiving stable treatment 
(no change in dose for 3 months prior to Screening) with octreotide or lanreotide 
monotherapy, who have IGF-1 ≤1.0×ULN at Screening Visit 1 and are willing to 
washout of their medication during the Screening Period. Any form of pretrial 
octreotide or lanreotide monotherapy (long- or short-acting, subcutaneous [SC] or 
oral) can be washed out and will determine the duration of the Screening Period. 
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acromegaly medication. IGF-1 must rise from the first Screening visit by at least 30% 
and be ≥1.1×ULN confirmed by the central laboratory test at S2 or S3 (if needed), to 
qualify for enrollment. 
The Screening Period for the Medically naïve group and the Previously Treated group (no 
treatment within previous 4 months) should be approximately 4 weeks in duration and will 
consist of 1 Screening Visit (S1).  
For those treated at the time of Screening with long- or short-acting octreotide or lanreotide 
monotherapy and who are willing to washout, initial eligibility (including IGF-1 ≤1.0×ULN) will 
be assessed at S1. At that time, subjects will begin washout of their pretrial acromegaly 
medication. Subjects taking long-acting octreotide or lanreotide will have a Screening Period of 
approximately 12 to 16 weeks. Subjects taking short-acting octreotide or lanreotide will have a 
Screening Period of approximately 8 weeks. Documentation of the washout criteria will be 
confirmed by the central laboratory test at S2. If a second post-washout IGF-1 measurement is 
needed to confirm eligibility (30% rise from the first Screening visit and IGF-1 ≥1.1× ULN) per 
the Investigator, the Medical Monitor should be consulted, and a sample collected at S3. S2 
should be performed approximately 2 months after last pretrial LA-octreotide or lanreotide 
injection or approximately 4 weeks after last dose of short-acting (SC or oral) octreotide or 
lanreotide. 
Treatment Period (Randomized, Controlled [RC] Phase)  
Once all screening assessments are completed, the subject’s eligibility is verified by the 
Investigator and confirmed by the Medical Monitor via submission of the Medical Monitor 
Eligibility Verification Form The subject will be randomized to treatment on Day 1 of the 
Treatment Period (Figure 1).  
The Treatment Period will be approximately 24 weeks. Subjects will receive their first dose of 
study drug at Visit 1 (Day 1) (paltusotine or placebo). 
It is anticipated that the study drug dose will be stable, and titration completed prior to or at 
Week 12, with no dose titrations/adjustments after Week 12. Up-titration after Week 12 should 
not occur; subjects who require dose up-titration after Week 12 will be considered 
nonresponders. Down-titration due to unacceptable tolerability is permitted.  
If rescue therapy is required during the RC phase, subjects will discontinue paltusotine or 
placebo, initiate rescue therapy, and should continue the study for the remainder of the 24-week 
RC phase (see Section 6.7.3 for Rescue Criteria). Rescue therapy with approved SRLs 
(octreotide LAR or lanreotide depot monotherapy) will be permitted during the study. 
If the subject withdraws consent or, in the opinion of the Investigator, should be permanently 
discontinued from the study, the early termination (ET) Visit should be completed as specified in 
the Schedules of Activities (SOA) and the subject should return to standard acromegaly 
treatment as prescribed by the Investigator. 
Open-Label Extension Phase  
Subjects who complete the 24-week RC phase or who meet rescue criteria and complete the 
24-week RC phase with rescue medication can continue participation in the OLE phase if, in the 
opinion of the Investigator, the subject may benefit from continued participation and treatment 
with paltusotine, and the subject is willing to participate. At completion of study enrollment, 

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subjects in the washout group that have entered screening, met initial eligibility criteria at S1, but 
have not completed S2 and/or S3, may be eligible to directly enroll into the OLE. The OLE 
Treatment Period is up to 200 weeks plus a 4-week follow-up. 
End of Study 
An End of Study Visit will occur, approximately 4 weeks after the last dose of study drug, at 
Week 228 to collect final safety data and other assessments as detailed in the SOA. 
Table 1: 
Objectives and Endpoints for the Controlled Part of the Study 
Objectives 
Endpoints 
Primary  
 To evaluate the effect of paltusotine 
versus placebo on IGF-1 response 
 Proportion of subjects who achieve 
biochemical response in IGF-1 (≤1.0× the 
upper limit of normal [ULN]) at the End of 
the Randomized Control Phase (EOR)  
Key Secondary  
 To evaluate the effect of paltusotine 
versus placebo on IGF-1 level 
 Change from baseline in IGF-1, in units of 
ULN, to EOR 
Secondary 
 To evaluate the effect of paltusotine 
versus placebo on IGF-1 response 
 Proportion of subjects who achieve IGF-1 
<1.3×ULN at EOR 
 To evaluate the effect of paltusotine 
versus placebo on GH response 
 Proportion of subjects with GH <1 ng/mL 
at Week 22 
 To evaluate the effect of paltusotine 
versus placebo on acromegaly symptoms 
 Change from baseline in Total Acromegaly 
Symptoms Diary (ASD) score to EOR 
Exploratory  
 To evaluate the effect of paltusotine 
versus placebo on GH level 
 Change from baseline to Week 22 in GH 
 To evaluate the effect of paltusotine 
versus placebo on the need for rescue 
therapy  
 Proportion of subjects who receive rescue 
therapy 
 To evaluate the time to need for rescue 
treatment of paltusotine versus placebo 
 Time from randomization to first dose of 
rescue treatment 
 To evaluate the effect of paltusotine 
versus placebo on GH response 
 Proportion of subjects with 
GH <2.5 ng/mL at Week 22 
 To evaluate the effect of paltusotine 
versus placebo on tumor volume 
 Change from baseline in residual pituitary 
volume at EOR 

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Objectives 
Endpoints 
Safety 
 To evaluate the safety and tolerability of 
paltusotine versus placebo 
 Incidence of treatment-emergent adverse 
events (TEAEs), including serious adverse 
events (SAEs) and TEAEs leading to 
discontinuation 
 Change in safety parameters: clinical 
laboratory tests (hematology, serum 
chemistry, lipid panel, and hormones), 
lipid panel, hormones, vital signs, and 
12-lead electrocardiogram (ECG) 
 Incidence of clinically significant changes 
in abdominal (gallbladder) ultrasound 
compared with baseline 
Pharmacokinetics 
 To evaluate the pharmacokinetic 
parameters of paltusotine in subjects with 
acromegaly 
 Descriptive summary of concentration data 
from postdose sparse PK sampling 
Table 2: 
Objectives and Endpoints for the Open-Label Extension 
Objectives 
Endpoints 
Efficacy 
 
To evaluate the long-term maintenance of 
efficacy of paltusotine in subjects with 
acromegaly 
 Change from baseline in IGF-1 and GH 
levels 
 Proportion of subjects with IGF-1 
≤1.0×ULN  
 Proportion of subjects with IGF-1 
≤1.3×ULN  
 Proportion of subjects who receive 
permitted adjunctive standard acromegaly 
treatment 
 Change from baseline in residual pituitary 
tumor volume 

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Objectives 
Endpoints 
Safety 
 To evaluate the long-term safety and 
tolerability of paltusotine in subjects with 
acromegaly 
 Incidence of TEAEs, including serious 
adverse events (SAEs) and TEAEs 
leading to discontinuation of study drug 
 Change in quantitative safety parameters: 
clinical laboratory tests, lipid panel, 
hormones, vital signs, and 12-lead ECG 
parameters 
 Ophthalmic assessments 
Pharmacokinetics 
 To evaluate long-term pharmacokinetic 
parameters of paltusotine in subjects with 
acromegaly 
 Descriptive summary of concentration 
data from postdose sparse PK sampling 
Duration and Intervention Groups  
Total Duration of the Study 
The Screening Period for this study may be approximately 2 to 4, 8, or 12 to 16 weeks, 
depending on prior treatment. The RC phase will last 24 weeks for all subjects while those who 
choose to participate in the OLE will be treated for 200 more weeks. Because there is a 4-week 
follow-up after completing treatment, the duration may vary from a minimum of approximately 
30 to a maximum of approximately 228 weeks. 
Study Drug 
Paltusotine will be provided as 20 mg tablets. Matching placebo tablets will be identical in 
appearance to paltusotine and will be administered according to the randomization scheme, on an 
identical schedule to those receiving paltusotine. Paltusotine and matching placebo tablets will 
each be packed in 
 Drug labels 
will comply with the legal requirements of each country and will be printed in local language.  
Scientific Rationale for Study Design 
A prospective randomized, placebo-controlled trial is the gold standard methodology to define 
the safety and efficacy profile of an experimental drug. Placebo-controlled trials have been 
successfully conducted and are feasible in rare orphan diseases, including acromegaly. Protocol 
safeguards are in place for subjects who experience worsening acromegaly (see Section 6.7.3 
(RC Phase Rescue Procedure) and Section 6.7.4 (OLE Phase Adjunctive Treatments). 
Dose Adjustment During the RC Phase  
The starting daily dose will be 20 mg (1×20 mg tablet of active paltusotine or matching placebo) 
for oral self-administration. After confirming tolerability with the subject, the dose should be 
increased to 40 mg/day (2×20 mg tablet of active paltusotine or matching placebo) at the Week 2 
visit. 

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Beginning with the Week 6 visit and prior to or at the Week 12 visit, further dose up-titration will 
be based on 2 criteria: 
 Acceptable tolerability at the current dose, as evaluated by the Investigator, 
AND 
 The subject’s most recent IGF-1 result is >0.9×ULN  
It is anticipated that the study drug dose will be stable, and titration completed prior to or at 
Week 12, with no dose titrations/adjustments after Week 12. Up-titration after Week 12 should 
not occur; subjects who require dose up-titration after Week 12 will be considered 
nonresponders. Down-titration due to unacceptable tolerability is permitted. If needed, an 
unscheduled dose titration (DT) Visit may be performed. The study drug dose may be decreased 
at any time during the study if study drug toleration is unacceptable in the judgment of the 
investigator. A dose reduction based on tolerability may be necessary for patients who are taking 
P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) inhibitors (see 
Section 6.7.1). 
Protocol specified dose adjustments are summarized in the following table: 
Table 3: 
Dose Titration Options 
Dose Titration/Adjustment 
IGF-1 Criteria 
Tolerability Criteria 
20 mg→40 mg 
-- 
Increase required at Week 2 visit if 
acceptable tolerability on 20 mg 
40 mg→60 mg 
Week 4 IGF-1 >0.9×ULN or at any 
time prior to or at the Week 12 visit 
Acceptable tolerability on 40 mg 
60 mg→40 mg 
-- 
Dose reduction required due to 
unacceptable tolerability on 60 mg 
40 mg→20 mg 
-- 
Dose reduction required due to 
unacceptable tolerability on 40 mg 
If the Investigator determines that a dose titration/adjustment after Week 12 is required, the Investigator should contact the 
Medical Monitor to ensure that a consistent approach to dose titration/adjustment is applied across the study. 
RC Phase Rescue Criteria (Auxiliary Medicinal Products) 
During the RC phase, acromegaly treatments other than study drug are prohibited, unless the 
subject meets the rescue criteria described as follows: 
 Significant worsening of 1 or more acromegaly symptoms or the development of a 
new acromegaly symptom, at the highest dose (60 mg) for at least 2 weeks, as 
assessed by the Investigator. Symptoms should be attributed to uncontrolled 
acromegaly in the opinion of the Investigator and could include, but are not limited to 
the following: headache, arthralgia, fatigue, hyperhidrosis, or soft tissue swelling. 
(“Significant worsening” in the opinion of the Investigator may be defined as 
symptoms requiring a substantial increase in level of clinical care (eg, significant 
intervention needed to avert hospitalization or clinically notable increase in frequency 
or intensity of subject contact required) or substantial clinical deterioration 
(eg worsening from a mild to severe adverse event (AE) or the onset of an SAE 
would meet these criteria). 

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AND 
 IGF-1 value ≥1.5×ULN* at the highest dose (60 mg) measured at 2 successive 
planned visits or at an unscheduled visit if an earlier result is needed (as evaluated by 
the Investigator). 
*In a large study of naïve acromegaly patients, octreotide LAR monotherapy achieved mean 
IGF-1 of 1.5×ULN (Colao 2014) at 3 months of treatment through 12 months. 
If rescue therapy is required during the RC phase, subjects will discontinue paltusotine or 
placebo, initiate rescue therapy, and should continue the visits and surveillance in the study for 
the remainder of the 24-week RC phase (see Section 6.7.3 for Rescue Criteria). Only rescue 
therapy with approved SRLs (octreotide LAR or lanreotide depot monotherapy) will be 
permitted during the study.  
Octreotide LAR or lanreotide depot monotherapy are considered auxiliary medicinal products. 
Rescue therapy should be used according to approved marketing authorization or standard 
clinical practice. 
Investigators should contact the Medical Monitor about any subject who does not meet the 
criteria for rescue, but for whom the Investigator recommends discontinuation of study drug and 
initiation of standard acromegaly medication, in order to discuss the possibility of continuation in 
the RC phase on standard acromegaly medication, and eligibility for OLE on a case-by-case 
basis. These situations may include the following: (1) there is worsening of acromegaly 
symptoms with no improvement from baseline in IGF-1 levels, however IGF-1 is <1.5×ULN; or 
(2) IGF-1 levels are ≥1.5×ULN without sufficiently worsening acromegaly symptoms.  
Dosage and Dose Adjustment During the Open-Label Extension 
The starting daily dose regimen for all subjects who participate in the OLE will be paltusotine 
20 mg (1×20 mg tablet), dispensed in an open-label manner; ie, subjects will be given a bottle of 
paltusotine containing 
tablets and instructed to take 1 tablet per day and then if 
tolerated, to increase to 40 mg once daily (QD) (2×20 mg tablets) at the Week 26 visit.  
Further up-titration in the OLE may occur once the first IGF-1 result is available. At that time, 
the Investigator can determine whether the dose can be up-titrated to 60 mg QD (3×20 mg 
tablets). Down-titration due to unacceptable tolerability is permitted. 
Open-Label Extension Adjunctive Treatments (Auxiliary Medicinal Products) 
If there is evidence of paltusotine efficacy and at 6 months, subjects have not reached therapeutic 
target goals, adjunctive treatment may be initiated if clinically appropriate beginning at Week 48. 
If these criteria are met, non-SRL acromegaly treatments, such as cabergoline or GH receptor 
antagonist (ie, pegvisomant), are permitted and may be initiated as an adjunct when a subject has 
experienced at least 2 consecutive elevated IGF-1 (≥1.3×ULN) measurements at the highest 
paltusotine dose level (60 mg), or otherwise not at the subject’s therapeutic target in the 
judgement of the Investigator. If adjunctive medications are not appropriate or not accessible 
under local regulations, and the subject is not under acceptable biochemical control while treated 
with paltusotine monotherapy at the maximal tolerated dose in the opinion of the Investigator, 
the subject should be discontinued from the OLE portion of the study. 

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 The adjunctive medications bromocriptine/cabergoline and pegvisomant are 
considered auxiliary medicinal products (AxMP). Use of any adjunctive medications 
should be discussed with the Medical Monitor and should be used according to 
approved marketing authorization or standard practice. Adjunct medications are not 
provided by the Sponsor. 
 If it is determined that adjunctive medication is required, cabergoline would be the 
expected first-line adjunct, as clinically appropriate. If after an adequate period of 
assessment, study medication combined with a cabergoline does not achieve 
therapeutic targets, then pegvisomant may be added as a second-line adjunct, if 
clinically appropriate (Katznelson, 2014). In this situation, the Investigator should 
assess if there was evidence of an IGF-1 lowering response from cabergoline. If so, 
the pegvisomant may be added to the paltusotine + cabergoline combination. If there 
was no evidence of a therapeutic response to combined paltusotine +cabergoline, 
cabergoline should be stopped and pegvisomant added to paltusotine therapy. 
 Short- and long-acting somatostatin receptor agonists (other than paltusotine) remain 
prohibited and are not permitted during the study (subjects will be discontinued from 
the study if these are needed and an ET Visit will be scheduled prior to resuming 
these treatments). 
Number of Subjects 
The primary endpoint assumes the overall rate of response at EOR, defined as IGF-1 ≤1.0×ULN, 
for paltusotine versus placebo is 
 and 
, respectively. The study population will be 
stratified to ensure equivalent active treatment versus placebo allocations in each stratum. 
Groups 1 and 2 constitute Stratum 1 and Group 3 constitutes Stratum 2. The number of subjects 
in each stratum is expected to be equally allocated (Melmed, 2010). The responder rates in 
Stratum 1 are expected to be 
 in paltusotine treated subjects and 
 in placebo treated 
subjects. The responder rates in Stratum 2 are expected to be 70% in paltusotine treated subjects 
and 20% in placebo treated subjects. Through simulations, power was estimated for the 
comparison of paltusotine versus placebo using an Exact Logistic Regression with strata as a 
covariate in the model and a 2-sided alpha of 0.05. Power of 
 was achieved with 76 subjects 
(38 per group) which accounts for a 
 drop-out rate (treating them as nonresponders).  
This sample size was generated based on the assumption that there will be an equal number of 
subjects in each stratum and a 
 drop put rate. If these assumptions are violated, there could 
be a reduction in statistical power. Therefore, when 
 of the projected 76 subjects 
(approximately 57) are randomized, enrollment into the strata will be assessed. If there are less 
than 
 subjects in Group 3 (subjects who washout of octreotide or lanreotide during the 
screening period), the sample size may be increased (see Section 9.2).  
A sample size of 54 subjects will provide 
 power to detect a difference in the key secondary 
endpoint of change from baseline to EOR in IGF-1 using Wilcoxon rank-sum test under the 
following assumptions: a difference of 
 in the mean change from baseline to EOR in IGF-1 
in units of ULN between placebo and paltusotine, a common standard deviation (SD) of 
, a 
2-tailed alpha of 0.05, and a 
 drop-out rate. With 76 subjects enrolled, the power increases to 
. 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
31 
Statistical Methods 
The primary efficacy analyses will test for superiority in IGF-1 response rates at EOR between 
placebo and paltusotine, at a 2-sided alpha level of 0.05, using an Exact Logistic Regression with 
a covariate for prior treatment (medically naïve or previously treated versus washout) in the Full 
Analysis Set (FAS).  
The key secondary endpoint of change from baseline in IGF-1 will be analyzed using a worst 
rank score analysis of covariance (ANCOVA) model including fixed effects for treatment group 
with prior treatment (medically naïve or previously treated versus washout) as a covariate for the 
FAS. All other secondary endpoints will be analyzed for the FAS using the same methodology as 
the primary endpoint. 
Data Monitoring Committee 
An unblinded Data Monitoring Committee (DMC), comprising independent subject matter 
experts, will be established to assess the risk versus benefit of the interventions during the trial. 
The DMC will meet at intervals as specified in the DMC charter and may convene for ad hoc 
meetings if there are immediate safety concerns identified during the study. An optional interim 
analysis may be performed using conditional power to assess futility and for a sample size re-
estimation. Further details are in the DMC charter and statistical analysis plan. 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
32 
1.2. 
Schedule of Activities: Screening Period for Medically Naïve or Previously Treated Groups 
(No treatment within previous 4 months) 
STUDY PROCEDURES 
SCREENING 
PERIOD 
REFs 
Week -4 to Day -1 a 
S1 
 
DAY/WEEK 
WINDOW (DAYS) 
- 
- 
Visit to be in-clinic 
X 
- 
Visit to be in-clinic or subject’s home/suitable alternate location 
- 
- 
Obtain informed consent  
X 
Section 10.1.3 
Register subject in IWRS 
X 
Section 6.3  
Verify eligibility  
Send Medical Monitor Eligibility Verification Form no later than D1 
X 
Section 5.1  
Section 5.2  
Health history, demographics, baseline characteristics 
X 
Section 8.1 
Pretrial acromegaly symptoms  
X 
Section 8.1 
Full physical exam, weight, ring size (height at screening only) 
X 
Section 8.3.1 
Vital signs  
X 
Section 8.3.2 
12-lead ECG (triplicate) 
X 
Section 8.3.3 
Biliary/gallbladder ultrasound  
Ultrasound may be done at any Screening visit, but results MUST be available to determine eligibility 
X 
Section 8.3.5  
Pituitary MRI 
MRI may be done at any Screening visit, but results MUST be available to determine eligibility 
X 
Section 8.3.6 
AE monitoring  
X 
Section 8.4 Appendix 3  
Prior & concomitant therapies 
X 
Section 6.7  
Pregnancy test  
X 
Section 8.4.5 Appendix 2 
Clinical laboratory tests (hematology, chemistry, urinalysis) 
X 
Section 8.3.4 Appendix 2 
HbA1c 
X 
Section 8.3.4 Appendix 2 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
33 
STUDY PROCEDURES 
SCREENING 
PERIOD 
REFs 
Week -4 to Day -1 a 
S1 
 
DAY/WEEK 
WINDOW (DAYS) 
- 
- 
Visit to be in-clinic 
X 
- 
Visit to be in-clinic or subject’s home/suitable alternate location 
- 
- 
Serology (HIV, Hepatitis B and Hepatitis C) 
X 
Section 8.3.4 Appendix 2 
TSH and Free T4  
X 
Section 8.3.4 Appendix 2 
Screening IGF-1  
X b 
Section 8.3.4 Appendix 2 
Screening fasting Integrated GH 
5 samples collected at least 30 minutes apart drawn within a 3-hour period 
X 
Section 8.3.4 Appendix 2 
ASD  
ASD should be completed by the subject daily at home beginning approximately 2 weeks prior to 
study drug dosing for the duration of the RC phase 
X 
Section 8.2.1  
X 
Section 8.2.4 
Notes:  
To the extent practical, conduct all study assessments at the same time of day, unless otherwise specified. 
MRI and/or ultrasound do not need to be performed on the same day as the screening visit. 
a. The Screening Period should be approximately 4 weeks in duration, and the S1 visit is to be at least 14 days prior to Day 1 to allow for IGF-1 test results to be obtained. 
b. The IGF 1 must be ≥1.3× ULN. 
Fasting integrated GH consists of 5 samples collected at least 30 minutes apart during a collection period of up to 3 hours. Integrated GH should be measured after at least a 4-hour 
fast and the subjects should remain fasting during the GH sampling.  
AE=adverse event, ASD=Acromegaly Symptoms Diary, D=Day, ECG=electrocardiogram, GH=growth hormone, HbA1c=hemoglobin A1c, HIV=human immunodeficiency virus, 
IGF-1=insulin-like growth factor-1, IWRS=interactive web response system, MRI=magnetic resonance imaging, 
, RC=randomized 
controlled phase, REFs=references, S=Screening, TSH=thyroid-stimulating hormone 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
34 
1.3. 
Schedule of Activities: Screening Period for Subjects Washing out of Short-acting Octreotide or 
Lanreotide (SC or oral) 
STUDY PROCEDURES 
SCREENING PERIOD 
REFs 
Week -8 
S1 
Week -4 
S2 
Week -2 
S3 
DAY/WEEK 
WINDOW (DAYS) 
- 
±2 
±2 
- 
Visit to be in-clinic 
X 
- 
- 
- 
Visit to be in-clinic or subject’s home/suitable alternate location 
- 
X 
X 
- 
Obtain informed consent  
X 
- 
- 
Section 10.1.3 
Register subject in IWRS 
X 
- 
- 
Section 6.3  
Verify eligibility  
Send Medical Monitor Eligibility Verification Form no later than D1 
X 
X 
X 
Section 5.1  
Section 5.2  
Demographics and Baseline Characteristics 
Health history, demographics, baseline characteristics 
X 
- 
- 
Section 8.1 
Pretrial acromegaly symptoms  
X 
- 
- 
Section 8.1 
Safety Assessments 
Full physical exam, weight, ring size (height at screening only) 
X 
- 
- 
Section 8.3.1 
Vital signs  
X 
- 
- 
Section 8.3.2 
12-lead ECG (triplicate) 
X 
- 
- 
Section 8.3.3 
Biliary/gallbladder ultrasound  
Ultrasound may be done at any Screening visit, but results MUST be available to 
determine eligibility 
X 
- 
- 
Section 8.3.5  
Pituitary MRI 
MRI may be done at any Screening visit, but results MUST be available to 
determine eligibility 
X 
- 
- 
Section 8.3.6 
AE monitoring  
X 
X 
X 
Section 8.4 Appendix 3  
Prior & concomitant therapies 
X 
X 
X 
Section 6.7  
Laboratory Tests 
Pregnancy test  
X 
X 
- 
Section 8.4.5 Appendix 2 
Clinical laboratory tests (hematology, chemistry, urinalysis) 
X 
- 
- 
Section 8.3.4 Appendix 2 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
35 
STUDY PROCEDURES 
SCREENING PERIOD 
REFs 
Week -8 
S1 
Week -4 
S2 
Week -2 
S3 
DAY/WEEK 
WINDOW (DAYS) 
- 
±2 
±2 
- 
Visit to be in-clinic 
X 
- 
- 
- 
Visit to be in-clinic or subject’s home/suitable alternate location 
- 
X 
X 
- 
HbA1c 
X 
- 
- 
Section 8.3.4 Appendix 2 
Serology (HIV, Hepatitis B and Hepatitis C) 
X 
- 
- 
Section 8.3.4 Appendix 2 
TSH and Free T4  
X 
- 
- 
Section 8.3.4 Appendix 2 
Screening IGF-1  
X a 
X a 
X a 
Section 8.3.4 Appendix 2 
Screening fasting Integrated GH 
5 samples collected at least 30 minutes apart drawn within a 3-hour period 
- 
X 
- 
Section 8.3.4 Appendix 2 
Subject-reported Assessments 
ASD  
ASD should be completed by the subject daily at home beginning approximately 
2 weeks prior to study drug dosing for the duration of the RC phase 
- 
X 
- 
Section 8.2.1  
 
X 
X 
- 
Section 8.2.4 
Notes:  
Week -2 Visit (S3) is optional.  
To the extent practical, conduct all study assessments at the same time of day, unless otherwise specified. 
MRI and/or ultrasound do not need to be performed on the same day as the screening visit. 
a. IGF-1 value at S1 will be used to determine if the subject is controlled on short-acting octreotide or lanreotide. If the subject is not controlled, the subject will be considered a 
screen failure. The IGF-1 value at S2 will be used to determine post-washout eligibility (IGF-1 ≥1.1× ULN and 30% rise from S1). If a second post-washout IGF-1 measurement is 
needed to confirm eligibility (IGF-1 ≥1.1× ULN and 30% rise from S1) per the investigator, the Medical Monitor should be consulted, and a sample collected at S3 (Week -2).  
Fasting integrated GH consists of 5 samples collected at least 30 minutes apart during a collection period of up to 3 hours. Integrated GH should be measured after at least a 4-hour 
fast and the subjects should remain fasting during the GH sampling.  
The date and dose level of the most recent short-acting octreotide or lanreotide prior to consent will be recorded as prior medication.  
AE=adverse event, ASD=Acromegaly Symptoms Diary, D=day, ECG=electrocardiogram, GH=growth hormone, HbA1c=hemoglobin A1c, HIV=human immunodeficiency virus, 
IGF-1=insulin-like growth factor-1, IWRS=interactive web response system, MRI=magnetic resonance imaging, 
, RC=randomized 
controlled phase, REFs=references, S=Screening, TSH=thyroid-stimulating hormone, ULN=upper limit of normal  

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
36 
1.4. 
Schedule of Activities: Screening Period for Subjects Washing out of Long-acting Octreotide or 
Lanreotide 
STUDY PROCEDURES 
SCREENING PERIOD 
REFs 
Week -16 to  
Week -12 
S1 
Week -8 to  
Week -4 
S2 
Week -2 
S3  
DAY/WEEK 
WINDOW (DAYS) 
- 
- 
±2 
- 
Visit to be in-clinic 
X 
- 
- 
- 
Visit to be in-clinic or subject’s home/suitable alternate location 
- 
X 
X 
- 
Obtain informed consent  
X 
- 
- 
Section 10.1.3 
Register subject in IWRS 
X 
- 
- 
Section 6.3  
Verify eligibility  
Send Medical Monitor Eligibility Verification Form no later than D1 
X 
X 
X 
Section 5.1  
Section 5.2  
Demographics and Baseline Characteristics 
Health history, demographics, baseline characteristics 
X 
- 
- 
Section 8.1 
Pretrial acromegaly symptoms  
X 
- 
- 
Section 8.1 
Safety Assessments 
Full physical exam, weight, ring size (height at screening only) 
X 
- 
- 
Section 8.3.1 
Vital signs  
X 
- 
- 
Section 8.3.2 
12-lead ECG (triplicate) 
X 
- 
- 
Section 8.3.3 
Biliary/gallbladder ultrasound  
Ultrasound may be done at any Screening visit, but results MUST be available to 
determine eligibility 
X 
- 
- 
Section 8.3.5  
Pituitary MRI 
MRI may be done at any Screening visit, but results MUST be available to 
determine eligibility 
An MRI must be done at the end of the washout period. 
- 
X 
- 
Section 8.3.6 
AE monitoring  
X 
X 
X 
Section 8.4 Appendix 3 
Prior & concomitant therapies 
X 
X 
X 
Section 6.7  
Laboratory Tests 
Pregnancy test  
X 
X 
- 
Section 8.4.5 Appendix 2 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
37 
STUDY PROCEDURES 
SCREENING PERIOD 
REFs 
Week -16 to  
Week -12 
S1 
Week -8 to  
Week -4 
S2 
Week -2 
S3  
DAY/WEEK 
WINDOW (DAYS) 
- 
- 
±2 
- 
Visit to be in-clinic 
X 
- 
- 
- 
Visit to be in-clinic or subject’s home/suitable alternate location 
- 
X 
X 
- 
Clinical laboratory tests (hematology, chemistry, urinalysis) 
X 
- 
- 
Section 8.3.4 Appendix 2 
HbA1c 
X 
- 
- 
Section 8.3.4 Appendix 2 
Serology (HIV, Hepatitis B and Hepatitis C) 
X 
- 
- 
Section 8.3.4 Appendix 2 
TSH and Free T4  
X 
- 
- 
Section 8.3.4 Appendix 2 
Screening IGF-1  
X a 
X a 
X a 
Section 8.3.4 Appendix 2 
Screening fasting Integrated GH 
5 samples collected at least 30 minutes apart drawn within a 3-hour period 
- 
X 
- 
Section 8.3.4 Appendix 2 
Subject-reported Assessments 
ASD  
ASD should be completed by the subject daily at home beginning approximately 
2 weeks prior to study drug dosing for the duration of the RC phase 
- 
X 
- 
Section 8.2.1  
X 
X 
- 
Section 8.2.4 
Notes:  
Week -2 Visit (S3) is optional.  
To the extent practical, conduct all study assessments at the same time of day, unless otherwise specified. 
MRI and/or ultrasound do not need to be performed on the same day as the screening visit. 
a. IGF-1 value at S1 will be used to determine if the subject is controlled on long-acting octreotide or lanreotide. If the subject is not controlled, the subject will be considered a 
screen failure. The IGF-1 value at S2 will be used to determine post-washout eligibility (IGF-1 ≥1.1× ULN and 30% rise from S1). If a second post-washout IGF-1 measurement is 
needed to confirm eligibility (IGF 1 ≥1.1× ULN and 30% rise from S1) per the investigator, the Medical Monitor should be consulted, and a sample collected at S3 (Week 2).  
Fasting integrated GH consists of 5 samples collected at least 30 minutes apart during a collection period of up to 3 hours. Integrated GH should be measured after at least a 4-hour 
fast and the subjects should remain fasting during the GH sampling. 
The date and dose level of the most recent octreotide or lanreotide prior to consent will be recorded as prior medication.  
AE=adverse event, ASD=Acromegaly Symptoms Diary, D=Day, ECG=electrocardiogram, GH=growth hormone, HbA1c=hemoglobin A1c, HIV=human immunodeficiency virus, 
IGF-1=insulin-like growth factor-1, IWRS=interactive web response system, MRI=magnetic resonance imaging, 
 REFs=references, 
S=Sreening, TSH=thyroid-stimulating hormone, ULN=upper limit of normal 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
38 
1.5. 
Schedule of Activities: Randomized, Controlled Phase 
STUDY PROCEDURES 
TREATMENT PERIOD (24 WEEKS) 
ET 
DT b 
F/U 
REFS 
DAY/WEEK 
D1 
TITRATION PERIOD 
STABLE DOSE 
W24 
EOR 
W28 
W2 a 
W4 
W6 
W8 
W12 
W16 
W20 
W22 
WINDOW (DAYS) 
- 
±2 
±2 
±2 
±2 
±4 
±4 
±4 
±4 
±3 
- 
 
±3 
- 
VISIT TO BE IN-CLINIC 
X 
X 
- 
X 
- 
X 
- 
- 
X 
X 
X 
X 
X 
- 
Visit to be in-clinic or subject’s 
home/suitable alternate location 
- 
- 
X 
- 
X 
- 
X 
X 
- 
- 
- 
- 
- 
- 
Verify eligibility  
Send Medical Monitor Eligibility 
Verification Form no later than D1 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 5.1  
Section 5.2  
Randomization 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 6.3  
Safety Assessments 
Full physical exam, weight, ring 
size (height at screening only) 
X 
- 
- 
- 
- 
X 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.1 
Symptom-directed physical exam 
- 
- 
X 
- 
X 
- 
X 
X 
X 
- 
- 
- 
X 
Section 8.3.1 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Section 8.3.2 
12-lead ECG (triplicate) 
X 
X 
X 
X 
X 
- 
X 
- 
- 
X 
X 
- 
X 
Section 8.3.3 
Biliary/gallbladder ultrasound  
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.5  
Pituitary MRI 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.6  
AE monitoring  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.4 Appendix 3  
Prior & concomitant therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 6.7  
Laboratory Tests 
Monthly pregnancy test  
X 
- 
X 
- 
X 
X 
X 
X 
- 
X 
X 
- 
X 
Section 8.3.4 Appendix 2 
Clinical laboratory tests 
(hematology, chemistry, urinalysis) 
X 
- 
X 
- 
X 
X 
- 
X 
- 
X 
X 
- 
X 
Section 8.3.4 Appendix 2 
HbA1c 
X 
- 
- 
- 
- 
X 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.4 Appendix 2 
Lipid panel (fasting) 
X 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.4 Appendix 2 
TSH and Free T4  
X 
- 
- 
 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.3.4 Appendix 2 
Genotype blood sample (optional) 
X c 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 8.6 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
39 
STUDY PROCEDURES 
TREATMENT PERIOD (24 WEEKS) 
ET 
DT b 
F/U 
REFS 
DAY/WEEK 
D1 
TITRATION PERIOD 
STABLE DOSE 
W24 
EOR 
W28 
W2 a 
W4 
W6 
W8 
W12 
W16 
W20 
W22 
WINDOW (DAYS) 
- 
±2 
±2 
±2 
±2 
±4 
±4 
±4 
±4 
±3 
- 
 
±3 
- 
VISIT TO BE IN-CLINIC 
X 
X 
- 
X 
- 
X 
- 
- 
X 
X 
X 
X 
X 
- 
Visit to be in-clinic or subject’s 
home/suitable alternate location 
- 
- 
X 
- 
X 
- 
X 
X 
- 
- 
- 
- 
- 
- 
PK  
(any time) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.5 
Fasting Integrated GH 
5 samples collected at least 
30 minutes apart within a 3-hour 
period. At W22, collection should 
be started approximately 1-2 hours 
after study drug dose  
- 
- 
- 
- 
- 
- 
- 
- 
X 
- 
X 
- 
- 
Section 8.3.4 Appendix 2 
Predose fasting IGF-1 
(W24 can be done any time) 
X 
X 
X 
X 
X 
X 
- 
X 
X 
X 
X 
- 
X 
Section 8.3.4 Appendix 2 
Predose fasting PK 
- 
- 
- 
X 
- 
X 
- 
X 
X 
- 
- 
- 
- 
Section 8.5  
Postdose PK, GH, and IGF-1  
One sample between 1 and 8 hours 
postdose 
- 
X 
- 
X 
- 
- 
X 
- 
- 
- 
- 
- 
- 
Section 8.3.4  
Section 8.5 
Appendix 2 
Drug Administration 
Dispense study drug (via IWRS) 
(W24 dispensation for subjects 
continuing into OLE only) 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
X 
- 
Section 6.1 
Study drug administration during 
the visit 
X 
X 
- 
X 
- 
X 
- 
X 
X 
X 
- 
- 
- 
Section 6.1 
Study drug compliance 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Section 6.4 
Study drug accountability 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Section 6.4  
Subject-reported Assessments 
ASD  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Section 8.2.1  
  
X 
- 
- 
- 
- 
X 
- 
- 
- 
X 
X 
- 
- 
Section 8.2.2 
Section 8.2.3  

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
40 
STUDY PROCEDURES 
TREATMENT PERIOD (24 WEEKS) 
ET 
DT b 
F/U 
REFS 
DAY/WEEK 
D1 
TITRATION PERIOD 
STABLE DOSE 
W24 
EOR 
W28 
W2 a 
W4 
W6 
W8 
W12 
W16 
W20 
W22 
WINDOW (DAYS) 
- 
±2 
±2 
±2 
±2 
±4 
±4 
±4 
±4 
±3 
- 
 
±3 
- 
VISIT TO BE IN-CLINIC 
X 
X 
- 
X 
- 
X 
- 
- 
X 
X 
X 
X 
X 
- 
Visit to be in-clinic or subject’s 
home/suitable alternate location 
- 
- 
X 
- 
X 
- 
X 
X 
- 
- 
- 
- 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Section 8.2.4 
  
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.2.4 
 
(excluding Medically naïve 
subjects) 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
- 
Section 8.2.5  
Notes:  
During the Stable Dose period, down-titration due to unacceptable tolerability is permitted. 
To the extent practical, conduct all study assessments at the same time of day, unless otherwise specified. MRI and/or ultrasound do not need to be performed on the same day as 
the study visit. The pituitary MRI and biliary/gallbladder ultrasound may be performed within ± 2 weeks of the Week 24/EOR visit. 
a. After confirming tolerability with the subject, the dose should be increased to 40 mg/day (2×20 mg tablet of active paltusotine or matching placebo) beginning at the W2 visit 
b. A DT Visit may occur as an unscheduled visit when an in-person dose adjustment visit is necessary. In cases of poor tolerability, the Investigator may reduce dose based on 
his/her assessment during a telemedicine (phone, video) evaluation. 
c. Genotype blood sample can be drawn at any post-baseline visit in China. 
d. The 
 will not be administered in India due to lack of available validated translations. Fasting integrated GH consists of 5 samples collected at least 30 minutes apart 
during a collection period of up to 3 hours. Integrated GH should be measured after at least a 4-hour fast and the subjects should remain fasting during the GH sampling. The 
integrated GH sampling at Week 22 should be started approximately 1-2 hours after study drug dose. 
At other indicated visits, single samples for GH will be collected. 
The last dose of study drug for the RC phase will be self-administered the day prior to the Week 24/EOR visit. The first dose of the OLE phase will be administered during the 
Week 24/EOR visit for subjects continuing into the OLE. 
Urinary pregnancy tests will be performed monthly for women of childbearing potential and may be obtained at any time during the study as an unscheduled test if clinically 
appropriate. 
Unscheduled visits for octreotide/lanreotide injections may be necessary for subjects who meet criteria for rescue therapy. 
Follow-up Visit is to occur approximately 4 weeks after the last dose of study drug for subjects who do not enter the OLE. 
, AE=adverse event, ASD=Acromegaly Symptoms Diary, D=Day, DT=dose titration, ECG=electrocardiogram, 
 EOR=End of Treatment (randomized controlled phase), ET=Early Termination Visit, F/U=follow-up, GH=growth hormone, HbA1c=hemoglobin A1c, 
IGF 1=insulin like growth factor 1, IWRS= interactive web response system, MRI=magnetic resonance imaging, OLE=open-label extension, 
 PK=pharmacokinetics, RC=randomized controlled phase, REFs=references, TSH=thyroid-stimulating hormone, 
W=Week 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
41 
1.6. 
Schedule of Activities: Open-Label Extension Phase 
STUDY PROCEDURES  
INITIAL OLE PERIOD 
2-YEAR EXTENSION 
EOS 
REFs 
WEEK 
EOR 
W24 
W26 a W36 
W48 
W60 
W72 
W84 
W96 
W108 
W120/ 
W144 
W168 
W192 
W216 
W132/ 
W156 
W180 
W204 
W224 
EOT/ 
ET 
DT b 
W228 
 
WINDOW (DAYS) 
±3 
±4 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
- 
±7 
 
Visit to be in-clinic 
X 
- 
X 
- 
X 
X 
X 
- 
X 
- 
X 
X 
X 
X 
 
Visit to be in-clinic or subject’s 
home/suitable alternate location 
- 
X 
- 
X 
- 
- 
- 
X 
- 
X 
- 
- 
- 
- 
 
Verify eligibility 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 5.1 
Section 5.2 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical exam, weight, ring 
size  
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
X 
- 
- 
Section 8.3.1 
Symptom directed physical exam 
- 
X 
- 
X 
- 
X 
- 
X 
- 
X 
- 
- 
- 
X 
Section 8.3.1 
Vital signs  
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Section 8.3.2 
12-lead ECG (triplicate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Section 8.3.3 
Biliary/gallbladder ultrasound  
X 
- 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
- 
- 
Section 8.3.5  
Pituitary MRI 
X 
- 
- 
X 
- 
- 
- 
- 
- 
Xd 
 
- 
X 
- 
- 
Section 8.3.6 
Ophthalmic Assessments 
 
 
 
 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
 
 
Section 8.3.7 
AE monitoring  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.4 
Appendix 3  
Concomitant therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 6.7 
Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monthly pregnancy test f 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
Section 8.4.5 
Appendix 2 
Clinical laboratory tests 
(hematology, chemistry, 
urinalysis) and HbA1c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Section 8.3.4 
Appendix 2 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
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42 
STUDY PROCEDURES  
INITIAL OLE PERIOD 
2-YEAR EXTENSION 
EOS 
REFs 
WEEK 
EOR 
W24 
W26 a W36 
W48 
W60 
W72 
W84 
W96 
W108 
W120/ 
W144 
W168 
W192 
W216 
W132/ 
W156 
W180 
W204 
W224 
EOT/ 
ET 
DT b 
W228 
 
WINDOW (DAYS) 
±3 
±4 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
- 
±7 
 
Visit to be in-clinic 
X 
- 
X 
- 
X 
X 
X 
- 
X 
- 
X 
X 
X 
X 
 
Visit to be in-clinic or subject’s 
home/suitable alternate location 
- 
X 
- 
X 
- 
- 
- 
X 
- 
X 
- 
- 
- 
- 
 
Lipid panel (fasting) 
X 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
X 
- 
- 
Section 8.3.4 
Appendix 2 
TSH and Free T4 
X 
- 
- 
- 
- 
X 
- 
- 
- 
X 
- 
X 
- 
- 
Section 8.3.4 
Appendix 2 
PK 
(any time) 
X 
 
 
X 
 
 
 
 
 
Xg 
 
X 
 
 
Section 8.3.4 
Appendix 2 
Predose fasting IGF 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.3.4 
Appendix 2 
GH and IGF-1 
(any time) 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Section 8.3.4 
Appendix 2 
Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study drug  
(via IWRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
X 
- 
Section 6.1 
Study drug administration at study 
site 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Section 6.1 
Study drug compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Section 6.4 
Study drug accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Section 6.4 
Subject-reported Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASD and 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Section 8.2.1 
Section 8.2.4  
  
X 
- 
- 
- 
- 
X 
- 
- 
- 
Xi 
- 
X 
- 
- 
Section 8.2.2 
Section 8.2.3  
 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Xi 
- 
X 
- 
- 
Section 8.2.4 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0  
Confidential 
43 
STUDY PROCEDURES  
INITIAL OLE PERIOD 
2-YEAR EXTENSION 
EOS 
REFs 
WEEK 
EOR 
W24 
W26 a W36 
W48 
W60 
W72 
W84 
W96 
W108 
W120/ 
W144 
W168 
W192 
W216 
W132/ 
W156 
W180 
W204 
W224 
EOT/ 
ET 
DT b 
W228 
 
WINDOW (DAYS) 
±3 
±4 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
- 
±7 
 
Visit to be in-clinic 
X 
- 
X 
- 
X 
X 
X 
- 
X 
- 
X 
X 
X 
X 
 
Visit to be in-clinic or subject’s 
home/suitable alternate location 
- 
X 
- 
X 
- 
- 
- 
X 
- 
X 
- 
- 
- 
- 
 
(Excluding Medically naïve 
subjects) 
X 
- 
- 
- 
- 
- 
- 
- 
- 
Xi 
- 
 
- 
- 
Section 8.2.5  
Notes:  
To the extent practical, conduct all study assessments at the same time of day, unless otherwise specified. The pituitary MRIs and biliary/gallbladder ultrasounds do not need to be 
performed on the same day as the study visit. They may be performed within ± 2 weeks of the study visit. 
EOS/Follow-up Visit is to occur approximately 4 weeks after the last dose of study drug for subjects. 
Fasting blood samples (unless otherwise indicated) should be collected after an overnight fast of at least 6 hours. 
The first dose of the OLE phase will be administered during the W24/EOR visit. 
a. After confirming tolerability with the subject, the dose should be increased to 40 mg/day (2×20 mg tablet) beginning at the W26 visit. 
b. One or more optional visits for dose titration and/or safety monitoring (unscheduled safety assessments) may be performed at the discretion of the Investigator. In cases of poor 
tolerability, the Investigator may reduce dose based on his/her assessment during a telemedicine (phone, video) evaluation. 
c. Biliary/gallbladder ultrasounds are required at Week 120 and Week 224/ET visits but may be performed at any time if clinically indicated in the opinion of the Investigator. 
d. Pituitary MRI performed at Week 120 and Week 168 only. 
e Visual Acuity, Fundus Photography, Optical coherence tomography, Visual Fields. Initial ophthalmic testing should be performed as soon as practical and then at approximately 
6-month intervals, preferably associated with scheduled visits whenever possible, through study completion. If the most recent ophthalmic assessment is performed within 3 
months of ET, there is no need to repeat at ET. 
f. Urinary pregnancy tests will be performed monthly for women of childbearing potential and may be obtained at any time during the study as an unscheduled test if clinically 
appropriate. 
g PK sample collections at Week 120, Week 168, and Week 216 only. 
h..The 
 will not be administered in India due to lack of available validated translations. 
i. 
 and 
 at Week 120, Week 144, Week 168, and Week 192 only. 
 at Week 120 only. 
 AE=adverse event, ASD=Acromegaly Symptoms Diary, DT=dose titration, ECG=electrocardiogram, EQ-5D-5L=EuroQol-5 
 
 EOR=End of Treatment (RC phase), EOS=End of Study, EOT=End of Treatment, ET=Early Termination Visit, GH=growth hormone, HbA1c=hemoglobin A1c, 
IGF-1=insulin-like growth factor-1, IWRS=interactive web response system, MRI=magnetic resonance imaging, OLE=open-label extension, 
, PK=pharmacokinetic, RC=randomized controlled phase, REFs=references, TSH=thyroid-stimulating hormone; 
W=Week 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
Confidential 
44 
2. 
INTRODUCTION 
2.1. 
Study Rationale 
Therapy for acromegaly is targeted at decreasing growth hormone (GH) and insulin-like growth 
factor-1 (IGF-1) levels, ameliorating patients' symptoms and decreasing any local compressive 
effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, 
radiotherapy, and medical therapies such as somatostatin receptor ligands (SRLs), dopamine 
agonists, and the GH receptor antagonist pegvisomant.  
When surgery, which is the usual first-line treatment, fails to correct GH/IGF-1 hypersecretion, 
medical treatment can be used. SRLs octreotide long-acting release (LAR) and lanreotide depot 
are, at present, the most widely used drugs to control acromegaly. Other treatments for 
acromegaly that are not widely available and/or used as second line or adjunct therapy include 
pasireotide, pegvisomant, cabergoline, and an oral formulation of octreotide. 
Paltusotine is a nonpeptide orally bioavailable somatostatin receptor 2 (SST2) agonist that is 
administered once per day. In Phase 2 studies, daily oral administration of paltusotine has been 
shown to maintain GH and IGF-1 levels in subjects with acromegaly that were previously on 
octreotide LAR or lanreotide depot monotherapy. An orally bioavailable somatostatin agonist 
should reduce acromegaly patient burden by eliminating the pain and complications 
(eg subcutaneous [SC], or intramuscular nodules) of injections and the cost and inconvenience of 
the health care provider office visits required for those injections. Additionally, it may allow 
physicians to determine an optimized dosing regimen more quickly compared with existing 
therapies. To our knowledge, paltusotine is the first nonpeptide oral somatostatin agonist being 
evaluated for the treatment of acromegaly. 
2.2. 
Background 
Acromegaly is typically caused by a GH secreting tumor (adenoma) in the pituitary. Excess GH 
secretion results in excess secretion of IGF-1 from the liver, which causes bone overgrowth, 
organ enlargement, and changes in glucose and lipid metabolism. The symptoms of acromegaly 
include abnormal growth of hands and feet and changes in shape of the bones that result in 
alteration of facial features. Overgrowth of bone and cartilage and thickening of tissue leads to 
arthritis, carpal tunnel syndrome, joint aches, enlargement of lips, nose, and tongue, deepening of 
voice due to enlarged vocal cords, sleep apnea due to obstruction of airways, and enlargement of 
heart, liver, and other organs. Additional symptoms include thick, coarse, oily skin, skin tags, 
excessive sweating and skin odor, fatigue and weakness, headaches, impaired vision, goiter, 
decreased libido, menstrual abnormalities in women, and erectile dysfunction in men 
(Melmed and Kleinberg, 2016; Carroll and Jenkins, 2016; NIDDK diseases online health 
information).  
The major goals of treatment are to normalize serum GH and IGF-1, relieve pressure of the 
growing tumors, treat hormonal deficiencies, and normalize pituitary function. Surgical removal 
of pituitary adenoma, if possible, is the first option and often results in rapid symptom 
improvement. Parenterally administered SRLs are the most commonly employed primary 
pharmacological treatment options for patients that are not candidates for surgical removal of the 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
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45 
tumor or when surgery is only partially successful or unsuccessful in achieving treatment goals 
(Melmed and Kleinberg, 2016; Carroll and Jenkins, 2016; NIDDK diseases online health 
information). Parenteral SRLs require large bore needles for monthly injections which often need 
to be administered by health care providers. Additionally, because these injections are depot 
preparations, dose optimization is prolonged, leading to delays in biochemical and symptomatic 
control of the disease. These agents when used as monotherapy achieve IGF-1 normalization in 
approximately 20 to 40% of patients.  
Paltusotine is a nonpeptide orally bioavailable SST2 agonist that is administered once daily (QD) 
under development for the treatment of acromegaly. Phase 1 clinical data suggest that QD 
paltusotine administration for up to 10 days can result in IGF-1 lowering in healthy volunteers. 
Phase 2 studies in subjects with acromegaly have shown subjects can successfully switch from 
long-acting octreotide or lanreotide therapy to QD oral paltusotine for a 13-week treatment 
period while maintaining IGF-1 levels, and that paltusotine appears to be well tolerated.  
Additional details on the background of acromegaly, treatment options, and nonclinical and 
clinical data on paltusotine can be found in the current Investigator’s Brochure (IB). 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of paltusotine may be found in the current IB. 
2.3.1. 
Risk Assessment 
Table 4: 
Risk Assessment Table 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk  
Mitigation Strategy 
Study Drug - Paltusotine 
Side effects 
Diarrhea, abdominal pain, nausea, 
abdominal discomfort, bradycardia 
(including sinus bradycardia and 
bradycardia), and cholelithiasis 
have been identified as ADRs 
associated with paltusotine. 
 
Rationale: These AEs are generally 
mild or moderate and did not lead 
to discontinuations. 
Clinical monitoring, symptomatic 
measures, study drug interruption if 
necessary. Regular safety 
surveillance, including laboratory 
testing, physical examinations, AE 
monitoring, ECG monitoring, and 
gall bladder monitoring, and 
evaluations for protocol specified 
study drug stopping criteria. 
Study Procedures 
Participation in a placebo-
controlled trial evaluating an 
experimental agent 
Rise in GH/IGF-1 and worsening in 
acromegaly symptoms 
Clinical monitoring including 
frequent assessment of symptoms, 
adverse events, safety laboratories, 
GH/IGF-1 monitoring, and protocol 
defined rescue criteria 
Blood draws 
Pain, bleeding, infection possible. 
Rationale: Needed for safety 
evaluation of study drug 
Symptomatic measures 

Study code: CRN00808-08 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk  
Mitigation Strategy 
Pituitary magnetic resonance 
imaging (MRI) 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: Needed for monitoring 
of residual pituitary tumor volume 
Standard of care symptomatic and 
preventative management measures  
Biliary/gallbladder ultrasound 
Ultrasound waves may heat the 
tissues slightly and, in some cases, 
it can also produce small pockets of 
gas in body fluids or tissues. 
Rationale: Needed for monitoring 
gallbladder and biliary ducts 
Symptomatic measures 
Distance-corrected visual acuity 
testing 
Visual field testing 
There are no known risks or 
complications associated with these 
tests 
None needed 
Fundus photography  
Optical coherence tomography of 
the macula 
Some participants may experience 
some eye dryness or fatigue 
Symptomatic measures 
ADR=adverse drug reaction, AE=adverse event, CT=computed tomography, ECG=electrocardiogram, 
MRI=magnetic resonance imaging 
2.3.2. 
Benefit Assessment 
On the basis of nonclinical data, paltusotine is expected to have benefit in the treatment of 
acromegaly.  
Completed Phase 2 studies CRN00808-02 and CRN00808-03 showed evidence for IGF-1 
maintenance in acromegaly subjects previously treated with long-acting injected octreotide or 
lanreotide who were switched to paltusotine oral monotherapy for a period of 13 weeks. Overall, 
IGF-1 levels after the switch to paltusotine were similar to those at baseline during treatment 
with long-acting injections. 
The overall safety profile of paltusotine appears to be consistent with those reported for other 
SRLs and common adverse events (AEs) observed with paltusotine are likely related to this 
mechanism of action. In addition to protocol specified safety surveillance, Investigators in 
clinical trials for paltusotine are advised to monitor subjects based on the known side effect 
profile of SRLs and manage as clinically appropriate. 
The ongoing COVID-19 pandemic has not presented a substantial new risk to the acromegaly 
subjects participating in the Phase 2 trials evaluating the safety and efficacy of paltusotine 
(CRN00808-02, CRN00808-03, and CRN00808-05). This protocol (Section 10.1.8) has 
incorporated flexibility in the need for in-person visits at study sites while safeguarding the 
health and well-being of trial participants and minimizing risk to trial and study data integrity. 

Study code: CRN00808-08 
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2.3.3. 
Overall Benefit: Risk Conclusion 
Based on the available information, the known and potential risks of treatment with paltusotine 
are considered acceptable in relation to the potential benefits of treatment in subjects with 
acromegaly. 

Study code: CRN00808-08 
Clinical Study Protocol 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
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48 
3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives and Endpoints for the Controlled Part of the Study 
Objectives 
Endpoints 
Primary  
 To evaluate the effect of paltusotine 
versus placebo on IGF-1 response 
 Proportion of subjects who achieve 
biochemical response in IGF-1 (≤1.0× the 
upper limit of normal [ULN]) at the End of 
the Randomized Control Phase (EOR)  
Key Secondary  
 To evaluate the effect of paltusotine 
versus placebo on IGF-1 level 
 Change from baseline in IGF-1, in units of 
ULN, to EOR 
Secondary 
 To evaluate the effect of paltusotine 
versus placebo on IGF-1 response 
 Proportion of subjects who achieve IGF-1 
<1.3×ULN at EOR 
 To evaluate the effect of paltusotine 
versus placebo on GH response 
 Proportion of subjects with GH <1 ng/mL 
at Week 22 
 To evaluate the effect of paltusotine 
versus placebo on acromegaly symptoms 
 Change from baseline in Total Acromegaly 
Symptoms Diary (ASD) score to EOR 
Exploratory  
 To evaluate the effect of paltusotine 
versus placebo on GH level 
 Change from baseline to Week 22 in GH 
 To evaluate the effect of paltusotine 
versus placebo on the need for rescue 
therapy  
 Proportion of subjects who receive rescue 
therapy 
 To evaluate the time to need for rescue 
treatment of paltusotine versus placebo 
 Time from randomization to first dose of 
rescue treatment 
 To evaluate the effect of paltusotine 
versus placebo on GH response 
 Proportion of subjects with 
GH <2.5 ng/mL at Week 22 
 To evaluate the effect of paltusotine 
versus placebo on tumor volume 
 Change from baseline in residual pituitary 
tumor volume at EOR 

Study code: CRN00808-08 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
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Objectives 
Endpoints 
Safety 
 To evaluate the safety and tolerability of 
paltusotine versus placebo 
 Incidence of treatment-emergent adverse 
events (TEAEs), including serious adverse 
events (SAEs) and TEAEs leading to 
discontinuation 
 Change in safety parameters: clinical 
laboratory tests (hematology, serum 
chemistry, lipid panel, and hormones), 
lipid panel, hormones, vital signs, and 
12-lead electrocardiogram (ECG) 
 Incidence of clinically significant changes 
in abdominal (gallbladder) ultrasound 
compared with baseline 
Pharmacokinetics 
 To evaluate the pharmacokinetic 
parameters of paltusotine in subjects with 
acromegaly 
 Descriptive summary of concentration data 
from postdose sparse PK sampling 
3.2. 
Objectives and Endpoints for the Open-Label Extension  
Objectives 
Endpoints 
Efficacy 
 To evaluate the long-term maintenance of 
efficacy of paltusotine in subjects with 
acromegaly 
 Change from baseline in IGF-1 and GH 
levels 
 Proportion of subjects with IGF-1 
≤1.0×ULN  
 Proportion of subjects with IGF-1 
≤1.3×ULN  
 Proportion of subjects who receive 
permitted adjunctive standard acromegaly 
treatment 
 Change from baseline in residual pituitary 
tumor volume 

Study code: CRN00808-08 
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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
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Objectives 
Endpoints 
Safety 
 To evaluate the long-term safety and 
tolerability of paltusotine in subjects with 
acromegaly 
 Incidence of TEAEs, including serious 
adverse events (SAEs) and TEAEs 
leading to discontinuation of study drug 
 Change in quantitative safety parameters: 
clinical laboratory tests, lipid panel, 
hormones, vital signs, and 12-lead ECG 
parameters 
 Ophthalmic assessments 
Pharmacokinetics 
 To evaluate long-term pharmacokinetic 
parameters of paltusotine in subjects with 
acromegaly 
 Descriptive summary of concentration 
data from postdose sparse PK sampling 
  

Study code: CRN00808-08 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study where 
subjects with nonpharmacologically treated acromegaly will be randomly allocated to receive 
either paltusotine or placebo. Three groups of subjects will be enrolled: (1) subjects with no prior 
medical therapy, (2) subjects who last received medical therapy at least 4 months prior to 
Screening, and (3) subjects who are controlled on medical therapy for at least 3 months but agree 
to washout prior to beginning study treatment. Groups 1 and 2 constitute Stratum 1 and Group 3 
constitutes Stratum 2. The study population will be stratified to ensure equivalent active 
treatment versus placebo allocations in each stratum. 
Approximately 76 subjects will be enrolled. This sample size was generated based on the 
assumption that there will be an equal number of subjects in each stratum. If this assumption is 
violated, there could be a reduction in statistical power. Therefore, when 
 of the projected 
76 subjects (approximately 
) are randomized, enrollment into the strata will be assessed. 
If there are less than 
 subjects in Group 3 (subjects who washout of octreotide or lanreotide 
during the screening period) at that time, the sample size may be increased (see Section 9.2).  
The Screening Period for this study may be approximately 2 to 4, 8, or 12 to 16 weeks, 
depending on prior treatment. After the Screening Period, subjects will be enrolled in a 24-week 
Randomized Controlled (RC) phase and randomly assigned in a 1:1 ratio to receive paltusotine 
or matching placebo stratified by prior treatment (medically naïve or previously treated versus 
washout). At the end of the RC phase (EOR), subjects who, in the opinion of the Investigator, 
may benefit from treatment with paltusotine, may be enrolled in a long-term open-label 
extension (OLE) study, during which they will receive paltusotine for up to 200 weeks. 
Subjects who meet rescue criteria in the RC Phase will have treatment with paltusotine or 
placebo discontinued and be considered nonresponders, but they should be encouraged to 
continue in the study on rescue therapy for assessment and observation. These subjects can 
participate in the OLE phase if they meet all eligibility requirements, and in the opinion of the 
Investigator, the subject may benefit from continued participation and treatment with paltusotine 
and the subject is willing to participate. See Figure 1 for the study schema. 
4.1.1. 
Screening 
Subjects ≥18 years of age at the time of Screening who fall into 1 of the following 3 groups are 
eligible to participate in the study. 
 Medically naïve group (Group 1): Those who have not been previously treated with 
acromegaly medications (including long-acting somatostatin receptor ligands 
[LA-SRLs]) who at Screening have IGF-1 ≥1.3×ULN confirmed by the central 
laboratory test at S1. Group 1 subjects must have had at least 1 pituitary surgery 
3 months or more prior to Screening. 
 Previously Treated group (no treatment within previous 4 months) (Group 2): 
Subjects who have last been treated with acromegaly medications at least 4 months 
prior to Screening and who have IGF-1 ≥1.3×ULN confirmed by the central 
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 Washout group (Group 3): Subjects at Screening who are receiving stable treatment 
(no change in dose for 3 months prior to Screening) with octreotide or lanreotide 
monotherapy, who have IGF-1 ≤1.0×ULN at Screening Visit 1 and are willing to 
washout of their medication during the Screening Period. Any form of pretrial 
octreotide or lanreotide monotherapy (long- or short-acting [subcutaneous (SC) or 
oral]) can be washed out and will determine the duration of the Screening Period. 
After informed consent is provided, the subject should not receive further pretrial 
acromegaly medication. IGF-1 must rise from the first Screening visit by at least 30% 
and be ≥1.1×ULN confirmed by the central laboratory test at S2 or S3 (if needed), to 
qualify for enrollment. 
The Screening Period for the Medically naïve group and the Previously Treated group (no 
treatment within previous 4 months) should be approximately 4 weeks in duration and will 
consist of 1 Screening Visit (S1).  
For those treated at the time of Screening with long- or short-acting octreotide or lanreotide 
monotherapy and who are willing to washout, initial eligibility (including IGF-1 ≤1.0×ULN) will 
be assessed at S1. At that time, subjects will begin washout of their pretrial acromegaly 
medication. Subjects taking long-acting octreotide or lanreotide will have a Screening Period of 
approximately 12 to 16 weeks. Subjects taking short-acting octreotide or lanreotide will have a 
Screening Period of approximately 8 weeks. Documentation of the washout criteria will be 
confirmed by the central laboratory test at S2. If a second post-washout IGF-1 measurement is 
needed to confirm eligibility (30% rise from the first Screening visit and IGF-1 ≥1.1×ULN) per 
the Investigator, the Medical Monitor should be consulted, and a sample collected at S3. S2 
should be performed approximately 2 months after last pretrial LA-octreotide or lanreotide 
injection or approximately 4 weeks after last dose of short-acting (SC or oral) octreotide or 
lanreotide.  
4.1.2. 
Treatment Period (Randomized, Controlled Phase)  
Once all screening assessments are completed, the subject’s eligibility is verified by the 
Investigator and confirmed by the Medical Monitor via submission of the Medical Monitor 
Eligibility Verification Form. The subject will be randomized to treatment on Day 1 of the 
Treatment Period (Figure 1).  
The Treatment Period will be approximately 24 weeks. Subjects will receive their first dose of 
study drug at Visit 1 (Day 1) (paltusotine or placebo). 
It is anticipated that the study drug dose will be stable, and titration completed prior to or at 
Week 12, with no dose titrations/adjustments after Week 12. Up-titration after Week 12 should 
not occur; subjects who require dose up-titration after Week 12 will be considered 
nonresponders. Down-titration due to unacceptable tolerability is permitted. 
If rescue therapy is required during the RC phase, subjects will discontinue paltusotine or 
placebo, initiate rescue therapy, and should continue the study for the remainder of the 24-week 
RC phase (see Section 6.7.3 for Rescue Criteria). Rescue therapy with approved SRLs 
(octreotide LAR or lanreotide depot monotherapy) will be permitted during the study. 
If the subject withdraws consent or, in the opinion of the Investigator, should be permanently 
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the Schedules of Activities (SOAs) and the subject should return to standard acromegaly 
treatment as prescribed by the Investigator. 
4.1.3. 
Open-Label Extension Phase 
Subjects who complete the 24-week RC phase or who meet rescue criteria and complete the 
24-week RC phase with rescue medication can continue participation in the OLE phase if, in the 
opinion of the Investigator, the subject may benefit from continued participation and treatment 
with paltusotine and the subject is willing to participate. At completion of study target enrollment 
for the R C Phase, remaining subjects in the washout group who have entered screening and met 
eligibility criteria may be eligible to directly enroll into the OLE. The OLE Treatment Period is 
up to 200 weeks plus a 4-week follow-up.  
Eligible subjects who enter the OLE following screening will initiate the study at Week 24 of the 
Schedule of Activities: Open-Label Extension Phase in Protocol Section 1.6. All procedures in 
this visit will be performed, except for the Pituitary magnetic resonance imaging scans (MRI) 
and Biliary/gallbladder ultrasound. The Pituitary MRI and Biliary/gallbladder ultrasound 
performed during screening will be utilized as the subject’s baseline assessment. 
4.1.4. 
End of Study 
An End of Study (EOS) Visit will occur approximately 4 weeks after the last dose of study drug, 
at Week 228 to collect final safety data and other assessments as detailed in the SOAs. The EOS 
is defined as the date of the last visit of the last subject in the study. 
4.1.5. 
Patient Input into Study Design 
Patient insight was collected over several meetings (November 2019-August 2020) through a 
formalized Patient Leadership Council made up of 12 individuals living with acromegaly. These 
patients had a range of experiences including treating physician, medication treatments, 
geographic location, and age of diagnosis. In these meetings, the following topics were 
discussed: treatment naïve and maintenance treatment study protocols, use of placebo, rescue 
therapy, frequency of visits, daily diary execution, study recruitment tactics, and participants’ 
preferred method of learning about potential studies. Results of these discussions were shared 
with the internal paltusotine study team and incorporated into study design where possible. 
4.2. 
Scientific Rationale for Study Design 
A prospective randomized, placebo-controlled trial is the gold standard methodology to define 
the safety and efficacy profile of an experimental drug. Placebo-controlled trials have been 
successfully conducted and are feasible in rare orphan diseases, including acromegaly. Protocol 
safeguards are in place for subjects who experience worsening acromegaly (see Section 6.7.3 
[RC Phase Rescue Procedure] and Section 6.7.4 [OLE Phase Adjunctive Treatments]). 
4.3. 
Justification for Dose and Treatment Duration 
The dose rationale and the proposed titration is designed to achieve lower IGF-1 values while 
minimizing the possibility to experience adverse effects. Based on dose and exposure analysis of 
data from completed studies CRN00808-02 and CRN00808-03, the 40 mg dose is expected to be 
an effective dose for majority of the subjects. The systemic exposures associated with the lower 

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20 mg dose are expected to be sub-therapeutic in a majority of the subjects, but this lower dose is 
available for the few subjects who do not tolerate the 40 mg dose. A higher 60 mg dose is 
available for those subjects who may not derive a full benefit from the 40 mg dose. The safety of 
these doses has been evaluated in healthy volunteers and found to be similar to that of lower 
doses and other SRLs.  
Treatment duration is extended up to 228 weeks (approximately 4 1/3 years) to allow participants 
who in the opinion of the Investigator, are benefiting from treatment with paltusotine to continue 
treatment. 
Data from an ongoing Phase 2 OLE clinical study (CRN00808-05) show that paltusotine lowered 
and maintained IGF-1 and GH at levels comparable to prior injected SRLs for up to 103 weeks. 
Additionally, RC Phase results from a placebo controlled pivotal study (CRN00808-09) show 
that paltusotine 40 or 60 mg QD provides sustained efficacy in terms of maintenance of disease 
control for up to 36 weeks in participants with acromegaly, who switched from being controlled 
on standard of care injectable SRLs. The durability of this clinical meaningful treatment effect 
was maintained in the OLE with participants continuing to experience clinical benefits. 
Paltusotine was well tolerated, with no unexpected safety findings with long-term treatment.  
4.4. 
End of Study Definition 
The EOS is defined as the date of the last visit of the last subject in the study. 
4.5. 
Treatment After End of Trial Participation 
After the end of the trial, participants may resume regionally licensed acromegaly treatment as 
prescribed by their healthcare provider. 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
1.  
Willing and able to provide written informed consent prior to any study-related 
procedures. 
2.  
Willing and able to comply with the study procedures as specified in the protocol 
and comply with the study treatment administration. 
Demographics and Medical History 
3.  
Subjects ≥18 years of age at the time of Screening who fall into 1 of the following 
3 groups are eligible to participate in the study. 
 Medically naïve group (Group 1): Those who have not been previously treated 
with acromegaly medications (including LA-SRLs) who at Screening have 
IGF-1 ≥1.3×ULN (the lower limit for eligibility is IGF-1 of 1.25×ULN when 
rounded to 2 decimal places) confirmed by the central laboratory test at S1. 
Group 1 subjects must have had at least 1 pituitary surgery 3 months or more 
prior to Screening. 
 Previously Treated group (no treatment within previous 4 months) (Group 2): 
Subjects who have last been treated with acromegaly medications at least 
4 months prior to Screening and who have IGF-1 ≥1.3×ULN (the lower limit for 
eligibility is IGF-1 of 1.25 when rounded to 2 decimal places) confirmed by the 
central laboratory test at S1.  
 Washout group (Group 3): Subjects at Screening who are receiving stable 
treatment (no change in dose for 3 months prior to Screening) with octreotide or 
lanreotide monotherapy, who have IGF-1 ≤1.0×ULN (the upper limit for 
eligibility is IGF-1 of 1.04 when rounded to 2 decimal places) at Screening 
Visit 1 and are willing to washout of their medication during the Screening 
Period. Any form of pretrial octreotide or lanreotide monotherapy (long- or 
short-acting [SC, IM, or oral]) can be washed out and will determine the duration 
of the Screening Period. After informed consent is provided, the subject should 
not receive further pretrial acromegaly medication. IGF-1 must rise at least 30% 
from the first Screening Visit to the last Screening Visit and to ≥1.1×ULN (the 
lower limit for eligibility is IGF-1 of 1.05 when rounded to 2 decimal places) 
confirmed by the central laboratory test at S2 or S3, if needed) to qualify for 
enrollment. 
4.  
Previous diagnosis of acromegaly confirmed by the Investigator and approved by the 
Medical Monitor. This requires evaluable documentation of a pituitary adenoma. 

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Screening and Testing Evaluations 
5.  
If currently using thyroid hormone therapy, the subject should be adequately treated 
based on clinical status and free thyroxine concentration measured during Screening 
and on a stable dose of thyroid hormone for at least 8 weeks prior to Screening. 
Lifestyle Restrictions 
6.  
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 either a highly effective or a clinically 
acceptable method of contraception from the beginning of Screening until at least 
30 days after the last dose of study drug. 
 Acceptable highly effective methods of contraception include: 
 Noncyclic, stable dose (monophasic) combined estrogen-progestin oral 
hormonal contraception associated with consistent inhibition of ovulation. 
Oral contraceptives containing estrogens should be in stable use for at least 
12 weeks prior to Screening.  
 Desogestrel-based progestin-only contraception associated with consistent 
inhibition of ovulation; this includes oral, injectable, and implantable 
methods 
 Intravaginal and transdermal hormone delivery methods  
 Intrauterine device (with or without hormone elution) 
 Bilateral tubal occlusion or ligation (must be documented) 
 Vasectomized partner (must be documented) or 
 Sexual abstinence (only when it is the usual and preferred lifestyle of the 
subject) 
 Clinically acceptable methods of birth control include: 
 Male or female condom with or without spermicide. 
 Norethindrone-based progestin-only oral contraceptives, or 
 Cap, diaphragm, or sponge with spermicide.  
 Withdrawal method (“coitus interruptus”) is not permitted.  

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7.  
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. 
5.2. 
Exclusion Criteria  
Medical History and Medications 
1.  
History of ineffectiveness or significant intolerance of octreotide or lanreotide 
treatment, as determined by the Investigator. 
2.  
History of pituitary radiation therapy within 3 years of Screening.  
3.  
Subjects with adrenal insufficiency, diabetes insipidus, or central hypogonadism 
who are not receiving adequate hormone replacement therapy at the time of 
Screening, as determined by the Investigator. 
4.  
High-risk pituitary tumor pattern as defined by: 
 Compression of the optic chiasm or invasion of adjacent brain structures 
(other than sphenoid sinus or cavernous sinus)  
 History of tumor growth within 1 year after surgery (if performed) or 
radiation (unless it occurred during a period of medical therapy interruption) 
 Anticipated requirement for neurosurgical intervention or radiation therapy 
within the time course of the study. 
 Pituitary carcinoma currently or at any time in the past. 
5.  
History of major surgery/surgical therapy for any cause within 4 weeks prior to 
Screening. 
6.  
Diabetes mellitus treated with insulin for less than 6 weeks prior to the study entry, 
or with change in total daily insulin dose by >15% within 6 weeks prior to 
Screening. 
7.  
History of unstable angina or acute myocardial infarction within the 12 weeks 
preceding the Screening Visit or other clinically significant cardiac disease at the 
time of screening as judged by the Investigator. 
8.  
Known history of hepatitis B or human immunodeficiency virus, or active 
hepatitis C infection. 

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9.  
Active malignant disease within the last 5 years with exception of basal and 
squamous cell carcinoma of the skin with complete local excision and resected 
carcinoma in situ of cervix. 
10.  
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. 
11.  
Use of the following medications as outlined:  
 Any history of acromegaly medication use (Group 1 only) 
 Lanreotide depot or octreotide LAR (within 16 weeks before Screening) 
(Group 2 only) 
 Pasireotide LAR (within 24 weeks prior to Screening) 
 Pegvisomant (within 16 weeks before Screening) 
 Dopamine agonists (within 16 weeks before Screening) 
 Any combination of 2 or more acromegaly medications at Screening  
 Proton pump inhibitors (from start of Screening) until the end of the study 
Note: Withdrawal of these medications should be part of the subject’s medical care 
plan prior to Screening; entry into the study should not be the sole reason for 
withdrawal of a prior medication. 
12.  
Current use of oral estrogen replacement therapy for <12 weeks prior to Screening. 
13.  
Current use of medications that are strong inducers of CYP3A4 within 2 weeks prior 
to Screening (refer to Section 6.7.2 Prohibited Medicine). 
14.  
Known allergy or hypersensitivity to any of the test materials or related compounds. 
Screening Tests and Evaluations 
15.  
Active COVID-19 confirmed or suspected based on clinical symptoms. 
16.  
Symptomatic cholelithiasis. 
17.  
Clinically significant concomitant disease including but not limited to cardiovascular 
disease, severe renal insufficiency (estimated glomerular filtration rate 
<30 mL/min/1.73 m2), or significant liver disease (including cirrhosis). 
18.  
Clinically significant abnormal findings during the Screening Period or any other 
medical condition(s) or laboratory findings that, in the opinion of the Investigator, 
might jeopardize the subject’s safety or ability to complete the study. 

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19.  
Systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg 
during Screening. If the initial measurement is out of range, it may be repeated 
2 more times after 15 minutes and the last assessment should be used to determine 
subject’s eligibility. 
20.  
Resting (at least 10 minutes) palpated pulse rate <45 bpm or >105 bpm during 
Screening. If either of these criteria is met, the assessment should be repeated 
2 more times and the last assessment should be used to determine the subject’s 
eligibility. 
21.  
QT interval corrected using Fridericia’s formula (QTcF) >480 msec (or corrected QT 
[QTc] interval >500 msec in the presence of complete bundle branch block) or PR 
interval >240 msec during Screening based on a central reading of an average of 
3 ECGs each separated in time by approximately 1 minute after the subject has 
rested quietly in the supine position for at least 10 minutes without significant 
stimulation (noise, television, etc.).  
22.  
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3×ULN, 
and/or total bilirubin >1.5×ULN during Screening. Subjects with previously 
diagnosed Gilbert’s syndrome not accompanied by other hepatobiliary disorders and 
associated with total bilirubin <3.5 mg/dL (<51.3 µmol/L) will be permitted. 
23.  
Poorly controlled diabetes mellitus defined as having a hemoglobin A1c (HbA1c) 
≥8.5% (≥69 mmol/mol), or estimated HbA1c based on fructosamine if HbA1c is not 
evaluable (eg, due to hemoglobinopathies). 
24.  
Female subjects who are pregnant or lactating. Subjects must have a negative 
pregnancy test during Screening and prior to the first dose of study drug. 
25.  
Known history of, or current alcohol or drug abuse, within the last year. 
Other 
26.  
An employee or immediate family member of an employee of Crinetics or 
investigator and clinical site staff. 
27.  
Participation in any previous clinical study with paltusotine. 
28.  
Subjects who have received an investigational drug (either approved or not 
approved) in any prior clinical study within 30 days or 5 half-lives (whichever is 
longer) prior to Screening. 

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5.3. 
Lifestyle Considerations 
5.3.1. 
Contraception 
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 either a highly 
effective or a clinically acceptable method of contraception from the beginning of Screening 
until at least 30 days after the last dose of study drug. 
 Acceptable highly effective methods of contraception include: 
 Noncyclic, stable dose (monophasic) combined estrogen-progestin oral hormonal 
contraception associated with consistent inhibition of ovulation. Oral 
contraceptives containing estrogens should be in stable use for at least 12 weeks 
prior to Screening.  
 Desogestrel-based progestin-only contraception associated with consistent 
inhibition of ovulation; this includes oral, injectable, and implantable methods 
 Intravaginal and transdermal hormone delivery methods  
 Intrauterine device (with or without hormone elution) 
 Bilateral tubal occlusion (must be documented) 
 Vasectomized partner (must be documented) or 
 Sexual abstinence (only when it is the usual and preferred lifestyle of the subject) 
 Clinically acceptable methods of birth control include: 
 Male or female condom with or without spermicide; 
 Norethindrone-based progestin-only oral contraceptives; or 
 Cap, diaphragm, or sponge with spermicide.  
 Withdrawal method (“coitus interruptus”) is not permitted.  
If the subject is male, the subject should agree to use a condom when sexually active with a 
female partner of childbearing potential from Screening until at least 30 days after the last dose 
of study drug (or be surgically sterile [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. 
5.4. 
Screen Failures 
Subjects who fail to meet the eligibility criteria at any point during the Screening Period are 
defined as screening failures. The reason for each screening failure will be recorded.  
Subjects who have failed screening based on findings which the Investigator believes are 
temporary and not reflective of the usual state of the subject (eg, HbA1c of ≥8.5% 

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[69 mmol/mol] when the subject is usually well below this value) can be considered for 
re-screening. These cases should be discussed with the Medical Monitor. 
5.5. 
Open-Label Extension Participation 
Subjects who complete the 24-week RC phase or for whom rescue is required during the RC 
phase can continue participation in the study in the OLE phase if, in the opinion of the 
Investigator, the subject may benefit from continued participation and treatment with paltusotine 
and the subject is willing to participate. 
Investigators should contact the Medical Monitor to discuss subjects who do not meet criteria for 
rescue, but for whom the Investigator recommends discontinuation of study drug and initiation of 
standard acromegaly medication, to discuss the possibility of continuation in the RC phase on 
pretrial medication and eligibility for OLE on a case-by-case basis. These situations may include 
the following: (1) when there is worsening of acromegaly symptoms with no improvement from 
baseline in IGF-1 levels, however IGF-1 is <1.5×ULN or (2) IGF-1 ≥1.5×ULN without 
sufficiently worsening acromegaly symptoms (see Section 6.7.3). 

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6. 
STUDY DRUG AND CONCOMITANT THERAPY 
Study drug is defined as any investigational drug or placebo intended to be administered to a 
study subject according to the study protocol. 
6.1. 
Study Drugs Administered 
Paltusotine will be provided as 20 mg tablets in 
. Matching 
placebo tablets will be identical in appearance to paltusotine tablets and will be administered 
orally according to the randomization scheme, on an identical schedule to those receiving 
paltusotine. Paltusotine and matching placebo tablets will each be packed in 
 Drug labels will comply with the legal 
requirements of each country and will be printed in local language.  
The starting daily dose will be 20 mg (1×20 mg tablet of active paltusotine or matching placebo) 
for oral self-administration.  
Study drug will be swallowed in the morning, with at least 8 ounces (237 mL) of water, 
after an overnight fast of at least 6 hours. No food or drink (except for water), or another 
medication will be allowed for at least 1 hour after drug administration. 
The last dose of study drug for the RC phase will be self-administered the day prior to the 
Week 24/EOR visit. The first dose of the OLE phase will be administered during the 
Week 24/EOR visit for those continuing into the OLE. 
Table 5: 
Study Interventions 
Arm Name 
Paltusotine Arm  
Placebo Arm  
Intervention Name 
Paltusotine 
Placebo 
Type  
Drug 
Drug (placebo) 
Dose Formulation 
Tablet 
Tablet 
Unit Dose Strength(s) 
20 mg 
Placebo for 20 mg tablet 
Dosage Level(s) 
Starting daily dose is 1×20 mg 
tablet. The dose can be titrated (in 
1×20 mg tablet increments) up to 
3×20 mg tablets daily. Dose levels 
may be decreased to 1×20 mg tablet 
daily. 
Starting daily dose is 1×20 mg 
tablet. The dose can be titrated (in 
1×20 mg tablet increments) up to 
3×20 mg tablets daily. Dose levels 
may be decreased to 1×20 mg tablet 
daily. 
Route of 
Administration 
Oral 
Oral 
Use 
Experimental 
Placebo  
IMP and NIMP 
IMP  
IMP  
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 

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Arm Name 
Paltusotine Arm  
Placebo Arm  
Packaging and 
Labeling 
Sponsor will package and label the 
study drug. Drug labels will comply 
with the legal requirements of each 
country and will be printed in the 
local language. The labels will 
supply no information about the 
subjects. Each bottle or pack will 
have a unique Dispensing Unit 
Number (DUN) for drug 
accountability purposes and 
traceability. The storage conditions 
for study drug will be described on 
the study drug label. 
Sponsor will package and label the 
study drug. Drug labels will comply 
with the legal requirements of each 
country and will be printed in the 
local language. The labels will 
supply no information about the 
subjects. Each bottle or pack will 
have a unique Dispensing Unit 
Number (DUN) for drug 
accountability purposes and 
traceability. The storage conditions 
for study drug will be described on 
the study drug label. 
DUN=dispensing unit number; IMP=investigational medicinal product; NIMP= noninvestigational medicinal 
product 
6.2. 
Preparation/Handling/Storage/Accountability 
The appointed team members will be identified at each center whose role in the study will be 
handling of the study drugs (ie, they will be responsible for the receipt and accountability of the 
study drug). Furthermore, other tasks can be delegated to them in a clear manner by the 
Investigator and that will be documented and completed in the Study Staff Signature and 
Delegation Log. 
The Investigator must ensure the availability of proper storage conditions. Staff at the study site 
will take all steps to maintain adequate records and will ensure that the study drug is stored as 
specified on the medication labels, in a strictly controlled, secure area, at appropriate temperature 
and in accordance with the protocol and any applicable regulatory requirements. Direct-to-
patient shipments of study drug will be allowed in exceptional cases (ie, where subjects would 
not be able to attend on-site visits and would risk continued access to study drug). Study drug 
will be provided by the Sponsor and are to be dispensed only in accordance with the protocol. 
Study drug must not be dispensed to any person not enrolled in the study. 
An accurate inventory and accountability records of the study drug will be kept by the appointed 
team member. Drug accountability must be performed for all delivered DUNs. Returned study 
drug (partly used or unused including empty packaging material) must be stored separately from 
nonallocated study drug. The storage temperature should be monitored by recording the actual, 
minimum, and maximum temperatures using a calibrated thermometer or thermocouple, or by 
continuous recording using a qualified temperature monitoring system. The temperature should 
be evaluated and documented at least on working days on a temperature log. This log must be 
included in the Investigator Site File upon study termination. 
The appointed study staff must contact the site monitor in case of temperature deviations outside 
the acceptable range. 
Paltusotine tablets and matching placebo tablets will each be packed in 
 Bottles of tablets should be stored at the study site at 
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Paltusotine and matching placebo will be provided by the Sponsor and the logistics of supply 
will be managed by the Sponsor/appropriate designee. 
All study drugs should be stored and inventoried according to applicable state and federal 
regulations and study procedures. 
At the end of the study (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. 
The study drugs (sufficient to last until the next planned visit) will be dispensed by the appointed 
study staff to the subjects at relevant study visits. 
Subjects will be instructed to store the study drug 
 in the 
original packaging and out of reach of children. The storage conditions will be carefully 
described to the subjects. 
If the Investigator, the site staff, or the site monitor suspect that the study drug is defective or 
potentially defective, Crinetics Pharmaceuticals or designee should be contacted immediately. 
Full details concerning study drug handling (eg, allocation, accountability, tracking, and 
recording) will be provided in a Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
The study is a double-blind study with subjects, investigators and site staff, and the Sponsor 
blinded to treatment allocation (paltusotine versus placebo). Subjects will be randomized to 
study treatment using Suvoda Interactive Response Technology (IRT), an interactive, automated 
system which has been validated for the intended use under the International Society of 
Pharmaceutical Engineers Good Automated Manufacturing Practice guidelines, 21 CFR 11 (FDA 
regulation for Electronic Records and Electronic Signatures) and the International Council for 
Harmonization (ICH) Guidance E6 for Industry on Good Clinical Practice.  
Randomization will be performed using a fixed-block randomization scheme. The randomization 
scheme will be generated prior to the initiation of the study by an independent 
statistician/programmer who will not be a member of the study team; all Investigators and the 
study team will not be aware of the block size of the randomization scheme. Randomization will 
be stratified by prior treatment (medically naïve or previously treated versus washout).  
Study drug will be dispensed at the study visits summarized in the SOAs.  
Returned study drug should not be re-dispensed to the subjects. 
The Interactive Voice Response System/Interactive Web Response System will be programmed 
with blind-breaking instructions. In case of an emergency, the Investigator has the sole 
responsibility for determining if unblinding of a subject’s intervention assignment is warranted. 
Subject safety must always be the first consideration in making such a determination. If the 
Investigator decides that unblinding is warranted, the Investigator should make every effort to 
contact the Medical Monitor prior to unblinding a subject’s intervention assignment unless this 
could delay emergency treatment of the subject. If a subject’s intervention assignment is 

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unblinded, the Medical Monitor must be notified within 24 hours after breaking the blind. The 
date and reason that the blind was broken must be recorded in the source documentation.  
Sponsor safety staff or designee may unblind the intervention assignment for any subject with an 
SAE. If the SAE requires that an expedited regulatory report be sent to 1 or more regulatory 
agencies, a copy of the report, identifying the subject’s intervention assignment, may be sent to 
Investigators in accordance with local regulations and/or Sponsor policy. 
6.4. 
Study Drug Compliance 
Subject randomization, study drug allocation, and dose titration must be performed in the 
interactive, automated system. 
When subjects are dosed during a study visit, they will receive study drug directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
during the visit will be recorded in the source documents. 
When subjects self-administer study drug at home, compliance will be assessed at each visit. 
Compliance will be assessed by either direct questioning and/or counting returned tablets during 
the site visits and documented in the source documents and relevant forms. Deviations from the 
prescribed dosage regimen should be recorded. 
A record of the quantity of study drug dispensed to and administered by each subject must be 
maintained and reconciled with study drug and compliance records. Study drug start and stop 
dates, including dates for study drug delays, drug interruptions and/or dose reductions, will also 
be recorded. 
Further details are provided in the Pharmacy Manual and relevant monitoring plan.  
Subjects will be instructed to return all used and unused study drugs at each study visit during 
the Treatment Period. All returned study drug and study drug materials should be stored, 
inventoried, reconciled, and returned according to applicable local regulations and study 
procedures. 
6.5. 
Dose Modification 
See Table 3 for the dose titration schema. 
6.5.1. 
During the RC Phase 
The starting daily dose will be 20 mg (1×20 mg tablet of active paltusotine or matching placebo) 
for oral self-administration. After confirming tolerability with the subject, the dose should be 
increased to 40 mg/day (2×20 mg tablet of active paltusotine or matching placebo) at the Week 2 
visit. At Week 6, the dose should be increased to 60 mg QD (3×20 mg tablets) if the 40 mg dose 
is acceptably tolerated, and the Week 4 IGF-1 is >0.9×ULN. If the Week 4 IGF-1 is ≤0.9×ULN, 
the dose will be maintained at 40 mg QD until the end of the RC phase, unless an unscheduled 
measurement obtained at any time from Week 4 to prior to or at Week 12 shows IGF-1 
>0.9×ULN, in which case the dose should be increased from 40 to 60 QD if the 40 mg dose is 
acceptably tolerated.  
A subject’s dose may be reduced during the RC phase due to poor tolerability, as evaluated and 
confirmed by the Investigator. A dose reduction based on tolerability may be necessary for 

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patients who are taking P-gp (P-glycoprotein) and/or BCRP (breast cancer resistance protein) 
inhibitors (see Section 6.7.1). In general, a TEAE of severe intensity for which there is a 
reasonable possibility it is caused by (related to) study drug would be expected to result in study 
drug dose reduction. If tolerance improves following a dose reduction, the Investigator may 
increase the dose in 20-mg increments, if needed, based on protocol specified dose titration 
criteria to a maximum of 60 mg QD (3×20 mg tablets). See Section 10.3.1 for the definition of a 
TEAE and Section 10.3.3 for definitions of intensity and causality.  
During the RC phase, planned study visits are to occur approximately every 2 to 4 weeks; 
however, unscheduled visits may be required for more frequent monitoring, dose titration, and to 
assess rescue criteria. 
6.5.2. 
During the OLE 
The starting daily dose regimen for all subjects who participate in the OLE will be paltusotine 
20 mg (1×20 mg tablet), dispensed in an open-label manner; ie, subjects will be given a bottle of 
paltusotine containing 
tablets and instructed to take 1 tablet per day and then if 
tolerated, to increase to 40 mg QD (2×20 mg tablets) at the Week 26 visit.  
Further up-titration in the OLE may occur once the first IGF-1 result is available. At that time, 
the Investigator can determine whether the dose can be up-titrated to 60 mg QD (3×20 mg 
tablets). 
The study medication may be held for up to a total of 14 days, but no more than 7 consecutive 
days per year in the OLE. If the study drug has to be stopped for longer due to appropriate 
medical care for the subject, the medical monitor should be contacted. 
If the administration of a prohibited concomitant medication is deemed to be medically 
necessary for ongoing treatment, the subject will need to discontinue from the study. PPI 
administration could be allowed for the treatment of a short medical intercurrence, but not for 
ongoing medical treatment while in the study. 
6.6. 
Treatment of Overdose 
There are no clinical data available on effects associated with overdose. No documented 
incidents of overdose have occurred with paltusotine to date. Preclinical animal studies indicate 
bradycardia or hypertension may result from overdose. The recommended treatment of overdose 
with paltusotine would include supportive and symptomatic measures employed in the 
management of overdose with a drug with potential cardiovascular events. 
6.7. 
Concomitant Therapy 
6.7.1. 
Permitted Medicine 
Concomitant medications allowed in this study are those nonprohibited medications used during 
Screening to control existing medical conditions and/or those initiated during the study if 
medically needed. All concomitant medications will be recorded in the subject’s electronic case 
report form (eCRF). If a new medication should become necessary for any reason during the 
course of the study, the subject is required to inform the Investigator immediately, who will 
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is responsible for ensuring the new medication is not prohibited by the protocol and to contact 
the Medical Monitor for any questions. 
Caution should be used when co-administering permitted concomitant medications that have the 
potential to interact with drug metabolizing enzymes or drug transporters shared with or affected 
by paltusotine (see current IB and Paltusotine Guidance on Concomitant Medications reference 
document for Investigators). In addition, caution should be used with concomitant medications 
that have been associated with QT prolongation/Torsades de Pointes or may be associated with 
significant heart rate slowing. For a regularly updated list of drugs with known and possible risk 
for Torsade des Pointes, refer to www.crediblemeds.org. 
6.7.2. 
Prohibited Medicine 
Any questions regarding prohibited medications should be discussed with the Medical Monitor 
or appropriate designee. If the administration of a prohibited concomitant medication is deemed 
to be medically necessary for ongoing treatment, the subject will need to discontinue from the 
study. Prohibited medications include: 
 Proton pump inhibitors; 
 Use of famotidine in the evenings;  
 Oral estrogen, except for monophasic estrogen-progestin oral contraception or stable 
estrogen replacement (see Section 5.1 Inclusion Criteria and Section 5.2 Exclusion 
Criteria); 
 Strong inducers of the drug metabolizing enzyme CYP3A4, including but not limited 
to: apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, 
St. John’s wort (because these medicines may decrease the concentration of 
paltusotine in the systemic circulation); 
 Any standard acromegaly drug that is not used as a rescue medication during the RC 
phase of the study or an allowed adjunctive medication in the OLE; 
 Octreotide (any form), lanreotide, or pasireotide during the OLE; 
 Any other investigational drug, unless approved by the Medical Monitor 
(eg, COVID-19 therapies). 
6.7.3. 
RC Phase Rescue Procedure – Auxiliary Medicinal Products 
During the RC phase, acromegaly treatments other than study drug are prohibited, unless the 
subject meets the rescue criteria described as follows. 
Criteria for rescue with approved SRLs (injected long-acting octreotide or lanreotide) consist of 
the following: 
 Significant worsening of 1 or more acromegaly symptoms or the development of a 
new acromegaly symptom, at the highest dose (60 mg) for at least 2 weeks, as 
assessed by the Investigator. Symptoms should be attributed to uncontrolled 
acromegaly in the opinion of the Investigator and could include, but are not limited 
to, the following: headache, arthralgia, fatigue, hyperhidrosis, or soft tissue swelling. 
(“Significant worsening” in the opinion of the Investigator may be defined as 

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symptoms requiring a substantial increase in level of clinical care [eg, significant 
intervention needed to avert hospitalization or clinically notable increase in frequency 
or intensity of subject contact required] or substantial clinical deterioration 
[eg, worsening from a mild to severe AE or the onset of an SAE would meet these 
criteria]) 
AND 
 IGF-1 value ≥1.5×ULN* at the highest dose (60 mg) measured at 2 successive 
planned visits or at an unscheduled visit if an earlier result is needed (as evaluated by 
the Investigator) 
*In a large study of naïve acromegaly patients, octreotide LAR monotherapy achieved mean 
IGF-1 of 1.5× ULN (Colao, 2014) at 3 months of treatment through 12 months. 
It is anticipated that the study drug dose will be stable, and titration completed prior to or at 
Week 12, with no dose titrations/adjustments after Week 12. Up-titration after Week 12 should 
not occur; subjects who require dose up-titration after Week 12 will be considered 
nonresponders. Down-titration due to unacceptable tolerability is permitted. If rescue therapy is 
required during the RC phase, subjects will discontinue paltusotine or placebo, initiate rescue 
therapy, and should continue the visits and surveillance in the study for the remainder of the 
24-week RC phase. Rescue therapy with approved SRLs (octreotide LAR or lanreotide depot 
monotherapy) will be permitted during the study. Rescue therapy should be used according to 
approved marketing authorization or standard clinical practice. 
Long-acting octreotide or lanreotide depot monotherapy are considered auxiliary medicinal 
products (AxMPs). 
6.7.4. 
OLE Phase Adjunctive Treatments – Auxiliary Medicinal Products  
If there is evidence of paltusotine efficacy and at 6 months, subjects have not reached therapeutic 
target goals, adjunctive treatment may be initiated if clinically appropriate beginning at Week 48. 
If these criteria are met, non-SRL acromegaly treatments, such as cabergoline or GH receptor 
antagonist (ie, pegvisomant) are permitted and may be initiated as an adjunct when a subject has 
experienced at least 2 consecutive elevated IGF-1 (≥1.3×ULN) measurements at the highest 
paltusotine dose level (60 mg), or otherwise not at the subject’s therapeutic target in the 
judgement of the Investigator. If adjunctive medications are not appropriate or not accessible 
under local regulations, and the subject is not under acceptable biochemical control while treated 
with paltusotine monotherapy at the maximal tolerated dose in the opinion of the Investigator, 
the subject should be discontinued from the OLE portion of the study. 
 Use of any adjunctive medications should be discussed with the Medical Monitor and 
should be used according to approved marketing authorizations or standard practice. 
Adjunct medications are not provided by the Sponsor. 
 If it is determined that adjunctive medication is indicated and it is accessible, then use 
of cabergoline would be the expected first-line adjunct, as clinically appropriate. If 
after an adequate period of assessment, study medication combined with a 
cabergoline does not achieve therapeutic targets, then pegvisomant may be added as a 
second-line adjunct, if clinically appropriate (Katznelson, 2014). In this situation, the 

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Investigator should assess if there was evidence of an IGF-1 lowering response from 
cabergoline. If so, the pegvisomant may be added to the paltusotine + cabergoline 
drug combination. If there was no evidence of a therapeutic response to combined 
paltusotine + cabergoline, the cabergoline should be stopped and pegvisomant added 
to paltusotine therapy. 
 Short- and long-acting somatostatin receptor agonists (other than paltusotine) remain 
prohibited and are not permitted during the study (subjects will be discontinued from 
the study if these are needed and an ET Visit will be scheduled prior to resuming 
these treatments). 
Adjunctive treatments such as cabergoline and pegvisomant are considered auxiliary medicinal 
products. 

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7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment/Participation 
All subjects will be informed that they have the right to withdraw from the study at any time, for 
any reason, without prejudice, and without having to justify their reasons or decisions. 
Additionally, the Investigator may discontinue a subject’s participation at any time if he/she 
considers that to be in the subject’s best interest or if the Investigator determines that continuing 
participation would result in a significant safety risk for that subject. A discontinuation of 
treatment occurs when an enrolled subject discontinues participation in the study, regardless of 
the circumstances, prior to completion of the study. However, every effort should be made to 
observe subjects who have been enrolled until the scheduled end of their observation without 
study discontinuation, even if they discontinue early from the study drug treatment, if clinically 
appropriate. A subject who discontinues from study drug early by meeting protocol criteria for 
rescue with approved SRLs and completes the 24-week RC phase may be eligible for 
participation in the OLE portion of the study. Subjects who do not meet criteria for rescue, but 
for whom the Investigator recommends discontinuation of study drug and resumption of 
approved SRLs should be discussed with the Medical Monitor to confirm that re-initiation of 
standard SRLs is clinically justified and not the result of poor protocol compliance. Examples of 
valid clinical reasons to resume standard SRL in the absence of protocol defined rescue criteria 
would include the following: (1) IGF-1 is not improved from baseline and is ≥1.5×ULN but 
without sufficiently worsening of acromegaly symptoms as per protocol criteria (see 
Section 6.7.3), or (2) there is intolerable worsening of acromegaly symptoms, however IGF-1 is 
<1.5×ULN. Such subjects may benefit from access to paltusotine in the OLE, either because they 
were randomized to placebo in the RC portion of the study, or, for those randomized to 
paltusotine during the RC, inadequate efficacy was not clearly demonstrated. Therefore, such 
cases will be considered for continuation in the RC phase on approved SRLs, and eligibility for 
the OLE will be decided on a case-by-case basis. Subjects in the OLE portion of the study who 
require rescue will discontinue both study drug and study participation. (In other words, no 
subject who after having enrolled in the OLE portion of the study and who subsequently requires 
rescue with standard acromegaly treatment will remain in the study.) 
If a subject discontinues the study early, the Investigator should schedule an early termination 
visit, particularly to ensure collection of AE follow-up data (if applicable) and to collect samples 
for laboratory evaluations. This visit should be documented as appropriate. The Investigator will 
record the reason for the study discontinuation, provide or arrange for appropriate follow-up, and 
ensure return to standard acromegaly treatment for such subjects. In addition, the Investigator 
will report the subject’s withdrawal to the responsible Medical Monitor within 24 hours.  
Reasons for a subject to discontinue the study treatment and/or participation in this clinical study 
include, but are not limited to:  
1. Withdrawal of informed consent by the subject; 
2. Occurrence of AEs for which study treatment and/or study participation discontinuation 
is desired by the subject or considered necessary by the Investigator or the Medical 
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3. Unacceptable tolerability of the lowest study drug dose (20 mg per day) in the opinion of 
the Investigator; 
4. Other clinically significant potentially drug-related abnormalities (eg, newly developed or 
worsening hypoglycemia, 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 fulfill study requirements and procedures; 
11. Death; 
12. After 6 months of treatment during the OLE phase, cabergoline and pegvisomant may be 
used as adjuncts to maximal dose paltusotine as clinically appropriate. Subjects who need 
to resume standard injected SRLs because paltusotine or paltusotine in combination with 
allowed adjuncts do not achieve adequate control of acromegaly will be discontinued 
from the study (see Section 6.7.4). 
7.1.1. 
Liver Chemistry Abnormality Monitoring and Study Drug Stopping Criteria 
Closely monitoring abnormalities of liver tests and discontinuation for evidence of liver injury 
will be performed according to the following process (FDA 2009): 
 Detection of Liver Test Abnormalities 
All subjects will have a chemistry panel as per the SOAs. Confirmation of detected 
liver test abnormalities is required for any subject with 1 or more of the following: 
 ALT or AST >3×ULN (for subjects with ALT and AST <ULN at baseline); 
 ALT or AST >3×ULN and >2×baseline (for subjects with ALT or AST >ULN at 
baseline); 
 Total bilirubin (TB) >2×ULN (for subjects with TB <ULN at baseline); 
 TB >2×ULN and >2×baseline (for subjects with TB >ULN at baseline); 
 Alkaline phosphatase (ALP) >3×ULN (for subjects with ALP <ULN at baseline); 
 ALP >3×ULN and >2×baseline (for subjects with ALP >ULN at baseline). 
 Confirmation of Detected Liver Test Abnormalities 

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If any of the above-listed liver test abnormalities are detected, they should be 
followed by repeat testing within 48 to 72 hours (of ALT, AST, ALP, and TB) to 
confirm the abnormalities and to determine if they are increasing or decreasing. 
There also should be inquiry made about symptoms. 
If the above-listed liver test abnormalities (and/or related symptoms) persist or 
worsen, it is appropriate to initiate close observation to determine whether the 
abnormalities are improving or worsening over time. (See Close Observation 
recommendations below.) If close monitoring is not possible, the drug should be 
discontinued. 
 Close Observation of Any Subject with Detected Liver Test Abnormalities 
Close observation includes: 
 Repeating ALT, AST, ALP, and TB tests 2 to 3 times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the study 
drug has been discontinued and the subject is asymptomatic; 
 Obtaining a more detailed history of symptoms and prior or concurrent diseases; 
 Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets;  
 Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary 
tract disease.  
 Obtaining a history of exposure to environmental chemical agents; 
 Obtaining additional tests to evaluate liver function, as appropriate 
(eg, international normalized ratio); 
 Considering gastroenterology or hepatology consultations.  
Discontinuation of study drug for abnormal liver tests is required when a subject meets 1 of the 
conditions outlined below: 
 ALT or AST >8×ULN; 
 ALT or AST >5×ULN for more than 2 weeks; 
 ALT or AST >3×ULN and TB >2×ULN or INR >1.5; 
 ALT or AST >3×ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
7.1.2. 
Amylase or Lipase Study Drug Stopping Criteria 
The Medical Monitor should be contacted promptly if amylase or lipase levels increase from 
baseline by more than 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 stopped. The Medical Monitor 
and Investigator will determine together the appropriateness of continued study participation.  

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7.1.3. 
Cardiac Study Drug Stopping Criteria 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
[average of triplicate ECGs] in QTcF after enrollment), the Investigator or qualified designee 
will determine if the subject can continue in the study and if any change in subject management 
is needed. Any new clinically relevant finding should be reported as an AE. 
Cardiology consultation should be obtained within 7 days for new clinically important symptoms 
or findings judged by the Investigator to be reasonably likely to be of cardiac origin, 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: 
 Based on the average of triplicate ECGs, QTcF >500 msec (or QTc >530 msec in 
subjects with a bundle branch block) repeated on a second set of ECGs at least 
2 hours apart and confirmed by a stat central ECG reading;  
 Any ventricular tachyarrhythmia associated with symptoms of hemodynamic 
response; 
 Sustained ventricular tachycardia (lasting >30 seconds) irrespective of symptoms; 
 Torsades de pointes; 
 Cardiac arrest; 
 Pause >5 seconds; 
 Type 2 second degree block or third degree atrioventricular block; 
 New occurrence of clinically significant, symptomatic bradycardia; 
 Based on the average of triplicate ECGs, an increase in QTcF >60 msec with an 
absolute QTcF <500 msec repeated on a second set of ECGs at least 2 hours apart and 
confirmed by a stat central ECG reading; 
 Any supraventricular tachyarrhythmia associated with symptoms of hemodynamic 
response. 
The Medical Monitor and Investigator will determine the appropriateness of any further study 
drug dosing after stabilization of any of the above events. 
7.2. 
Lost to Follow up 
If a subject fails to attend scheduled assessments, the Investigator must determine the reasons 
and the circumstances as completely and accurately as possible.  
For subjects who are lost to follow-up (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 
include but are not limited to the following: 

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 Inefficacy of the study medication 
 Results from ongoing safety monitoring 
 Unacceptable changes in the benefit-risk profile of the study medication; 
 Other medical or ethical reasons 
Regulatory Authorities/Institutional Review Boards/Independent Ethics Committees (IRBs/IECs) 
also have the right to terminate the study for any reason. In the event the study is terminated, the 
IRBs/IECs and Competent Authorities will be notified of the relevant decision. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Demographics and Baseline Characteristics 
Demographics will include age, sex, ethnicity, and race. Baseline characteristics will include 
acromegaly history, medical history, and concomitant medications.  
Pretrial acromegaly symptoms including assessment of the most bothersome symptom will be 
recorded. 
8.2. 
Subject-reported Assessments 
Planned time points for all subject-reported assessments are provided in the SOAs. When these 
assessments are done at the same visit, the order will be as follows: (1) ASD, (2) 
 (3) 
, (4) 
, 
(5) 
 and (6) 
Questionnaire. 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). A 
paper questionnaire may be used if an electronic device cannot be utilized or is unavailable. 
8.2.1. 
Acromegaly Symptoms Diary 
Subjects will be asked to complete the ASD, a brief symptom diary, daily at home beginning 
approximately 2 weeks prior to study drug dosing for the duration of the randomized controlled 
phase. Sparse periodic administrations at home or at study visits will be performed during the 
OLE. The ASD should be completed at approximately the same time of day, as consistently as 
possible. Site staff will review subject compliance with ASD completion at each study visit. 
Responses to the ASD will not be reconciled with AE data.  
The ASD consists of 9 items (headache pain; joint pain; sweating; fatigue; weakness in legs; 
swelling; numbness or tingling; difficulty sleeping; and a question on short-term memory), each 
ranked in intensity from 0-10. The total ASD score will be computed by adding the individual 
symptom intensities for headache pain; joint pain; sweating; fatigue; weakness in legs; swelling; 
and numbness or tingling, therefore total ASD score can range from 0-70. All individual item 
scores, including difficulty sleeping and the question on short-term memory will be collected and 
analyzed in individual item scoring. 
8.2.2. 
 
Note that the
 will not be administered in India due to lack of available validated 
translations. 

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8.2.3. 
 
8.2.4. 
8.2.5. 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SOAs. 
8.3.1. 
Physical Examinations 
A complete physical examination includes assessment of head (external), eyes, ears, nose and 
throat, lungs, cardiovascular system, abdomen, musculoskeletal system, skin, lymph nodes, 
central nervous system, ring size, and, where appropriate, other body systems. Symptom-directed 
physical examinations (with weight measurement as appropriate) will also be performed. 
Physical examination will include height measurement at Screening and weight measurement at 
certain study visits. The study site must use calibrated equipment with subjects required to 
remove their shoes and heavy objects from their clothing prior to height and weight 
measurement, respectively. 
Any confirmed clinically significant physical examination abnormalities occurring after the 
moment of signing informed consent form (ICF) are to be recorded as AEs. 
8.3.2. 
Vital Signs 
Vital signs (blood pressure at rest, pulse rate, respiratory rate, and oral (or equivalent) body 
temperature) will be assessed as per standard practice at relevant study visits. When possible, 
vital signs should be performed while fasting after the study drug dosing. 

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Blood pressure (resting) should be measured with calibrated digital equipment after resting 
quietly for 5 minutes.  
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Blood pressure and pulse rate measurements will be repeated at the Investigator’s 
discretion. Any confirmed clinically significant vital sign measurements occurring before signing 
the ICF are to be designated as medical history. 
8.3.3. 
Electrocardiograms 
A standard 12-lead ECG will be performed in triplicate (approximately 1 minute apart) after the 
subject has rested quietly in the supine position for at least 10 minutes without significant 
stimulation (noise, television, etc.). When possible, the ECGs should be performed while fasting 
after the study drug dosing. The ECG parameters that will be assessed include a summary of 
findings as well as measurement of the heart rate, QT, QTcF, and PR intervals, and QRS duration 
based on the ECG machine readings.  
All ECG assessments will be initially assessed by the Investigator for any findings that require 
immediate medical attention and will also be read by an ECG central reader. The clinical 
significance of any ECG findings will be determined by the Investigator, including after the 
central reading result is available. Only the Investigator’s assessment will be recorded in the 
eCRF. Any potentially significant outlier values should be confirmed by the central ECG reader. 
Any ECG measurement determined to be clinically significant (occurring after signing the ICF) 
will be noted as an AE on the appropriate eCRF page(s). Such abnormalities will be monitored 
until the end of the study or until resolution if considered related to the study drug. 
Refer to Section 7.1.3 for cardiac withdrawal criteria and any additional QTc readings that may 
be necessary. 
8.3.4. 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and to the SOAs for the 
timing and frequency. 
All analyses must be done with the minimally required blood amount and the number of needle 
insertions should be minimized during the blood collection.  
Laboratory management and shipping details are described in a Laboratory Manual.  
After sampling, blood collection tubes will be labelled and handled as defined in the Laboratory 
Manual. 
All results (except pharmacokinetics 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. 

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8.3.5. 
Biliary/Gallbladder Ultrasound 
Biliary/gallbladder ultrasound will be performed according to the study site procedures for the 
evaluation of presence or absence of lithiasis or sludge or other significant biliary abnormalities. 
An ultrasound can be performed at any time if clinically indicated in the opinion of the 
investigator. An ultrasound is required for all subjects, including those that have had surgical 
removal of the gallbladder (cholecystectomy). The ultrasound does not need to be performed on 
the same day as the study visit. Ultrasounds may be performed within ± 2 weeks of the study 
visit. The results will be recorded. 
8.3.6. 
Magnetic Resonance Imaging 
Pituitary MRI should be performed locally and does not need to be performed on the same day as 
the study visit. MRIs may be performed within ± 2 weeks of the study visit. Tomography is not 
permitted as a replacement for MRI. Image acquisition standards will be provided and must be 
followed to allow proper evaluation of tumor volume. All MRI assessments will be assessed by 
the Investigator for any findings that require immediate medical attention and will also be read 
by an MRI central radiologist. The clinical significance of any MRI findings will be determined 
by the Investigator, including after the central reading result is available. However, only MRI 
results provided by the local report will be recorded in the eCRF. Management of subjects prior 
to and during the MRI should follow standard local procedures. 
8.3.7. 
Ophthalmic Assessments 
Ophthalmic assessments will be conducted on all subjects. Initial ophthalmic testing should be 
performed as soon as practical and then at 6-month intervals, preferably associated with 
scheduled visits whenever possible, through study completion. If the most recent ophthalmic 
assessment is performed within 3 months of ET, there is no need to repeat at ET. Assessments 
will be performed at a local facility with appropriate testing equipment and qualified personnel. 
The following assessments will be conducted: 
 Corrected distance visual acuity evaluation 
 Threshold visual fields 
 Fundus photography of the macula (single photograph centered on macula in each 
eye) and 
 Optical coherence tomography of the macula 
Detailed specifications for acceptable instrumentation, data acquisition, data collection, and test 
results distribution processes will be provided to the investigative sites in separate ophthalmic 
assessment guidance documents.  
Visual acuity and threshold visual field results and images for fundus photography of the macula 
and optical coherence tomography of the macula will be transferred from the local testing facility 
to the designated data processing portal accessible by the 
8.4. 
Adverse Events and Serious Adverse Events Reporting 
The definitions of AEs and SAEs can be found in Appendix 3. 

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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 study drug 
administration has started will be considered as TEAEs. 
Investigators will be asked to assess whether each reported adverse event is a symptom of 
acromegaly. If adverse events are attributed to acromegaly, they will be reported as adverse 
events of special interest. 
The Investigator or qualified designee is obliged to interview a subject at every visit and 
clarify/discuss with him/her any abnormality that may indicate any potential AE/TEAE. 
Subjects should be informed that they do not have to wait for scheduled visits to report 
AEs/TEAEs. 
Adverse events related to the study drug that are ongoing at the end of the study will be followed 
for outcome information until resolution or stabilization. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Adverse events will be recorded from after the moment of signing ICF, up to 4 weeks after the 
last dose of the study drug. 
All SAEs will be recorded and reported to the Sponsor or designee immediately (and under no 
circumstance should this exceed 24 hours) of knowledge of the event, as indicated in 
Appendix 3. The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of it being available. 
Investigators are not obligated to actively seek information on TEAEs or SAEs after conclusion 
of the study participation. However, if the Investigator learns of any SAE, including a death, at 
any time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
8.4.2. 
Method of Detecting AEs  
Care will be taken not to introduce bias when screening for AEs. Open-ended and nonleading 
verbal questioning of the subject is the preferred method to inquire about AE or 
TEAE occurrences. 
8.4.3. 
Follow-up of AEs  
After the initial AE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. 
Any AE that occurs in the course of a clinical study must be monitored and followed up until 
either: 
 it has resolved, 
 laboratory abnormalities have returned to normal, OR 

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

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8.4.5. 
Pregnancy 
Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening Visit S1. All other pregnancy tests will be urine tests. If the result of a urine test is 
positive the result will be confirmed with a serum pregnancy test. Urinary pregnancy tests will be 
performed monthly at Screening, during the RC phase, and during the OLE phase when the 
duration between the visits is longer than 4 weeks. Pregnancy tests may also be obtained at any 
time during the study as an unscheduled test if clinically appropriate. Subjects must discontinue 
study drug immediately in the event of pregnancy in a female subject. Any pregnancy will be 
reported by telephone (optional) and by emailing a completed Crinetics Pregnancy Exposure  
Report Form to the Sponsor’s Pharmacovigilance Group at 
 within 24 hours 
of knowledge of the pregnancy. The pregnancy will not be processed as a SAE. However, the 
Investigator will follow-up with the subject or female partner of the male subject (after obtaining 
informed consent, as appropriate) until completion of the pregnancy and must determine the 
outcome of the pregnancy in the shortest possible time. The Investigator should notify the 
Sponsor’s Pharmacovigilance Group of the pregnancy outcome by submitting a follow-up 
Pregnancy Exposure Report Form. If the outcome of the pregnancy meets the criteria for 
immediate classification as a SAE (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 telephone (optional) and by 
e-mailing a completed SAE Report Form to the Sponsor’s Pharmacovigilance Group within 
24 hours of knowledge of the event. 
8.5. 
Pharmacokinetics 
Plasma samples will be collected for measurement of plasma concentration of study drug as 
specified in the SOAs.  
PK samples are not required during the Randomized Controlled Phase for subjects on rescue 
medication. 
To minimize patient burden, only sparse pharmacokinetic (PK) samples are to be collected at 
various study visits. Plasma paltusotine concentrations and elapsed time from the last paltusotine 
dose taken will be listed. A summary of concentrations by paltusotine dose for each timepoint 
will be presented. 
In addition, PK concentration data from this study will be pooled with data from other 
paltusotine studies for the planned population PK analysis to assess relevant intrinsic and 
extrinsic factors on paltusotine PK dispositions. 
Instructions for the collection 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. 
8.6. 
Pharmacogenomics 
On Day 1, blood may be drawn for genotyping for the determination of the
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obtained before the blood sample is collected. Genotype blood sample can be drawn at any post-
baseline visit in China. 
Direct glucuronidation by
 has been identified as a relevant metabolic pathway that 
contributes to the systemic clearance of paltusotine. 
 is polymorphic, and genotyping 
has been conducted in selected Phase 1 and both Phase 2 paltusotine studies. Data suggest 
normal and intermediate metabolizers have similar exposures; however, poor metabolizers have 
approximately 30% higher exposures than normal/intermediate metabolizers. The 
pharmacogenomics data collected from this study will be pooled with data from other paltusotine 
studies for the planned population PK analysis, which will allow for a more quantitative estimate 
of these effects in healthy volunteers and acromegaly subjects while controlling for other 
potential covariates (eg, body weight, age). 
8.7. 
Biomarkers 
Blood will be drawn at the time points on the SOAs to measure IGF-1 and GH. 
For subjects on rescue medication during the Randomized Controlled Phase, IGF-1 and GH 
samples should still be collected at each of the remaining scheduled visits per the SOA. The 
terms ‘pre-dose’ and ‘post-dose’ do not apply to these samples, as study medication is no longer 
being administered.  
8.8. 
Immunogenicity Assessments 
Antidrug antibodies are not evaluated in this study.  
8.9. 
Collection and Storage of Biological Samples 
The Sponsor will comply with the applicable rules for the collection, storage, and future use of 
biological samples from clinical trial subjects. The Sponsor will comply with national 
requirements including those set in the Clinical Trial Regulation (CTR) (EU) No 536/2014, 
Article 7.1 (h). 
A description of the arrangements to comply with CTR (EU) No 536/2014, Article 7.1 (h) is 
provided in the form ‘Compliance with Member State applicable rules for the collection, storage 
and future use of human biological samples (Article 7.1h)’ submitted as a Part 2 document of 
this trials’ Clinical Trials Information System (CTIS) submission. 

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9. 
STATISTICAL CONSIDERATIONS 
The Statistical Analysis Plan (SAP) will be finalized prior to the interim analysis (if undertaken), 
and it will include a more technical and detailed description of the statistical analyses described 
in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and secondary endpoints. 
There will be 2 formal database locks of all data, 1 at the end of the EOR and the other at the end 
of the OLE. 
9.1. 
Statistical Hypotheses 
The primary hypothesis:  
 
Ho: ꞵ = 0 
 
Ha: ꞵ ≠ 0 
Where ꞵ is the parameter estimate for treatment group when used in a model with response of 
IGF-1 ≤1×ULN or IGF-1 >1×ULN and prior treatment (medically naïve or previously treated 
versus washout) as a covariate in the Exact Logistic Regression model (see Section 9.4.2). 
9.2. 
Sample Size Determination 
The primary endpoint assumes the overall rate of response at EOR, defined as IGF-1 ≤1.0×ULN, 
for paltusotine versus placebo is 
 and 
, respectively. The study population will be 
stratified to ensure equivalent active treatment versus placebo allocations in each stratum. 
Groups 1 and 2 constitute Stratum 1 and Group 3 constitutes Stratum 2. The number of subjects 
in each stratum is expected to be equally allocated (Melmed, 2010). The responder rates in 
Stratum 1 are expected to be 
 in paltusotine-treated subjects and 
 in placebo-treated 
subjects. The responder rates in Stratum 2 are expected to be 
 in paltusotine-treated subjects 
and 
 in placebo-treated subjects. Through simulations, power was estimated for the 
comparison of paltusotine versus placebo using an Exact Logistic Regression with stratum as a 
covariate in the model and a 2-sided alpha of 0.05. Power of 
 was achieved with 76 subjects 
(38 per group), which accounts for a 
 rate of drop-outs (who are treated as nonresponders). 
For subjects in Stratum 1, the expectation is that placebo subjects will have little to no response, 
based on clinical practice. Assuming that paltusotine and octreotide have similar response rates, 
the sample size estimate was based on the rates observed in a similar patient population in the 
registrational trial for pasireotide LAR in which octreotide LAR was used as an active 
comparator (Colao, 2014). For Stratum 2, the estimates are based on the Phase 2 ACROBAT 
Edge study (CRN00808-03) with paltusotine, as well as the observed placebo response in a 
similarly designed clinical study for oral octreotide (Chiasma Inc.; Optimal Study; 
EudraCT:2017-000737-31). 
For the Phase 2 ACROBAT Edge study (CRN00808-03) in subjects with acromegaly previously 
treated with stable dose octreotide LAR or lanreotide depot, 20/23 patients (87%) who completed 
the dosing period achieved IGF-1 levels at end of treatment that were within biological 
variability of the assay (20% of baseline) or lower. The estimated maintenance of baseline 
response used in PATHFINDR-1 samples size calculation (
) is considered conservative. 

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In ACROBAT Edge, all subjects who completed 13 weeks of treatment were washed out of 
paltusotine and followed for 4 additional weeks. In the primary analysis population, 18% of the 
patients did not show a meaningful rise in IGF-1 during the washout, consistent with data from 
the OPTIMAL trial (Samson, 2020), in which 19.4% of patients randomized to placebo 
maintained normal IGF-1 after 9 months of treatment. 
This sample size was generated based on the assumption that there will be an equal number of 
subjects in each stratum and that 
will drop out. If these assumptions are violated, there 
could be a reduction in statistical power. Therefore, when 
 of the projected 76 subjects 
(approximately 
) are randomized, enrollment into the strata will be assessed. If there are less 
than 
 subjects in Group 3 (subjects who washout of octreotide or lanreotide during the 
screening period), the sample size may be increased as follows: 
Subjects in Group 3 (Washouts of 
SRLs) 
Minimum Power 
New Sample Size 
16-22 
80% 
78 
10-15 
80% 
88 
0-9 
80% 
98 
A sample size of 54 subjects will provide 
 power to detect a difference in the key secondary 
endpoint of change from baseline to EOR in IGF-1 using a Wilcoxon-rank sum test under the 
following assumptions: a difference of 
 in the mean change from baseline to EOR in IGF-1 
in units of ULN between placebo and paltusotine, a common standard deviation (SD) of 
, a 
2-tailed alpha of 0.05, and a 
 drop-out rate. With 76 subjects enrolled, the power increases to 
9.3. 
Analysis Sets 
The following analysis sets will be evaluated and used for presentation and analysis of the data in 
this study:  
 The Full Analysis Set (FAS) is defined from the intention-to-treat principle and will 
include all randomized subjects. The FAS will be the primary analysis set used for 
efficacy analyses. Treatment assignment will be based on the randomized treatment. 
 The Per Protocol (PPS) Analysis Set is defined as all randomized dosed subjects 
assigned to the treatment received, with no major protocol violations that would affect 
efficacy, and at least 75% treatment compliance based on pill counts. This PPS will 
be used as a sensitivity analysis for the primary endpoint. All major protocol 
violations will be defined prior to unblinding the study. 
 The Safety Analysis Set (SS) will include all subjects who received study drug with 
treatment assignment based on the treatment received. If a subject receives any 
amount of paltusotine then the subject will be assigned to the paltusotine group. 
The SS will be the primary analysis set used for safety analyses.  

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Analysis Sets for Open Label Extension 
 The OLE SS will include all subjects who received any amount of paltusotine in the 
OLE.  
9.4. 
Statistical Analyses 
9.4.1. 
General Considerations 
All continuous endpoints will be summarized showing the N, mean, median, SD, minimum and 
maximum values. Discrete endpoints will be presented showing the N and percentage.  
All efficacy and safety will be evaluated at the end of the EOR. A second database lock will 
occur at the end of the OLE for long-term safety and efficacy evaluation. 
9.4.2. 
Efficacy Analyses 
The primary efficacy analyses will test for superiority in IGF-1 response rates at EOR between 
placebo and paltusotine, at a 2-sided alpha level of 0.05, using an Exact Logistic Regression 
model with treatment group as a factor and a covariate for prior treatment (medically naïve or 
previously treated versus washout) in the FAS. Response is defined as an IGF-1 level ≤1.0×ULN 
(rounded to 2 significant figures) based on the average of last 2 measurements collected at Weeks 
22 and 24. If only one IGF-1 result is available at Weeks 22 or 24, then that result will be used 
alone to define response. Nonresponse is defined as an IGF-1 level >1.0×ULN based on the 
average of the same last 2 measurements at EOR (Weeks 22 and 24) or if a subject has a missing 
IGF-1 value at both of these time points. Subjects who discontinue treatment for any reason prior 
to EOR or receive rescue procedures as described in Section 6.7.3 will be considered 
nonresponders. Subjects who titrate up in dose after Week 12 will also be considered 
nonresponders.  
9.4.2.1. 
Primary Endpoint 
The following sensitivity analyses will be performed on the primary endpoint. The following 
sensitivity analyses will be performed on the primary endpoint: 
 Multiple imputations will be used to impute missing values. The same analysis will 
be performed as described above. Additional details will be defined in the SAP. 
 LOCF will be used to carry the last IGF-1 value prior to treatment discontinuation 
due to withdrawal or rescue medication forward. For subjects who dose titrate up 
after Week 12, the last IGF-1 value prior to this dose titration will be carried forward.  
 A completers analysis will be performed to include only FAS subjects who complete 
24 weeks of treatment. The same analysis will be performed as described above.  
 All primary endpoint analyses will be performed on the PPS in addition to the FAS 
which will be the primary analysis set.  
 The current analysis of the primary endpoint will be performed without treating 
subjects who dose titrate up after Week 12 as non-responders.  

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 An exact logistic regression will be used to analyze the primary endpoint for each 
stratum separately. The stratum will no longer be needed as a covariate in the model. 
9.4.2.2. 
Key Secondary Endpoint: 
The key secondary endpoint of change from baseline to EOR in IGF-1 will be analyzed using a 
worst-rank score analysis of covariance (ANCOVA) model including treatment group as a factor 
with prior treatment (medically naïve or previously treated versus washout) as a covariate for the 
FAS. The treatment difference in ranks with associated 95% confidence interval (CI) will also be 
presented. Baseline IGF-1 will be defined as the average of the measurements taken on Day 1 of 
first dose of study drug and the last IGF-1 value measured just prior to this day. EOR will be 
defined as the average of the last 2 IGF-1 results captured at 22 and 24 weeks of treatment. If 
only one IGF-1 result is available at Weeks 22 and 24, then that result will be used alone. EOR 
for subjects who discontinue treatment, receive prohibited standard acromegaly treatment, or 
dose titrate up after Week 12 will be assigned a rank based on the reason for the missing data.  
A sensitivity analysis for the FAS will also be performed where multiple imputations are used to 
impute missing data then analyzed using an ANCOVA. Change from Baseline to EOR will be 
compared between treatment groups after adjusting for prior treatment. Baseline and EOR will 
be defined in the same manner as above. EOR for subjects who discontinue treatment, receive 
prohibited standard acromegaly treatment, or dose titrate up after Week 12 will be considered 
missing and imputed per the multiple imputations.  
Secondary endpoints in order of clinical importance along with their corresponding analyses are 
as follows: 
1. A response of IGF-1 <1.3×ULN at EOR will be analyzed for the FAS using the same 
methodology as the primary endpoint. Response is defined as an IGF-1 level <1.3×ULN 
based on the average of last 2 measurements collected at EOR (Weeks 22 and 24). If only 
one IGF-1 result is available at Weeks 22 and 24, then that result will be used alone to 
define this response. Nonresponse is defined as an IGF-1 level ≥1.3×ULN based on the 
average of the same last 2 measurements at EOR (Weeks 22 and 24) or if a subject has 
missing IGF-1 values at these visits. Subjects who discontinue treatment for any reason 
prior to EOR, receive prohibited standard acromegaly treatment, or dose titrate upward 
after Week 12 will be considered nonresponders. 
2. Growth hormone response will be analyzed for the FAS using the same methodology as 
the primary endpoint. Response is defined as GH <1 ng/mL at Week 22. Nonresponse is 
defined as GH ≥1 ng/mL or missing at Week 22. Subjects who discontinue treatment for 
any reason prior to Week 22, take prohibited standard acromegaly treatment, or dose 
titrate upward after Week 12 will be considered nonresponders.  
3. Change from baseline in Total ASD score will be analyzed for the FAS using the same 
methodology specified for the key secondary endpoint of change from baseline in IGF-1. 
Exploratory endpoints will include nominal p-values with descriptive statistics. Continuous 
endpoints will be analyzed using parametric or nonparametric methods as applicable (to be 
defined in the SAP) and summarized with the number of nonmissing observations, mean, SD, 
median, minimum, and maximum. Binary endpoints will be analyzed using the same 
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percentage of subjects for each category. Subgroup analyses will be performed for prior 
treatment with lanreotide or octreotide and within each strata.  
9.4.2.3. 
Open Label Extension 
The OLE is designed to descriptively evaluate long term safety and efficacy of paltusotine for the 
endpoints that are defined in the randomized controlled phase. Summary statistics defined as the 
number of subjects, mean, median, standard deviations and range will be presented for 
continuous endpoints by visit. Change from Baseline will also be summarized by visit during the 
OLE. The number and percentage of subjects with categorical endpoints will be presented by 
visit. Shift tables from Baseline to OLE visits may also be evaluated for certain endpoints. 
Additional details for the endpoints and analyses for the OLE will be defined in the SAP.  
9.4.2.4. 
Multiplicity 
All hypothesis testing will be performed using the gatekeeping test strategy based on a fixed 
sequential method. The primary, key secondary, and secondary efficacy analyses will have an 
overall 2-sided level of significance at an alpha of 0.05. The secondary endpoints will be tested 
in the order they are listed in Section 9.4.2.2. The hypothesis testing of secondary endpoints will 
be conducted only if the primary efficacy endpoint comparison is statistically significant at the 
predefined alpha level of 0.05. If this comparison is not statistically significant, then the 
comparison of secondary efficacy endpoints will be considered nominal, descriptive, and 
exploratory.  
9.4.3. 
Safety Analyses 
The subject incidence of TEAEs, SAEs, and TEAEs leading to discontinuation will be 
summarized overall by system organ class and preferred term, and similarly by dose level. 
Treatment-emergent AEs by severity and relationship will be summarized as well as and TEAEs 
leading to discontinuation or death. TEAEs will also be summarized by those on paltusotine 
monotherapy and paltusotine plus adjunctive therapy. 
Vital signs, clinical laboratory results (including lipid panel and thyroid hormone levels), and 
ECG data will be summarized descriptively by treatment group. Subject level listings for all 
safety endpoints (including ophthalmic assessments) will be provided. 
9.4.4. 
Protocol Deviations 
Protocol deviations are defined as any variation from the protocol, including enrollment of a 
subject who did not meet all inclusion and exclusion criteria and failure to perform the 
assessments and procedures within the required time frame. Protocol deviations will be 
categorized as major or minor based on Sponsor review. 
The Sponsor or designee will be responsible for producing the final protocol deviation file, in 
collaboration with the data monitoring group as applicable. This file will be finalized prior to 
database lock. 

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9.5. 
Interim Analysis 
An optional interim analysis for superiority of the primary endpoint may occur when 50% of the 
subjects complete or withdraw from the RC treatment period. If an interim analysis is performed, 
a conditional power calculation will be performed to evaluate futility defined as a conditional 
power of <30%. If futility is not declared, and the conditional power is between 30% and 80%, 
then a sample size re-estimation will be performed to ensure that the study accrues enough 
subjects for at least 80% power. The conditional power calculation and sample size re-estimation 
will be generated by an independent biostatistician and communicated to the Sponsor by the 
unblinded DMC. Additional details can be found in the SAP and the DMC charter. 
If patient recruitment completes rapidly, there could arise a situation in which the results of the 
interim analysis cannot be made available in time to have a meaningful impact prior to study 
completion. This is a scenario in which the Sponsor may not perform the interim analysis.  

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

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10.1.3. 
Informed Consent Process 
For each study subject, written informed consent will be obtained prior to any protocol-related 
activities. An ICF must be signed and dated personally by the subject and by the Investigator 
and/or the study team member designated by the Investigator to conduct the informed consent 
procedure. 
As part of this procedure, the Investigator or 1 of his/her associates must explain orally and in 
writing the nature, duration, and purpose of the study, and the action of the drug in such a 
manner that the study is aware of the potential risks, inconveniences, or adverse effects that may 
occur. The subject should be informed that he/she may withdraw from the study at any time, and 
the subject will receive all information that is required by local regulations and ICH guidelines. 
The subject must provide free and willing consent to enroll in the study. (Note that the Sponsor 
does not consider persons who are housed in an institution under a court or official order capable 
of providing free and willing consent.) The Investigator will provide the Sponsor or its 
representative with a copy of the IRB/IEC approved ICF prior to the start of the study. 
10.1.4. 
Data Protection 
The Sponsor, as Data Controller, ensures that all processing activities involving personal data 
performed in the scope of this Study are compliant with, but not limited to, the requirements set 
by EU General Data Protection Regulation (GDPR 679/2016), its subsequent amendments and 
any additional national laws on Data Protection, recommendations, and guidelines as applicable. 
To maintain participant privacy, data capture tools, study drug accountability records, study 
reports, and communications will identify participants by their unique identifier (assigned 
participant number) generated and assigned by the electronic data capture (EDC) system. Any 
participant records or datasets that are transferred to the Sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable will not be 
transferred. 
The participant will be informed both verbally and in written form (ICF) that their personal 
study-related data will be used by the Sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who may be required to give consent 
for their data to be used as described in the ICF, including use of their data that may require a 
separate consent. The participant will also be informed that his/her medical records may be 
examined by Clinical Quality Assurance auditors, Monitors or other authorized personnel 
appointed by the Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
To comply with the applicable rules on the protection of personal data, specifically regarding the 
implementation of the organizational and technical arrangements aiming to avoid unauthorized 
access, disclosure, dissemination, alteration or loss of information and processed personal 
data, the Sponsor has implemented and maintains the following measures: 
 restriction and monitoring of physical access to the offices and information processing 
facilities to employees, personnel and approved visitors; 
 ensuring appropriate and restricted user access relevant to the function and type of 
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 implementing the pseudonymisation and encryption of personal data, as appropriate; 
 implementing the ability to ensure the ongoing confidentiality, integrity, availability and 
resilience of processing systems and services; 
 implementing network, application, and database security by means of firewalls and 
antivirus/anti-malware; ensuring detection of malware purposed for unauthorized 
deletion, blocking, copying of information, disabling security measures and response to 
such attacks; 
 means to restore the availability and access to personal information in a timely manner in 
the event of a physical or technical incident; 
 logging of security events/incidents in information systems; 
 implementing procedures that cover reporting, analysis, monitoring and resolution of 
security incidents; 
 ensuring that information systems, computers and software involved in the performance 
of the services provided in the study are backed up; 
 a process for regularly testing, assessing and evaluating the effectiveness of technical and 
organizational measures for ensuring the security of the processing; 
 implementing procedures to capture within a reasonable time any personal data breaches; 
 implementing procedures and practices for the destruction of paper documents containing 
personal data; 
 implementing business continuity procedures ensuring continued provision of services 
through operational interruption 
All locations, personnel and information systems that are used to perform services for the Study 
will be covered. The Sponsor will ensure the technical and organizational security measures 
described above are regularly reviewed and updated considering any evolution of technological 
developments. 
The Sponsor may apply additional specific statutory requirements, where applicable in national 
laws, and will implement the necessary security measures even if they are not expressly listed 
above. 
In addition to the already mentioned technical and organizational measures, the Sponsor by 
means of internal measures and imposed standard contractual clauses to the selected contractors, 
service providers, vendors, or sub-contractors (collectively, “Representatives”), ensures the 
confidentiality of records and personal data of subjects. 
With exception of activities in the scope of on-site monitoring, the name of the patient will 
neither be asked for, nor recorded by Sponsor. An identification number will be allocated to each 
patient registered in the Study. This number will identify the patient and will be included on all 
case report forms and corresponding material and data associated with the patient. 
Monitors acting on behalf of Sponsor will have access to fully identifiable information only in 
the scope of the on-site monitoring visits, and only for mandatory source data verification, 
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performance of this task are bound by any additional stricter confidentiality clauses imposed 
upon them, as compared to other staff members. 
The Sponsor has implemented a functional process for reporting of any data breach occurring 
at Crinetics’ or its Representatives’ facilities and premises. Investigators must promptly report to 
the Sponsor's Data Protection Officer (DPO) any suspected data breaches relevant to personal 
study-related data the Sponsor holds about the participants. If there is a suspected breach related 
to data that the Sponsor holds, the Sponsor’s DPO will be responsible for investigating suspected 
data breaches and notifying authorities, where appropriate. In case of the occurrence of any data 
breach, the Sponsor will immediately apply relevant measures to mitigate the risks to data 
subjects as appropriate in relation to the specific context of the data breach, considering its 
source, underlying intentions, possibilities of recovery etc. Any data breach presenting risks to 
the rights and freedoms of data subjects will be reported to the relevant supervisory data 
protection authority within 72 hours of the Sponsor becoming aware of the data breach. In 
addition, in case of a high-risk data breach, subjects will be informed by the Sponsor. 
Investigators must promptly report to the Sponsor's DPO any participant request to know what 
personal study-related data the Sponsor holds about the participant. 
10.1.5. 
Data Monitoring Committee 
An unblinded DMC, comprising independent subject matter experts, will be established to 
evaluate the underlying disease and to assess the risk versus benefit of the interventions during 
the trial. The DMC will meet at intervals as specified in the DMC charter and may convene for 
ad hoc meetings if there are immediate safety concerns identified during the study.  
10.1.6. 
Dissemination of Clinical Study Data 
Once the study is completed and the CSR written, appropriate information will be provided for 
the clincialtrials.gov or clinicaltrialsregister.eu websites as required. All IRBs/IECs will receive 
appropriate documentation with study results. 
10.1.7. 
Data Quality Assurance 
The study will be conducted according to GCP (as outlined by ICH topic E6, step 5 guidelines) 
and in compliance with applicable local legislation including the EU CTR (EU No 536/2014). 
The contract research organization maintains a quality assurance system with written Standard 
Operating Procedures (SOPs) to ensure that clinical trials are conducted, and data are generated, 
documented, and reported in compliance with the Clinical Study Protocol, GCP, and applicable 
regulatory requirements. 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study. However, responsibility for the accuracy, completeness, and reliability of the study 
data presented to the Sponsor lies with the Investigator generating the data. 
The Sponsor will arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the Clinical Study Protocol, SOP, GCP, and all 
applicable local regulatory requirements including the EU CTR (EU No 536/2014). Audits will 
be independent of and separate from the routine monitoring and quality control functions. 

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Quality assurance procedures will be performed at the study sites and during data management to 
assure that safety and efficacy data are adequate and well documented.  
Investigators/Institution will permit trial related audits, IRB/IEC review, and regulatory 
inspections, providing direct access to source data/documents. 
Study records and source documents must be preserved for at least 25 years after the completion 
or discontinuation of/withdrawal from the study or 2 years after the last approval of a marketing 
application in an ICH region or as per local requirements, whichever is the longer time period. 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information. The Investigator shall ensure 
that study subjects authorize the use and disclosure of their personal data 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. 
 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 on-site 
monitoring) are provided in the Monitoring Plan. 
 The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
 The Sponsor assumes accountability for actions delegated to other individuals 
(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. 

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

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

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10.2. 
Appendix 2: Clinical Laboratory Tests 
 The tests detailed below will be performed by the central laboratory. 
 Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5 of the protocol. 
 Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 6: 
Protocol-Required Safety Laboratory Tests 
Laboratory 
Tests 
Parameters 
Hematology 
Hemoglobin  
RBC Indices: 
Mean corpuscular volume 
Mean corpuscular 
hemoglobin 
Mean corpuscular 
hemoglobin concentration 
WBC count with 
differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Hematocrit  
RBC count 
Platelet count 
Clinical 
Chemistry 
Total protein 
Sodium 
Phosphate 
Aspartate 
aminotransferase 
Blood urea 
nitrogen 
Potassium 
Magnesium 
Alkaline 
phosphatase 
Creatinine 
Chloride 
Albumin 
Amylase 
Uric acid 
Calcium 
Total, direct, and 
indirect bilirubin 
Lipase 
Fasting lipid panel: total cholesterol, 
LDL, HDL, and triglycerides 
Alanine 
aminotransferase 
Glucose 
Thyroid 
Hormones and 
HbA1c 
Free T4, and TSH 
HbA1c 
IGF-1 and GH 
IGF-1 and growth hormone* 
Pregnancy 
testing 
Serum and urine human chorionic gonadotropin pregnancy test (as needed for 
women of childbearing potential) 
Routine 
Urinalysis 
 
Specific gravity and appearance 
 
White blood cells, protein, bilirubin, nitrites, ketones, blood, and pH, by 
dipstick 
Other Screening 
Tests 
 
Serology (HIV antibody, hepatitis B surface antigen, and hepatitis C virus 
antibody) 
Notes: 
Investigators must document their review of each laboratory safety report.  
*Fasting integrated GH consists of 5 samples collected at least 30 minutes apart during a collection period of up to 
3 hours. Integrated GH should be measured after at least a 4-hour fast and the subjects should remain fasting during 
the GH sampling. The integrated GH sampling at Week 22 should be started approximately 1-2 hours after study 
drug dose. 
Fasting blood samples (unless otherwise indicated) should be collected after an overnight fast of at least 6 hours. 
Subjects receiving pegvisomant as an adjunctive medication during the OLE portion of the study will not have 
growth hormone results analyzed while receiving this agent. 

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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with study participation, whether or not considered related to the study 
intervention. 
 NOTE: A TEAE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated in either intensity or frequency) that is 
temporally associated with the use of study drug. 
  
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (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 (ie, not related to progression of underlying 
disease). 
 New conditions initially detected or diagnosed after study drug administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected interaction between a concomitant 
medication and study drug. 
 Exacerbation of a chronic or intermittent 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. 
  

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

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A SAE is defined as any serious event that, at any dose: 
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. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (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 eCRF and on 
appropriate forms for the reporting of SAEs. 
 It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to the pharmacovigilance unit in lieu of completion of the required form. 
 There may be instances when copies of medical records for certain cases are requested 
by the pharmacovigilance unit. In this case, all subject identifiers, with the exception of 
the subject number, will be redacted on the copies of the medical records before 
submission. 
 The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 Any SAE occurring after the ICF has been signed and up until 4 weeks after the last 
dose must be reported on the Crinetics SAE Report Form (see Section 10.3.4). 

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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. 
Assessment of Causality 
 The Investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 The Investigator will use clinical judgment to determine the relationship using the 
following descriptors: not related, unlikely related, possibly related, probably related, 
and definitely related.  
NOT RELATED: This category applies to those AEs that are clearly and incontrovertibly 
due to extraneous causes (disease, environment, etc.). 
UNLIKELY: This category applies to those AEs that are judged to be unrelated to the IMP, 
but for which no extraneous cause may be found. An AE may be considered unlikely to be 
related to the IMP if or when it meets 2 of the following criteria: (1) it does not follow a 
reasonable temporal sequence from administration of the IMP; (2) it could readily have been 
produced by the subject’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the subject; (3) it does not follow a known pattern of response to the 
IMP; or (4) it does not reappear or worsen when the IMP is re‐administered. 
POSSIBLY: This category applies to those AEs for which a connection with the IMP 
administration appears unlikely but cannot be ruled out with certainty. An AE may be 
considered possibly related if or when it meets 2 of the following criteria: (1) it follows a 
reasonable temporal sequence from administration of IMP; (2) it could not readily have 
been produced by the subject’s clinical state, environmental or toxic factors, or other modes 
of therapy administered to the subject; or (3) it follows a known pattern of response to the 
IMP. 

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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 re-exposure to the IMP (if re-challenge occurs); and (4) it 
follows a known pattern of response to the IMP. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study drug administration 
will be considered and investigated. 
 The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
 For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which a SAE has occurred, and the Investigator has 
minimal information to include in the initial report to the pharmacovigilance unit. 
However, it is very important that the Investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the 
pharmacovigilance unit. 
 The Investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. Possibly, probably, or definitely related will be recorded as 
related for regulatory reporting purposes. 
  

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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. 
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. 
  

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10.3.4. 
Reporting of SAEs 
SAE Reporting to the Pharmacovigilance Unit via SAE Report Form 
The primary mechanism for reporting a SAE to the pharmacovigilance unit will be via 
the SAE Report Form. Any such SAE due to any cause, whether or not related to the 
study drug, must be reported on the Crinetics SAE Report Form immediately (and 
under no circumstances should this exceed 24 hours of occurrence) or when the 
Investigator becomes aware of the event. 
The Crinetics SAE Report Form should be sent within 24 hours of knowledge of the 
event to: 
. If a site receives updated data on a previously reported 
SAE, then the site can report the follow-up information on the Crinetics SAE Report 
Form and send to the pharmacovigilance group via 
.  
  

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Study Sponsor: Crinetics Pharmaceuticals, Inc. 
Version 5.0 
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10.4. 
Appendix 4: Abbreviations 
Abbreviation 
Definition 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ASD 
Acromegaly Symptoms Diary 
AST 
Aspartate aminotransferase 
AxMP 
Auxiliary medicinal product 
BCRP 
Breast cancer resistance protein 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CSR 
Clinical Study Report 
CTIS 
Clinical Trials Information System 
CYP 
Cytochrome 
DMC 
Data Monitoring Committee 
DPO 
Data Protection Officer 
DUN 
Dispensing unit number 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOR 
End of the Randomized Controlled phase 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GH 
Growth hormone 
HbA1c 
Hemoglobin A1c 

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Abbreviation 
Definition 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like growth factor-1 
IM 
Intramuscular 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
LAR 
Long-acting release 
LA-SRL 
Long-acting somatostatin receptor ligand 
LDL 
Low-density lipoprotein 
MRI 
Magnetic resonance imaging 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Disease 
NIMP 
Non-investigational medicinal product 
OLE 
Open-label extension 
 
 
P-gp 
P-glycoprotein 
PPS 
Per Protocol Set 
QD 
Once daily 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected using Fridericia’s formula 
QTL 
Quality tolerance limits 
RBC 
Red blood cell 
RC  
Randomized, controlled phase 
S1, S2, S3 
Screening Visit 1, etc. 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 

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Abbreviation 
Definition 
SOAs 
Schedules of Activities 
SOP 
Standard Operating Procedure 
SRL 
Somatostatin receptor ligand 
SS 
Safety Set 
SST2 
Somatostatin receptor 2 
TB 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
W 
Week 
WBC 
White blood cell 

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11. 
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