Conditions: Acromegaly
Keywords: Acromegaly ACROBAT EVOLVE Paltusotine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 13
Healthy volunteers: no

Brief summary:
A Phase 2 double-blind, placebo-controlled, randomized withdrawal study is designed to evaluate the safety, efficacy, and pharmacokinetics of paltusotine (formerly CRN00808) in subjects with acromegaly that are responders to octreotide LAR or lanreotide depot.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Paltusotine intervention 2: Placebo
Intervention descriptions: intervention 1: Paltusotine, capsules, once daily by mouth intervention 2: Placebo, capsules, once daily by mouth

Protocol document:
Prot_000.pdf: 
       
 
 
Crinetics Pharmaceuticals, Inc. 
  
Protocol #: CRN00808-02   
EudraCT # 2018-001833-42 
NCT # 03792555 
 
A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED WITHDRAWAL STUDY 
TO EVALUATE THE SAFETY, PHARMACOKINETICS AND EFFICACY OF CRN00808 IN 
PATIENTS WITH ACROMEGALY THAT ARE RESPONDERS TO OCTREOTIDE LAR OR 
LANREOTIDE DEPOT (ACROBAT EVOLVE) 
 
  
Document Type: 
Clinical Study Protocol  
Investigational Medicinal Product: 
CRN00808 (non-peptide small molecule 
investigational drug) 
Oral SST2 Agonist 
Phase of Development: 
Phase 2 
Indication: 
Acromegaly in adult patients 
Sponsor: 
Crinetics Pharmaceuticals, Inc. 
10222 Barnes Canyon Road, Building #2 
San Diego, CA 92121 
USA 
Protocol Version: 
3.0 
Protocol Date: 
06 June 2019  
 
 
STATEMENT OF CONFIDENTIALITY 
The information contained in this document is considered privileged and confidential and is the 
property of Crinetics Pharmaceuticals, Inc. It is provided to you in confidence in accordance 
with the terms of your confidentiality agreement with Crinetics Pharmaceuticals, Inc. 
The recipient agrees that no information contained herein will be published or disclosed 
without the written approval of Crinetics Pharmaceuticals, Inc. This document may be disclosed 
to applicable institutional review boards, or other duly authorized regulatory agency 
representatives as applicable, under the condition that confidentiality is maintained. 
 


Study code: CRN00808-02  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
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Page 2 of 91 
 
 
 
 
SPONSOR APPROVAL PAGE 
 
Protocol #: CRN00808-02   
 
A double-blind, placebo-controlled, randomized withdrawal study to evaluate 
the safety, pharmacokinetics and efficacy of CRN00808 in patients with 
acromegaly that are responders to octreotide LAR or lanreotide depot 
(ACROBAT EVOLVE) 
 
 
Protocol Version: 3.0 
Protocol Date: 06 June 2019 
 
 
 
 
This protocol has been reviewed and approved by Crinetics Pharmaceuticals, Inc.: 
 
 
 
 
 
____________________________________ 
 
________________ 
, MD  
 
 
 
 
Date 
 
 
 
 
 
 
 


Study code: CRN00808-02  
 
CLINICAL STUDY PROTOCOL 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
Protocol #: CRN00808-02 
A double-blind, placebo-controlled, randomized withdrawal study to evaluate 
the safety, pharmacokinetics and efficacy of CRN00808 in patients with 
acromegaly that are responders to octreotide LAR or lanreotide depot 
(ACROBAT EVOLVE) 
 
Protocol Version: 3.0 
Protocol Date: 06 June 2019 
 
I have read and I understand this protocol. I will conduct this protocol as outlined therein 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), 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: ______________________________________________________ 
 
 


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CONTACT LIST 
A separate contact information sheet will be provided to each clinical site. 
Serious Adverse Event (SAE) reporting information is found in Section 6.1.2.  
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site.   
 
Contact Type 
Contact Information 
Medical Monitoring 
, MD 
  
Accelsiors CRO and Consultancy Services Ltd.  
66, Šarplaninska Str.  
21000 Novi Sad, Serbia  
Cell: 
 
 
CRO Pharmacovigilance 
(SAE and pregnancy reporting, emergency 
unblinding)  
Accelsiors CRO and Consultancy Services Ltd.  
66, Šarplaninska Str.  
21000 Novi Sad, Serbia  
e-mail:
  
Telephone number: +
 
 
 


Study code: CRN00808-02  
 
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STUDY VENDOR LIST  
(Refer to the Study Reference Manual for full contact information) 
 
Study Responsibility 
Vendor 
Central IGF-1 Reader 
, MD 
Medizinische Klinik und Poliklinik IV,  
Klinikum der Universitaet Muenchen, 80336 
Munich, Germany 
 
Central Laboratory (All safety and 
bioanalytical labs will be shipped to Q2 in 
Valencia, CA or Scotland, UK) 
Q2 Solutions – North America 
27027 Tourney Road, Suite 2E  
Valencia, CA  91355 
United States 
 
Q2 Solutions – Europe 
The Alba Campus 
Rosebank 
Livingston 
West Lothian, EH54 7EG 
Scotland, United Kingdom 
 
Bioanalytical Laboratory (CRN00808 PK) 
Q2 Solutions 
19 Brown Road 
Ithaca, NY 14850  
 
Pharmacogenetics Laboratory (UGT1A1 
genotype Sample)  
Genelex Labs, LLC 
301 Western Avenue, Suite 100 
Seattle, WA 98121 
 
Cardiac Monitoring  
eResearchTechnology (ERT) 
1818 Market Street, Suite 1000 
Philadelphia, PA 19103 
United States 
 
eResearchTechnology (ERT) 
Peterborough Business Park 
Lynch Wood, Peterborough, PE2 6FZ, UK 
 
Bioanalytical Laboratory (lanreotide and 
octreotide PK) 
Algorithme Pharma 
575 Armand-Frappier Boulevard 
Laval, QC H7V 4B3 
Canada 
 


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Study Responsibility 
Vendor 
Drug Product Packaging and Distribution  
PCI Pharma Services (AndersonBrecon, Inc) 
4545 Assembly Drive  
Rockford, IL 61109 
United States 
 
PCI Pharma Services (Biotech Services 
International Ltd) 
Biotec House, Western Ave., 
Bridgend Industrial Estate, 
Bridgend, Mid Glamorgan, 
CF31 3RT, UK 
 
 
Subject Travel and Reimbursement Support 
(Optional Service) 
Colpitts Clinical 
10 Cottage Street 
Norwood, MA 02062 
United States 
 
Mobile Research (Optional Service) 
PCM Trials 
1600 Emerson ST 
Denver, CO 80218 
United States 
 
 
 


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PROTOCOL SYNOPSIS  
 
Name of Sponsor/Company: Crinetics Pharmaceuticals, Inc. 
Title of Study: A double-blind, placebo-controlled, randomized withdrawal study to evaluate 
the safety, pharmacokinetics and efficacy of CRN00808 in patients with acromegaly that are 
responders to octreotide LAR or lanreotide depot (ACROBAT EVOLVE) 
Study Code: CRN00808-02 
Phase of Development: Phase 2 
Name of Investigational Product: CRN00808 (non-peptide small molecule investigational drug) 
- Oral SST2 Agonist 
Name of Active Ingredient: 
 (
) 
Study Centers: Approximately 50 centers in the United States, Europe, South America, and 
Oceania. 
Study Objectives: 
• To determine the efficacy of CRN00808 in acromegaly subjects that are complete 
responders to parenteral octreotide LAR or lanreotide depot monotherapy; 
• To evaluate the safety and tolerability of CRN00808 in acromegaly subjects; 
• To evaluate the pharmacokinetics (PK) of CRN00808 in acromegaly subjects. 
Study Duration: The expected duration of study participation for each subject is up to 23 weeks, 
including up to 6 weeks of Screening, up to 13 weeks of Treatment Period and up to 4 weeks of 
Follow-up Period. 
Study Design and Methodology: This double-blind, placebo-controlled, randomized withdrawal 
study is designed to evaluate the safety, PK and efficacy of CRN00808 in subjects with 
acromegaly that are responders to octreotide LAR or lanreotide depot and will consist of the 
following periods: 
• Screening Period (4-6 weeks); 
• Treatment Period (up to 13 weeks); 
o Titration Period (9 weeks) 
o Randomized Withdrawal Period (4 weeks) 
• Follow-up Period (up to 4 weeks). 
Approximately 40 subjects on stable doses of octreotide LAR or lanreotide depot for the 
treatment of acromegaly will enter the Treatment Period for this clinical trial in order to have 


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approximately 36 randomized at Visit 11/Week 10 (V11/W10). Approximately 50% of the 
subjects randomized will have been treated with lanreotide depot pre-study. 
SCREENING PERIOD   
The purpose of the 4-6-week Screening Period is to perform all investigations required to 
establish a subject’s eligibility for the study. Once all assessments are completed and eligibility 
of the subjects are verified by the Investigator and confirmed by Medical Monitor (MM), the 
subject will be enrolled in the Treatment Period of the study.  
Informed and written consent will be obtained from the subjects at V1a prior to any study 
specific procedure. Eligibility for enrollment into the Treatment Period of the study will be in 
part determined by two IGF-1 values measured during the Screening Period. The first 
measurement will occur at V1b (0-2 weeks after V1a) and will be drawn immediately prior to 
the subject’s regularly scheduled dose of octreotide LAR or lanreotide depot. The second IGF-1 
measurement will be performed at V2, which will occur 1-2 weeks after V1b. In order to be 
eligible to enter the Treatment Period of the study, the mean of screening IGF-1 measurements 
must be ≤ULN. 
All other assessments performed during the Screening Period are detailed in Table 1. 
TREATMENT PERIOD  
The Treatment Period consists of a Titration Period followed by a Randomized Withdrawal 
Period. During the 13-week Treatment Period, subjects will attend 12 study visits which include 
study drug dispensing, blood sample collection, safety assessments, and other study procedures 
as indicated in Table 1. The Treatment Period starts with the first dose of study drug (
 for 
all subjects) at V3, which occurs approximately 4 weeks after V1b. Subjects enrolling into the 
Treatment Period will not receive the depot injection or any other standard acromegaly 
treatment until study completion or early termination. While in the Treatment Period, the 
subjects will self-administer the study drug at approximately the same time in the morning, once 
daily after an overnight fast of at least 6 hours. Fasting will continue for at least two hours post-
dose. At visits V3/W1, V6/W4, V9/W7, V11/W10, and V14/W13 the study drug is to be 
administered at the study center, also under fasting conditions. During the entire Treatment 
Period, including the Randomized Withdrawal Period, the subjects are expected to swallow 
three capsules (Size 2) with water every day.    
Titration Period 
At V6/W4, the study drug dose may be titrated up in a blinded fashion, provided that the current 
dose is tolerated by the subject and the IGF-1 value at V4/W2 is >0.9×ULN. Again, at V9/W7, the 
study drug may be up-titrated in a blinded fashion if the current dose is tolerated by the subject 
and the IGF-1 value at V7/W5 is >ULN.  
The investigator will assess whether the subject is tolerating the current dose and is blinded to 
IGF-1 results. The central IGF-1 reader will have access to the unblinded IGF-1 data and will 
determine if the IGF-1 results meet criteria for potential increase in study drug dose. The 
Investigator will confirm the subject is eligible for an increase in the study drug dose based on 
tolerability at V5/W3, V6/W4, V8/W6, and V9/W7. If tolerability is confirmed and the IGF-1 


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reader has determined that IGF-1 has not met adequate suppression criteria, a blinded 
 
containing the appropriate higher dose will be assigned at the V6/W4 and/or V9/W7. Dose 
increases in 
 increments will be allowed only at the V6/W4 (from 
) and 
V9/W7 (from 
) visits. No further up-titrations will be 
allowed. The daily dose will not exceed 
.     
If IGF-1 suppression as defined above has been achieved with a tolerated dose, the dose will not 
be changed. At any time during study drug dosing, including at V6/W4 and V9/W7, study drug 
dosing may be reduced in a blinded fashion on one occasion if the investigator determines that 
the subject is not adequately tolerating the study drug. In general, a suspected CRN00808-
related AE sufficient to result in the study drug dose reduction would be expected to be of Grade 
3 (Severe) intensity.   
An unblinded CRO designate will oversee the correct assignment of new blinded dose 
 
taking into account information from the investigator and from the central IGF-1 reader. 
Randomized Withdrawal Period 
Eligibility for randomization into the Randomized Withdrawal Period will be made based on 
information at the V10/W8 and V11/W10. To be eligible for randomization, the subject must 
have V10/W8 IGF-1 value ≤ULN and an investigator determination at V11/W10 that the subject 
is tolerating the study drug. Subjects who do not meet both criteria will not be randomized but 
will be allowed to stay in the study continuing a study drug dose that is tolerated until the 
subject completes all study visits or until criteria to resume standard acromegaly therapy and 
discontinuation from the study are met. The dose of the study drug used at V9/W7 will remain 
stable through V11/W10 if tolerated. If determined to be eligible for randomization, the subject 
will be randomized at V11/W10 in a blinded manner to continue the current dose of CRN00808 
or to be switched to placebo in a 1:1 ratio. 
Randomization will be stratified based on the subject’s prior somatostatin therapy 
(i.e., octreotide LAR or lanreotide depot). Recruiting will continue until approximately 
36 subjects that have IGF-1 levels ≤ULN at V10/W8 are randomized. Subjects whose IGF-1 is 
>ULN at V10/W8 will not be randomized but may continue the study on their V9/W7 dose if 
tolerated. Subjects who do not tolerate a dose of the study drug necessary to achieve IGF-1 
≤ULN will also not be randomized but may continue in the study on a tolerated dose. 
Subjects will be monitored throughout the Randomized Withdrawal Period at study visits and 
will return to the study center at the end of W13 (i.e., V14) on the last day of dosing. No further 
treatment with the study drug will be allowed after completion of V14/W13.  
FOLLOW-UP PERIOD  
During this 4-week-period subjects will attend 2 study visits (V15/W15 and V16/W17) and are 
expected to be off any acromegaly treatment, including CRN00808. All other assessments during 
the Follow-up Period are described in Table 1. Criteria for resumption of standard acromegaly 
treatment are provided in detail in Section 3.1. 


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Number of Subjects (planned): Approximately 40 male and female subjects with a confirmed 
acromegaly diagnosis are planned to enter the Treatment Period in order to have approximately 
36 randomized.  
Diagnosis and Main Criteria for Inclusion:  
Approximately 40 adult subjects will be considered for entry into the Treatment Period if they 
meet all the inclusion and none of the exclusion criteria.  
Inclusion criteria: 
1. Medically stable male and female subjects 18 to 75 years of age, inclusive, with a 
confirmed acromegaly diagnosis that is controlled (mean of IGF-1 ≤ULN values, as 
confirmed by central laboratory on two occasions measured 1-2 weeks apart during the 
Screening Period) on a stable approved dose of octreotide LAR or lanreotide depot 
(stable defined as no change in dose for the last 3 months); 
2. Diagnosis of active acromegaly confirmed by the Investigator and approved by the 
Medical Monitor. At a minimum, there must be documentation available of a pituitary 
tumor and elevated IGF-1 in the past. In subjects who have undergone pituitary surgery, 
elevated IGF-1 measured three or more months after surgery must be documented. A 
head MRI (or CT Scan for subjects unable to undergo MRI) with pituitary imaging will be 
performed during the Screening Period unless recent documented scan performed 
within 6 months prior to Screening is available; 
3. Subjects with hypothyroidism must be on stable treatment for at least 3 months with 
normal free T4 levels and should be clinically euthyroid at Screening as determined by 
the investigator; 
4. Subjects with adrenal insufficiency must be on adequate adrenal replacement therapy 
at the time of Screening as determined by the investigator; 
5. If the subject is female, she must be of non-childbearing potential (defined as either 
surgically sterilized [i.e., hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy] or at least 1 year of amenorrhea) OR must agree to use highly effective 
or two clinically acceptable methods of contraception from the beginning of Screening 
to the last study visit. 
• Acceptable highly effective methods of contraception include intrauterine device 
(IUD); intrauterine system (IUS); bilateral tubal occlusion (must be documented); 
non-oral hormonal contraceptives; desogestrel-based progestin-only oral 
contraceptives; 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. Note that 


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simultaneous use of male and female condoms with or without any other 
contraception methods is not permitted. Oral hormonal contraceptives 
containing estrogens are not permitted. 
6. If the subject is male, the subject must use a condom, or his female partner of 
childbearing potential must use an effective form of contraception as described above, 
from the beginning of Screening to the last study visit. Male subjects must also agree not 
to donate sperm for the duration of the study and until at least 3 months after the last 
dose of the study drug; 
7. Subjects must be willing and able to comply with the study procedures as specified in 
the protocol and comply with the study treatment; 
8. Negative results on a test for the following drugs during Screening: amphetamine, 
barbiturates, cocaine, methamphetamine, methadone, opiates, phencyclidine, and 
methylenedioxymethamphetamine; 
9. Written Informed Consent provided prior to any study related procedures. 
Exclusion criteria: 
1. Treatment naïve acromegaly subjects; 
2. Acromegaly subjects who had pituitary surgery within 6 months prior to Screening or 
who have undergone pituitary radiation therapy at any time prior to the study entry. If 
a subject has undergone pituitary radiation therapy ≥4 years prior to Screening and has 
had a documented IGF-1 ≥1.3×ULN within 2 years prior to Screening OR if a subject has 
undergone pituitary radiation therapy between 3 and 4 years prior to Screening and has 
had a documented IGF-1 ≥1.3×ULN within 1 year prior to Screening, the subject may be 
included in the study; 
3. Subjects with any clinically significant concomitant disease including but not limited to 
cardiovascular 
disease; 
moderate 
or 
severe 
renal 
insufficiency 
(eGFR<60 mL/min/1.73 m2); or significant liver disease (including cirrhosis); 
4. History or evidence of any of the following within the previous 6 months: myocardial 
infarction, cardiac surgery revascularization (coronary artery bypass grafting or 
percutaneous transluminal coronary angioplasty), cerebrovascular accident or stroke or 
transient ischemic attack (TIA). Syncope or marked presyncope that is unexplained or 
related to cardiovascular disease within the last 5 years; 
5. Any of the following conditions: personal history of cardiac arrest or long QT syndrome, 
evidence for a familial sudden death syndrome, hemodynamically significant cardiac 
valvulopathy, greater than Canadian Cardiovascular Society Class 1 angina pectoris or 
unstable angina, greater than NYHA Class 1 congestive heart failure, ongoing episodes 
of symptomatic bradycardia (i.e., bradycardia associated with significant dizziness, 
lightheadedness, or loss of consciousness), known history of sustained ventricular 


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tachycardia, hemodynamically significant pulmonary arterial hypertension; uncontrolled 
symptomatic supraventricular tachycardia, uncontrolled atrial fibrillation (chronic 
persistent atrial fibrillation that is appropriately rate controlled and anticoagulated is 
acceptable for inclusion), type 2 second degree or third degree atrioventricular block; 
6. Based on Holter monitor performed during the Screening Period: symptomatic 
bradycardia (i.e., bradycardia associated with significant dizziness, lightheadedness, or 
loss of consciousness), type 2 second degree or third degree atrioventricular block, 
pause >3 sec, sustained ventricular or supraventricular tachycardia, previously 
undiagnosed paroxysmal atrial fibrillation, or torsades de pointes; 
7. Supine systolic blood pressure >150 mmHg and/or supine diastolic blood pressure 
>95 mmHg at Screening (if the initial measurement is out of range, may be repeated 2 
more times after 15 min and exclusion will be based on the average of the three 
measurements); 
8. Resting (at least 10 minutes) palpated pulse rate <50 bpm or >105 bpm at Screening. 
If either of these criteria are met, the assessment should be repeated 2 more times and 
the average should be used to determine the subject’s eligibility; 
9. QTcF interval >450 msec (or QTc >480 msec in the presence of a bundle branch block) or 
PR interval >240 msec at 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 supine 
for at least 10 minutes;   
10. Currently receiving medications that are known to be associated with torsades de 
pointes listed in Appendix 2 - Medications Associated with Torsades De Pointes; 
11. Currently receiving medications that are known to cause heart rate slowing (beta-
blockers, verapamil, diltiazem, or ivabradine) if resting heart rate at Screening is <60 
bpm; 
12. Currently receiving medications that are strong inducers or inhibitors of CYP3A4 (see 
Protocol Section 4.8.2); 
13. Subjects with autonomic disease (caused by diabetes or Parkinson’s disease); 
14. Subjects with symptomatic cholelithiasis; 
15. Subjects with amylase and/or lipase levels >2×ULN, alanine aminotransferase (ALT) 
and/or aspartate aminotransferase (AST) >2×ULN, total bilirubin >1.5×ULN, and/or 
creatinine >1.5×ULN at Screening. Subjects with previously diagnosed Gilbert’s 
syndrome not accompanied by other hepatobiliary disorders and associated with total 
bilirubin <3 mg/dL (<51.3 µmol/L) and direct bilirubin ≤ULN will be permitted; 
16. Subjects who have been taking the following prior medications: pegvisomant (within the 
last 3 months), dopamine agonists (within the last 3 months) and pasireotide LAR (within 
the last 6 months); 


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17. Subjects taking octreotide LAR at a dose higher than 40 mg or lanreotide depot at a dose 
higher than 120 mg; 
18. Subjects who usually take octreotide LAR or lanreotide depot less frequently than every 
4 weeks (e.g., every 6 weeks or 8 weeks); 
19. Subjects who have undergone major surgery/surgical therapy for any cause within 
4 weeks prior to Screening; 
20. Subjects with poorly controlled diabetes mellitus defined as having a HbA1c ≥8.5% 
(69 mmol/mol); 
21. Subjects with diabetes treated with insulin for less than 6 weeks prior to the study entry, 
or with an unstable insulin dose in 6 weeks prior to the study entry; 
22. Subjects with clinically significant abnormal findings during the Screening Period, and 
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; 
23. Female subjects who are pregnant or lactating. Absence of pregnancy will be confirmed 
by serum human chorionic gonadotropin (hCG) pregnancy test at Screening and a 
negative urine hCG pregnancy test at V3 prior to drug administration; 
24. Subjects with hepatitis B, Human Immunodeficiency Virus (HIV), or hepatitis C infection.  
Subjects with previous hepatitis C infection that is now cured may be eligible; 
25. Subjects with known history of, or current alcohol or drug abuse, within the last 
12 months; 
26. Subjects with any 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; 
27. Subjects with a known allergy or hypersensitivity to any of the test materials or related 
compounds; 
28. Subjects who have been treated with proton pump inhibitors and/or H2 blockers within 
2 weeks prior to Screening;   
29. Subjects with 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; 
30. An employee or immediate family member of an employee of Crinetics; 
31. Participation in any previous trial with CRN00808, except for subjects who have screen 
failed study CRN00808-03; 
32. Subjects who have been dosed with 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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Investigational Product, Dosage and Mode of Administration (CRN00808) 
Active substance: 
 
Indication: acromegaly in adult subjects 
Strength: 
 or 
 (based on freebase CRN00808) 
Dosage form: capsules 
During the titration portion of the Treatment Period, subjects will receive an oral once daily 
dose of either 
 CRN00808 based on the titration schedule. During 
the Randomized Withdrawal Period, subjects will receive either matching placebo or 
 
 CRN00808 based on their previously optimized dose. 
Subjects should avoid exposure of skin or eyes to direct sunlight or UV light for the duration of 
the study and for at least 10 days after receiving the last dose of study drug.  
Reference Product Dosage and Mode of Administration (placebo) 
Matching placebo capsules are identical in appearance to CRN00808 and will be orally 
administered in a double-blinded manner according to the randomization scheme on an 
identical schedule to those receiving CRN00808. 
Dose selection: The dose range of CRN00808 was selected based on PK and PD data collected 
in healthy volunteers, and a comparison of octreotide and lanreotide PK and PD data in healthy 
volunteers with efficacy data in acromegaly patients. 
In the previous study in healthy volunteers, daily administration of up to 
 CRN00808 for 
up to 10 days identified 
 as the lowest dose that achieved maximal suppression of IGF-1 
in healthy volunteers. Therefore, 
 CRN00808 was selected as the starting dose in 
acromegaly subjects. 
Dosing holidays and discontinuation of dosing: When in the Investigator’s judgment the study 
drug is not tolerated, the study drug may be held for up to 7 days on one occasion during the 
study followed by resumption of the study drug at a reduced dose. 
Subjects can be discontinued from study treatment or the study as defined in Section 3.2.3. 


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Study Endpoints 
EFFICACY ENDPOINTS: 
Primary endpoint: 
The primary endpoint is the proportion of subjects who meet responder criteria (based on the 
mean of two consecutive IGF-1 measurements ≤ULN) at W13.   
Key Secondary endpoints: 
• Change in IGF-1 levels between W10 and W13; 
• Change in GH levels between W8 and W13; 
• Change in symptoms of acromegaly as measured by total 
 score between W10 and 
W13. 
Exploratory endpoints: 
• Proportion of subjects who achieve serum GH <5.0 ng/mL at W13; 
• Proportion of subjects who achieve serum GH <2.5 ng/mL at W13; 
• Time to loss of response (IGF-1 >ULN) after withdrawal of CRN00808; 
• Increase in serum IGF-1 levels 3+ weeks after withdrawal of CRN00808; 
• Increase in serum GH levels 1+ weeks after withdrawal of CRN00808; 
• Increase in serum 
 levels 3+ weeks after withdrawal of CRN00808; 
• Changes from baseline in serum GH, IGF-1, and 
 levels measured at W10 and 
W13, compared to baseline (D1; [V2 for GH]); 
• Change in symptoms of acromegaly as measured by individual 
score between W10 
and W13; 
• Change from baseline in symptoms of acromegaly as measured by total 
 score at 
W10; 
• Change from baseline in symptoms of acromegaly as measured by individual 
 score 
at W10; 
• Change from baseline in
 score at W10 and between W10 and W13; 
• Change from baseline in 
 at W10 and 
between W10 and W13; 
• Change in investigator-assessed symptoms of acromegaly between W10 and W13; 
• Change from baseline in investigator-assessed symptoms of acromegaly at W10; 
• Change in 
scores between W10 and W13; 
• Change from baseline in 
scores at W10; 
• 
 scores at W10 and W13; 
• Plasma concentrations of CRN00808. 
 


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SAFETY ENDPOINTS: 
• Adverse events (AEs)/Treatment-emergent Adverse Events (TEAEs) throughout the 
study; 
• Clinical laboratory tests (hematology, serum chemistry and urinalysis) at each post-
baseline study visit; 
• Vital signs at each post-baseline study visit; 
• Physical examinations at each post-baseline study visit; 
• 12-lead ECG at each post-baseline study visit; 
• fT3, fT4, anti-thyroid antibody, TSH, cortisol, ACTH, LH, FSH and prolactin at each post-
baseline study visit; 
• Gall bladder ultrasound. 
STATISTICAL CONSIDERATIONS 
Sample Size Calculation 
With 36 randomized subjects (i.e., subjects that have IGF-1 ≤ULN at W8), assuming a 
60% response rate in the CRN00808 arm and a 10% response rate in the placebo arm (allocation 
ratio between two arms 1:1), the exact power to conclude superiority of the CRN00808 arm 
over placebo, applying an exact unconditional score test at a significance level of 5% (two-sided) 
is 92.2%.  
The exact power was computed based on the binomial distribution by evaluating all possible 
(N1+1) (N2+1) outcomes, weighted by their probability of occurrence for given true R1, 
R2  response rates in the two arms (0.6 and 0.1, respectively).  
No adjustment for dropout rate was made because enrollment will continue until approximately 
36 subjects with IGF-1 <ULN are randomized in the Randomized Withdrawal Period. 
Analysis Datasets 
Safety Analysis Set comprises all subjects who received at least one dose of study medication. 
The Safety Analysis Set will be used for all safety analyses. Treatment group assignments for 
safety analyses during the Randomized Withdrawal Period will be based on the treatment that 
was received (if this differs from the randomized treatment). Data from all subjects dosed prior 
to Randomized Withdrawal Period, regardless of eligibility to randomize, will be pooled. 
Intent-to-Treat Analysis Set (ITT) comprises all subjects who received at least one dose of the 
study medication. The ITT analysis set will be used for analyses of exploratory endpoints. During 
the Randomized Withdrawal Period, subjects will be included in the treatment group to which 
they were randomized. Data from all subjects dosed prior to Randomized Withdrawal Period, 
regardless of eligibility to randomize, will be pooled. 


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Modified Intent-to-Treat Analysis Set (mITT) comprises all subjects from ITT who were 
randomized. The mITT analysis set will be used for the analysis of primary and secondary 
endpoints. Subjects will be included in the treatment group to which they were randomized. 
Per Protocol Analysis Set (PP) comprises all subjects from the mITT having no major protocol 
deviation affecting treatment efficacy. The PP analysis set will be used for supportive efficacy 
analyses. 
Efficacy Evaluation 
For the primary analysis, responders are defined as subjects having the mean of two consecutive 
IGF-1 measurements ≤ULN at Week 13 (Visit 13 and Visit 14). If one of these measurements is 
missing, then the other measurement must be ≤ULN for a subject to be classified as a responder. 
If both measurements are missing, then the subject is classified as non-responder.  
Superiority of CRN00808 versus placebo will be tested based on the exact unconditional score 
test for the difference between two binomial proportions, as implemented in SAS 9.4.  
The two-sided 95% exact Clopper-Pearson confidence interval (CI) for the responder rates will 
be estimated for each treatment arm separately. 
Subjects in the Treatment Period who do not achieve protocol defined IGF-1 normalization or 
who do not tolerate a study drug dose which allows for IGF-1 normalization will not be 
randomized or included into the primary analysis. Primary efficacy results from these treated, 
non-randomized subjects will be summarized descriptively. 
Safety Evaluation 
Safety endpoints will be summarized with descriptive statistics and shift tables where 
applicable. 
The number and incidence of all AEs will be presented, and acromegaly symptoms as AEs of 
special interest will be presented separately.  
PK Evaluation 
Plasma concentration will be summarized by treatment arm and dose using descriptive 
statistics. 
 
 
 


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Table of Contents 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .............................................................................. 3 
CONTACT LIST ................................................................................................................................. 4 
PROTOCOL SYNOPSIS ...................................................................................................................... 7 
List of Tables ................................................................................................................................. 21 
List of Figures ................................................................................................................................ 21 
List of Abbreviations and Acronyms ............................................................................................. 22 
1 
INTRODUCTION ..................................................................................................................... 27 
1.1 
Rationale ........................................................................................................................ 27 
1.1.1 
Justification of Dose and Dose Regimen ............................................................................. 28 
2 
STUDY OBJECTIVES ................................................................................................................ 29 
3 
INVESTIGATIONAL PLAN ........................................................................................................ 30 
3.1 
Overall Study Design ...................................................................................................... 30 
3.2 
Study Population ............................................................................................................ 34 
3.2.1 
Inclusion Criteria ................................................................................................................. 35 
3.2.2 
Exclusion Criteria ................................................................................................................. 36 
3.2.3 
Withdrawal, Removal, and Replacement of Subjects ......................................................... 38 
3.2.4 
Follow-Up for Drug Discontinuation/Subject Withdrawal from the Study ......................... 40 
3.2.5 
Discontinuation of the Study .............................................................................................. 41 
4 
TREATMENT PROCEDURES .................................................................................................... 42 
4.1 
CRN00808 (Investigational Medicinal Product) ............................................................. 42 
4.2 
Placebo (Reference Product) ......................................................................................... 42 
4.3 
Packaging and Labeling .................................................................................................. 42 
4.4 
Treatment Assignment and Blinding .............................................................................. 42 
4.5 
Method of Administration ............................................................................................. 43 
4.5.1 
CRN00808 Dosing and Administration ................................................................................ 43 
4.5.2 
Placebo Dosing and Administration .................................................................................... 43 
4.5.3 
Background Medication ...................................................................................................... 43 
4.6 
Study Drug Supply, Storage and Tracking ...................................................................... 43 
4.7 
Drug Accountability and Treatment Compliance ........................................................... 44 


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4.8 
Medical History and Prior/Concomitant Medications ................................................... 44 
4.8.1 
Permitted Concomitant Medications .................................................................................. 45 
4.8.2 
Prohibited Concomitant Medications ................................................................................. 45 
4.9 
Contraception ................................................................................................................. 46 
5 
STUDY PROCEDURES .............................................................................................................. 47 
5.1 
Screening Period (V1a, V1b, V2) .................................................................................... 47 
5.1.1 
Screening Failures ............................................................................................................... 48 
5.1.2 
Re-screening ........................................................................................................................ 48 
5.2 
Treatment Period ........................................................................................................... 49 
5.3 
Follow-up Period ............................................................................................................ 52 
5.4 
Unscheduled visits .......................................................................................................... 53 
6 
SAFETY ANALYSIS ................................................................................................................... 58 
6.1 
Safety Assessments ........................................................................................................ 58 
6.1.1 
Adverse Events .................................................................................................................... 58 
6.1.2 
Serious Adverse Events ....................................................................................................... 61 
6.1.3 
Physical Examination ........................................................................................................... 62 
6.1.4 
Vital Signs ............................................................................................................................ 62 
6.1.5 
ECG Assessment .................................................................................................................. 62 
6.1.6 
Outpatient 24-hour Holter .................................................................................................. 63 
6.1.7 
Cardiovascular Safety Monitoring ....................................................................................... 63 
6.1.8 
Laboratory Assessments ..................................................................................................... 64 
6.1.9 
Gall bladder Ultrasound ...................................................................................................... 66 
6.1.10 
Magnetic Resonance Imaging (MRI) ................................................................................... 66 
6.1.11 
Investigator Assessed Symptoms of Acromegaly ............................................................... 66 
6.1.12 
................. 67 
6.1.13 
 .................................................... 67 
6.1.14 
 ................................................... 68 
7 
STATISTICAL ANALYSIS ........................................................................................................... 69 
7.1 
Study Endpoints ............................................................................................................. 69 
7.2 
Statistical Methods and Analyses .................................................................................. 70 
7.2.1 
Determination of Sample Size ............................................................................................. 70 


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7.2.2 
Analysis Datasets................................................................................................................. 70 
7.2.3 
Demographic and Baseline Characteristics ......................................................................... 71 
7.2.4 
Treatment Assignment and Study Medication ................................................................... 71 
7.2.5 
Efficacy Analysis .................................................................................................................. 71 
7.2.6 
Safety Analysis .................................................................................................................... 72 
7.2.7 
Interim Analysis ................................................................................................................... 72 
7.2.8 
Measures to Minimize Bias ................................................................................................. 72 
8 
DATA MANAGEMENT ............................................................................................................ 73 
8.1 
Data Handling ................................................................................................................. 73 
8.1.1 
Source Documents .............................................................................................................. 73 
8.1.2 
Coding Dictionaries ............................................................................................................. 73 
8.2 
Data Management and Quality Control ......................................................................... 73 
8.3 
Database lock ................................................................................................................. 74 
9 
STUDY MANAGEMENT/PROCEDURES AND INSTRUCTIONS .................................................. 75 
9.1 
Safety Related Procedures ............................................................................................. 75 
9.1.1 
Rapid Notification on Serious Adverse Events .................................................................... 75 
9.1.2 
Rapid Notification on Pregnancies ...................................................................................... 75 
9.1.3 
Overdose ............................................................................................................................. 76 
9.1.4 
Emergency Procedure for Un-blinding................................................................................ 76 
9.1.5 
Central IGF-1 Reader ........................................................................................................... 76 
9.2 
Regulatory Issues, Ethics and Good Clinical Practice ..................................................... 76 
9.2.1 
Regulatory Guidelines and Ethical Considerations ............................................................. 76 
9.2.2 
Institutional Review Board/Independent Ethics Committee .............................................. 77 
9.2.3 
Informed Consent ............................................................................................................... 77 
9.2.4 
Sponsor ............................................................................................................................... 77 
9.2.5 
Principal Investigator .......................................................................................................... 77 
9.3 
Administrative Procedures ............................................................................................. 78 
9.3.1 
Protocol Amendment and Protocol Deviations .................................................................. 78 
9.3.2 
Monitoring Procedures ....................................................................................................... 78 
9.3.3 
Record Retention ................................................................................................................ 79 
9.3.4 
Quality Control and Quality Assurance ............................................................................... 79 


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9.3.5 
Financing and Insurance ..................................................................................................... 79 
9.3.6 
Publication Policy/Disclosure of Data ................................................................................. 80 
10 
REFERENCES ....................................................................................................................... 81 
Appendix 1 - World Medical Association Declaration of Helsinki ................................................ 82 
Appendix 2 - Medications Associated with Torsades De Pointes ................................................. 88 
 
 
List of Tables 
Table 1 - Overall Visit Schedule..................................................................................................... 54 
Table 2 - Classification of Adverse Events by Intensity ................................................................. 59 
Table 3 - Classification of Adverse Events by Relationship to Investigational Medicinal Product 59 
Table 4 - Adverse Event Outcome ................................................................................................ 60 
 
 
List of Figures 
Figure 1 - Screening Period ........................................................................................................... 30 
Figure 2 - Overall Study Design ..................................................................................................... 31 
 
 
 


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List of Abbreviations and Acronyms 
 
  
ACTH 
Adrenocorticotropic hormone 
AE  
Adverse Event 
ALT  
Alanine Aminotransferase  
ALP 
Alkaline Phosphatase 
AST  
Aspartate Aminotransferase  
AUC 
Area under the plasma concentration-time curve 
AUC0-24 
Area under the plasma concentration-time curve from time 0 to 24 hours 
Ba 
Basophils  
CA 
Competent Authority 
cAMP 
Cyclic adenosine monophosphate  
CBC 
Complete blood count 
CFR 
Code of Federal Regulations  
CI 
Confidence Interval  
CNS 
Central nervous system 
CRA  
Clinical Research Associate 
CRO  
Contract Research Organization 
CSR 
Clinical Study Report 
Cmax 
Maximum plasma concentration 
ECG  
Electrocardiogram 
eCRF  
Electronic Case Report Form 
EDC 
Electronic Data Capture  


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EMA 
European Medicines Agency 
Eo 
Eosinophils 
EU  
European Union 
FSH 
Follicle stimulating hormone  
fT3 
Free triiodothyronine 
fT4 
Free thyroxin 
GCP  
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GH 
Growth hormone 
GHRH 
Growth hormone-releasing hormone  
GLP 
Good Laboratory Practice 
GMP  
Good Manufacturing Practice 
h 
Hour(s) 
HBV 
Hepatitis B virus 
HCT 
Hematocrit  
HCV 
Hepatitis C virus 
HEENT 
Head (external), Eyes, Ears, Nose and Throat  
hERG 
Human-ether-a-go-go-related gene  
Hgb 
Hemoglobin  
HIV  
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure  
ICF 
Informed Consent Form 
ICH  
International Council for Harmonization  


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IEC  
Independent Ethics Committee  
IGF-1 
Insulin-like growth factor-1  
 
  
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board  
IRT 
Interactive response technology system 
ITT 
Intent-to-Treat Analysis Set 
IUD 
Intrauterine device 
IUS 
Intrauterine system  
kg 
Kilogram 
L 
Liter 
LDH  
Lactate Dehydrogenase 
LH 
Luteinizing hormone 
Lym 
Lymphocytes 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat Analysis Set 
mL 
Milliliter 
MCH  
Mean Corpuscular Hemoglobin  
MCHC  
Mean Corpuscular Hemoglobin Concentration 
MCV  
Mean Corpuscular Volume 
mg 
Milligram 
min 
Minutes 


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MM 
Medical Monitor 
MNAR 
Missing not at random  
Mono 
Monocytes  
µg 
Microgram 
Ne 
Neutrophils  
NOAEL 
No observed adverse effect level 
ng 
Nano gram 
OGTT 
Oral glucose tolerance test 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetics  
PLT 
Platelets  
PP 
Per-protocol Analysis Set 
QA 
Quality Assurance 
QC 
Quality Control  
RBC 
Red Blood Cell  
SAE  
Serious Adverse Event 
SAD 
Single Ascending Dose 
SAP 
Statistical Analysis Plan  
SAS 
Safety Analysis Set  
SOP  
Standard Operating Procedure 
SSA 
Somatostatin Analogues 
SST2 
Somatostatin receptor 2  


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SST3 
Somatostatin receptor 3 
SST5 
Somatostatin receptor 5 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent Adverse Events  
TIA 
Transient ischemic attack  
TSH 
Thyroid stimulating hormone 
t1/2  
Terminal half-life 
tmax 
Time to maximum serum concentration 
ULN 
Upper limit of normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WMA 
World Medical Association 
 
 
 


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1 INTRODUCTION 
Acromegaly is typically caused by a growth hormone (GH) secreting tumor in the pituitary. Excess 
GH secretion results in excess secretion of insulin-like growth factor-1 (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 somatostatin agonists are the primary pharmacological 
treatment options for patients that are not candidates for surgical removal of the tumor or when 
surgery is only partially successful or unsuccessful in achieving treatment goals (Melmed and 
Kleinberg, 2016; Carroll and Jenkins, 2016; NIDDK diseases online health information). Parenteral 
somatostatin analogs require large bore needles for monthly injections which often need to be 
administered by health care providers. Additionally, because these injections are depot 
preparations, it is difficult to titrate or individualize treatment goals for optimal patient 
outcomes. These agents when used as monotherapy achieve IGF-1 normalization in 
approximately 50% of patients. The inability of physicians to quickly adjust doses and dosing 
regimens likely contributes to reduced responder rates for somatostatin analog-based 
pharmacotherapy. 
CRN00808 is a non-peptide, orally bioavailable, somatostatin agonist that is under development 
for the treatment of acromegaly. Clinical data to date suggest that once daily CRN00808 
administration for up to 10 days can result in IGF-1 lowering in healthy volunteers, however it 
has not yet been evaluated in patients with acromegaly. The purpose of this study is to evaluate 
the safety and efficacy of CRN00808 in acromegaly patients who have achieved IGF-1 
normalization using either octreotide LAR or lanreotide depot monotherapy. 
Additional details on the background of acromegaly, treatment options, and nonclinical and 
clinical data on CRN00808 can be found in the current Investigator’s Brochure. 
1.1 Rationale 
An orally bioavailable nonpeptide somatostatin agonist that normalizes hormone levels in 
acromegaly patients should improve patient compliance and quality of life by eliminating painful 
injections and reduce the need for frequent physician office visits. Additionally, it potentially 
allows physicians to quickly determine a dosing regimen for superior outcomes compared to 


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existing therapies. To our knowledge, CRN00808 will be the first nonpeptide oral somatostatin 
agonist to enter clinical trials in patients with acromegaly. 
1.1.1 Justification of Dose and Dose Regimen  
In this study, subjects will switch from their current monthly depot regimen of octreotide LAR or 
lanreotide depot to once daily regimen of oral CRN00808 without a washout to loss of IGF-1 
control. A complete washout would require 8-12 weeks after last dose due to the long half-life 
of the depot preparations. Such a design is not reasonable because the hormone levels would 
become uncontrolled (i.e., return to elevated GH and IGF-1 levels) and patients would likely 
experience a return of symptoms for an extended period (washout plus achieving steady state 
with an optimal dose of CRN00808). The proposed randomized withdrawal design minimizes the 
time that subjects spend in uncontrolled state and affords the ability to measure efficacy of 
CRN00808 compared to placebo. Data from healthy volunteers demonstrate that withdrawal 
from CRN00808 resulted in a return of IGF-1 to almost baseline levels after 10 days, which is 
consistent with the half-life of CRN00808 (34-50 hours) and IGF-1 (approximately 24 hours). 
Based on these results, it is expected that the subjects’ IGF-1 levels will become uncontrolled 
(return to untreated baseline) in approximately 10 days after withdrawal of CRN00808. Finally, 
the current trial has established criteria to return patients to their original pharmacotherapy if 
IGF-1 levels rise significantly in conjunction with a return of acromegaly symptoms, thus 
minimizing the duration of uncontrolled period and discomfort.  
The starting dose of 
 CRN00808 was found to be the lowest dose that was maximally 
effective in suppressing IGF-1 in healthy volunteers at steady state and this level of suppression 
mirrored that achieved by either octreotide or lanreotide. For both of these peptide drugs, the 
trough plasma concentrations that result in maximal IGF-1 suppression in healthy volunteers 
(Tiberg et al, 2015 and Kuhn et al, 1994) are similar to trough concentrations that result from 
approved doses at steady state (approved FDA labels for octreotide and lanreotide). Therefore, 
 CRN00808 is considered to be a suitable starting dose in subjects. 
The rationale for the proposed titration design is also supported by the goal of maintaining 
subjects in a controlled state and optimizing their dose while minimizing the duration of being 
uncontrolled (i.e., elevated IGF-1) and experiencing the return of symptoms. Subjects will be 
switched from their depot to 
 CRN00808. It is possible that some subjects will require a 
higher dose, and only those will be titrated up to a dose of 
. It is also possible that 
some subjects will not tolerate a 
 dose, for whom a dose reduction to
 will be allowed. 
A parallel dose design was rejected because, at the initiation of treatment with CRN00808, a 
majority of the subjects will have residual systemic concentrations of octreotide or lanreotide 
that could be sufficient to contribute to the overall agonistic activity at the SST2 receptor. This 
complicates the interpretation of any dose response information that could be obtained from a 
parallel dose design. The dose titration design allows the dose of CRN00808 to be increased (if 
necessary) as the plasma concentrations of octreotide or lanreotide taper down. It is expected 
that by the end of titration period the concentrations of octreotide or lanreotide will be 
undetectable or too low to contribute to efficacy. Finally, the dose-titration design reflects how 
the drug is likely to be used in clinical practice for majority of the patients.  


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2 STUDY OBJECTIVES 
• To determine the efficacy of CRN00808 in acromegaly subjects that are complete 
responders to parenteral octreotide LAR or lanreotide depot monotherapy; 
• To evaluate the safety and tolerability of CRN00808 in acromegaly subjects; 
• To evaluate the pharmacokinetics (PK) of CRN00808 in acromegaly subjects.  
 
 


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3 INVESTIGATIONAL PLAN 
3.1 Overall Study Design 
This double-blind, placebo-controlled, randomized withdrawal study is designed to evaluate the 
safety, PK and efficacy of CRN00808 in subjects with acromegaly that are responders to 
octreotide LAR or lanreotide depot and will consist of the following periods: 
• Screening Period (4-6 weeks); 
• Treatment Period (up to 13 weeks); 
o Titration Period (9 weeks) 
o Randomized Withdrawal Period (4 weeks) 
• Follow-up Period (up to 4 weeks). 
Therefore, the total study duration for the individual subject is up to 23 weeks. 
The study design is displayed in Figure 1 and Figure 2. 
Figure 1 - Screening Period 
 
 
 
 
 
 
 
 
 
 


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Figure 2 - Overall Study Design 
 
Approximately 40 subjects on stable doses of octreotide LAR or lanreotide depot for the 
treatment of acromegaly will enter the Treatment Period in order to have approximately 
36 randomized at V11/W10. Approximately 50% of the subjects randomized will have been 
treated with lanreotide depot pre-study.    
Subjects will not be allowed to change their routine exercise regimen during the course of the 
study.  
SCREENING PERIOD  
The purpose of the 4-6-week Screening Period is to perform all investigations required to 
establish a subject’s eligibility for the study. Once all assessments are completed and eligibility of 
the subjects are verified by the Investigator and confirmed by Medical Monitor (MM), the subject 
will be enrolled in the Treatment Period of the study.  
Informed and written consent will be obtained from the subjects at Visit 1a (V1a) prior to any 
study specific procedure. Eligibility for enrollment into the Treatment Period of the study will be 
in part determined by two IGF-1 values measured during the Screening Period. The first 
measurement will occur at V1b (0-2 weeks after V1a) and will be drawn immediately prior to the 
subjects regularly scheduled dose of octreotide LAR or lanreotide depot. The second IGF-1 
measurement will be performed at V2 which will occur 1-2 weeks after V1b. In order to be eligible 
to enter the Treatment Period of the study, the mean of screening IGF-1 measurements must be 
≤ULN. 
A washout (i.e., demonstration of increased IGF-1 levels and/or return of symptoms) before 
switching from parenteral to oral therapy is not required.  


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For additional details on screening procedures, refer to Section 5.1 and Table 1. 
TREATMENT PERIOD  
The Treatment Period consists of a Titration Period followed by a Randomized Withdrawal 
Period. During the 13-week-period Treatment Period, subjects will attend 12 study visits which 
include study drug dispensing, blood sample collection, safety assessments, and other study 
procedures as indicated in Table 1. The Treatment Period starts with the first dose of study drug 
(
 for all subjects) at V3, which occurs approximately 4 weeks after V1b, when the last dose 
of standard acromegaly treatment was administered. Subjects enrolling into the Treatment 
Period will not receive any depot injections or other standard acromegaly treatment until study 
completion or early termination. While in the Treatment Period, the subjects will self-administer 
the study drug at approximately the same time in the morning, once daily after an overnight fast 
of at least 6 hours. Fasting will continue for at least two hours post-dose. At visits V3/W1, V6/W4, 
V9/W7, V11/W10, and V14/W13 the study drug is to be administered at the study center, also 
under fasting conditions. During the entire Treatment Period, including the Randomized 
Withdrawal Period, the subjects are expected to swallow three capsules (Size 2) with water every 
day.    
Titration Period 
At V6/W4, the study drug dose may be titrated up in a blinded fashion, provided that the current 
dose is tolerated by the subject and the IGF-1 value at V4/W2 is >0.9×ULN. Again, at V9/W7, the 
study drug may be up-titrated in a blinded fashion if the current dose is tolerated by the subject 
and the IGF-1 value at V7/W5 is >ULN.  
The investigator will assess whether the subject is tolerating the current dose and is blinded to 
IGF-1 results. The central IGF-1 reader will have access to the unblinded IGF-1 data and will 
determine if the IGF-1 results meet criteria for potential increase in study drug dose. 
The Investigator will confirm the subject is eligible for an increase in the study drug dose based 
on tolerability at V5/W3, V6/W4, V8/W6, and V9/W7. If tolerability is confirmed and the IGF-1 
reader has determined that IGF-1 has not met adequate suppression criteria, a blinded 
 
 containing the appropriate higher dose will be assigned at the V6/W4 and/or V9/W7. Dose 
increases in 
 increments will be allowed only at the V6/W4 (from 
) and 
V9/W7 (from 
) visits. No further up-titrations will be 
allowed. The daily dose will not exceed 
.     
If IGF-1 suppression as defined above has been achieved with a tolerated dose, the dose will not 
be changed. At any time during study drug dosing, including at V6/W4 and V9/W7, study drug 
dosing may be reduced in a blinded fashion on one occasion if the investigator determines that 
the subject is not adequately tolerating the study drug. In general, a suspected CRN00808-related 
AE sufficient to result in the study drug dose reduction would be expected to be of Grade 3 
(Severe) intensity.   
An unblinded CRO designate will oversee the correct assignment of new blinded dose 
 
 taking into account information from the investigator and from the central IGF-1 reader. 


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Dose Decreases During Titration Period  
At any point during the Titration Period of the study, subjects treated with 
 per day 
who are judged by the investigator as intolerant of the current dose of the study drug should 
undergo a one-time dose reduction (
). Initiation of the lower dose 
may be preceded by up to a 7-day interruption in the study drug dosing as clinically appropriate. 
In subjects whose dose is reduced from 
 per day, a resumption of 
 per day 
may be allowed at the next up titration adjustment opportunity visit (V6/W4 or V9/W7) if IGF-1 
control is inadequate while taking 
 per day and the subject is tolerating the
 dose well. 
Subjects whose dose is reduced from 
 per day will not be allowed to re-challenge 
with 
 dose, however the subject may be allowed to randomize if IGF-1 suppression is 
achieved at V10/W8 and the subject is tolerating the 
 dose as of the V11/W10.   
Subjects who receive the maximal dose of 
 per day at the V9/W7, who are subsequently 
judged to be intolerant of this dose may have their dose reduced to 
 per day, but the subject 
will not be randomized at the V11/W10. 
The Investigator will be responsible for communicating the need for a dose decrease to the 
unblinded CRO delegate. The CRO delegate will oversee the correct assignment of the 
appropriate dose 
 containing the new dose. 
Randomization Withdrawal Period 
Eligibility for randomization into the Randomized Withdrawal Period will be made based on 
information at the V10/W8 and V11/W10. To be eligible for randomization, the subject must 
have V10/W8 IGF-1 value ≤ULN and an investigator determination at V11/W10 that the subject 
is tolerating the study drug. Subjects who do not meet both criteria will not be randomized but 
will be allowed to stay in the study continuing a study drug dose that is tolerated until the subject 
completes all study visits or until criteria to resume standard acromegaly therapy and 
discontinuation from the study are met (see below). The dose of the study drug used at V9/W7 
will remain stable through V11/W10 if tolerated. If determined to be eligible for randomization, 
the subject will be randomized at V11/W10 in a blinded manner to continue the current dose of 
CRN00808 or to be switched to placebo in a 1:1 ratio. 
Randomization will be stratified based on the subject’s prior somatostatin therapy 
(i.e., octreotide LAR or lanreotide depot). Recruiting will continue until approximately 36 subjects 
that have IGF-1 levels ≤ULN at V10/W8 are randomized. Subjects whose IGF-1 is >ULN at V10/W8 
will not be randomized but may continue the study on their V9/W7 dose if tolerated. Subjects 
who do not tolerate a dose of the study drug necessary to achieve IGF-1 ≤ULN will also not be 
randomized but may continue in the study on a tolerated dose. 
Subjects will be monitored throughout the Randomized Withdrawal Period at study visits and will 
return to the study center at the end of W13 (i.e., V14) on the last day of dosing. No further 
treatment with the study drug will be allowed after completion of V14/W13. 
For other details and procedures performed during Treatment Period, refer to Section 5.2 and 
Table 1. 
 


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FOLLOW-UP PERIOD  
During this 4-week-period subjects will attend 2 study visits (V15/W15 and V16/W17) and are 
expected to be off any acromegaly treatment, including CRN00808.  
For other details and procedures performed during the Follow-up Period, refer to Section 5.3 and 
Table 1. 
Criteria for Resumption of Standard Acromegaly Treatment  
At any time during the study drug treatment (Titration Period or Randomized Withdrawal Period), 
a standard acromegaly treatment (e.g., octreotide LAR or lanreotide depot) should be resumed 
if all of the following criteria are met: (a) an increase of at least 50% in serum IGF-1 levels 
compared to baseline*, (b) the IGF-1 level is >ULN and (c) the subject is experiencing a significant 
worsening of symptoms associated with acromegaly. For purposes of this determination, 
symptoms include those defined in Section 6.1.11 and others at the discretion of the Investigator.  
“Significant worsening” in the opinion of the Investigator may be defined as symptoms requiring 
a substantial increase in level of clinical care (e.g., significant intervention needed to avert 
hospitalization or clinically notable increase in frequency or intensity of patient contact required) 
or substantial clinical deterioration (e.g., worsening from a mild to severe AE or the onset of an 
SAE would meet this criteria). 
The investigator will be responsible for reporting such symptoms to the unblinded CRO designate 
within 24 hours. The unblinded CRO designate will determine if the above IGF-1 criteria have 
been met. Subjects meeting all these criteria will be discontinued from the study and an early 
termination visit will be scheduled, prior to resuming standard pharmacotherapy whenever 
possible. 
*During the Titration Period, baseline will be defined as the IGF-1 value measured at V3/W1. 
During the Randomized Withdrawal Period, baseline will be defined as the IGF-1 value measured 
at V11/W10. 
During the Follow Up Period, a standard acromegaly treatment should be resumed if the subject 
experiences significant worsening of acromegaly symptoms (as defined above) and the most 
recent IGF-1 value is >ULN. Such subjects should have a V16/W17 visit performed prior to 
resumption of standard acromegaly treatment whenever possible. These subjects will be 
considered study completers. 
3.2 Study Population 
Approximately 40 adult subjects will be considered for entry into the Treatment Period if they 
meet all the inclusion and none of the exclusion criteria. Recruiting will continue until 
approximately 36 subjects are randomized at V11/W10. 
The subject’s eligibility will be verified by the Investigator and confirmed by the Medical Monitor 
before entry into the Treatment Period. 


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3.2.1 Inclusion Criteria 
Subjects must meet all the following criteria to be eligible for entry into the Treatment Period: 
1. Medically stable male and female subjects 18 to 75 years of age, inclusive, with a 
confirmed acromegaly diagnosis that is controlled (mean of IGF-1 ≤ULN values, as 
confirmed by central laboratory on two occasions measured 1-2 weeks apart during the 
Screening Period) on a stable approved dose of octreotide LAR or lanreotide depot (stable 
defined as no change in dose for the last 3 months); 
2. Diagnosis of active acromegaly confirmed by the Investigator and approved by the 
Medical Monitor. At a minimum, there must be a documentation available of a pituitary 
tumor and elevated IGF-1 in the past. In subjects who have undergone pituitary surgery, 
elevated IGF-1 measured three or more months after surgery must be documented. A 
head MRI (or CT Scan for subjects unable to undergo MRI) with pituitary imaging will be 
performed during the Screening Period unless recent documented scan performed within 
6 months prior to Screening is available; 
3. Subjects with hypothyroidism must be on stable treatment for at least 3 months with 
normal free T4 levels and should be clinically euthyroid at Screening as determined by the 
investigator; 
4. Subjects with adrenal insufficiency must be on adequate adrenal replacement therapy at 
the time of Screening as determined by the investigator; 
5. If the subject is female, she must be of non-childbearing potential (defined as either 
surgically 
sterilized [i.e., 
hysterectomy, 
bilateral 
salpingectomy, 
or 
bilateral 
oophorectomy] or at least 1 year of amenorrhea) OR must agree to use highly effective 
or two clinically acceptable methods of contraception from the beginning of Screening to 
the last study visit. 
• Acceptable highly effective methods of contraception include intrauterine device 
(IUD); intrauterine system (IUS); bilateral tubal occlusion (must be documented); 
non-oral hormonal contraceptives; desogestrel-based progestin-only oral 
contraceptives; 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. Note that simultaneous use of male 
and female condoms with or without any other contraception methods is not 
permitted. Oral hormonal contraceptives containing estrogens are not permitted. 
6. If the subject is male, the subject must use a condom, or his female partner of childbearing 
potential must use an effective form of contraception as described above, from the 
beginning of Screening to the last study visit. Male subjects must also agree not to donate 


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sperm for the duration of the study and until at least 3 months after the last dose of the 
study drug; 
7. Subjects must be willing and able to comply with the study procedures as specified in the 
protocol and comply with the study treatment; 
8. Negative results on a test for the following drugs during Screening: amphetamine, 
barbiturates, cocaine, methamphetamine, methadone, opiates, phencyclidine, and 
methylenedioxymethamphetamine; 
9. Written Informed Consent provided prior to any study related procedures. 
3.2.2 Exclusion Criteria 
Subjects meeting any of the following criteria will be ineligible to participate in the study:  
1. Treatment naïve acromegaly subjects; 
2. Acromegaly subjects who had pituitary surgery within 6 months prior to Screening or who 
have undergone pituitary radiation therapy at any time prior to the study entry. If a 
subject has undergone pituitary radiation therapy ≥4 years prior to Screening and has had 
a documented IGF-1 ≥1.3×ULN within 2 years prior to Screening OR if a subject has 
undergone pituitary radiation therapy between 3 and 4 years prior to Screening and has 
had a documented IGF-1 ≥1.3×ULN within 1 year prior to Screening, the subject may be 
included in the study; 
3. Subjects with any clinically significant concomitant disease including but not limited to 
cardiovascular 
disease; 
moderate 
or 
severe 
renal 
insufficiency 
(eGFR<60 mL/min/1.73 m2); or significant liver disease (including cirrhosis); 
4. History or evidence of any of the following within the previous 6 months: myocardial 
infarction, cardiac surgery revascularization (coronary artery bypass grafting or 
percutaneous transluminal coronary angioplasty), cerebrovascular accident or stroke or 
transient ischemic attack (TIA). Syncope or marked presyncope that is unexplained or 
related to cardiovascular disease within the last 5 years; 
5. Any of the following conditions: personal history of cardiac arrest or long QT syndrome, 
evidence for a familial sudden death syndrome, hemodynamically significant cardiac 
valvulopathy, greater than Canadian Cardiovascular Society Class 1 angina pectoris or 
unstable angina, greater than NYHA Class 1 congestive heart failure, ongoing episodes of 
symptomatic bradycardia (i.e., bradycardia associated with significant dizziness, 
lightheadedness, or loss of consciousness), known history of sustained ventricular 
tachycardia, hemodynamically significant pulmonary arterial hypertension; uncontrolled 
symptomatic supraventricular tachycardia, uncontrolled atrial fibrillation (chronic 
persistent atrial fibrillation that is appropriately rate controlled and anticoagulated is 
acceptable for inclusion), type 2 second degree or third degree atrioventricular block; 


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6. Based on Holter monitor performed during the Screening Period: symptomatic 
bradycardia (i.e., bradycardia associated with significant dizziness, lightheadedness, or 
loss of consciousness), type 2 second degree or third degree atrioventricular block, pause 
>3 sec, sustained ventricular or supraventricular tachycardia, previously undiagnosed 
paroxysmal atrial fibrillation, or torsades de pointes; 
7. Supine systolic blood pressure >150 mmHg and/or supine diastolic blood pressure 
>95 mmHg at Screening (if the initial measurement is out of range, may be repeated 2 
more times after 15 min and exclusion will be based on the average of the three 
measurements); 
8. Resting (at least 10 minutes) palpated pulse rate <50 bpm or >105 bpm at Screening. 
If either of these criteria are met, the assessment should be repeated 2 more times and 
the average should be used to determine the subject’s eligibility; 
9. QTcF interval >450 msec (or QTc >480 msec in the presence of a bundle branch block) or 
PR interval >240 msec at 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 supine for 
at least 10 minutes;   
10. Currently receiving medications that are known to be associated with torsades de pointes 
(Appendix 2 - Medications Associated with Torsades De Pointes) 
11. Currently receiving medications that are known to cause heart rate slowing (beta-blockers, 
verapamil, diltiazem, or ivabradine) if resting heart rate at Screening is <60 bpm; 
12. Currently receiving medications that are strong inducers or inhibitors of CYP3A4 (see 
Protocol Section 4.8.2); 
13. Subjects with autonomic disease (caused by diabetes or Parkinson’s disease); 
14. Subjects with symptomatic cholelithiasis; 
15. Subjects with amylase and/or lipase levels >2×ULN, alanine aminotransferase (ALT) 
and/or aspartate aminotransferase (AST) >2×ULN, total bilirubin >1.5×ULN (except when 
there is known Gilbert’s Syndrome) and/or creatinine >1.5×ULN at Screening. Subjects 
with previously diagnosed Gilbert’s syndrome not accompanied by other hepatobiliary 
disorders and associated with total bilirubin <3 mg/dL (<51.3 µmol/L) and direct bilirubin 
≤ULN will be permitted; 
16. Subjects who have been taking the following prior medications: pegvisomant (within the 
last 3 months), dopamine agonists (within the last 3 months) and pasireotide LAR (within 
the last 6 months); 
17. Subjects taking octreotide LAR at a dose higher than 40 mg or lanreotide depot at a dose 
higher than 120 mg; 
18. Subjects who usually take octreotide LAR or lanreotide depot less frequently than every 
4 weeks (e.g., every 6 weeks or 8 weeks); 


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19. Subjects who have undergone major surgery/surgical therapy for any cause within 
4 weeks prior to Screening; 
20. Subjects with poorly controlled diabetes mellitus defined as having a HbA1c ≥8.5% 
(69 mmol/mol); 
21. Subjects with diabetes treated with insulin for less than 6 weeks prior to the study entry, 
or with an unstable insulin dose in 6 weeks prior to the study entry; 
22. Subjects with clinically significant abnormal findings during the Screening Period, and 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; 
23. Female subjects who are pregnant or lactating. Absence of pregnancy will be confirmed 
by serum human chorionic gonadotropin (hCG) pregnancy test at Screening and a 
negative urine hCG pregnancy test at V3 prior to drug administration; 
24. Subjects with hepatitis B, Human Immunodeficiency Virus (HIV), or hepatitis C infection.  
Subjects with previous hepatitis C infection that is now cured may be eligible; 
25. Subjects with known history of, or current alcohol or drug abuse, within the last 
12 months; 
26. Subjects with any 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; 
27. Subjects with a known allergy or hypersensitivity to any of the test materials or related 
compounds; 
28. Subjects who have been treated with proton pump inhibitors and/or H2 blockers within 
2 weeks prior to Screening;    
29. Subjects with 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; 
30. An employee or immediate family member of an employee of Crinetics; 
31. Participation in any previous trial with CRN00808, except for subjects who have screen 
failed study CRN00808-03; 
32. Subjects who have been dosed with 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. 
3.2.3 Withdrawal, Removal, and Replacement of Subjects  
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 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 
the participation would result in a significant safety risk for that subject. A discontinuation of 


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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. However, if 
subjects meet criteria for resumption of standard acromegaly treatment during the Treatment 
Period, they will need to discontinue from the study.    
In case of early discontinuation of study participation, 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 in the appropriate 
electronic Case Report Form (eCRF). The investigator will record the reason for the study 
discontinuation and provide or arrange for appropriate follow-up and ensure return to standard 
acromegaly treatment for such subject. In addition, the investigator will report the subject’s 
withdrawal to the responsible MM 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 a subject; 
2. Occurrence of adverse events for which study treatment and/or study participation 
discontinuation is desired by the subject or considered necessary by the investigator or 
the MM; 
3. Indication of clinically significant cardiac symptoms or findings (see Section 6.1.7): 
a. 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;  
b. Any ventricular tachyarrhythmia associated with symptoms of hemodynamic 
response; 
c. Sustained ventricular tachycardia (lasting >30 sec) irrespective of symptoms; 
d. Torsades de pointes; 
e. Cardiac arrest; 
f. Pause >5 sec; 
g. Type 2 second degree block or third degree AV block; 
h. New occurrence of clinically significant, symptomatic bradycardia; 
i. An increase in QTcF >75 msec with an absolute QTcF <500 msec (confirmed by the 
central ECG laboratory); 
j. Initiation of a concomitant medication during the Treatment Period which 
prolongs the QT interval (regardless of association with torsades de pointes). 
Medications associated with torsades de pointes (as listed in Appendix 2 - 
Medications Associated with Torsades De Pointes) are exclusionary during the 
screening process and are not allowed as a concomitant medication at any time 
during the study (see Section 4.8.2); 


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k. Any 
supraventricular 
tachyarrhythmia 
associated 
with 
symptoms 
of 
hemodynamic response. 
4. Indication of drug-induced liver injury: 
a. ALT or AST >8×ULN 
b. ALT or AST >5×ULN for more than 2 weeks 
c. ALT or AST >3×ULN and (TBL >2×ULN or INR >1.5) 
d. ALT or AST >3×ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
5. Other clinically significant drug-related abnormalities (e.g., newly developed or 
worsening hyperglycemia, hypersensitivity, symptomatic cholelithiasis, or pancreatitis); 
6. Investigator’s decision (i.e., if in the investigator’s opinion it is not in the best medical 
interest for the subject to continue participation in the study for reasons other than AEs); 
7. Need for administration of a non-permitted concomitant medication; 
8. Any other protocol deviation that may result in a significant risk to the subject’s safety or 
protocol deviations that will interfere with assessment of the efficacy endpoints of this 
study, including subject’s non-compliance with the study procedures/study protocol;  
9. Pregnancy; 
10. Lost to follow-up (the subject stopped coming for visits, and study personnel are unable 
to contact the subject); 
11. Inability to fulfil study requirements and procedures; 
12. Death. 
Enrolment will continue until approximately 36 subjects are randomized. Once this is achieved, 
subjects withdrawn from the study will NOT be replaced. 
3.2.3.1 Termination of Study Participation   
If early study termination is necessary, discontinuation of a subject from the study should be 
discussed with MM in order to plan the transition to a standard treatment. Adverse events 
related to the study drug will be followed for outcome information until resolution or 
stabilization. 
3.2.4 Follow-Up for Drug Discontinuation/Subject Withdrawal from the Study 
If a subject discontinues or is permanently discontinued from study drug treatment, the 
investigator should: 
• Record withdrawal reason in the eCRF;  
• Complete Early Termination Visit (i.e., V16). Whenever possible, this should occur prior 
to resumption of standard acromegaly therapy. Refer to Section 5.3. 
If a subject fails to attend scheduled assessments, the investigator must determine the reasons 
and the circumstances as completely and accurately as possible.  


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If a subject is discontinued from the treatment due to an AE, the investigator will arrange proper 
follow-up with the subject at his/her discretion until the event has been resolved or stabilized. 
For subjects who are lost to follow-up (i.e., subjects whose status is unclear because they fail to 
appear for the study visits without stating an intention to withdraw), the investigator should 
document in the source documents all steps taken to contact the subject (e.g., dates of telephone 
calls, registered letters). 
Subjects who withdraw the informed consent will not have further information or data collected 
from them, with the exception of follow-up information about AEs related to the Investigational 
Medicinal Product (IMP) that are ongoing at the time of withdrawal. Every effort will be made to 
follow up subjects who are withdrawn from the study for SAEs considered related to the IMP. 
If a withdrawal is caused by a Suspected Unexpected Serious Adverse Reaction (SUSAR), it will be 
reported to the Regulatory Authorities and Institutional Review Boards/Independent Ethics 
Committees (IRBs/IECs). 
3.2.5 Discontinuation of the Study 
The Sponsor reserves the right to discontinue the study at any time for any appropriate reason. 
Such reasons may include, but are not limited to, the following:  
• Inefficacy of the study medication;  
• Results from ongoing safety monitoring;  
• Other medical or ethical reasons. 
Regulatory Authorities also have the right to terminate the study for any reason. 
In the event the study is terminated, the IRB/IEC and Competent Authority will be notified of the 
relevant decision. 


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4 TREATMENT PROCEDURES  
4.1 CRN00808 (Investigational Medicinal Product) 
CRN00808 is an orally administered nonpeptide somatostatin agonist that is expected to lower 
serum IGF-1 and GH levels in acromegaly patients.  
 is the active pharmaceutical ingredient.  
 is available as
 (
 Size 2) and 
 (
 Size 2) 
solid dose capsules.  
The IMP contains the following excipients: 
 
 
 
. These excipients are commonly used in solid oral formulations and are Generally 
Regarded as Safe and are found on the FDA Interactive Ingredient Guide (IIG) list. 
The 
 capsules are packaged in 
 and stored at 
 
 
4.2 Placebo (Reference Product) 
Matching placebo capsules are identical in appearance to CRN00808 (available as 
 
capsules [
 Size 2]) and will be orally administered in a double-blinded manner 
according to the randomization scheme on an identical schedule to those receiving CRN00808. 
In the matching placebo, the active ingredient is replaced with the diluents. 
4.3 Packaging and Labeling  
Capsules (
, and matching placebo) will be supplied in 
 
  
The capsules will be manufactured, packaged and labelled according to the principles of Good 
Manufacturing Practices (GMP) and applicable regulatory requirements of each country. 
The study drug labels will be printed in local languages and the label content will comply with 
GMP, Annex 13 to GMP-Guideline “Manufacture of Investigational Medicinal Products” as well 
as specific requirements of each country. The Pharmacy Manual contains all the details and 
instructions for labelling, storage and handling of the IMP and reference. The storage conditions 
for the study drug will be described on the medication label as well.  
4.4 Treatment Assignment and Blinding 
Subjects who are determined to be eligible to enter the study drug Treatment Period will all begin 
treatment with CRN00808 at 
 per day. All subsequent dose changes will be blinded. 
At V11/W10, subjects who are eligible for randomization (see Section 3.1) will be randomly 
assigned to continue CRN00808 vs. switch to placebo in a blinded fashion. Randomization will be 


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stratified based on pre-trial somatostatin therapy (i.e., octreotide LAR or lanreotide depot). 
Approximately 50% of the randomized subjects will have been treated with lanreotide depot pre-
study. The relevant randomization steps will be fully described in a Study Specific Randomization 
Instructions document.   
4.5 Method of Administration  
4.5.1 CRN00808 Dosing and Administration 
CRN00808 will be taken once a day in the morning after an overnight fast (at least 6 hours). 
The subjects must swallow three capsules (Size 2) with water every day. No food will be allowed 
for at least 2 hours after drug administration including time of the study drug administration. 
Subjects should avoid exposure of skin or eyes to direct sunlight or UV light for the duration of 
the study and for at least 10 days after receiving the last dose of study drug. 
Refer to Section 3.1 for dose titration instructions. 
Subjects will be provided with daily diaries in which to record confirmation of fasting prior to 
dosing and for two hours after dosing including the time of the study drug administration; time 
of last meal prior to study drug administration; and time of meal following fasting.  
For details regarding the study drug administration, refer to Pharmacy Manual. 
Additional information about the study drug is provided in the current version of the IB. 
4.5.2 Placebo Dosing and Administration 
Matching placebo will be taken in the same manner as CRN00808 (i.e., orally administered, 
swallowed with water under fasting conditions). No food will be allowed for at least 2 hours after 
drug administration.  
Subjects will be provided with daily diaries in which to record confirmation of fasting prior to 
dosing and for two hours after dosing including time of study drug administration. 
4.5.3 Background Medication 
Subjects will receive their final injection of pre-trial acromegaly medication (octreotide LAR or 
lanreotide depot) during screening at V1b, approximately 4 weeks prior to entry into the 
Treatment Period of the study (V3). 
4.6 Study Drug Supply, Storage and Tracking  
Study drug must be received by the appointed study staff at the study site that 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. Clinical supplies will 
be provided by the Sponsor and are to be dispensed only in accordance with the protocol. 
An accurate inventory and accountability records of the study drug will be kept by the appointed 
team member.    


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All drug supplies will be provided by the Sponsor and the logistics of supply would be managed 
by the Sponsor/appropriate designee. The study drug will be provided with appropriate labelling.  
The capsules are to be stored at 
. 
All study drug should be stored and inventoried according to applicable state and federal 
regulations and study procedures. 
At the end of the study (i.e., close-out visit) and following reconciliation and documentation by 
the site monitor, all study drugs and related materials will be either returned to the Sponsor or a 
designee, or destroyed locally following the review and approval of the site’s destruction 
procedures. 
The study drugs (sufficient to last until the next planned visit) will be dispensed by the appointed 
study staff to the subjects at relevant study visits and should be stored at controlled
 
 out of reach of children. The storage conditions will be carefully 
described to the subjects. 
Full details concerning accountability, tracking and recording will be provided in a Pharmacy 
Manual. 
4.7 Drug Accountability and Treatment Compliance 
The appointed team members will be identified at each center whose role in the study will be 
handling of the study drugs (i.e., they will be responsible for the receipt and accountability of the 
study drug). Furthermore, other tasks can be delegated to them in a clear manner by the Principal 
Investigator and that will be documented and completed in the Study Staff Signature Verification 
Form. 
Records of the study drugs used, dosages administered, and intervals between visits will be kept 
during the study. 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. A compliance check will be performed by counting the capsules returned 
at each study visit. All returned study drug and study drug materials should be stored, 
inventoried, reconciled, and returned according to applicable local regulations and study 
procedures. 
4.8 Medical History and Prior/Concomitant Medications  
The investigator should document medications, medical conditions, prior illnesses with 
diagnosis(es), surgeries, allergies that the subject has experienced before the study entry, i.e., 
before signing ICF, as well as ongoing illnesses in the eCRF Medical History Page. Additional 
illnesses present from the time when ICF is signed and up to the end of the study are to be 
documented as AEs on the eCRF Adverse Event Page.  


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Prior medication/therapy (i.e., any therapy given within 3 months before signing Informed 
Consent) and each medication/therapy that is ongoing will be recorded in the eCRFs 
Prior/Concomitant Medications or Non-Pharmacological Treatment Page.  
Concomitant therapy is considered any medication other than the investigational or reference 
product that is administered at any time from the first day of the study medication administration 
until the end of the study. For details, refer to eCRF completion guideline. 
In case a new concomitant therapy becomes necessary during the study, this must be 
documented and appropriately listed within the Prior/Concomitant Medications or Non-
Pharmacological Treatment Page in the eCRF. 
Any change in concomitant medication after signing the ICF must be recorded in the eCRF, noting 
the type of medication, the dose, route, duration, and indication. If during the study, the 
administration of a prohibited concomitant medication (see below) is deemed to be medically 
necessary, the subject will need to discontinue from the study. 
All subjects should agree to the following restrictions during the study: 
• Not to start any new prescription medication, except as prescribed or approved by the 
investigator or if required in an emergency; 
• Not to start any over-the-counter medication, homeopathic preparations, or herbal 
supplements, except as instructed or approved by the investigator. 
4.8.1 Permitted Concomitant Medications 
Concomitant medications allowed in this study are those non-prohibited medications used at 
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 medical file and 
on the appropriate eCRF page. If a new medication should become necessary for any reason 
during the course of the study, the subject is required to inform the Investigator immediately, 
who will record the drug, the dose and the time of administration in the subject’s eCRF. 
4.8.2 Prohibited Concomitant Medications 
Any questions regarding prohibited medications should be discussed with the Medical Monitor 
or appropriate designee. 
• Oral estrogens (including estrogen-containing oral contraceptives); 
• Proton pump inhibitors, H2 blockers;  
• OTC antacids ([alkali based that directly neutralize hydrogen ions] or other drugs that can 
inhibit gastric acid secretions shall be restricted 4 hours before and after administration 
with CRN00808); 
• Strong inducers of the drug metabolizing enzyme CYP3A4, including but not limited to: 
carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort; 
• Strong inhibitors of the drug metabolizing enzyme CYP3A4, including but not limited to: 
boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and ritonavir, 


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grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and 
ritonavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, 
ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, troleandomycin, 
voriconazole, clarithromycin, diltiazem, idelalisib, nefazodone, nelfinavir; 
• Any drug that is used for the treatment of acromegaly including but not limited to 
octreotide, lanreotide, pasireotide, cabergoline, bromocriptine, pegvisomant;  
• QT-prolonging drugs known to be associated with torsades de pointes (as listed in 
Appendix 2 - Medications Associated with Torsades De Pointes). Drugs that are associated 
with QT interval prolongation regardless of listed association with torsades de pointes or 
drugs that cause heart rate slowing should prompt study drug cessation and discussion of 
the case with the Medical Monitor within 24 hours (see Section 6.1.7); 
• Medications that are known to cause heart rate slowing (e.g., beta-blockers, verapamil, 
diltiazem, or ivabradine) may be started during the study if resting pulse is ≥60 bpm and 
if approved by the Medical Monitor. An unscheduled ECG should be performed 
approximately 5 days after starting the new medication to assess HR and QTcF. 
• Any other investigational drug. 
4.9 Contraception 
If the subject is female, she must be of non-childbearing potential (defined as either surgically 
sterilized [i.e., hysterectomy, bilateral salpingectomy, or bilateral oophorectomy] or at least 
1 year of amenorrhea) OR must agree to use highly effective or two clinically acceptable methods 
of contraception from the beginning of Screening to the last study visit. 
Acceptable highly effective methods of contraception include intrauterine device (IUD); 
intrauterine system (IUS), bilateral tubal occlusion (must be documented); non-oral hormonal 
contraceptives; desogestrel-based progestin-only oral contraceptives; 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. Note that simultaneous use of male and female condoms 
with or without any other contraception methods is not permitted. Oral hormonal contraceptives 
containing estrogen are not permitted. 
If the subject is male, the subject must use a condom, or his female partner of childbearing 
potential must use an effective form of contraception as described above, from the beginning of 
Screening to the last study visit. Male subjects must also agree to not donate sperm for the 
duration of the study and until at least 3 months after the last dose of the study drug. 
 
 


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5 STUDY PROCEDURES 
Table 1 outlines the timing of the procedures and assessments to be performed throughout the 
study. Additional details of the study procedures are given below. Designated visits as noted in 
Table 1 may be performed either at the study center, via telephone contact, and/or in the 
subject’s home or suitable alternate location by qualified study staff. 
5.1 Screening Period (V1a, V1b, V2) 
Prior to performing any study-related procedures, the investigator (or his/her designated staff 
member) will obtain written Informed Consent from the subject.  
The Screening Period will last 4-6 weeks in order to collect current clinical data and to perform 
all required investigations needed to verify subject’s eligibility for the study and to obtain 
baseline data on the subject’s acromegaly symptoms. See Section 3.1 for more information about 
the Screening Period. Note that Visit 1a and Visit 1b may either be combined into a single 
visit/day or may be separated by as much as two weeks. 
During this period, the subject will have at least 2-3 study visits. The following assessments, 
procedures and data collection will be performed during the Screening Period:  
• Obtaining written Informed Consent (V1a) - to be completed before any other study 
procedure;  
• Eligibility verification (V2); 
• Medical history/Acromegaly History (V1a);  
• Complete physical examination (including weight, height and ring size, at V1a);  
• Vital signs (V1a and V2);  
• 24-hour-outpatient Holter will be conducted during Screening. An adequate Holter 
recording should be confirmed by the central laboratory as soon as possible after 
completion, so that a repeat Holter monitor may be performed, if necessary, prior to 
Treatment Period;  
• 12-lead ECG in triplicate (V1a and V2);  
• Serum pregnancy test (applicable only for women of childbearing potential, at V1a); 
• HBV, HCV and HIV testing (V1a);  
• Assessments of routine safety, hematology and biochemistry (including HbA1c) – non-
fasting (V1a); 
• Urinalysis (V1a)  
• Urine drug screen (V1a);   
• Head MRI with pituitary imaging (if a recent documented scan conducted within 6 months 
of V1a is not available);  
• Injection of pre-trial pharmacotherapy (octreotide LAR or lanreotide depot, at V1b) 


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• Measurement of GH, levels (integrated [set of three values taken at least 30 minutes apart 
over 2 hours]), sample set 1: at V1b (prior to dosing with the depot), sample set 2: at V2; 
• Measurement of IGF-1 levels and 
levels, sample 1: at V1b before the last depot 
dose; sample 2: at V2, 7-14 days after the last depot dose);  
• Assessment of hormones (fT3, fT4, thyroid antibody, TSH, cortisol, ACTH, LH, FSH, and 
prolactin, at V1b before the last dose of depot);  
• Residual octreotide/lanreotide plasma sample (V1b before the last depot dose and V2);  
• Gall bladder ultrasound completed by V2, (if a recent documented ultrasound within 
3 months of V1a is not available); 
• Acromegaly baseline investigator assessed symptoms (at the study entry, at V1a ONLY); 
• AE assessment (V1a, V1b, and V2), including investigator assessed changes in symptoms 
of acromegaly (V1b and V2);  
• 
 (V1a, V1b, and V2); 
• 
daily beginning the day after V1b through V3); 
• Prior and concomitant medication review (V1a, V1b, and V2).  
5.1.1 Screening 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 in the 
appropriate eCRF page.  
Subjects who have screen failed based on findings which are felt by the investigator to be 
temporary and not reflective of the usual state of the patient (e.g., HbA1c of >8.5% when the 
subject is usually well below 8.5%) can be considered for re-screening. These cases should be 
discussed with the Medical Monitor. 
Subjects who screen fail based on their IGF-1 results may be considered for screening in the 
CRN00808-03 study.   
Subjects who have screen failed study CRN00808-03 will be discussed with the medical monitor 
and when possible, previously obtained screening information may be used for the purpose of 
eligibility determination for study CRN00808-02. Informed consent for CRN00808-02 is required 
to be obtained prior to initiating any new CRN00808-02 procedures.  
5.1.2 Re-screening  
The decision on re-screening will be made on a case by case basis by the PI in consultation with 
the MM. Re-screened subjects will receive a new subject number. A subject who is re-screened 
must meet all inclusion and exclusion criteria as part of their re-screening to be eligible for the 
study. The separate subject numbers for the same subject will be linked. 


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5.2 Treatment Period  
During this 13-week-period, subjects will self-administer the study drug once daily in the morning 
after an overnight fast [at least 6 hours] and fasting will continue for at least two hours post-
dose. The study drug will be administered at approximately the same time. However, the study 
drug is to be administered at the study center at V3/W1, V6/W4, V9/W7, V11/W10, and 
V14/W13. The first dosing with the study drug will occur on V3/W1 (approximately 4 weeks 
following the last depot dose at V1b) after all relevant procedures have been completed. The 
subjects are expected to swallow three capsules (Size 2) with water every day.  
Subjects will not be allowed to change their routine exercise regimen during the course of the 
study. See Section 3.1 for more information about the Treatment Period. 
In case of early termination, all efforts to perform the V16/Early Termination assessments 
should be taken. 
The allowed visit window in the treatment period is ±2 days for most visits. The exceptions are 
V4 and V7 for which the visit window is +4 days, V11 for which the visit window is ±1 day, V13 
which can occur on D85-D86, and V14 which can occur on D90-91. In addition, Visit 7 and Visit 10 
must be at least 7 days after Visit 6 and Visit 9, respectively. 
During this period there will be 12 study visits when the following assessments, procedures and 
data collection will be performed: 
V3 (W1/D1) prior to the first dosing 
• Eligibility verification (inclusion/exclusion criteria);  
• Complete physical examination (including weight and ring size);  
• Vital signs;  
• 12-lead ECG (in triplicate);  
• Urine pregnancy test (applicable only for women of childbearing potential); 
• Assessments of routine safety, hematology, lipid panel, HbA1c, and biochemistry 
parameters – to be drawn fasting; 
• Urinalysis;  
• Genotype blood sample (it will be collected for characterizing UGT1A1 genotype; subjects 
may opt out of this testing);  
• Measurement of IGF-1 levels, sample 3: before the first dose of the study drug;  
• 
 questionnaires;  
• Study drug dispense (a 3-week-supply of the 
 dose of the study drug sufficient to 
last until V6; one card/week); 
• AE assessment, including changes in symptoms of acromegaly;  
• 
; 
• Concomitant medications; 
• Study drug administration at the study center.  


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V4 (W2/D8), V6 (W4/D22), V7 (W5/D29), V9 (W7/D43) and V10 (W8/D50) 
• Symptom directed physical examination; 
• Vital signs;  
• 12-lead ECG (in triplicate, ONLY on V4, V7 and V10);  
• Urine pregnancy test (ONLY on V6 and V9); 
• Assessments of routine safety, hematology and biochemistry parameters – V6 and V9 to 
be drawn fasting; 
• Urinalysis;  
• Measurement of GH levels (integrated [set of three values taken at least 30 minutes apart 
over 2 hours]): sample set 3: at V4 (1-15 hours post dose), sample set 4: at V7 (1-15 hours 
post dose), sample set 5: at V10 (1-15 hours post dose); 
• Measurement of IGF-1 levels, sample 4: at V4 (1-15 hours post dose); sample 6: at V6 
(prior to dosing); sample 7: at V7 (1-15 hours post dose); sample 9: at V9 (prior to dosing); 
sample 10: at V10 (1-15 hours post dose).  
• Measurement of 
 levels will be done only for sample 4, sample 7 and sample 10; 
• PK plasma sample (pre-dose and 2 hours (+/- 15 min) post-dose at V6 and V9; 1-15 hours 
post-dose at V4, V7 and V10);  
• Study drug dispense (V6: TITRATION 3-week-supply (3 cards; one card/week), 
V9: TITRATION 3-week-supply (3 cards; one card/week)); 
• Study drug return and accountability; 
• AE assessment, including changes in symptoms of acromegaly;  
• 
; 
• 
 (daily beginning the day after V10 through V11 ONLY); 
• Concomitant medications; 
• Assessment of tolerability for potential dose up-titration (V6 and V9 only); 
• Dose titration decision (ONLY on V6 and V9); 
• Study drug administration at the study center (V6 and V9 ONLY).  
V5 (W3/D15), V8 (W6/D36) - Phone Call Assessment 
• AE assessment, including changes in symptoms of acromegaly;  
• 
; 
• Concomitant medications; 
• Assessment of tolerability for potential dose up-titration; 
 V11 (W10/D64) and V14 (W13/D90-91) – Randomized Withdrawal Period 
• Confirmation of tolerability and randomization (ONLY on V11); 
• Complete physical examination (ONLY on V11) (including weight and ring size);  


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• Symptom directed physical examination (ONLY on V14). Ring size should be measured 
on V14; 
• Vital signs;  
• 12-lead ECG (in triplicate, ONLY on V14);  
• Urine pregnancy test; 
• Assessments of routine safety, hematology, lipid panel, HbA1c, and biochemistry 
parameters – to be drawn fasting; 
• Urinalysis;  
• Assessment of hormones (fT3, fT4, thyroid antibody, TSH, cortisol, ACTH, LH, FSH and 
prolactin);  
• Measurement of GH levels (integrated [set of three values taken at least 30 minutes apart 
over 2 hours]): sample set 6: at V14/D90-91 (1-8 hours post dose); 
• Measurement of IGF-1 levels, sample 11: at V11 (prior to dosing); sample 14: on the last 
day of dosing in W13 (V14) (prior to dosing).  
• Measurement of 
 levels will be done for sample 11 and sample 14; 
• PK plasma sample (pre-dose and 2 hours (+/- 15 min) post-dose at V11 and 1-8 hours post 
dose at V14);  
• Residual octreotide/lanreotide plasma sample; 
• Gall bladder ultrasound (ONLY on V11); 
• 
;  
• Study drug dispense (a 4-week-supply of the study medication [either placebo or active 
drug in a double-blinded fashion], 4 cards; one card/week, ONLY on V11); 
• Study drug return and accountability; 
• AE assessment, including changes in symptoms of acromegaly;  
• 
;  
• 
; 
• Concomitant medications; 
• Study drug administration at the study center. 
V12 (W11/D71), V13 (W13/D85-86) 
• Measurement of IGF-1 levels:  
o sample 12: at V12 (1-15 hours post dose); 
o sample 13: at V13 (prior to dosing, with at least 3 days apart from sample 14); 
• AE assessment, including changes in symptoms of acromegaly;  
• 
;  
• 
(daily beginning the day after V12 through V14); 
• Concomitant medications. 


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5.3 Follow-up Period 
During this 4-week-period, subjects are expected to be off all acromegaly treatment, including 
CRN00808. At the end of this period, all subjects should resume their standard acromegaly 
treatment as clinically appropriate. 
If a subject meets criteria for resumption of standard acromegaly treatment during the Follow-
Up Period (see Section 3.1), the subject should undergo V16 procedures prior to resuming 
standard acromegaly treatment whenever possible. Such subjects will be considered study 
completers.   
The allowed visit window in the follow-up period is ±2 days. 
During this period there will be 2 study visits when the following assessments, procedures and 
data collection will be performed: 
V15 (W15/D105 and V16 (W17/D119) 
• Complete physical examination (including weight and ring size – ONLY on V16);  
• Symptom directed physical examination (ONLY on V15); 
• Vital signs;  
• 12-lead ECG (in triplicate, ONLY on V16);  
• Urine pregnancy test (ONLY on V16); 
• Assessments of routine safety, hematology and biochemistry parameters (including 
HbA1c and lipid panel at V16 only) – V16 to be drawn fasting; 
• Urinalysis;  
• Measurement of GH levels (integrated [set of three values taken at least 30 minutes apart 
over 2 hours]): sample set 7: at V16 or early termination (anytime);   
• Measurement of IGF-1 levels, sample 15: at V15 (anytime), sample 16: at V16 (anytime). 
• Measurement of 
levels will be done only for sample 16;  
• PK plasma sample;  
• 
, ONLY at V16;  
• AE assessment, including changes in symptoms of acromegaly;  
• 
;  
• 
; 
• 
 (daily beginning the day after V15 through V16); 
• Concomitant medications; 
• Re-institute standard acromegaly treatment as clinically appropriate (V16) after all study 
procedures have been completed. 
 


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5.4 Unscheduled visits  
Unscheduled visits are those visits that occur between regularly scheduled visits. Reasons for 
unscheduled visits may include, but are not limited to, follow up of adverse events or abnormal 
laboratory results. In such cases, the investigator may at his/her discretion arrange for a subject 
to have an unscheduled visit. The unscheduled visit page in the eCRF must be completed.  
 
    






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the start of the Randomized Withdrawal Period (i.e., W10). Such subjects should have all the V16 assessments performed prior to the resumption of standard 
acromegaly treatment whenever possible. 
d During the RANDOMIZED WITHDRAWAL PERIOD (W10-W13), subjects will receive either placebo or active drug in a double-blinded fashion. 
e Day 1 is the first day of dosing in Week 1. This will occur approximately 4 weeks after V1b, when the last dose of depot was administered. 
f Final visit for subjects who have completed the study. In case of early termination, V16 assessments will be performed. 
g Blood pressure, pulse rate, respiratory rate, and body temperature. All measurements are to be taken at rest. 
h An outpatient 24-hour Holter monitor recording will be conducted during Screening. An adequate Holter recording should be confirmed by the central 
laboratory as soon as possible after completion, so that a repeat Holter monitor may be performed, if necessary, prior to Treatment Period.   
i A standard 12-lead ECG will be performed in triplicate (approximately 1 minute apart) after the subject has rested quietly in the supine position for at least 
10 minutes without significant stimulation (noise, TV, etc.). It will be performed at V1a, V2, V3 (pre-dose), V4, V7, V10, V14 and V16 only. When possible, the ECGs 
should be performed while fasting approximately 2 hours after the study drug dosing. 
j Applicable only for women of childbearing potential. Serum pregnancy tests (S) will be done at Screening. A urine pregnancy test (U) will be done prior to starting 
dosing on D1 and other visits as indicated above.  
k Samples for clinical laboratory tests including hematology, biochemistry, and urinalysis will be obtained after overnight fast except at Screening, V4, V7, V10, 
and V15 which can be drawn fasting or non-fasting. HbA1c will be drawn at V1a, V3, V11, V14, and V16/ET only. Fasting lipid profile will be drawn at V3, V11, V14 
and V16/ET only. 
l Blood sample for genotyping will be analyzed for randomized subjects only and will be collected for the determination of the UGT1A1 genotype. Subjects may 
opt out of this testing. 
m Head MRI with pituitary imaging will be performed. A recent documented scan conducted within 6 months of V1a is acceptable. The MRI should be documented 
at V2 or if necessary as late as Day -1 (prior to the Treatment Period). Pituitary CT scanning may serve as an alternative to MRI for subjects who are not eligible 
for MRI scanning. 
n Integrated is defined as three values taken at least 30 min apart over 2 hours. The following serum GH (integrated) samples will be collected: Screening Period: 
sample set 1: at V1b (prior to dosing with the depot), sample set 2: at V2 (anytime), Treatment Period: sample set 3: at V4 (collected 1-15 hours post study drug 
dose), sample set 4: at V7 (collected 1-15 hours post study drug dose), sample set 5: at V10 (collected 1-15 hours post study drug dose), Randomized Withdrawal 
Period: sample set 6: at V14/D90-D91 (collected 1-8 hours post study drug dose), Follow-up Period: sample set 7: at V16 or early termination (anytime).   
o Serum IGF-1 levels will be collected twice during the Screening Period (sample 1: at V1b before the last depot dose; sample 2: at V2, 7-14 days after the last 
depot dose). Once at Baseline (sample 3: at V3 before the first dose of the study drug). Treatment Period: sample 4: at V4 (1-15 hours post study drug dose); 
sample 6: at V6 prior to dosing; sample 7: at V7 (1-15 hours post study drug dose); sample 9: at V9 (prior to dosing); sample 10: at V10 (1-15 hours post study 
drug dose). Randomized Withdrawal Period: sample 11: at V11 (prior to dosing); sample 12: at V12 (1-15 hours post study drug dose); sample 13: at V13 (prior 
to dosing); sample 14: at V14 (prior to dosing). In W13 sample 13 and sample 14 are to be collected at least 3 days apart, where the sample 14 at V14 will be 
collected on the last day of study drug dosing. Follow-up Period: sample 15: at V15 (anytime); sample 16: at V16 (anytime). Note: Sample 5 and sample 8 
collections were eliminated as part of protocol Version 3.0; however, the original numbering of the samples was retained. 
levels will be measured only for samples 1 (V1b), 2 (V2), 4 (V4), 7 (V7), 10 (V10), 11 (V11), 14 (V14) and 16 (V16). 
p Gall bladder ultrasound is to be performed during Screening (by V2 if a recent documented ultrasound conducted within 3 months of V1a is not available), and 
on V11. 


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q PK sample should be collected at the following time-points: pre-dose and 2 hours (+/- 15 min) post-dose at V6, V9, and V11; 1-15 hours post-dose at V4, V7, 
and V10; 1-8 hours post-dose at V14; and anytime on V15 and V16. Dosing times will be recorded in eCRF on the days during the Treatment Period when blood 
PK samples are collected. 
r Acromegaly symptoms will be assessed by investigator site staff as described in Section 6.1.11. 
s Subjects will self-administer the study drug once daily (in the morning after an overnight fast of at least 6 hours and fasting will continue for at least two hours 
post-dose. The study drug will be administered daily at approximately the same time of day. At visits V3, V6, V9, V11, and V14, the study drug is to be administered 
at the study center. The subject will record the daily date and time of dosing on the diary provided. 
t At each study visit during the Treatment Period a compliance check will be performed by counting the capsules remaining. At study center visits, subjects will 
return all used and unused study drug. 
u At V6/W4 and V9/W7 the dose may be up-titrated up in a blinded fashion (see Section 3.1) 
v As clinically indicated in the judgement of the investigator. 
w Ring size should be measured at the V14 during symptom directed physical examination. 
x Quality of Life Questionnaires will be completed by the subject at designated study visits prior to performing other study procedures. See Section 6.1.13. 
y Subjects will complete the
 at home on a daily basis beginning the day after V1b through V3; daily beginning the day after V10 
through V11; daily beginning the day after V12 through V14; and daily beginning the day after V15 through V16. Please see Section 6.1.12. 
z 
 will be completed by the subject at designated study visits after Quality of Life questionnaires and prior to other study procedures. See Section 
6.1.14. 
 


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6 SAFETY ANALYSIS 
6.1 Safety Assessments 
Safety assessments will consist of monitoring and recording all adverse events (AEs), including 
serious adverse events (SAEs), complete physical examination, vital sign assessment, ECG 
recording, outpatient 24-hour Holter, clinical laboratory results (hematology, biochemistry 
(including HbA1c), hormone levels, urinalysis, GH and IGF-1 levels, and gall bladder ultrasound. 
6.1.1 Adverse Events  
An adverse event (AE) is any undesirable sign, symptom or medical condition, whether or not 
considered drug related and occurring after the moment of signing ICF. Information about all AEs, 
whether volunteered by the subject, discovered by Investigator questioning, or detected through 
physical examination, laboratory test or other means, will be collected and recorded on the AE 
eCRF page and followed as appropriate.  
All medical conditions present prior to the study entry will be documented in the Medical History 
eCRF. 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.  
The investigator is obliged to interview a subject at every visit and clarify/discuss with him/her 
any abnormality that may indicate any potential AE. 
Subjects should be informed that they do not have to wait for scheduled visits to report AEs. 
Adverse events will be recorded from after the moment of signing ICF, up to 4 weeks after the 
last dose of the study medication. All AEs occurring after the study drug administration has 
started will be considered as Treatment-emergent Adverse Events (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. 
Any AE that occurs in the course of a clinical study must be monitored and followed up until: 
• it has resolved; 
• laboratory abnormalities have returned to normal; 
• steady state of the symptoms has been achieved. 
It is the responsibility of the investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. 
As far as possible, each AE will also be described by: 
• its duration (start and end dates); 
• the severity grade; 
• its relationship to the study drug; 
• the action(s) taken;  
• the outcome. 


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If there is a change in severity of an AE, it must be recorded as a separate event. Any change in 
severity should be recorded in the source data and eCRF accordingly until a stop date is provided. 
Specific guidelines for classifying AEs by intensity and relationship to the IMP are given in Table 
2 and Table 3. 
Table 2 - Classification of Adverse Events by Intensity 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated (AE is transient and easily tolerated by the subject) 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental daily activities (AE causes the subject discomfort and interrupts the 
subject's usual activities) 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care daily activities 
 
An AE that is assessed as severe should not be confused with a SAE. Severity is a category utilized 
for rating the intensity of an event; both AEs and SAEs can be assessed as severe. An event is 
defined as “serious” when it meets 1 of the pre-defined outcomes as described below in Protocol 
Section 6.1.2. 
The following judgments of the causal relationship are to be used as described in Table 3.   
The investigator will assess any causal relationship of an AE with respect to the IMP. 
Table 3 - Classification of Adverse Events by Relationship to Investigational Medicinal Product 
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 two 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 two 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 
three of the following criteria: (1) it follows a reasonable temporal sequence from 
administration of the IMP; (2) it could not be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the subject; (3) it disappears or decreases on cessation or reduction 
in dose. There are exceptions when an AE does not disappear upon discontinuation of the IMP, 
yet drug-relatedness clearly exists (e.g., as in bone marrow depression, fixed drug eruptions, 
or tardive dyskinesia); or (4) it follows a known pattern of response to the IMP. 
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. 
 
AE outcome 
If the same AE occurs several times in the same subject, then the AE in question must be 
documented and assessed as a new event for each new occurrence unless the event is considered 
to be a continuation of the previously reported event rather than reoccurrence of the event. 
Outcome of the AE will be recorded as defined in Table 4. 
Table 4 - Adverse Event Outcome 
1. 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. 
2. 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. 
3. 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. 
4. 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. 


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5. Continuing with Changed Intensity - One of the possible results of an adverse event 
outcome where the subject experiences a continuation of an AE but its severity is either 
increased or decreased compared to last report. 
6. Fatal - The AE directly caused death. Record the date of death as the AE stop date. 
0. Unknown - There is an inability to access the subject or the subject’s records to determine 
the outcome (i.e., subject withdraws consent or is lost to follow-up). No AE stop date should 
be recorded. 
6.1.2 Serious Adverse Events  
An AE is considered “serious” if in the view of either the investigator or Sponsor, it meets one or 
more of the following criteria:  
• Is fatal; 
• Is life-threatening; 
• Results in subject hospitalization or prolongation of existing hospitalization; 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• Is a congenital anomaly/birth defect; 
• Is an important medical event. 
Important medical events are those that may not be immediately life-threatening or result in 
death or hospitalization, based upon appropriate medical judgment, are considered SAEs if they 
are thought to jeopardize the subject and/or require medical or surgical intervention to prevent 
one of the outcomes defining an SAE.  
Since SAEs are critically important for the identification of significant safety problems, it is 
important to take into account both the investigator’s and the Sponsor’s assessment. If either 
the Sponsor or the investigator believes that an event is serious and related to IMP (i.e., assessed 
as possibly, probably, or definitely related), the event must be considered serious and evaluated 
by the Sponsor for expedited reporting.   
Information about all SAEs will be collected and recorded on the Serious Adverse Event Report 
Form and must be reported to Contract Research Organization (CRO) Pharmacovigilance group 
within 24 hours of learning of its occurrence. 
Events not to be reported as SAEs are hospitalizations for the following:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition; 
• treatment, which was elective or pre-planned, for a pre-existing condition that is 
unrelated to the indication under study and did not worsen; 


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• admission to a hospital or other institution for general care, not associated with any 
deterioration in condition; 
• treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of SAE given above and not resulting in hospital admission.  
Any SAE occurring after the moment of signing ICF and up until 4 weeks after the last dose of the 
study medication must be reported to the CRO’s Pharmacovigilance Unit. SAEs occurring after 
the study termination must be reported only if considered IMP related as per investigator 
judgment.    
Instructions about completing initial and follow-up SAE Report Forms and reporting to the CRO 
are given in Section 9.1.1 Serous Adverse Event Reporting. 
6.1.3 Physical Examination 
A complete physical examination that includes assessment of head (external), eyes, ears, nose 
and throat (HEENT), lungs, cardiovascular system, abdomen, musculoskeletal system, skin, lymph 
nodes, central nervous system, ring size, and, where appropriate, other body systems, will be 
performed at Screening (V1a), V3, V11 and V16 as indicated in the relevant table.  
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. 
At V4, V6, V7, V9, V10, V14 and V15 a symptom related physical examination (with weight 
measurement as appropriate) will be performed. Ring size should be measured at V14. 
Any confirmed clinically significant physical examination abnormalities occurring after the 
moment of signing ICF are to be recorded as AEs. 
6.1.4 Vital Signs  
Vital signs (blood pressure at rest, pulse rate, respiratory rate and body temperature) will be 
assessed as per standard practice at relevant study visits as indicated in Table 1. 
Blood pressure (resting) should be measured with calibrated digital equipment in the supine 
position after resting quietly for 5 minutes.   
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur. Out-of-range 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. 
6.1.5 ECG Assessment  
A standard 12-lead ECG will be performed in triplicate (approximately 1 minute apart) after the 
subject has rested quietly in the supine position for at least 10 minutes without significant 
stimulation (noise, TV, etc.) will be performed at V1a, V2, V3 (pre-dose), V4, V7, V10, V14 and 
V16 only. When possible, the ECGs should be performed while fasting approximately 2 hours 


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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. However, only ECG results provided by the central reader will be 
recorded in the eCRF and clinical database. 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. 
6.1.6 Outpatient 24-hour Holter 
An outpatient 24-hour Holter monitoring and recording will be conducted during the Screening 
Period. An adequate Holter recording should be confirmed by the central laboratory as soon as 
possible after completion, so that a repeat Holter monitor may be performed, if necessary, prior 
to Treatment Period.  
6.1.7 Cardiovascular Safety Monitoring 
Cardiology consultation should be obtained within 7 days for new clinically important symptoms 
or findings judged by the investigator reasonably likely to be of cardiac origin, e.g., evidence for 
new arrhythmia, significant chest discomfort/pain, presyncope or syncope. 
Study drug must be stopped, and the medical monitor notified within 24 hours for any of the 
following: 
• 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 sec) irrespective of symptoms; 
• Torsades de pointes; 
• Cardiac arrest; 
• Pause >5 sec; 
• Type 2 second degree block or third degree AV block; 
• New occurrence of clinically significant, symptomatic bradycardia; 
• An increase in QTcF >75 msec with an absolute QTcF <500 msec (confirmed by the central 
ECG laboratory); 
• Initiation of a concomitant medication during the Treatment Period which prolongs the 
QT interval (regardless of association with torsades de pointes). Medications associated 
with torsades de pointes (as listed in Appendix 2 - Medications Associated with Torsades 


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De Pointes) are exclusionary during the screening process and are not allowed as a 
concomitant medication at any time during the study (see Section 4.8.2); 
• Any supraventricular tachyarrhythmia associated with symptoms of hemodynamic 
response. 
The MM and investigator will determine the appropriateness of any further study drug dosing 
after stabilization of any of the above events. 
Medications that are known to cause heart rate slowing (beta-blockers, verapamil, diltiazem, or 
ivabradine) may be started during the study if resting pulse is ≥60 bpm and if approved by the 
Medical Monitor. An unscheduled ECG should be performed approximately 5 days after starting 
the new medication to assess HR and QTcF.  
6.1.8 Laboratory Assessments 
All analyses must be done with the minimally required blood amount and the number of needle 
insertions should be minimized during the blood collection.  
With the exception of the screening visit, V4, V7, V10, and V15, all clinical laboratory assessments 
will be obtained from fasted subjects. 
All laboratory samples will be shipped to Q2 Solutions. 
Laboratory management 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 PK, GH, IGF-1 and 
) 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 and the data recorded in the eCRF. 
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 6.1.1.  
Hematology, HbA1C 
The complete blood count (CBC) with differentials will be evaluated as one of the safety 
parameters. The full panel of hematology analysis will comprise the following parameters: 
hemoglobin (Hgb), hematocrit (HCT), red blood cell (RBC) count, white blood cell (WBC) count 
with differential [neutrophils (Ne), eosinophils (Eo), basophils (Ba), monocytes (Mono) and 
lymphocytes (Lym)], and platelets (PLT), mean corpuscular hemoglobin (MCH), Mean corpuscular 
hemoglobin concentration (MCHC), mean corpuscular volume (MCV), will be evaluated at study 
visits, as indicated in the relevant table.  
HbA1C will also be evaluated from this sample. HbA1c will be measured at selected visits as 
indicated in Table 1. 


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Serum chemistry 
Blood collected for serum chemistry will be evaluated at study visits, as indicated in Table 1. 
The following parameters will be evaluated: total protein, urea, creatinine, uric acid, sodium, 
potassium, chloride, calcium, phosphate, magnesium, albumin, total bilirubin, direct bilirubin, 
indirect bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), amylase, lipase and glucose. Fasting lipid panels (total cholesterol, LDL, HDL 
and triglycerides) will be measured at selected visits as indicated in Table 1. 
Serum pregnancy test 
Serum pregnancy test will be performed in women of childbearing potential at Screening only. 
Urine pregnancy tests will be performed thereafter as scheduled in Table 1. 
Urine Analyses 
The urinalysis profile will include the following: glucose, white blood cells (WBC), urine protein, 
bilirubin, nitrites, ketones, blood, pH, gravity and appearance. Urine samples will be collected 
and assessed by dipstick at all study visits as indicated in Table 1. 
In addition, a urine pregnancy test will be performed in women of childbearing potential and will 
be performed at relevant study visits as indicated in Table 1. 
Furthermore, a urine drug screen (for amphetamine, barbiturates, cocaine, methamphetamine, 
methadone, opiates, phencyclidine, and methylenedioxymethamphetamine) will be performed 
at Screening in all subjects. 
Hormone levels 
Thyroid hormone levels (fT3, fT4, TSH), thyroid antibody, cortisol, ACTH, LH, FSH and prolactin 
will be checked at Screening (V1b), on V11 and V14 as indicated in Table 1. 
Serology Parameters 
All subjects will be tested for HBV, HCV and HIV at Screening (V1a), as indicated in Table 1. 
Genotype analysis 
Blood sample for genotyping will be analyzed for randomized subjects only and will be collected 
for characterizing UGT1A1 genotype. Subjects may opt out of this genotype analysis. 
IGF-1 levels and 
levels (PD analysis) 
Serum IGF-1 levels and 
 levels will be assessed throughout the study as safety and efficacy 
parameters at relevant time-points, as indicated in Table 1 and will be determined by 
immunoassay using the IDS-iSYS assay platform.   
levels will be measured for certain samples, i.e., only for samples 1, 2, 4, 7, 10, 11, 14 
and 16. 
GH levels (integrated) 
Integrated is defined as three values taken at least 30 min apart over 2 hours. These samples will 
be collected as indicated in Table 1. 


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CRN00808 levels (PK analysis)  
Blood samples to evaluate plasma concentrations of CRN00808 will be collected during the 
Treatment Period and during the Follow-up Period, as indicated in Table 1. Measurement of 
CRN00808 concentration will be done by a central bioanalytical laboratory using validated 
methods. Any remaining plasma may be used for metabolite profiling or measuring 
concentration of CRN00808 metabolites. 
Residual octreotide/lanreotide plasma sample 
Blood samples to evaluate plasma concentrations of octreotide or lanreotide will be collected 
during the Screening and Treatment Period, as indicated in Table 1. Measurement of octreotide 
or lanreotide concentration will be done by a central bioanalytical laboratory using validated 
methods. 
6.1.9 Gall bladder Ultrasound 
A gall bladder ultrasound will be performed at Screening (completed by V2 if a recent 
documented ultrasound conducted within 3 months of V1a is not available) and V11 as indicated 
in Table 1. 
It will be performed according to the study site procedures for the evaluation of presence or 
absence of lithiasis or sludge. The results will be recorded in the eCRF specific. 
6.1.10 Magnetic Resonance Imaging (MRI)  
Magnetic resonance imaging of the head with pituitary imaging will be performed at Screening. 
A recent documented scan conducted within 6 months of V1a is also acceptable to qualify a 
subject for the study.  
If it is necessary to obtain an MRI during the Screening Period, it should be performed by the 
relevant department of the hospital or a private radiological practice, according to the usual 
practice. Management of subjects prior to and during the MRI should follow standard local 
procedures. 
Pituitary CT scanning may serve as an alternative to MRI for subjects who are not eligible for MRI 
scanning. 
6.1.11 Investigator Assessed Symptoms of Acromegaly 
At V1a, the investigator will record specified acromegaly symptoms, including assessment of 
symptom intensity (mild, moderate or severe). At V1a only, there will also be an assessment of 
which symptom, if any, is most bothersome. These symptoms will be reassessed and monitored 
at all subsequent visits and occurrence of new symptoms or changes in symptom intensity 
compared to V1a assessment will be recorded as AEs as appropriate. 


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Acromegaly symptoms that will be assessed at the study entry and followed-up throughout the 
study include: 
• Headache; 
• Excessive sweating (hyperhidrosis); 
• Swelling of extremities; 
• Joint pain; 
• Symptoms of sleep apnea; 
• Fatigue; 
• Paresthesia. 
In case that any of these AEs are considered to represent a significant worsening of symptoms 
associated with acromegaly as judged by the investigator, the investigator will be responsible for 
reporting these AEs to the unblinded CRO designate within 24 hours in order to assess criteria 
for resumption of standard acromegaly treatment (see Section 3.1). 
6.1.12
 
Subjects will be asked to complete the 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
6.1.13
 
  
 
 
 
 


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6.1.14
 
 
 
 
 
 
 
 
 


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7 STATISTICAL ANALYSIS 
7.1 Study Endpoints 
EFFICACY ENDPOINTS 
Primary endpoint: 
The primary endpoint is the proportion of subjects who meet responder criteria (based on the 
mean of two consecutive IGF-1 measurements ≤ULN) at W13.   
Key Secondary endpoints: 
• Change in IGF-1 levels between W10 and W13; 
• Change in GH levels between W8 and W13; 
• Change in symptoms of acromegaly as measured by total 
score between W10 and 
W13. 
Exploratory endpoints: 
• Proportion of subjects who achieve serum GH <5.0 ng/mL at W13; 
• Proportion of subjects who achieve serum GH <2.5 ng/mL at W13; 
• Time to loss of response (IGF-1 >ULN) after withdrawal of CRN00808; 
• Increase in serum IGF-1 levels 3+ weeks after withdrawal of CRN00808; 
• Increase in serum GH levels 1+ weeks after withdrawal of CRN00808; 
• Increase in serum 
levels 3+ weeks after withdrawal of CRN00808; 
• Changes from baseline in serum GH, IGF-1, and 
levels measured at W10 and W13, 
compared to baseline (D1; [V2 for GH]); 
• Change in symptoms of acromegaly as measured by individual 
 score between W10 
and W13; 
• Change from baseline in symptoms of acromegaly as measured by total 
score at W10; 
• Change from baseline in symptoms of acromegaly as measured by individual 
 score at 
W10; 
• Change from baseline in 
 score at W10 and between W10 and W13; 
• Change from baseline in 
 at W10 and between W10 and W13; 
• Change in investigator assessed symptoms of acromegaly between W10 and W13; 
• Change from baseline in investigator assessed symptoms of acromegaly at W10; 
• Change in 
 scores between W10 and W13; 
• Change from baseline in 
scores at W10; 
• 
scores at W10 and W13; 
• Plasma concentrations of CRN00808. 


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SAFETY ENDPOINTS: 
• AEs/TEAEs throughout the study; 
• Clinical laboratory tests (hematology, serum chemistry and urinalysis) at each post-
baseline study visit; 
• Vital signs at each post-baseline study visit; 
• Physical examinations at each post-baseline study visit; 
• 12-lead ECG at each post-baseline study visit; 
• fT3, fT4, anti-thyroid antibody, TSH, cortisol, ACTH, LH, FSH and prolactin at each post-
baseline study visit; 
• Gall bladder ultrasound. 
7.2 Statistical Methods and Analyses 
7.2.1 Determination of Sample Size 
The sample size is justified with respect to the number of subjects meeting criteria to be 
randomized. With 36 randomized subjects, assuming a 60% response rate in the CRN00808 arm 
and a 10% response rate in the placebo arm (allocation ratio between two arms 1:1), the exact 
power to conclude superiority of the CRN00808 arm over placebo, applying an exact 
unconditional score test at a significance level of 5% (two-sided) is 92.2%.   
No adjustment for dropout rate was made because enrollment will continue until approximately 
36 subjects with IGF-1 <ULN are randomized in the Randomized Withdrawal Period. 
The exact power was computed based on the binomial distribution by evaluating all possible 
(N1+1) (N2+1) outcomes, weighted by their probability of occurrence for given true R1, 
R2 response rates in the two arms (0.6 and 0.1, respectively).  
7.2.2 Analysis Datasets 
Safety Analysis Set comprises all subjects who received at least one dose of study medication. 
The Safety Analysis Set will be used for all safety analyses. Treatment group assignments for 
safety analyses during the Randomized Withdrawal Period will be based on the treatment that 
was received (if this differs from the randomized treatment). Data from all subjects dosed prior 
to Randomized Withdrawal Period, regardless of eligibility to randomize, will be pooled. 
Intent-to-Treat Analysis Set (ITT) comprises all subjects who received at least one dose of the 
study medication. The ITT analysis set will be used for analyses of exploratory endpoints. During 
the Randomized Withdrawal Period, subjects will be included in the treatment group to which 
they were randomized. Data from all subjects dosed prior to Randomized Withdrawal Period, 
regardless of eligibility to randomize, will be pooled. 
Modified Intent-to-Treat Analysis Set (mITT) comprises all subjects from ITT who were 
randomized. The mITT analysis set will be used for analysis of primary and secondary endpoints. 
Subjects will be included in the treatment group to which they were randomized. 


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Per Protocol Analysis Set (PP) comprises all subjects from the mITT having no major protocol 
deviation affecting treatment efficacy. The PP analysis set will be used for supportive efficacy 
analyses. 
7.2.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized in a descriptive manner. 
7.2.4 Treatment Assignment and Study Medication 
Randomization will be performed at V11/W10, in a ratio 1:1 to one of the two treatment arms: 
CRN00808 or placebo. Randomization will be stratified by prior treatment received (lanreotide 
or octreotide), with a cap on the number of subjects who received octreotide, ensuring that 
approximately 50% of the subjects randomized will have been treated with lanreotide depot pre-
study. 
7.2.5 Efficacy Analysis 
7.2.5.1 Analysis of Primary Endpoint 
For the primary analysis, responders are defined as subjects having the mean of two consecutive 
IGF-1 measurements ≤ULN at Week 13 (Visit 13 and Visit 14). If one of these measurements is 
missing, then the other measurement must be ≤ULN for a subject to be classified as a responder. 
If both measurements are missing, then the subject is classified as non-responder.  
Superiority of CRN00808 versus placebo will be tested based on the exact unconditional score 
test for the difference between two binomial proportions, as implemented in SAS 9.4.  
The two-sided 95% exact Clopper-Pearson confidence interval (CI) for the responder rates will be 
estimated for each treatment arm separately. 
Subjects in the Treatment Period who do not achieve protocol defined IGF-1 normalization or 
who do not tolerate a study drug dose which allows for IGF-1 normalization will not be 
randomized or included into the primary analysis. Primary efficacy results from these treated, 
non-randomized subjects will be summarized descriptively. 
The null hypothesis of H0: 1=2 will be tested against Ha: 1≠2 at the two-sided 5% significance 
level (where 1 is the responder rate in the CR00808 treatment arm, and 2 is the responder rate 
in the placebo arm). 
7.2.5.2 Analysis of Secondary and Exploratory Endpoints 
Secondary and exploratory endpoints that are defined as proportion variables will be 
summarized and analyzed using the same type of methods as described for the primary endpoint. 
Measured endpoints that are defined in terms of the change from baseline will be analyzed using 
one-way analysis of covariance models with treatment arm as a factor and the baseline value of 
the corresponding endpoint as a covariate. The distributions of time-to-event secondary and 
exploratory endpoints will be summarized descriptively using the Kaplan-Meier method. 
All secondary and exploratory analyses will be conducted using two-sided tests at the 
5% significance level. 


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Changes from baseline in IGF-1 levels, serum GH levels, and total ASD scores measured at W13 
and other post-baseline visits will be presented descriptively.  
Plasma concentrations will be summarized by treatment arm and dose using descriptive 
statistics. Concentration-related parameters will be assumed to be log-normally distributed. 
Mean and 95% CI of mean will be computed on the log-transformed data and back-transformed 
to the original scale by exponentiation. 
An exploratory subgroup analysis will be performed where subgroups will be defined based on 
the prior treatment received by the subjects (octreotide or lanreotide), evaluating response rates 
in the two treatment arms in the two subgroups. The two-sided 95% exact Clopper-Pearson CI 
for the responder rates will be estimated within each subgroup and each treatment arm 
separately. 
Changes from baseline in 
 will be presented descriptively. Treatment arms 
will be compared by estimating the mean differences (95% CI) between treatment arms. 
7.2.6 Safety Analysis 
Safety endpoints will be summarized with descriptive statistics and shift tables where applicable. 
7.2.7 Interim Analysis  
No interim analysis is planned. 
7.2.8 Measures to Minimize Bias  
Subjects will be randomized in a 1:1 ratio stratified by previous treatment. The assignments will 
be based on a pre-generated permuted-block randomization schedule. Blinding will be assured 
by restricting access to the treatment codes to only those authorized to distribute 
 
numbers to sites and to the central IGF-1 reader. The study drug is blinded and is provided in 
identical packaging for the study drug and placebo treatments. 
For the final analysis, the treatment codes for all subjects will be released only after all subjects 
have completed the study and the clinical database is locked. 
Unblinding of individual treatment assignment during the study is discouraged. The Investigator 
at a site may break the blind for a given subject in the event of a medical emergency, where 
knowledge of the subject’s study drug dose during the Titration Period or treatment assignment 
(study drug or placebo) during the Randomized Withdrawal Period must be known in order to 
facilitate appropriate emergency medical treatment. If possible, the Investigator should attempt 
to contact the study Medical Monitor before unblinding a subject’s treatment identity in order 
to obtain concurrence that unblinding a subject’s treatment assignment is necessary. Details of 
the process to be followed are provided in a separate manual. 


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8 DATA MANAGEMENT 
8.1 Data Handling 
Data will be collected by means of electronic Case Report Forms (eCRFs). The eCRF must be kept 
current to reflect subject status during the course of the study. A subject identification number 
will be used to identify the subject. Completion instructions will be provided in the eCRF 
Completion Guidelines document or as prompts and short instruction on the eCRF pages.  
The study will use an Electronic Data Capture (EDC) system to collect the clinical trial data at the 
investigational sites. The system complies with 21 CFR Part 11 and ICH E6 Good Clinical Practice. 
Queries are generally sent to the investigational site using an electronic data query system which 
provides an automatic audit trail of the corrections made by designated investigator staff. 
All changes to the data have an electronic audit trail, in accordance with 21 CFR 11.10(e). 
Electronic signatures will be used in conformance with 21 CFR Part 11. 
Source documents are to be retained to enable a reconstruction and evaluation of the trial. 
No original observations will be entered directly into the computerized system without source 
documentation. 
Access to the EDC system is controlled with user ID and password and can only be granted to 
appropriately trained users. Different types of users will have different privileges assigned in the 
EDC system. A user access list is maintained throughout the study. 
The Investigator will receive a CD/DVD or USB pen drive of the subject data for archiving at the 
investigational site following the database lock and before the study site close out visit. 
8.1.1 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. 
8.1.2 Coding Dictionaries 
Concomitant medications entered into the database will be coded using the most recent version 
of the World Health Organization (WHO) Drug Dictionary which employs the Anatomical 
Therapeutic Chemical classification system. Coexistent diseases, medical history and AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary version 21.0 or 
higher. 
8.2 Data Management and Quality Control 
Database quality will be assessed early in the study conduct. Data queries will be quantified and 
reviewed by site and by data type and program to highlight any data issues which can be 
addressed through additional training or enhancements to the data validation programs.  
A formal quality control (QC) will be conducted prior to database lock.  


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Any required changes to the database design and programming will be managed through a 
detailed change control process. 
8.3 Database lock 
The database will be locked prior to unblinding.  
Details of database lock will be documented in appropriate Data Management Plan. 
 
 
 


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9 STUDY MANAGEMENT/PROCEDURES AND INSTRUCTIONS 
9.1 Safety Related Procedures 
9.1.1 Rapid Notification on Serious Adverse Events 
Any SAE occurring after the moment of signing ICF and up until 4 weeks after the last dose of 
study medication must be reported to the CRO’s Pharmacovigilance Unit. SAEs occurring after 
the study termination must be reported only if considered IMP related as per investigator 
judgment.   
Any such SAE due to any cause, whether or not related to the IMP, must be reported on the SAE 
reporting form within 24 hours of occurrence or when the investigator becomes aware of the 
event. Properly completed SAE reporting form should be sent via email. However, notification 
can also be made using the telephone line for the CRO’s Pharmacovigilance Unit: 
CRO Pharmacovigilance Group e-mail: 
 
CRO Pharmacovigilance Group Telephone Number: 
 
If the investigator contacts the CRO’s Pharmacovigilance Unit by telephone, then a written report 
must follow within 24 hours and is to include a full description of the event and sequelae (if any) 
in the format detailed in the SAE reporting form. 
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 IMP. 
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 CRO’s Pharmacovigilance Unit within 24 hours. All SAEs will be 
followed until the investigator and Sponsor agree the event is satisfactorily resolved. 
SUSARs 
(i.e., 
unexpected 
SAEs 
considered 
drug 
related 
as 
assessed 
by 
the 
Investigator/Sponsor/authorized person) will qualify for expedited reporting and cross reporting 
to the IRB/EC, Competent Authorities, and participating Investigators.  
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. 
9.1.2 Rapid Notification on Pregnancies  
Female subjects of childbearing potential must have a negative pregnancy test at Screening.  
Following administration of the IMP, any known cases of pregnancy in female subjects will be 
reported by telephone (optional) and by emailing a completed Pregnancy Report to the 
Sponsor/CRO’s Pharmacovigilance Unit within 24 hours of knowledge of the event. 
The pregnancy will not be processed as an SAE. However, the investigator will follow-up with the 


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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/CRO’s Pharmacovigilance Unit 
of the pregnancy outcome by submitting a follow-up Pregnancy Report. If the outcome of the 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or 
therapeutic abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), the Investigator will report the event by 
telephone and by e-mailing a completed SAE form to the Sponsor/CRO’s Pharmacovigilance Unit 
within 24 hours of knowledge of the event.  
9.1.3 Overdose 
The Investigator must notify the CRO’s Pharmacovigilance Unit of any occurrence of overdose 
with IMP by telephone (optional) and by emailing a completed “Overdose Notification Form” 
within 24 hours. 
Overdose will not be automatically recorded as AE. However, any undesirable medical 
occurrence resulting from an accidental overdose is an AE and should be recorded and reported 
on the appropriate AE eCRF. Since accidental overdoses of the study medications could have 
serious clinical consequences and/or represent compliance issue, they should be reported to and 
evaluated by the Sponsor. The investigator should record the event in the source document and 
should monitor the subject.  
9.1.4 Emergency Procedure for Un-blinding  
The investigator should contact the CRO’s Pharmacovigilance Unit to request the unblinding of 
the study drug dose during the Titration Period or the study drug assignment during the 
Randomized Withdrawal Period.  
9.1.5  Central IGF-1 Reader 
Investigators and subjects will be blinded to IGF-1 results during the study.  The unblinded central 
IGF-1 reader will determine if protocol specified criteria are met for dose up-titrations based on 
IGF-1 results. An up-titration also requires the investigator’s assessment of tolerability of the 
study drug. An unblinded CRO delegate will ensure that appropriate blinded 
 are 
assigned based on information from the central reader and from the investigator. All appropriate 
measures will be taken to keep the blinded study team members and investigational site 
personnel blinded to subjects’ treatment throughout the study. Further details on responsibilities 
and procedures will be described in a separate document (Central IGF-1 Reader Procedures 
Manual).   
9.2 Regulatory Issues, Ethics and Good Clinical Practice 
9.2.1 Regulatory Guidelines and Ethical Considerations 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 54, 56, and 312 of Title 21 
of the Code of Federal Regulations (CFR), in compliance with GCP guidelines, and as per all 


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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 (EMA) 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/ 
9.2.2 Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC). Approval is required for the Clinical Study 
Protocol, Investigational Drug Brochure, protocol amendments, ICFs, and subject information 
sheets.   
9.2.3 Informed Consent  
For each study subject, written informed consent will be obtained prior to any protocol-related 
activities. It 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 Principal Investigator or one of his/her associates must explain 
orally and in writing the nature, duration, and purpose of the study, and the action of the drug in 
such a manner that the 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 
International Council for Harmonization (ICH) guidelines. The PI will provide the Sponsor or its 
representative with a copy of the IRB/IEC approved ICF prior to the start of the study. 
9.2.4 Sponsor 
The Sponsor or its designee (e.g., CRO) will provide protocol training to the site study personnel, 
as appropriate. Clinical monitors will conduct site visits, as needed, to ensure the site procedures 
are being carried out in accordance with the Clinical Study Protocol and GCP. Throughout the 
study period, the clinical monitor will be available to address any issues that may arise. This 
availability includes access by phone and e-mail. 
Injury in subjects possibly arising from participating in this trial is covered by the liability insurance 
of the Investigator or Sponsor. This insurance provides coverage for damage to the subjects 
through injury or death caused by the trial. 
9.2.5 Principal Investigator 
The Principal Investigator, together with any designated co-investigators, has the overall 
responsibility for the conduct and compliance of this clinical trial according to this Clinical Study 
Protocol and GCP. 


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Investigators and other key personnel shall provide curriculum vitae or equivalent, that will 
confirm their suitability for the clinical study. All investigators and key personnel should be listed 
together with their responsibilities in the study on a signature and delegation log. 
It is the responsibility of the investigator to ensure that all personnel involved in the study are 
fully informed of all relevant aspects of the study, including detailed knowledge of and training 
in all procedures to be followed. 
Language: All written information and other material to be used by subjects and investigative 
staff must use vocabulary and language that are clearly understood. 
9.3 Administrative Procedures 
9.3.1 Protocol Amendment and Protocol Deviations  
Protocol Amendment 
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 classed 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. 
Protocol Deviations 
Should protocol deviations that affect subject safety occur, the Sponsor must be informed as 
soon as possible. Protocol deviations and/or violations will be included in the Clinical Study 
Report (CSR). Reporting of the protocol deviations to the IRB/IEC and in accordance with 
applicable Regulatory Authority mandates will be performed. 
No prospective entry criteria protocol deviations are allowed; 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-enrolment 
participation in the trial it is discovered that the subject did not meet all eligibility criteria, the 
subject will be discontinued. 
9.3.2 Monitoring Procedures 
The study will be monitored to ensure that it is conducted and documented properly according 
to the Clinical Study Protocol, GCP, and all applicable regulatory requirements. 
Before the study start, at a site initiation visit or at an investigator’s meeting, a Sponsor 
representative will review the protocol and the eCRF with the investigators and their staff. 
During the study, on-site monitoring visits will be made at appropriate times. Clinical 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, 


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and to ensure that IMP is being stored, dispensed, and accounted for according to specifications. 
Key study personnel must be available to assist the clinical monitor during these visits. 
The investigator must give the 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. 
9.3.3 Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study or 2 years after the last approval of a marketing 
application in an ICH region or as per local requirements, whichever is the longer time period. 
The investigator agrees to comply with all applicable federal, state, and local laws and regulations 
relating to the privacy of subject health information. The investigator shall ensure that study 
subjects authorize the use and disclosure of protected health information in accordance with 
Directive 95/46/EC: Directive on the protection of individuals with regard to the processing of 
personal data and on the free movement of such data and in a form satisfactory to the Sponsor. 
9.3.4 Quality Control and Quality Assurance 
The study will be conducted according to GCP as outlined by ICH topic E6, step 5 guidelines. 
The CRO maintains a quality assurance system with written 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, Standard Operating 
Procedures (SOP), GCP, and all applicable regulatory requirements. Audits will be independent 
of and separate from the routine monitoring and quality control functions. Quality assurance 
procedures will be performed at the study sites and during data management to assure that 
safety and efficacy data are adequate and well documented.  
Investigators/Institution will permit trial related audits, IRB/IEC review, and regulatory 
inspections, providing direct access to source data/documents. 
9.3.5 Financing and Insurance 
Prior to the study commencing, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement will 
be documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee).  


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The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The Sponsor will provide insurance coverage for the clinical study as required 
by national regulations. 
9.3.6 Publication Policy/Disclosure of Data  
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 REFERENCES 
Carmichael JD, Bonert VS, Nuno M et al. (2014, May). Acromegaly clinical trial methodology 
impact on reported biochemical efficacy rates of somatostatin receptor ligand 
treatments: A Meta-Analysis. J. Clin. Endocrinol. Metab. 99(5):1825–1833; 
Carroll PV and Jenkins PJ. Acromegaly. In: De Groot LJ, Chrousos G, Dungan K, et al, eds. Endotext. 
https://www.ncbi.nlm.nih.gov/books/NBK279097. Last updated Feb 1, 2016; 
Chan IS and Zhang Z. (1999, Dec.). Test-based exact confidence intervals for the difference of two 
binomial proportions. Biometrics, 55(4): 1202–1209; 
Colao A, Cuocolo A, Marzullo P et al. (1999, Jan). Effects of 1-year treatment with octreotide on 
cardiac performance in patients with acromegaly. J. Clin. Endocrinol. Metab. 84(1):17-23; 
Kuhn JM, Legrand A, Ruiz JM, et al. (1994, Sep). Pharmacokinetic and pharmacodynamic 
properties of a long-acting formulation of the new somatostatin analogue, lanreotide, in 
normal healthy volunteers. British Journal of Clinical Pharmacology 38(3):213-219; 
Melmed S and Kleinberg D. Pituitary masses and tumors. Chapter 9. pages 232-299. In: Melmed 
S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 13th 
Edition. Elsevier Inc. Copyright 2016; 
NIDDK diseases online health information. Acromegaly. https://www.niddk.nih.gov/health-
information/health-topics/endocrine/acromegaly. Last accessed Jan 24, 2017; 
Tiberg F, Roberts J, Cervin C et al. (2015, Sep). Octreotide s.c. depot provides sustained octreotide 
bioavailability and similar IGF-1 suppression to octreotide LAR in healthy volunteers. 
British Journal of Clinical Pharmacology 80(3):460-472. 
 
 
 
 
 


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Appendix 1 - World Medical Association Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI - Ethical Principles for Medical 
Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles.  
 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfillment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 


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8. While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research 
subjects must always rest with the physician or other health care professionals and never 
with the research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic 
or therapeutic value and if the physician has good reason to believe that participation in 
the research study will not adversely affect the health of the patients who serve as 
research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
Risks, Burdens and Benefits  
16. In medical practice and in medical research, most interventions involve risks and burdens.  
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected 
by the condition under investigation.  
Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  
18. Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed.  
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study.            


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Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm.  
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a 
non-vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
 
Scientific Requirements and Research Protocols  
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol.  
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, Sponsor, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study.  
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the 
researcher, the Sponsor and any other undue influence and must be duly qualified. It must 
take into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers 
must submit a final report to the committee containing a summary of the study’s findings 
and conclusions.  
 


Study code: CRN00808-02  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 06 June 2019 
 
CRN00808 
CONFIDENTIAL 
Page 85 of 91 
 
Privacy and Confidentiality  
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
Informed Consent  
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members 
or community leaders, no individual capable of giving informed consent may be enrolled 
in a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, post-
study provisions and any other relevant aspects of the study. The potential subject must 
be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to 
deliver the information.  
After ensuring that the potential subject has understood the information, the physician 
or another appropriately qualified individual must then seek the potential subject’s 
freely-given informed consent, preferably in writing. If the consent cannot be expressed 
in writing, the non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorized representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the 
potential subject, the research cannot instead be performed with persons capable of 
providing informed consent, and the research entails only minimal risk and minimal 
burden. 
29. When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorized representative. The 
potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research group. 
In such circumstances the physician must seek informed consent from the legally 


Study code: CRN00808-02  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 06 June 2019 
 
CRN00808 
CONFIDENTIAL 
Page 86 of 91 
 
authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorized representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in bio banks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances:  
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or  
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention and the 
patients who receive any intervention less effective than the best proven one, placebo, 
or no intervention will not be subject to additional risks of serious or irreversible harm as 
a result of not receiving the best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34. In advance of a clinical trial, Sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researchers, authors, Sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have 
a duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere 
to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 


Study code: CRN00808-02  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 06 June 2019 
 
CRN00808 
CONFIDENTIAL 
Page 87 of 91 
 
institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not 
be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, 
with informed consent from the patient or a legally authorized representative, may use 
an unproven intervention if in the physician's judgment it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available. 


Study code: CRN00808-02  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 06 June 2019 
 
CRN00808 
CONFIDENTIAL 
Page 88 of 91 
 
Appendix 2 - Medications Associated with Torsades De Pointes  
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Aclarubicin (only on non-
US market) 
Aclacin, Aclacinomycine, 
Aclacinon, Aclaplastin, 
Jaclacin 
Anti-cancer 
Cancer 
Amiodarone 
Cordarone, Pacerone, 
Nexterone 
Antiarrhythmic 
Arrhythmia 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 
inhibitor 
Thrombocythemia 
Arsenic trioxide 
Trisenox 
Anti-cancer 
Cancer (leukemia) 
Astemizole (removed 
from market) 
Hismanal 
Antihistamine 
Allergic rhinitis 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bacterial infection 
Bepridil (removed from 
market) 
Vascor 
Antianginal 
Angina Pectoris (heart 
pain) 
Chloroquine 
Aralen 
Antimalarial 
Malaria 
Chlorpromazine 
Thorazine, Largactil, 
Megaphen 
Antipsychotic/Antiemetic 
Schizophrenia, nausea, 
many others 
Cilostazol 
Pletal 
Phosphodiesterase 3 
inhibitor 
Intermittent claudication 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Bacterial infection 
Cisapride (removed from 
market) 
Propulsid 
GI stimulant 
Increase GI motility 
Citalopram 
Celexa, Cipramil 
Antidepressant, SSRI 
Depression 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Bacterial infection 
Cocaine 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
Disopyramide 
Norpace 
Antiarrhythmic 
Arrhythmia 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Arrhythmia 
Domperidone (only on 
non-US market) 
Motilium, Motillium, 
Motinorm Costi, Nomit 
Antiemetic 
Nausea, vomiting 
Donepezil 
Aricept 
Cholinesterase inhibitor 
Dementia (Alzheimer's 
Disease) 
Dronedarone 
Multaq 
Antiarrhythmic 
Arrhythmia 
Droperidol 
Inapsine, Droleptan, 
Dridol, Xomolix 
Antipsychotic/Antiemetic 
Anesthesia (adjunct), 
nausea 
Erythromycin 
E.E.S., Robimycin, EMycin, 
Erymax, Ery-Tab, Eryc 
Ranbaxy, Erypar, Eryped, 
Erythrocin Stearate 
Filmtab, Erythrocot, E-
Base, Erythroped, Ilosone, 
Antibiotic 
Bacterial infection, 
increase GI motility 


Study code: CRN00808-02  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 06 June 2019 
 
CRN00808 
CONFIDENTIAL 
Page 89 of 91 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
MY-E, Pediamycin, 
Abboticin, Abboticin-ES, 
Erycin, PCE Dispertab, 
Stiemycine, Acnasol, 
Tiloryth 
Escitalopram 
Cipralex, Lexapro, Nexito, 
Anxiset-E (India), Exodus 
(Brazil), Esto (Israel), 
Seroplex, Elicea, Lexamil, 
Lexam, Entact (Greece), 
Losita (Bangladesh), 
Reposil (Chile), Animaxen 
(Colombia), Esitalo 
(Australia), Lexamil (South 
Africa) 
Antidepressant, SSRI 
Depression (major), 
anxiety disorders 
Flecainide 
Tambocor, Almarytm, 
Apocard, Ecrinal, Flécaine 
Antiarrhythmic 
Arrhythmia 
Fluconazole 
Diflucan, Trican 
Antifungal 
Fungal infection 
Gatifloxacin (removed 
from market) 
Tequin 
Antibiotic 
Bacterial infection 
Grepafloxacin (Removed 
from Market) 
Raxar 
Antibiotic 
Bacterial infection 
Halofantrine (only on 
non-US market) 
Halfan 
Antimalarial 
Malaria 
Haloperidol 
Haldol (US & UK), 
Aloperidin, Bioperidolo, 
Brotopon, Dozic, 
Duraperidol (Germany), 
Einalon S, Eukystol, 
Halosten, Keselan, Linton, 
Peluces, Serenace, 
Serenase, Sigaperidol 
Antipsychotic 
Schizophrenia, agitation 
Ibogaine (only on non-US 
market) 
None 
Psychedelic 
Narcotic addiction, 
unproven 
Ibutilide 
Corvert 
Antiarrhythmic 
Arrhythmia 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Bacterial infection 
Levomepromazine 
(methotrimeprazine) 
(only on non-US market) 
Nosinan, Nozinan, 
Levoprome 
Antipsychotic 
Schizophrenia 


Study code: CRN00808-02  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 06 June 2019 
 
CRN00808 
CONFIDENTIAL 
Page 90 of 91 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Levomethadyl acetate 
(removed from market) 
Orlaam 
Opiate 
Narcotic dependence 
Levosulpiride (only on 
non-US market) 
Lesuride, Levazeo, Enliva 
(with rabeprazole) 
Antipsychotic 
Schizophrenia 
Mesoridazine (removed 
from market) 
Serentil 
Antipsychotic 
Schizophrenia 
Methadone 
Dolophine, Symoron, 
Amidone, Methadose, 
Physeptone, Heptadon 
Opiate 
Narcotic dependence, 
pain 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 
Bacterial infection 
Ondansetron 
Zofran, Anset, Ondemet, 
Zuplenz, Emetron, 
Ondavell, Emeset, 
Ondisolv, Setronax 
Antiemetic 
Nausea, vomiting 
Oxaliplatin 
Eloxatin 
Anti-cancer 
Cancer 
Papaverine HCl (Intra-
coronary) 
none 
Vasodilator, Coronary 
Diagnostic adjunct 
Pentamidine 
Pentam 
Antifungal 
Fungal infection 
(Pneumocystis 
pneumonia) 
Pimozide 
Orap 
Antipsychotic 
Tourette's Disorder 
Probucol (removed from 
market) 
Lorelco 
Antilipemic 
Hypercholesterolemia 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Arrhythmia 
Propofol 
Diprivan, Propoven 
Anesthetic, general 
Anesthesia 
Quinidine 
Quinaglute, Duraquin, 
Quinact, Quinidex, Cin-
Quin, Quinora 
Antiarrhythmic 
Arrhythmia 
Roxithromycin (only on 
non-US market) 
Rulide, Xthrocin, Roxl-150, 
Roxo, Surlid, Rulide, 
Biaxsig, Roxar, Roximycinv, 
Roxomycin, Rulid, 
Tirabicin, Coroxin 
Antibiotic 
Bacterial infection 
Sevoflurane 
Ultane, Sojourn 
Anesthetic, general 
Anesthesia 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic 
Arrhythmia 
Sparfloxacin (removed 
from market) 
Zagam 
Antibiotic 
Bacterial infection 
Sulpiride (only on non-US 
market) 
Dogmatil, Dolmatil, 
Eglonyl, Espiride, Modal, 
Sulpor 
Antipsychotic, atypical 
Schizophrenia 


Study code: CRN00808-02  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 06 June 2019 
 
CRN00808 
CONFIDENTIAL 
Page 91 of 91 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Sultopride (only on non-
US market)  
Barnetil, Barnotil, Topral 
Antipsychotic, atypical 
Schizophrenia 
Terfenadine (removed 
from market) 
Seldane 
Antihistamine 
Allergic rhinitis 
Terlipressin (only on non-
US market) 
Teripress, Glypressin, 
Terlipin, Remestyp, Tresil, 
Teriss and others 
Vasoconstrictor 
Septic shock 
Terodiline (only on non-
US market) 
Micturin, Mictrol (not 
bethanechol) 
Muscle relaxant 
Bladder spasm 
Thioridazine 
Mellaril, Novoridazine, 
Thioril 
Antipsychotic 
Schizophrenia 
Vandetanib 
Caprelsa 
Anti-cancer 
Cancer (thyroid) 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan for Protocol CRN00808-02 (ACROBAT EVOLVE) 
A double-blind, placebo-controlled, randomized withdrawal study to evaluate 
the safety, pharmacokinetics and efficacy of CRN00808 in patients with 
acromegaly that are responders to octreotide LAR or lanreotide depot 
(ACROBAT EVOLVE) 
 
Investigational Product: 
CRN00808 
US IND Number: 
137912 
ClinicalTrials.gov Identifier: 
NCT03792555 
EudraCT Number: 
2018-001833-42 
Protocol Version and Date: 
Version 3.0, 06 June 2019 
Phase: 
Phase 2 
Methodology: 
Double-Blind, Placebo-Controlled,  
Randomized Withdrawal Study 
Sponsor: 
Crinetics Pharmaceuticals, Inc. 
10222 Barnes Canyon Road, Building #2 
San Diego, CA 92121 
Analysis Plan Date: 
08 September 2020 
Analysis Plan Version: 
Final, Version 1.0  
 
STATEMENT OF CONFIDENTIALITY 
The information contained in this document is considered privileged and confidential and is the 
property of Crinetics Pharmaceuticals, Inc. It is provided to you in confidence in accordance with 
the terms of your confidentiality agreement with Crinetics Pharmaceuticals, Inc. The recipient 
agrees that no information contained herein will be published or disclosed without the written 
approval of Crinetics Pharmaceuticals, Inc. This document may be disclosed to applicable 
institutional review boards, or other duly authorized regulatory agency representatives as 
applicable, under the condition that confidentiality is maintained. 


Statistical Analysis Plan   
08 September 2020
CRN00808-02 (ACROBAT EVOLVE) 
Page 2
 
Confidential and Proprietary 
APPROVAL PAGE 
 
Statistical Analysis Plan for Protocol CRN00808-02 (ACROBAT EVOLVE) 
Analysis Plan Date:  
08 September 2020 
Analysis Plan Version: 
Final, Version 1.0 
 
 
 
Authored by: 
, DrPH 
 
Crinetics Pharmaceuticals, Inc. 
Date 
 
 
Approved by: 
 
 
 
, MD 
 
Crinetics Pharmaceuticals, Inc. 
Date 
 
 
, PhD 
 
Crinetics Pharmaceuticals, Inc. 
Date 
 
 
, MS 
 
Crinetics Pharmaceuticals, Inc. 
Date 
 
 
See last page for electronic signature manifestation 
See last page for electronic signature manifestation 
See last page for electronic signature manifestation 
See last page for electronic signature manifestation 


Statistical Analysis Plan   
08 September 2020
CRN00808-02 (ACROBAT EVOLVE) 
Page 3
 
Confidential and Proprietary 
TABLE OF CONTENTS 
List of Abbreviations and Definition of Terms ............................................................................. 7 
1. 
Introduction ...................................................................................................... 10 
2. 
Information from the Study Protocol ............................................................... 11 
2.1. 
Study Objectives ....................................................................................................11 
2.2. 
Study Design ..........................................................................................................11 
2.2.1. 
Overall Study Design .................................................................................11 
2.2.2. 
Study Population ........................................................................................12 
2.2.3. 
Study Drug .................................................................................................12 
2.2.4. 
Treatment Assignment, Blinding, and Randomization Methodology .......13 
2.2.5. 
Study Procedures .......................................................................................13 
2.3. 
Study Endpoints .....................................................................................................13 
2.3.1. 
Primary Efficacy Endpoint ........................................................................13 
2.3.2. 
Secondary Efficacy Endpoints ...................................................................13 
2.3.2.1. 
Change in IGF-1 Levels between Week 10 and Week 13 ................13 
2.3.2.2. 
Change in GH Levels between Week 8 and Week 13 ......................14 
2.3.2.3. 
Change in 
 
 between Week 10 and Week 13 ......................14 
2.3.3. 
Exploratory Efficacy Endpoints .................................................................14 
2.3.3.1. 
Biomarkers ........................................................................................15 
2.3.3.2. 
Patient and Investigator Assessed Reported Outcomes Endpoints ...16 
2.3.3.3. 
Pharmacokinetics (PK) .....................................................................18 
2.3.4. 
Safety Endpoints ........................................................................................18 
3. 
Sample Size Justification .................................................................................. 19 
4. 
General Statistical Methods .............................................................................. 20 
4.1. 
Reporting Conventions ..........................................................................................20 
4.2. 
Computing Environment ........................................................................................20 
4.3. 
Partial Dates ...........................................................................................................21 
4.4. 
Data Conventions ...................................................................................................22 
4.5. 
Standard Calculations ............................................................................................22 
4.6. 
Treatments..............................................................................................................23 
4.7. 
Visits ......................................................................................................................23 
4.7.1. 
Windows ................................................................................................................23 
4.7.2. 
Repeat or Unscheduled Assessments .....................................................................24 
4.7.3. 
Definition of Baseline(s) ........................................................................................24 
5. 
Analysis Sets .................................................................................................... 26 
6. 
Examination of Subgroups ............................................................................... 27 
7. 
Study Population .............................................................................................. 28 
7.1. 
Subject Disposition ................................................................................................28 


Statistical Analysis Plan   
08 September 2020
CRN00808-02 (ACROBAT EVOLVE) 
Page 4
 
Confidential and Proprietary 
7.2. 
Demographics and Baseline Characteristics ..........................................................28 
7.3. 
Baseline Acromegaly Disease Characteristics .......................................................29 
7.4. 
Acromegaly Symptoms at Study Entry..................................................................29 
7.5. 
General Medical History ........................................................................................29 
7.6. 
Protocol Deviations ................................................................................................29 
7.7. 
Pretreatment, Prior, and New Concomitant Medications or Non-Pharmacological 
Treatments..............................................................................................................30 
8. 
Efficacy Analyses ............................................................................................. 31 
8.1. 
Adjustments for Covariates....................................................................................31 
8.2. 
Handling of Dropouts or Missing Data ..................................................................31 
8.2.1. 
Responder Endpoints .................................................................................31 
8.2.2. 
Continuous Endpoints ................................................................................31 
8.3. 
Interim Analyses and Data Monitoring..................................................................31 
8.3.1. 
Interim Analysis .........................................................................................31 
8.4. 
Multicenter Studies ................................................................................................32 
8.5. 
Use of an “Efficacy Subset” of Patients ................................................................32 
8.6. 
Multiple Comparisons/Multiplicity .......................................................................32 
8.7. 
Primary Efficacy Analysis .....................................................................................32 
8.7.1. 
Additional Analyses of the Primary Endpoint ...........................................32 
8.8. 
Key Secondary Efficacy Analyses .........................................................................32 
8.8.1. 
Change in IGF-1 Levels Between Week 10 to Week 13 ...........................32 
8.8.2. 
Change in GH Levels Between Week 8 and Week 13 ..............................33 
8.8.3. 
Change in 
 Between Week 10 and Week 13 ..................33 
8.9. 
Exploratory Efficacy Analyses ..............................................................................33 
8.9.1. 
Biomarker Endpoint Analyses ...................................................................34 
8.9.1.1. 
IGF-1 .................................................................................................34 
8.9.1.2. 
GH .....................................................................................................34 
8.9.1.3. 
 ............................................................................................34 
8.9.2. 
Patient and Investigator Assessed Reported Outcomes Endpoint Analyses
....................................................................................................................34 
8.9.2.1. 
 
 ......................................................................................34 
8.9.2.2. 
Investigator Assessed Symptoms of Acromegaly.............................34 
8.9.2.3. 
 .........................................................................................34 
8.9.2.4. 
 ...........................................................................................34 
8.9.2.5. 
 .................................................................34 
8.9.3. 
Pharmacokinetic (PK) Analyses ................................................................34 
9. 
Safety Analyses ................................................................................................ 36 
9.1. 
Extent of Exposure .................................................................................................36 
9.2. 
Adverse Events ......................................................................................................36 


Statistical Analysis Plan   
08 September 2020
CRN00808-02 (ACROBAT EVOLVE) 
Page 5
 
Confidential and Proprietary 
9.3. 
Clinical Laboratory Evaluations ............................................................................38 
9.3.1. 
Serum Chemistry, Hematology, and HbA1c .............................................38 
9.3.2. 
Hormones ...................................................................................................38 
9.3.3. 
Genotyping .................................................................................................39 
9.4. 
Vital Signs ..............................................................................................................39 
9.5. 
Ring Size, Weight and BMI ...................................................................................39 
9.6. 
12-Lead Electrocardiograms (ECGs) .....................................................................39 
9.7. 
Gall Bladder Ultrasound ........................................................................................40 
9.8. 
Other Safety Assessments ......................................................................................40 
10. 
Changes to Protocol Planned Analyses ............................................................ 41 
 


Statistical Analysis Plan   
08 September 2020
CRN00808-02 (ACROBAT EVOLVE) 
Page 6
 
Confidential and Proprietary 
LIST OF TABLES 
Table 1: 
Treatment Period Visit Windows, Except 
............................................23 
Table 2: 
Follow Up Visit Windows ...............................................................................24 
 
LIST OF FIGURES 
Figure 1: 
Screening Period ..............................................................................................11 
Figure 2: 
Overall Study Design .......................................................................................12 
 


Statistical Analysis Plan   
08 September 2020
CRN00808-02 (ACROBAT EVOLVE) 
Page 7
 
Confidential and Proprietary 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
ACTH 
adrenocorticotropic hormone 
 
 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ASD 
Acromegaly Symptom Diary 
ATC  
Anatomical Therapeutic Chemical 
BMI 
body mass index 
C 
Celsius 
CI 
confidence interval 
cm 
centimeter 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
corona virus disease 2019 
CRF 
case report form 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOB 
date of birth 
DOIC 
date of informed consent 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EoT 
End of Treatment 
EQ 
EuroQol 
FDA 
Food and Drug Administration 
FP 
Follow up Period 
FSH 
follicle stimulating hormone 
fT3 
free triiodothyronine hormone 
fT4 
free thyroxine hormone 
G 
(NCI CTCAE) grade 
GH 
growth hormone 
H 
High 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 


Statistical Analysis Plan   
08 September 2020
CRN00808-02 (ACROBAT EVOLVE) 
Page 8
 
Confidential and Proprietary 
Abbreviation 
Term 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
identification 
IGF-1 
insulin-like growth factor 1 
 
 
IMP 
investigational medicinal product 
in 
inches 
ITT 
Intent-to-Treat 
kg 
kilogram  
L 
liter or low (context dependent) 
lb 
pounds 
LH 
luteinizing hormone 
LLOQ 
less than the limit of quantitation 
m 
meter 
m2 
meters squared 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram  
mg/dL 
milligrams per deciliter 
min 
minimum or minute (context dependent) 
mITT 
modified Intent-to-Treat 
mL 
milliliters 
mm 
millimeters 
mmHg 
millimeters of mercury 
MRI 
magnetic resonance imaging 
msec 
milliseconds 
NCI 
National Cancer Institute 
ng 
nanogram 
ng/L 
nanograms per liter 
PD 
pharmacodynamics 
PE 
physical examination 
 
 
 
 


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Abbreviation 
Term 
 
 
PK 
pharmacokinetic 
PT 
preferred term 
QoL 
quality of life 
QT 
measure of time between start of Q wave and end of T wave  
QTcF 
QT interval corrected by Fridericia’s formula 
RWP 
Randomized Withdrawal Period 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI 
standard international unit 
SOC 
system organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
treatment-emergent adverse event 
temp 
temperature 
TFL 
tables, figures, and listings 
TP 
Treatment Period 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
VAS 
Visual Analogue Scale 
vs 
versus 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of Study 
CRN00808-02 (ACROBAT EVOLVE) data collected within the scope of the Crinetics-
sponsored protocol. The purpose of this plan is to provide details on analysis populations and on 
how the variables will be derived, how missing data will be handled, as well as details on 
statistical methods to analyze the safety and efficacy data. If there are any deviations from 
protocol planned analyses, these are documented in Section 10, and the SAP takes precedence.  
The document may evolve over time, for example, to reflect the requirements of protocol 
amendments or regulatory requests.  However, the final SAP must be finalized, approved by the 
Sponsor, and placed on file prior to database lock and unblinding.  Any deviations from this 
statistical analysis plan will be documented in the clinical study report (CSR). 
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 (Addendum 1) guideline entitled, “Guidance for Industry: 
Statistical Principles for Clinical Trials” and the ICH E3 guideline entitled, “Guidance for 
Industry: Structure and Content of Clinical Study Reports.” 
A detailed description of the planned tables, figures, and listings (TFLs) to be presented in the 
CSR is provided in an accompanying TFL shell document. 


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2. 
INFORMATION FROM THE STUDY PROTOCOL 
2.1. 
Study Objectives 
• To evaluate the efficacy of CRN00808 in acromegaly subjects that are complete 
responders to parenteral octreotide LAR or lanreotide depot monotherapy; 
• To evaluate the safety and tolerability of CRN00808 in acromegaly subjects; 
• To evaluate the pharmacokinetics (PK) of CRN00808 in acromegaly subjects. 
2.2. 
Study Design 
2.2.1. 
Overall Study Design 
This double-blind, placebo-controlled, randomized withdrawal study is designed to evaluate the 
safety, PK and efficacy of CRN00808 in subjects with acromegaly that are responders to 
octreotide LAR or lanreotide depot and will consist of the following periods: 
• Screening Period (4-6 weeks); 
• Treatment Period (TP; up to 13 weeks); 
o Titration Period (9 weeks) 
o Randomized Withdrawal Period (RWP; 4 weeks) 
• Follow-up Period (FP; up to 4 weeks). 
Therefore, the total study duration for the individual subject is up to 23 weeks. 
The study design is displayed in Figure 1 and Figure 2. 
Figure 1: 
Screening Period 
 
 


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Figure 2: 
Overall Study Design 
 
Approximately 40 subjects on stable doses of octreotide LAR or lanreotide depot for the 
treatment of acromegaly were to enter the TP in order to have approximately 36 randomized at 
Week 10 (Visit 11). However, a business decision was made to stop recruiting activity for this 
study  as of 31MAR2020.  The final number of subjects dosed in the TP will be 13.  It is 
unknown how many will end up completing the RWP at the time of writing this document. 
2.2.2. 
Study Population 
Approximately 13 adult subjects entered into the TP because they meet all the inclusion and 
none of the exclusion criteria.  
2.2.3. 
Study Drug 
Study drug consists of CRN00808 or placebo.  
CRN00808 is an orally administered nonpeptide somatostatin agonist that is expected to lower 
serum IGF-1 and GH levels in acromegaly patients. 
 is the active pharmaceutical 
ingredient available as 
 (
 Size 2) and 
 (
 Size 2) solid 
dose capsules. Please refer to the protocol for complete product details. 
Matching placebo capsules are identical in appearance to CRN00808 (available as 
 and 
 
capsules [
 Size 2]) and will be orally administered in a double-blinded 
manner according to the randomization scheme on an identical schedule to those receiving 
CRN00808.  


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2.2.4. 
Treatment Assignment, Blinding, and Randomization Methodology 
Subjects who are determined to be eligible to enter the study drug TP will all begin treatment 
with CRN00808 at 
 per day. All subsequent dose changes will be blinded. At Week 10 
(Visit 11), subjects who are eligible for randomization will be randomly assigned, in a ratio 1:1 
to one of the two treatment arms: CRN00808 or placebo. The assignments will be based on a 
pre-generated permuted-block randomization schedule. Randomization will be stratified based 
on pre-trial somatostatin therapy (i.e., octreotide LAR or lanreotide depot). Approximately 50% 
of the randomized subjects will have been treated with lanreotide depot prestudy. 
Blinding will be assured by restricting access to the treatment codes to only those authorized to 
distribute blister card numbers to sites and to the central IGF-1 reader. The study drug is blinded 
and is provided in identical packaging for the study drug and placebo treatments. All instances of 
unblinding either due to protocol deviation or because of regulatory requirements (i.e., 
unblinding for purpose of Suspected Unexpected Serious Adverse Reactions [SUSARs] 
submission) will be documented in the CSR. 
2.2.5. 
Study Procedures 
The overall visit schedule is outlined in Table 1 of the study protocol.  See study protocol for 
complete details. 
2.3. 
Study Endpoints 
2.3.1. 
Primary Efficacy Endpoint 
The primary endpoint is the proportion of subjects who meet IGF-1 responder criteria, defined as 
the mean of two consecutive IGF-1 measurements ≤ULN at Week 13 (Visit 13 and Visit 14).  
The mean of the IGF-1 values at Visit 13 and Visit 14 will be calculated for each subject, and 
rounded to two significant figures.  If the mean is ≤ULN, the subject will be counted as a 
responder, otherwise if the mean is >ULN, the subject will be counted as a non-responder. If 
either Visit 13 or Visit 14 value is missing, the individual value (instead of the mean) will be 
used.  If both Visit 13 and Visit 14 IGF-1 values are missing, the subject will be counted as a 
non-responder. Data from the central lab, i.e. the source data will be used for analyses. 
2.3.2. 
Secondary Efficacy Endpoints  
The secondary endpoints, in order of priority are: 
2.3.2.1. 
Change in IGF-1 Levels between Week 10 and Week 13  
The first key secondary endpoint is the change in IGF-1 levels between RWP Baseline / Week 10 
and Week 13.  The RWP Baseline / Week 10 value is the value taken prior to dosing in the RWP.  
The Week 13 value will be defined as the mean of the IGF-1 values at Visit 13 and Visit 14.  If 
either the Visit 13 or Visit 14 value is missing, the individual value will be used instead of the 
mean.  The change between the calculated Week 13 value and RWP Baseline / Week 10 value 
(Week 13 – Week 10) will be calculated for each subject. Data from the central lab, i.e. the 
source data will be used for analyses. 


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2.3.2.2. 
Change in GH Levels between Week 8 and Week 13  
The second key secondary endpoint is the change in GH levels between RWP Baseline / Week 8 
and Week 13.  The RWP Baseline / Week 8 and Week 13 values will be defined as the mean of 
the three values obtained at the specified visit. If any of the three values are missing, the 
available values at the specified visit will be used to calculate the mean for that subject. The 
change between the calculated Week 13 value and calculated RWP Baseline / Week 8 value 
(Week 13 – Week 8) will be derived for each subject. Data from the central lab, i.e. the source 
data will be used for analyses. 
2.3.2.3. 
Change in Patient Assessed Symptoms of Acromegaly as Measured by Total 
ASD Score between Week 10 and Week 13  
The Acromegaly Symptom Diary (ASD) consists of 9 items (headache pain; joint pain; sweating; 
fatigue; weakness in legs; swelling; numbness or tingling; sleeping; short term memory), where 
the subject ranks the intensity from 0 – 10.  The short term memory item was not part of the 
ASD in previous versions of the protocol (Version 1 and 2).  In addition, previous versions of the 
protocol referenced swelling in the “hands, arms or legs”, while the current protocol generally 
refers to swelling. Response to the sleeping item changed from previous versions of the protocol 
to the current protocol, from 0 = No difficulty sleeping and 10 = Worst possible difficulty 
sleeping to remove the word “sleeping” from the response for consistency with other item 
responses. For the purposes of analyses within this SAP, no adjustment for differences in 
question or response wording will be accounted for. 
The total ASD score will be computed by adding each of the individual symptom intensities 
(headache pain; joint pain; sweating; fatigue; weakness in legs; swelling; numbness or tingling), 
therefore, the total ASD score can range from 0 - 70.  If more than one diary is entered on a 
single day, the worst (i.e. the highest) score will be used in analyses. In the current protocol 
(Version 3), subjects are to complete the ASD daily beginning the day after Screening Visit 1b 
through Week 1/Day 1/Visit 3; daily beginning the day after Week 8/Visit 10 through Week 
10/Visit 11; daily beginning the day after Week 11/Visit 12 through Week 13/Visit 14; and daily 
beginning the day after Week 15/Visit 15 through Week 17/Visit 16.  The previous version of the 
protocol (Version 2), collected ASD daily after Screening Visit 1b.  Only visits based on the 
current protocol (Version 3) will be considered for summaries, while all data will be listed. 
The third key secondary endpoint is the change in the total ASD score between RWP Baseline / 
Week 10 and Week 13.  The RWP Baseline / Week 10 value will be defined as the mean of the 
available total ASD score values on the 7 days prior to first dose in the RWP.  The Week 13 
value will be defined as the mean of the available total ASD score values 7 days prior to their 
last dose, inclusive of the date of last dose.  Assessments used in the definition of Week 13 must 
be greater than 10 days after randomization.  If there are only assessments in the first 10 days 
after randomization, then no imputation of missing data will be performed. If any of the 7 days 
are missing, the available, non-missing values will be used to calculate the mean. A minimum of 
4 days should be available to calculate a mean.  The change between the calculated Week 13 
value and calculated Week 10 value (Week 13 – Week 10) will be derived for each subject. 
2.3.3. 
Exploratory Efficacy Endpoints  
The following exploratory efficacy endpoints will be evaluated: 


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2.3.3.1. 
Biomarkers 
2.3.3.1.1. IGF-1 
The following change in IGF-1 levels, in units of ULN, will be calculated for each subject:  
• In addition to the key secondary endpoint, change between RWP Baseline / Week 10 and 
each RWP scheduled visit value (i.e. Week 11, Week 13/Visit 13, and Week 13/Visit 14). 
The RWP Baseline / Week 10 value is the value taken prior to dosing in the RWP.   
• Change between the TP Baseline value and each scheduled TP scheduled visit value 
through Week 13/Visit 14, and the mean of the last Week 13 visits (Visit 13 and Visit 
14). TP Baseline is defined as the mean of all available values prior to first dose of study 
drug (Visit 1b, Visit 2, Visit 3).   
• Change from end of CRN00808 treatment to 1, 2, 3, 4, 6, and 8 weeks after withdrawal of 
CRN00808.  End of CRN00808 treatment for subjects randomized to placebo in the RWP 
is defined as the Week 10 visit, therefore, 1 week after withdrawal is defined as the Week 
11 visit, 3 weeks after withdrawal is defined as the first Week 13 (Visit 13) visit, 4 weeks 
after withdrawal is defined as the second Week 13 (Visit 14) visit, and 6 and 8 weeks 
after withdrawal is defined as Week 15/Visit 15 and Week 17/Visit 16 respectively.  End 
of CRN00808 treatment is defined as the Week 13/Visit 14 visit for those subjects who 
were not randomized into the RWP and continued treatment or those randomized to 
CRN00808 in the RWP, therefore 2 and 4 weeks after withdrawal are defined as visits 
Week 15/Visit 15 and Week 17/Visit 16 respectively.  For subjects who withdraw early 
and have a follow up visit, the time from last dose to the follow up visit will be calculated 
and included in the applicable weeks after withdrawal.    
The above change endpoints will also be calculated for percent change as well.   
Data from the central lab, i.e. the source data will be used for analyses. 
2.3.3.1.2. GH 
The following changes in GH will be calculated for each subject: 
• Change between the TP Baseline value and each scheduled TP scheduled visit value 
through Week 13/Visit 14. TP Baseline is defined as the mean of all available integrated 
values prior to the first dose of study drug (Visit 1b, Visit 2).  TP visit values will be 
defined as the mean of the three values obtained at the specified visit. If any of the three 
values are missing, the available values at the specified visit will be used. 
• Change from end of CRN00808 treatment to 4 and 8 weeks after withdrawal of 
CRN00808.  End of CRN00808 treatment for subjects randomized to placebo in the RWP 
is defined as the Week 10 visit, therefore, 4 weeks after withdrawal is defined as the 
second Week 13 (Visit 14) visit, and 8 weeks after withdrawal is defined as Week 
17/Visit 16 respectively.  End of CRN00808 treatment is defined as the Week 13/Visit 14 
visit for those subjects who were not randomized into the RWP and continued treatment 
or those randomized to CRN00808 in the RWP, therefore 4 weeks after withdrawal is 
defined as Week 17/Visit 16 respectively.  For subjects who withdraw early and have a 


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follow up visit, the time from last dose to the follow up visit will be calculated and 
included in the applicable weeks after withdrawal. 
The above change endpoints will be calculated using SI units of GH and for percent change as 
well. 
Data from the central lab, i.e. the source data will be used for analyses. 
2.3.3.1.3. 
 
All the changes in IGF-1 endpoints specified above for IGF-1 (Section 2.3.3.1.1) will also be 
calculated for
 at applicable visits.  Data from the central lab, i.e. the source data will be 
used for analyses. 
2.3.3.2. 
Patient and Investigator Assessed Reported Outcomes Endpoints 
2.3.3.2.1. Patient Assessed Symptoms of Acromegaly 
The ASD is described in Section 2.3.2.3.  
The following change in total ASD score and the change in each of the 9 individual ASD scores 
will be calculated for each subject (in addition to the key secondary endpoint):   
• Change between the RWP Baseline/Week 10 and calculated TP Baseline value. The 
RWP Baseline / Week 10 value will be defined as the mean of the available total ASD 
score values on the 7 days prior to first dose in the RWP.  The TP Baseline value will be 
defined as the mean of the available scores on the 7 days prior to first dose of study drug.   
• Change from end of CRN00808 treatment to 4 weeks after withdrawal of CRN00808.  
End of CRN00808 treatment for subjects randomized to placebo in the RWP is defined as 
the Week 10 visit, therefore, 4 weeks after withdrawal is defined as the second Week 13 
(Visit 14) visit.  End of CRN00808 is defined as the Week 13/Visit 14 visit for those 
subjects who were not randomized into the RWP and continued treatment or those 
randomized to CRN00808 in the RWP, therefore, 4 weeks after withdrawal is defined as 
the Week 17/Visit 16 respectively. For subjects who withdraw early and have follow up 
visit, the value will be included as 4 weeks after withdrawal. 
2.3.3.2.2. Investigator Assessed Symptoms of Acromegaly 
The investigator assesses symptoms of acromegaly through adverse event monitoring.  Initial 
assessment of symptoms is captured on the Acromegaly Symptoms at Study Entry eCRF.  Any 
significant worsening from the initial assessment are captured on the Adverse Event eCRF as 
appropriate. Symptoms assessed include headache, excessive sweating (hyperhidrosis), swelling 
of extremities, joint pain, symptoms of sleep apnea, fatigue, and paresthesia.  Each symptom is 
graded in severity/intensity as mild (Grade=1), moderate (Grade=2), or severe (Grade=3).  If the 
symptom is not present, a grade of 0 will be assigned. The categorical change from study entry 
(as recorded on the Acromegaly Symptoms at Study Entry eCRF) to RWP Baseline/Week 10 and 
the change from RWP Baseline/Week 10 to RWP Week 13 (Visit 14) will be calculated for each 
subject (range, -3 to 3).  


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The most bothersome symptom at study entry is indicated on the Acromegaly Symptoms at 
Study Entry CRF.  Changes in the most bothersome symptom will be calculated in same manner 
as defined above for the individual symptoms. 
2.3.3.2.3. Patient Assessed 
 
 
 
 
 
 
 
 
 
  
 
 
• Change between the Week 13 value and RWP Baseline/Week 10 value. RWP 
Baseline/Week 10 value is defined as the Visit 11 value.  Week 13 value is defined as the 
Visit 14 value. 
• Change between the Baseline/Week 10 value and TP Baseline value. TP Baseline is 
defined as the Day 1 (Visit 3) value.  RWP Baseline/Week 10 value is defined as the 
Visit 11 value.   
• Change from end of CRN00808 treatment to 4 weeks after withdrawal of CRN00808.  
End of CRN00808 treatment for subjects who do not enter the RWP or subjects 
randomized to placebo in the RWP is defined as the Week 10 visit.  End of CRN00808 
treatment for subjects randomized to CRN00808 in the RWP is defined as the Week 
13/Visit 14 visit. For subjects randomized to CRN00808 in the RWP and who complete 
treatment in the RWP or subjects who do not enter the RWP, 4 weeks after withdrawal is 
defined as the Week 17/Visit 16 respectively.  For subjects randomized to placebo in the 
RWP, 4 weeks after withdrawal is defined as the second Week 13 (Visit 14) visit.  For 
subjects who withdraw early and have follow up visit, the value will be included as 4 
weeks after withdrawal. 
2.3.3.2.4. Patient Assessed 
 
 
 
 
 
 
 


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2.3.3.2.5. 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.3.3. 
Pharmacokinetics (PK) 
Plasma CRN00808 concentrations will be measured for each subject throughout the study.  
Values less than the limit of quantitation (LLOQ) will be included in analyses as LLOQ/2. 
LLOQ is 1 ng/mL. 
Plasma concentrations of octreotide or lanreotide will be measured for each subject throughout 
the study. Values LLOQ will be included in analyses as LLOQ/2. LLOQ is 100 pg/mL. 
2.3.4. 
Safety Endpoints 
Safety and tolerability of CRN00808 as assessed by vital signs; 12-lead ECGs; clinical 
laboratory tests (hematology, serum chemistry and urinalysis); fT3, fT4, anti-thyroid antibody, 
TSH, cortisol, ACTH, LH, FSH and prolactin; gall bladder ultrasounds; and treatment emergent 
adverse events (TEAEs). 
 


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3. 
SAMPLE SIZE JUSTIFICATION 
The sample size is justified with respect to the number of subjects meeting criteria to be 
randomized. With 36 randomized subjects, assuming a 60% response rate in the CRN00808 arm 
and a 10% response rate in the placebo arm (allocation ratio between two arms 1:1), the exact 
power to conclude superiority of the CRN00808 arm over placebo, applying an exact 
unconditional score test at a significance level of 5% (two-sided) is 92.2%. No adjustment for 
dropout rate was made because enrollment will continue until approximately 36 subjects with 
IGF-1 <ULN are randomized in the RWP. The exact power was computed based on the binomial 
distribution by evaluating all possible (N1+1) (N2+1) outcomes, weighted by their probability of 
occurrence for given true R1, R2 response rates in the two arms (0.6 and 0.1, respectively). 
Recruiting activity for this study was stopped as of 31MAR2020.  The final number of subjects 
dosed in the TP will be 13.  At the time of writing this document, it was unknown how many 
subjects completed the RWP. 


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4. 
GENERAL STATISTICAL METHODS 
4.1. 
Reporting Conventions 
Individual subject data obtained from electronic case report forms (eCRFs), central laboratories, 
external sources, and any derived data will be presented in data listings by subject. The primary 
data source will be used for all analyses. All data listings that contain an evaluation date will 
contain a relative study day. Pre-treatment and on-treatment study days are numbered relative to 
the day of the first dose of study drug which is designated as Day 1. The preceding day is Day -1, 
the day before that is Day -2, etc.  
All output will be incorporated into Microsoft Word rich text format (.rtf) files, sorted and 
labeled according to the ICH recommendations, and formatted to the appropriate font type, font 
size, page size, and margin sizes per FDA guidance “Portable Document Format Specifications”. 
For categorical variables, summary tabulations of the number and percentage of subjects within 
each category (with a category for missing data) of the parameter will be presented. Percentage 
calculations will be based on non-missing data, unless otherwise specified. Percentages are 
rounded to 1 decimal place, unless otherwise specified.  
For frequency counts of categorical variables, categories whose counts are zero will be displayed 
for the sake of completeness. For example, if none of the subjects discontinue due to “lost to 
follow-up,” this reason will be included in the table with a count of 0. Percentages based on 
frequency counts will be presented to one decimal place, and values less than 0.1% will be 
presented as “<0.1%.” Values less than 100% but greater than 99.9% will be presented as 
“>99.9%.”  
For continuous variables, the number of subjects, mean, standard deviation (SD), median, 25th 
(Q1) and 75th (Q3) quartiles, minimum, and maximum values will be presented. The precision of 
summary statistics, unless otherwise, specified will be as follows:  mean, median, Q1, and Q3 to 
1 more decimal place than the raw data, SD to 2 decimal places more than the raw data, and 
minimum and maximum to the same decimal places as the raw data. In general, the number of 
decimal places should not exceed 3 decimal places unless appropriate. Confidence intervals (CIs) 
will be provided and will be rounded to 1 decimal place, unless otherwise specified, in the table 
and listing shell.  
For tables where rounding is required, rounding will be done to the nearest round-off unit. For 
example, when rounding to the nearest integer, values ≥XX.5 will be rounded up to XX+1 (e.g., 
97.5 will round up to 98), while values <XX.5 will be rounded down to XX (e.g., 97.4 will round 
down to 97). 
All statistical tests comparing groups will be conducted at the 2-sided, 0.05 level of significance, 
unless otherwise specified. Summary statistics for each treatment will be presented, as well as 
two-sided 95% CIs comparing groups will be provided. 
4.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS software Version 9.4 or higher, 
unless otherwise noted. Medical history and AEs will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) version 21.0. Concomitant medications will be coded using 
World Health Organization (WHO) Drug Dictionary, B3 September 2019. 


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4.3. 
Partial Dates  
If only a partial date is available and is required for calculation, the following standards will be 
applied: 
• Death Date  
o The last date that each subject was known to be alive will be identified as the 
greatest date associated with the subject’s completed assessments, including 
telephone contacts at which the subject was confirmed to be alive.  
o For missing day only – Day will be imputed as the first day of the month (i.e., 1) 
with the following exception:  if the partial date falls in the same month as the last 
known alive date, then the partial date will be imputed to equal the last known 
alive date. 
o For missing day and month – Day and month will be imputed as the first day of 
the year (i.e., 1 January) with the following exception:  if the partial date falls in 
the same year as the last known alive date, then the partial date will be imputed to 
equal the last known alive date.  
• Diagnosis Date  
o For missing day only – Day will be imputed as the first day of the month (i.e., 1). 
o For missing day and month – Day and month will be imputed as the first day of 
the year (i.e., 1 January). 
• Start Dates (e.g., event date, adverse event [AE] onset date, or start date of medication) 
o For missing start day only – Day will be imputed as the first day of the month 
(i.e., 1) with the following exception:  if the partial date falls in the same month 
and year as the first study drug administration date, then the partial date will be 
imputed to equal the first study drug administration date being used for the 
calculation. 
o For missing start day and month – Day and month will be imputed as the first day 
of the year (i.e., 1 January) with the following exception:  if the partial date falls 
in the same year as the first study drug administration date, then the partial date 
will be imputed to equal the first study drug administration date being used for the 
calculation. 
o Imputed start dates must be prior to the stop date. 
• Stop Dates (e.g., AE resolution date or stop date of medication) 
o For missing stop day only – Day will be imputed as the last day of the month (i.e., 
28, 29, 30, or 31). 
o For missing stop day and month – Day and month will be imputed as the last day 
of the year (i.e., 31 December). 
o Imputed stop dates must be on or after the start date. 


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Dates will be presented on the listing as recorded, without imputation. All data recorded on the 
case report form will be included in data listings that will accompany the CSR. 
4.4. 
Data Conventions 
The precision of original measurements will be maintained in listings and used in calculations.  
Derived values greater than 3 decimal places will be rounded to 3 decimal places for display in 
the listings. 
Quantitative laboratory tests containing less than (<) and greater than (>) symbols are test results 
that are below and above quantifiable limits, respectively. In order to retain these values for 
analysis purpose, the following will be imputed and stored within the analysis datasets: 
• For values with <, the imputed value will be the numeric portion × 0.9. 
• For values with >, the imputed value will be the numeric portion × 1.1. 
4.5. 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
• Days – A duration expressed in days between one date (date1) and another later date 
(date2) will be calculated using the following formulas:   
duration in days = date2 – date1 + 1, where date1 ≥first administration date 
duration in days = date2 – date1, where date1 <first administration date 
• Weeks – A duration expressed in weeks is calculated as the number of days divided by 7 
• Months – A duration expressed in months is calculated as the number of days divided by 
30.4375 
• Years – A duration expressed in years between one date (date1) and another date (date2) 
is calculated using the following formulas: 
duration in years = (date2 – date1 + 1)/365.25, where date1 ≥first administration 
date 
duration in years = (date2 – date1)/365.25, where date1<first administration date 
• Height – Height entries made in inches (in) are converted to centimeters (cm) using the 
following formula: 
height (cm) = height (in) × 2.54 
• Weight – Weight entries made in pounds (lb) are converted to kilograms (kg) using the 
following formula: 
weight (kg) = weight (lb) / 2.205 
• Temperature – Temperature entries in degrees Fahrenheit are converted to degrees 
Celsius using the following formula: 
temp (degrees Celsius) = 5 / 9 × (temp [degrees Fahrenheit] – 32) 


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• Body Mass Index (BMI) – BMI is calculated using height (cm) and weight (kg) using the 
following formula: 
BMI (kg/m2) = weight (kg) / ([height (cm)/100]2) 
• Change– Change will be calculated as: 
Change = later value – earlier (i.e. baseline) value 
• Percent change– Percent change will be calculated as: 
Percent change = ([Change] / earlier (i.e. baseline) value) × 100 
4.6. 
Treatments  
Unless otherwise specified, summaries will be presented by the following treatment groups:  
• Paltusotine (CRN00808): To be used for ITT, mITT, and Safety summaries 
• Placebo: to be used for mITT and Safety summaries 
• Total: to be presented for all summaries except efficacy summaries 
Some summaries, where specified, may be broken out by dose, where doses will be presented in 
ascending order as Paltusotine (CRN00808) 
 Paltusotine (CRN00808) 
, Paltusotine 
(CRN00808) 
, Paltusotine (CRN00808) 
, and Total. 
4.7. 
Visits 
4.7.1. 
Windows   
Nominal, scheduled visits will be used for all by-visit analyses, visit windows will not be 
calculated for scheduled visits.  Each visit will be denoted by its visit “Week ” and “Visit” 
number, e.g. Week 2 (Visit 4). The first dose day is denoted as Day 1. In data listings, the 
relative study day of all dates from first dose will be presented. 
In the event of unscheduled visits or EoT assessments, these will be reassigned to a scheduled 
visit for analysis purposes according to Table 1 for on treatment assessments and  
Table 2 for assessments after last dose.  This includes combined visits due to COVID-19, any 
combined visits will be assigned to the nearest appropriate window as defined by the tables 
below. If multiple assessments occur within a single visit window, after reassignment of 
unscheduled visits and EoT assessments, then the assessment closest to the target day of the visit 
window will be used in the analysis. If there is a tie, the later assessment will be used in the 
analysis. Any unscheduled visits assessments during screening, i.e. prior to the first dose of 
CRN00808, will not be windowed. 
Table 1: 
Treatment Period Visit Windows, Except 
 
Target Scheduled Visit 
Target 
Study 
Day a 
Analysis Window Study Day a 
Low 
High 
TP Baseline (Visit 3)b 
1 
See Section 4.7.3 
TP Week 2 (Visit 4) 
8 
2 
15 


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Target Scheduled Visit 
Target 
Study 
Day a 
Analysis Window Study Day a 
Low 
High 
TP Week 4 (Visit 6) 
22 
16 
24 
TP Week 5 (Visit 7) 
29 
25 
36 
TP Week 7 (Visit 9) 
43 
37 
45 
TP Week 8 (Visit 10)c 
50 
46 
57 
RWP Baseline / Week 10 
(Visit 11) b, d 
64 
58 
68 
RWP Week 11 (Visit 12) 
71 
69 
78 
RWP Week 13 (Visit 13) 
85 
79 
86 
RWP Week 14 (Visit 14) 
91 
87 
95 
a Study day will be calculated from first dose of CRN00808.  
b Baseline is defined in Section 4.7.3. 
c Also the RWP Baseline for GH. 
d Only includes assessments PRIOR to randomization.  
e Also used for assessments only obtained at Visit 14. Visits used for Week 13, must not be used for FP Week 15. 
 
Table 2: 
Follow Up Visit Windows  
Target Scheduled Visit 
Target 
Day a 
Analysis Window Day a 
Low 
High 
2 Weeks Withdrawal of 
CRN00808 
14 
7 
21 
4 Weeks Withdrawal of 
CRN00808 
28 
≥22 
 
a Study will be calculated from last dose of CRN00808.  
4.7.2. 
Repeat or Unscheduled Assessments   
Repeat assessments occur when the original vital signs or ECG result requires confirmation. 
Repeat assessments are labelled as “Repeat” in the vital signs or ECG listings.    
All results not taken at a scheduled timepoint are unscheduled. Unscheduled assessments are 
labelled as ‘Unscheduled’ in the listings.  
In data listings, the relative study day from first dose of all dates will be presented. 
4.7.3. 
Definition of Baseline(s) 
For IGF-1 and IGBP-3, TP Baseline is defined as the mean of all available values prior to first 
dose of study drug (Visit 1b, Visit 2, Visit 3).  For GH, TP Baseline is defined as the mean of all 
available integrated values prior to the first dose of study drug (Visit 1b, Visit 2).  For ASD, the 
TP Baseline value will be defined as the mean of the available scores on the 7 days prior to first 


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dose of study drug. For baseline characteristics, safety assessments and other efficacy 
assessments, TP Baseline is as the last non-missing value prior to the first dose of CRN00808 
and RWP Baseline is the last non-missing value prior to the first dose of in the RWP. 
For IGF-1 and IGBP-3, the RWP Baseline / Week 10 value is the value taken prior to dosing in 
the RWP.  For GH, the RWP Baseline / Week 8 values will be used for TP Baseline. For ASD, 
the RWP Baseline / Week 10 value will be defined as the mean of the available total ASD score 
values on the 7 days prior to first dose in the RWP.   
Unknown, Not Done, Not Applicable and other classifications of missing data will not be 
considered when calculating baseline observations. In addition, non-missing results from 
unscheduled and repeat assessments prior to first study drug administration may also be 
considered in the calculation of baseline observations. 


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5. 
ANALYSIS SETS  
The following subject Analysis Sets will be evaluated and used for presentation and analysis of 
the data: 
• The Intent-to-Treat (ITT) Analysis Set will include all subjects who received at least one 
dose of the study drug. The ITT Analysis Set will be used for analyses of some of the 
secondary and exploratory efficacy endpoints. During the RWP, subjects will be included in 
the treatment group to which they were randomized. Data from all subjects dosed prior to 
RWP, regardless of eligibility to randomize, will be pooled. 
• The Modified Intent-to-Treat (mITT) Analysis Set will include all subjects from ITT who 
were randomized and dosed in the RWP. The mITT Analysis Set will be used for the primary 
analysis of all efficacy endpoints. Subjects will be included in the treatment group to which 
they were randomized. 
• The Safety Analysis Set will include all subjects who received at least one dose of study 
drug. The Safety Analysis Set will be used for all safety analyses. Treatment group 
assignments for safety analyses during the RWP will be based on the treatment that was 
received (if this differs from the randomized treatment). Data from all subjects dosed prior to 
RWP, regardless of eligibility to randomize, will be pooled. 
The Safety and ITT Analysis Sets are the same with the exception of using the actual treatment 
(Safety) versus the randomized treatment (ITT), in case a subject receives a treatment different 
than what he/she was randomized to.  If the analysis sets are identical, TFLs will use the ITT 
Analysis Set. 


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6. 
EXAMINATION OF SUBGROUPS 
Due to the small sample size, no summaries by subgroup will be presented. 


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7. 
STUDY POPULATION 
7.1. 
Subject Disposition 
Subject disposition will be tabulated and will include the number of subjects screened, the 
number screened but not randomized with reasons for screen failure, the number treated in the 
Titration Period of the TP, the number randomized to the RWP, the number randomized and not 
treated in the RWP, the number in each Analysis Set, the number who withdraw from the study 
prior to completing the study and reason(s) for withdrawal, and the number who discontinued 
treatment early and reason(s) for discontinuation of treatment. If a subject discontinues to due 
COVID-19 logistical reasons, instead of summarizing as part of Other, it will be separated out on 
the summary table.  Similarly, if a subject discontinues due to an adverse event of COVID-19, 
this will be presented as a subcategory of Adverse Event, combining the preferred terms of 
Corona virus infection and/or Coronavirus test positive as COVID-19. 
By-subject data listings of all the above study disposition data including randomization schedule 
with stratification factor, study completion and any reasons for premature treatment and/or study 
withdrawal will be presented. Also, by-subject listings of informed consent, re-consent, and 
eligibility criteria details will be presented. 
7.2. 
Demographics and Baseline Characteristics 
The following demographic variables and associated subgroups will be summarized: 
• Age at informed consent 
o <65 vs ≥65 years 
• Sex 
• Race 
o White vs All Other Races (Black or African American, Asian, Native Hawaiian or 
Other Pacific Islander, American Indian or Alaska Native) 
• Ethnicity 
• Geographic Region:  North America (USA) vs Europe (United Kingdom, Germany, 
Hungary, Romania, Slovakia, Italy, Poland, Serbia) vs Rest of World (Brazil, Australia, 
New Zealand) 
Other baseline characteristics, from TP Baseline, will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) including frequency of the following subgroup: <30, ≥30 kg/m2 
• Ring size 
• UGT1A1 genotype and phenotype 


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Demographics and baseline characteristics will be presented by treatment and overall for ITT, 
mITT, and Safety Analysis Sets. If the ITT and Safety Analysis Sets are equivalent, only the ITT 
Analysis Set will be included. 
No inferential statistical comparisons will be performed. 
All demographic and baseline characteristics data will be presented in by-subject data listings. 
7.3. 
Baseline Acromegaly Disease Characteristics 
The following disease characteristics and associated subgroups will be summarized: 
• Duration (months) since acromegaly diagnosis from informed consent date 
o <Median vs ≥Median  
• Tumor size (mm) prior to pituitary surgery 
• Prior pituitary surgery: Yes vs No 
• For those with pituitary surgery, IGF-1 (nmol/L) value at least 3 months after surgery 
• Pre-Trial Acromegaly Treatment (Octreotide LAR vs Lanreotide Depot) 
o Doses pre-trial acromegaly treatments administered as recorded on the 
Concomitant Medications eCRF.  If a subject has more than one of these 
treatments recorded, the last observation, as determined by start date, consistent 
with treatment recorded on the Administration of Pre-Trial Acromegaly 
Treatment eCRF, will be used.  
Where the median is specified as the cut point, the median of the total study population at TP 
Baseline will be used. 
Baseline disease characteristics will be presented by treatment and overall for the ITT, mITT, 
and Safety Analysis Sets. If the ITT and Safety Analysis Sets are equivalent, only the ITT 
Analysis Set will be included.   
No inferential statistical comparisons will be performed.  
Baseline disease characteristics will be presented in by-subject data listings. 
7.4. 
Acromegaly Symptoms at Study Entry 
Acromegaly symptoms at study entry will be presented in a by-subject data listing. 
7.5. 
General Medical History 
General medical history will be presented in a by-subject data listing. Any medical history of 
COVID-19 will appear as per their MedDRA SOC Infections and infestations and PTs of either 
Coronavirus infection and/or Coronavirus test positive. 
7.6. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any significant way without 
prior notification to the Sponsor (or designee) as described in the protocol.  


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Important protocol deviations that could potentially affect the efficacy conclusions of the study 
will be identified prior to database lock and unblinding of individual subject treatment or dose 
information. Important protocol deviations include, but are not limited to  
• Subjects who entered the study, or RWP, even though they did not satisfy the entry 
criteria.  
• Subjects who received the wrong treatment or incorrect dose.  
• Subjects who received a prohibited concomitant treatment. 
All protocol deviations and separately only important protocol deviations will be summarized by 
deviation category and treatment using the ITT Analysis Set. Protocol deviations specific to 
COVID-19 will be summarized separately in the same manner. 
All protocol deviations and separately only important protocol deviations will be presented in a 
by-subject data listing. A separate listing for COVID-19 specific protocol deviations will be 
presented. 
7.7. 
Pretreatment, Prior, and New Concomitant Medications or Non-
Pharmacological Treatments 
Pretreatment medications are those medications with start and stop prior to the first 
administration of study drug. Prior concomitant medications are those medications/treatments 
started prior and continued after the first administration of study drug. New concomitant 
medications are those medications/treatments that were started on or after the first administration 
of study drug. If it cannot be determined whether the medication/treatment was a new 
concomitant medication due to a partial start or stop date or if the medication/treatment is taken 
on the same date as the first administration of study drug, then it will be counted as a new 
concomitant medication.  
Non-pharmacological treatments will be listed separately. Pretreatment, prior and new 
concomitant medications will be listed. 
 


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8. 
EFFICACY ANALYSES  
All efficacy analyses will use the mITT Analysis Set. Exploratory analyses will also use the ITT 
Analysis Set.   
All efficacy endpoints, recorded and derived, will be presented in by-subject data listings.  
8.1. 
Adjustments for Covariates 
For comparison of treatment groups with respect to change and percent change, rank analysis of 
covariance (ANCOVA) models will be used. The corresponding ranked TP Baseline or RWP 
Baseline/Week 10 value will be used as a covariate in the model.  
8.2. 
Handling of Dropouts or Missing Data 
The following methods will be implemented to address missing data for relevant primary, key 
secondary, and select exploratory efficacy endpoints. 
8.2.1. 
Responder Endpoints 
For categorical efficacy endpoints in which subjects are classified as either a responder or a non-
responder (binary outcome) based on dichotomizing a continuous variable at each visit, any 
subject who does not provide an assessment at the specified time point for the response 
definition will be considered as a non-responder, regardless of treatment group.  
8.2.2. 
Continuous Endpoints 
Due to the small sample sizes, a simple approach to imputation of continuous endpoints will be 
employed.  Only end of treatment period visits will be imputed, i.e. Week 8/Visit 10 (GH only), 
Week 10/Visit 11, and Week 13/Visit 14. 
For IGF-1 and GH, subjects who missed a visit will also have their missing visit values imputed 
using last observation carried forward (LOCF). Visit values will only be carried forward within 
the same study period.   
• Only TP visit values prior to randomization in the RWP will be used for missing visit 
values after Week 1/Day 1/Visit 3 and before Week 10/Visit 11.   
• Only RWP visit values will be used for missing visit values after Week 10/Visit 11 up to 
Week 13/Visit 14.   
• Follow up visit (FP Week 15 and FP Week 17) data will not be imputed. 
For analyses using a rank ANCOVA, the value will be imputed using LOCF prior to ranking. 
Missing data will not be imputed for patient or investigator assessment reported outcomes. 
8.3. 
Interim Analyses and Data Monitoring 
8.3.1. 
Interim Analysis  
No interim analyses are planned for this study. 


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8.4. 
Multicenter Studies 
The randomization is not stratified by site. Likewise, analyses of efficacy data will not be 
stratified by study site. The number and percentage of subjects randomized by geographical 
region and study site will be summarized by treatment group and for all subjects. 
8.5. 
Use of an “Efficacy Subset” of Patients 
Not Applicable. 
8.6. 
Multiple Comparisons/Multiplicity 
No adjustment for multiple comparisons will be made due to the small sample size. 
8.7. 
Primary Efficacy Analysis 
The primary efficacy analysis will test the following hypothesis: 
• H0:  The percentage of IGF-1 responders at Week 13 is equal between placebo and 
CRN00808. 
• H1:  The percentage of IGF-1 responders at Week 13 is different between placebo and 
CRN00808.  
The primary efficacy analyses, using the mITT Analysis Set, will compare placebo and 
CRN00808 on the distribution of responders at Week 13, at alpha level of 0.05, using the 
exact unconditional score test for the difference between two binomial proportions. The 
number and percentage, with associated two-sided exact (Clopper-Pearson) 95% CIs, of 
subjects in each category (response, non-response) will be presented by treatment.  
8.7.1. 
Additional Analyses of the Primary Endpoint 
Sensitivity analyses using observed cases will be presented. 
The number and percentage, with associated two-sided exact (Clopper-Pearson) 95% CIs, of 
subjects in each category (response, non-response) will be presented by treatment using 
observed cases at each scheduled visit starting at TP Baseline through FP Week 17 (Visit 16) 
for the ITT Analysis Set.  Response is defined as IGF-1 ≤ULN and non-response is defined 
as >ULN. Subjects missing IGF-1 measurement are counted as a non-responder. 
8.8. 
Key Secondary Efficacy Analyses 
Key secondary efficacy endpoints are described in Section 2.3.2 and missing data 
conventions in Section 8.2. 
8.8.1. 
Change in IGF-1 Levels Between Week 10 to Week 13 
The key secondary efficacy analysis will test the following hypotheses: 
• H0:  The median IGF-1 change from RWP Baseline/Week 10 to Week 13 is equal 
between placebo and CRN00808. 
• H1:  The median IGF-1 change from RWP Baseline/Week 10 to Week 13 is different 
between placebo and CRN00808.  


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CRN00808 and placebo will be compared for the mITT Analysis Set on change from RWP 
Baseline/Week 10 to Week 13 using a rank ANCOVA model including fixed effects for 
randomization strata and treatment, and with the ranked RWP Baseline/Week 10 value included 
as a covariate. The Hodges-Lehman estimate of the median treatment difference with associated 
95% CI will be presented. Descriptive statistics of ranks will not be presented. 
Descriptive statistics for IGF-1 values, change from RWP Baseline/Week 10, and percent change 
from RWP Baseline/Week 10 will be presented for the RWP and FP visits by treatment.  
Sensitivity analyses using observed cases will be presented.  
8.8.2. 
Change in GH Levels Between Week 8 and Week 13 
The key secondary efficacy analysis will test the following hypotheses: 
• H0:  The median GH change from RWP Baseline/Week 8 to Week 13 is equal between 
placebo and CRN00808. 
• H1:  The median GH change from RWP Baseline/Week 8 to Week 13 is different 
between placebo and CRN00808.  
CRN00808 and placebo will be compared for the mITT Analysis Set on change from RWP 
Baseline/Week 8 to Week 13 using a rank ANCOVA model including fixed effects for 
randomization strata and treatment, and with the ranked RWP Baseline/Week 8 value included as 
a covariate. The Hodges-Lehman estimate of the median treatment difference with associated 
95% CI will be presented. Descriptive statistics of ranks will not be presented. 
Descriptive statistics for GH values, change from RWP Baseline/Week 8, and percent change 
from RWP Baseline/Week 8 will be presented for the RWP and FP visits by treatment.  
Sensitivity analyses using observed cases will be presented.  
8.8.3. 
Change in Total ASD Score Between Week 10 and Week 13 
The key secondary efficacy analysis will test the following hypotheses: 
• H0:  The median total ASD score change from RWP Baseline/Week 10 to Week 13 is 
equal between placebo and CRN00808. 
• H1:  The median total ASD score change from RWP Baseline/Week 10 to Week 13 is 
different between placebo and CRN00808.  
CRN00808 and placebo will be compared for the mITT Analysis Set on change from RWP 
Baseline/Week 10 to Week 13 using a rank ANCOVA model including fixed effects for 
randomization strata and treatment, and with the ranked RWP Baseline/Week 10 value included 
as a covariate. The Hodges-Lehman estimate of the median treatment difference with associated 
95% CI will be presented. Descriptive statistics of ranks will not be presented. 
Descriptive statistics for total ASD scores and change from RWP Baseline/Week 10 will be 
presented for each RWP visit by treatment.  
8.9. 
Exploratory Efficacy Analyses  
Statistical analysis of exploratory efficacy endpoints will be considered nominal and descriptive. 


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8.9.1. 
Biomarker Endpoint Analyses 
8.9.1.1. 
IGF-1 
Changes in IGF-1 levels specified in Section 2.3.3.1.1 will presented using observed cases, in the 
same manner as specified for the first secondary endpoint (Section 8.8.1) for the mITT Analysis 
Set, and separately without hypothesis testing for the ITT Analysis Set.  
8.9.1.2. 
GH 
Changes in serum GH as specified in Section 2.3.3.1.2 will presented using observed cases, in 
the same manner as specified for the first key secondary endpoint (Section 8.8.1) for the mITT 
Analysis Set, and separately without hypothesis testing for the ITT Analysis Set.   
8.9.1.3. 
 
and changes in 
 will presented in a by-subject listing only.  
8.9.2. 
Patient and Investigator Assessed Reported Outcomes Endpoint Analyses 
8.9.2.1. 
Patient Assessed Symptoms of Acromegaly: 
 
The change in the 
 will be presented 
using the same methods specified in Section 8.8.3 for the mITT Analysis Set, and separately 
without hypothesis testing for the ITT Analysis Set.  
8.9.2.2. 
Investigator Assessed Symptoms of Acromegaly 
Investigator assessed symptoms of acromegaly will be presented in a by-subject listing only. 
8.9.2.3. 
 
 index score, VAS, and each of the 5 dimension scores and their respective 
changes will be presented in a by-subject listing only.   
8.9.2.4. 
 
 each of the 22 individual items, and their respective changes will be 
presented will be presented in a by-subject listing only.     
8.9.2.5. 
 
 will be presented in a by-subject listing only.  
8.9.3. 
Pharmacokinetic (PK) Analyses 
Plasma CRN00808 concentrations and elapsed time from the last CRN00808 dose taken will be 
listed. The results at each visit and the percent change in CRN00808 concentration from end of 
CRN00808 treatment to each visit will be calculated for each subject.   
Residual plasma concentration levels of octreotide and lanreotide will be presented in by-subject 
data listings. The percent change in concentration from Screening Visit 2 and separately the 
percent change from Week 13 (Visit 11) will be calculated for each subject.   


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PK concentrations will be reported to 3 significant figures. 


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9. 
SAFETY ANALYSES 
Safety analyses will be conducted using the Safety Analysis Set.  
No inferential comparison of safety endpoints will be performed, unless otherwise specified.  
9.1. 
Extent of Exposure 
The number and percentage of subjects exposed to each dose of CRN00808 will be presented for 
the Safety Analysis Set.  The number and percentage of subjects on each CRN00808 dose when 
entering the RWP will be presented for the mITT Analysis Set. 
Duration of exposure is defined in days as the last date study drug administration – the first date 
study drug administration + 1.  Duration of total CRN00808 exposure and exposure to each dose 
level will be summarized with descriptive statistics by CRN00808 dose using the Safety 
Analysis Set.  In addition, duration of exposure will be summarized categorically for subjects 
exposed to CRN00808 by week, i.e. ≥1 week, …, ≥12 weeks, ≥13 weeks. 
Treatment compliance will be calculated based on on-site/diary dosing and separately based on 
study drug accountability. Compliance based on the on-site dosing and at home dosing diary will 
be calculated as 100 x (total number of days with dosing / (last dose date – first dose date + 1)).  
Compliance based on study drug accountability will be calculated as 100 x ((total number of 
capsules dispensed – total number of capsules returned) / total number of capsules dispensed).  
Treatment compliance will be summarized with descriptive statistics using the Safety Analysis 
Set.   
Compliance with fasting conditions will be presented in the data listings. 
9.2. 
Adverse Events 
An adverse event (AE) is any undesirable sign, symptom or medical condition, whether or not 
considered drug related and occurring after the moment of signing ICF.  Pretreatment AEs are 
those AEs with a start date prior to the first administration of study drug. All AE summaries will 
be restricted to TEAEs, which are defined as any AE that newly appears, increases in frequency, 
or worsens in severity following initiation of study drug. If it cannot be determined whether the 
AE is treatment emergent due to a partial onset date, then it will be counted as such.  
Each AE summary will be displayed  
1) For All CRN00808 dosed subjects and by CRN00808 dose using the Safety Analysis Set 
for any AE occurring after first dose of CRN00808 
2) By treatment for the Safety Analysis Set for any AE occurring on or after the date of first 
dose of double-blind study drug in the RWP 
Each summary will be presented by treatment and total.  Separate summaries will be presented 
by each CRN00808 dose and total.  TEAEs will be determined to have occurred on a specific 
dose based on the adverse event start date and dose titration dates. For example, if the adverse 
event starts on or after the first dose, before any dose titration, the adverse event will be counted 
as occurring on 
 or if the adverse event starts on or after the first dose titration, before the 
second dose titration, the adverse event will be counted as occurring on 
 if the subject was 


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up-titrated or 
 if the subject was not up-titrated. A similar process will be followed for all 
up and down titrations to assign an adverse event to a dose. 
Any adverse events of COVID-19 will appear as per their MedDRA SOC Infections and 
infestations and PTs of either Coronavirus infection and/or Coronavirus test positive.  Separate 
summary tables will not be produced. 
Summaries that are displayed by SOC and PT will be ordered by descending order of CRN00808 
incidence of SOC and PT within each SOC. Summaries of the following types will be presented: 
• Overall summary of AEs including the number and percent of subjects with at least one 
of the following: 
o Any TEAE 
o Severe TEAE 
o Serious TEAE 
o Fatal TEAE 
o Treatment-related TEAE 
o Treatment-related severe TEAE 
o Treatment-related serious TEAE 
o Treatment-related fatal TEAE  
o TEAE leading to study drug discontinuation or withdrawal from study 
− TEAE leading to study drug discontinuation 
− TEAE leading to withdrawal from study  
• Subject incidence of TEAEs by MedDRA SOC and PT.  
• Subject incidence of TEAEs by maximum severity, MedDRA SOC and PT. At each level 
of subject summarization, a subject is classified according to the highest severity if the 
subject reported 1 or more events. AEs with missing severity will be considered severe 
for this summary.  
• Subject incidence of related TEAEs by MedDRA SOC and PT. Related is defined as 
Relationship to IMP of “Possibly”, “Probably”, or “Definitely”. At each level of subject 
summarization, a subject is classified according to the closest relationship to study drug if 
the subject reported 1 or more events. AEs with a missing relationship will be considered 
related for this summary. 
• Subject incidence of related, severe TEAEs by MedDRA SOC and PT. At each level of 
subject summarization, a subject is classified according to the highest severity if the 
subject reported 1 or more events. AEs with missing severity will be considered severe 
for this summary. AEs with a missing relationship will be considered related for this 
summary. 


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• Subject incidence of TEAEs leading to study drug discontinuation or withdrawal from 
study by MedDRA SOC and PT. This is a subset of the AEs where Discontinuation from 
the study due to AE? = “Yes” or Action Taken to IMP = “Drug Discontinued”. 
The following listings will be presented by treatment and subject: 
• All AEs 
• SAEs (this is a subset of the AEs where serious is marked as “Yes”) 
• Severe AEs (this is a subset of AEs where severity is marked as Severe) 
• Related AEs (this is a subset of the AEs where relationship marked as Possibly, Probably, 
or Definitely Related) 
• AEs leading to study drug discontinuation or withdrawal from study by MedDRA SOC 
and PT. (this is a subset of the AEs where Discontinuation from the study due to AE? = 
“Yes” or Action Taken to IMP = “Drug Discontinued”. 
• Fatal AEs (this is a subset of the AEs where outcome is indicated as “Fatal”) 
9.3. 
Clinical Laboratory Evaluations 
All laboratory assessments are given in protocol section 6.1.8. The data from the central lab is 
uploaded to the EDC to assist with safety review and assignment of clinical significance.  Data 
from the central lab, i.e. the source data will be used for analyses. Laboratory parameters will be 
summarized in standard international (SI) system of units. Quantitative clinical chemistry, 
hematology, coagulation, and urinalysis laboratory tests will be assigned grades based on 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 5.0, where applicable. The by-subject data listings will include flags for out of range (L 
for Low and H for High) and NCI CTCAE grade (G1, G2, G3, G4). 
All clinical laboratory data will be presented in by-subject data listings.  
Additional listings for each laboratory category will be presented for any subject with a post- TP 
Baseline CTCAE grade 3 or 4 laboratory value.  
Normal ranges provided by the central laboratory will be presented in a listing. 
Where applicable, if the quantitative criteria for grading are equivalent for two grades, only 
differentiated by clinical interventions, the clinical intervention will be ignored and the highest 
CTCAE grade will be used. If a value fits into multiple grades, the worst grade will be assigned. 
9.3.1. 
Serum Chemistry, Hematology, and HbA1c 
Quantitative serum chemistry, hematology, and HbA1c results for each scheduled visit, TP 
baseline through FP Week 17 (Visit 16), and changes from TP Baseline will be listed using the 
Safety Analysis Set.  Similarly, changes from RWP Baseline/Week 10 through FP Week 17 
(Visit 16), will be listed separately using the Safety Analysis Set.  
9.3.2. 
Hormones 
Hormone levels of free triiodothyronine hormone (fT3), free thyroxine hormone (fT4), anti-
thyroid antibody, thyroid stimulating hormone (TSH), cortisol, adrenocorticotropic hormone 


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(ACTH), lutenizing hormone (LH), follicle stimulating hormone (FSH) and prolactin will be 
assessed at Screening (Visit 1b), Week 10 (Visit 11), and Week 13 (Visit 14). 
Hormone levels will be listed using the Safety Analysis Set. In addition, change and percent 
change from TP Baseline will also be presented. Similar listings will be presented including 
changes from RWP Baseline/Week 10 to Week 13. 
9.3.3. 
Genotyping 
The UGT1A1 genotype will be summarized with baseline characteristics (Section 7.2) and 
provided in a separate by-subject data listing. 
9.4. 
Vital Signs  
Vital sign parameters including body temperature (C), systolic and diastolic pressure (mmHg), 
pulse rate (beats/min) and respiratory rate (breaths/min) will be presented in a data listing using 
the Safety Analysis Set. 
Listings will include change from TP Baseline through FP Week 17 (Visit 16). Similar listings 
will be presented for changes from RWP Baseline/Week 10 to each post- RWP Baseline/Week 
10 visit through FP Week 17 (Visit 16). If a subject has repeat assessments at a specified visit, 
the last value will be used to calculate the change. 
9.5. 
Ring Size, Weight and BMI 
Ring size (mm), weight (kg) and BMI (kg/m2) will be presented in a data listing. In addition, 
change and percent change from TP Baseline will be also be included. Similar listings will be 
presented for changes from RWP Baseline/Week 10 to each post- RWP Baseline/Week 10 visit 
through FP Week 17 (Visit 16). 
9.6. 
12-Lead Electrocardiograms (ECGs) 
ECGs measurements will be made in triplicate and assessed by a central reader. The data from 
the central reader is uploaded to the EDC to assist with safety review and assignment of clinical 
significance.  Data from the central reader, i.e. the source data will be used for analyses. The 
mean of the three measurements will be used.  If any of the three measurements are not available 
or additional measurements are available, the available measurements will be used. If one of the 
triplicates is the same date and time as first dose, the triplicate will be included in the calculation 
of TP Baseline.  
ECG parameters including heart rate, PR interval, QRS duration, QT (uncorrected) interval, and 
QT interval corrected by the Fridericia’s formula [QTcF] will be listed for each triplicate 
measurement and the average of the triplicates using the Safety Analysis Set. In addition, change 
from baseline will be presented. Similar listings will be presented from RWP Baseline/Week 10 
to each post- RWP Baseline/Week 10 visit through FP Week 17. 
A separate listing for those subjects with any QTcF >450 msec or a QTcF change from TP 
Baseline >30 msec, based on the average of the triplicates, will be presented. All of the subject’s 
values will be included in the listing and the observation(s) meeting criteria for inclusion will be 
flagged.  


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The investigator interpretation results are collected as normal, abnormal not clinically 
significant, and abnormal clinically significant. Subjects whose interpretation shifts from normal 
at TP Baseline to abnormal clinically significant or not clinically significant post TP Baseline 
will be listed separately including description of the abnormality and any associated comments. 
All ECG results will be presented in by-subject data listings. 
9.7. 
Gall Bladder Ultrasound 
Gall bladder ultrasound data for absence or presence of gallstones or gall bladder sludge will be 
listed including any changes as Newly Appeared and No Longer Present. 
9.8. 
Other Safety Assessments 
The following additional data will be provided in by-subject listings only: 
• Physical examination findings based on body systems entered on the eCRF  
• Screening outpatient Holter data collection details 
• Pregnancy Testing including reproductive status 
• Serology (HBV, HCV, HIV testing) 
• Urine drug screen 
• Head MRI/CT Scan 
• Urinalysis 
• Study drug dispensing and accountability 
• Confirmation of tolerability for potential dose up-titration and potential dose titration 
CRF details 
 
 


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10. 
CHANGES TO PROTOCOL PLANNED ANALYSES 
Given the reduced, small sample size, the Per Protocol Analysis Set was removed. 
The protocol includes change from W10 to W13 in GH, however, since GH is not measured at 
W10, this endpoint will not be evaluated. 
The protocol specified physical examination at each post-baseline study visit as an endpoint.  
However, any clinically significant findings are recorded as an AE.  Therefore, results from 
physical examination are listed only. 
To assess the protocol specified endpoint of the amount of increase in IGF-1 or GH levels after 
withdrawal of CRN00808, the change from end of CRN00808 treatment will be used. 
The following exploratory endpoints will be listed only, instead of being summarized, due to the 
small sample size: 
• Changes from baseline in serum GH, IGF-1, and 
levels measured at W10 and 
W13 
• compared to baseline (D1; [V2 for GH]) 
• Change from baseline in 
 score at W10 and between W10 and W13 
• Change from baseline in 
 at W10 and between W10 and W13 
• Change in investigator assessed symptoms of acromegaly between W10 and W13 
• Change from baseline in investigator assessed symptoms of acromegaly at W10 
• Change in 
 scores between W10 and W13 
• Change from baseline in 
 scores at W10 
• 
 scores at W10 and W13. 
The following exploratory endpoints will not be summarized, due to the small sample size: 
• Proportion of subjects who achieve serum GH <5.0 ng/mL at W13 
• Proportion of subjects who achieve serum GH <2.5 ng/mL at W13 
• Time to loss of response (IGF-1 >ULN) after withdrawal of CRN00808 
• Increase in serum 
 levels 3+ weeks after withdrawal of CRN00808.