Clinical trial NCT03789656
Conditions: Acromegaly
Keywords: Acromegaly ACROBAT EDGE Paltusotine
Sponsor: Crinetics Pharmaceuticals Inc.
Start date: 2019-03-12; Completion date: 2020-08-31
Enrollment: 47 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
An open label exploratory study designed to evaluate the safety, efficacy, and pharmacokinetics of paltusotine (formerly CRN00808) in subjects with acromegaly that are treated with somatostatin analogue (SSA) based treatment regimens.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Paltusotine
Intervention descriptions: intervention 1: Paltusotine, capsules, once daily by mouth

Protocol documents:
Prot_000.pdf: 
       
 
 
Crinetics Pharmaceuticals, Inc. 
  
Protocol #: CRN00808-03  
EudraCT # 2018-002230-20 
NCT # 03789656 
 
AN OPEN LABEL EXPLORATORY STUDY TO EVALUATE THE SAFETY, 
PHARMACOKINETICS AND EFFICACY OF CRN00808 IN PATIENTS WITH 
ACROMEGALY TREATED WITH SOMATOSTATIN ANALOGUE BASED TREATMENT 
REGIMENS (ACROBAT EDGE) 
 
  
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: 
07 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: CRN00808-03  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
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SPONSOR APPROVAL PAGE 
 
Protocol #: CRN00808-03 
 
An open label exploratory study to evaluate the safety, pharmacokinetics and 
efficacy of CRN00808 in patients with acromegaly treated with somatostatin 
analogue based treatment regimens  
(ACROBAT EDGE) 
 
 
Protocol Version: 3.0 
Protocol Date: 07 June 2019 
 
 
 
 
This protocol has been reviewed and approved by Crinetics Pharmaceuticals, Inc.: 
 
 
 
 
 
____________________________________ 
 
________________ 
, MD  
 
 
 
 
Date 
 
 
 
 
 
 


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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
Protocol #: CRN00808-03 
An open label exploratory study to evaluate the safety, pharmacokinetics and 
efficacy of CRN00808 in patients with acromegaly treated with somatostatin 
analogue based treatment regimens  
(ACROBAT EDGE) 
 
Protocol Version: 3.0 
Protocol Date: 07 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: ______________________________________________________ 


Study code: CRN00808-03  
 
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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 
CRO Senior Director, Drug Safety and Regulatory  
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: 
 
 
 


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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 
  
) 
 
                
 
 
 
 
 
 
 
 
 
 
Bioanalytical Laboratory (CRN00808 PK) 
 
 
  
 
Bioanalytical Laboratory (UGT1A1 genotype 
Sample)  
 
 
 
 
Cardiac Monitoring  
 
 
 
 
 
 
 
 
 
Bioanalytical Laboratory (lanreotide and 
octreotide PK) 
 
 
 
 
 


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Study Responsibility 
Vendor 
Drug Product Packaging and Distribution  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Travel and Reimbursement Support 
(Optional Service) 
 
 
 
 
 
Mobile Research (Optional Service) 
 
 
 
 
 
 
 


Study code: CRN00808-03  
 
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PROTOCOL SYNOPSIS  
 
Name of Sponsor/Company: Crinetics Pharmaceuticals, Inc. 
Title of Study: An open label exploratory study to evaluate the safety, pharmacokinetics and 
efficacy of CRN00808 in patients with acromegaly treated with somatostatin analogue based 
treatment regimens (ACROBAT EDGE)  
Study Code: CRN00808-03 
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 evaluate the efficacy of CRN00808 in acromegaly subjects treated with somatostatin 
analogue based treatment regimens; 
• 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 is an open label dose blinded exploratory study designed 
to evaluate the safety, PK and efficacy of CRN00808 in subjects with acromegaly that are treated 
with somatostatin analogue (SSA) based treatment regimens. The study will consist of the 
following periods: 
• Screening Period (4-6 weeks); 
• Treatment Period (up to 13 weeks); 
• Follow-up Period (up to 4 weeks). 
Approximately 45 subjects on stable doses of SSA based pharmacotherapy for the treatment of 
acromegaly will be recruited for this clinical trial.  


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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, lanreotide depot or pasireotide LAR.  
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, the Screening IGF-1 measurements 
(performed by the study central laboratory) must fall into the ranges specified for one of the 
following groups: 
• Group 1: Partial responders on a stable treatment of octreotide LAR or lanreotide depot 
(at least one Screening IGF-1 value must be >ULN, and the V2 value must be ≤2.5×ULN); 
• Group 2: Partial responders on a stable combination treatment of SSA (i.e., octreotide 
LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (at 
least one Screening IGF-1 value must be >ULN, and the V2 value must be ≤2.5×ULN); 
• Group 3: Complete responders on a stable combination treatment of SSA 
(i.e., octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or 
cabergoline) (mean of Screening IGF-1 values must be ≤ULN); 
• Group 4: Complete responders on a stable dose of pasireotide LAR (mean of Screening 
IGF-1 values must be ≤ULN); 
• Group 5: Complete responders on a stable combination treatment of SSA (i.e., octreotide 
LAR or lanreotide depot) and pegvisomant (mean of Screening IGF-1 values must be 
≤ULN). 
All other assessments performed during the Screening Period are detailed in Table 1. 
TREATMENT 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 continue their 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, V12/W10, and V14/W13 the study drug is to be administered at the study center, also 


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under fasting conditions. During the entire Treatment Period, the subjects are expected to 
swallow four capsules (Size 2) with water every day.    
During the V6/W4 and V9/W7, the dose may be titrated up in a blinded fashion, provided the 
preceding IGF-1 values collected in V4/W2, and in V7/W5, respectively, are >0.9×ULN and the 
current dose is tolerated by the subject. At V12/W10, the dose may be titrated up in a blinded 
fashion, provided the preceding IGF-1 value collected in V10/W8 is >ULN and the current dose 
is tolerated by the subject.  
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, V9/W7, V11/W9 and V12/W10. If tolerability is confirmed 
and the IGF-1 reader has determined that IGF-1 has not met adequate suppression criteria at 
the previous visit, a blinded blister card containing the appropriate higher dose will be assigned 
at the V6/W4, V9/W7 and/or V12/W10. Dose increases in 
 increments will be allowed only 
at the V6/W4 (from 
) V9/W7 (from 
) 
and V12/W10 (from 
). 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, V9/W7 and V12/W10, 
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 a 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 blister 
cards taking into account information from the investigator and from the central IGF-1 reader. 
Subjects 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. 
Number of Subjects (planned): Approximately 45 male and female subjects with a confirmed 
acromegaly diagnosis who fall into one of the five groups as described above.  
Groups 1 and 2 will contribute at least 30 of the approximately 45 subjects enrolled. 


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Diagnosis and Main Criteria for Inclusion:  
Approximately 45 adult subjects will be considered for enrollment in the study 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, who meet the protocol defined criteria (see 
Section 3.2) for a partial or complete responder to somatostatin analogue based 
therapy. A stable dose is defined as no changes in acromegaly medication doses in 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 
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. 


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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 
subjects in Group 3, 4, or 5 who have undergone pituitary radiation therapy at any time 
prior to the study entry. A history of radiation therapy is not a restriction for subjects in 
Group 1 or 2. If a subject in Group 3, 4, or 5 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 


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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 4.7.2); 
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 are complete responders (both Screening IGF-1 values ≤ULN) to octreotide 
LAR or lanreotide depot monotherapy; 
17. Subjects taking octreotide LAR at a dose higher than 40 mg, or lanreotide depot at a dose 
higher than 120 mg, or pasireotide LAR higher than 60 mg; 
18. Subjects who usually take octreotide LAR, lanreotide depot or pasireotide LAR 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 CRN00808-02; 
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 Treatment Period, subjects will receive an oral once daily dose of either 
 
 based on the titration schedule. 
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  
Not applicable. 
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, single doses up to 
 and 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. 
It is expected that partial responders to current pharmacotherapies used for the treatment of 
acromegaly will require a higher dose. Therefore, titration is allowed up to a dose of 
 
CRN00808 in subjects whose IGF-1 is not normalized by lower doses.  
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. 
Study Endpoints 
EFFICACY ENDPOINTS: 
Primary endpoint: 
The primary endpoint is the change from baseline (mean of Screening values) in IGF-1 level at 
W13. 


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Key Secondary endpoints: 
• Proportion of subjects with the mean of their last two consecutive IGF-1 measurements 
≤ULN;   
• Proportion of subjects with the mean of their last two consecutive IGF-1 measurements 
≤1.5×ULN;  
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; 
• Change from baseline in serum GH levels measured at W13; 
• Change from baseline in serum 
 levels measured at W13; 
• Increase in serum GH, IGF-1, and 
 levels 3+ weeks after withdrawal of CRN00808; 
• Change from baseline in symptoms of acromegaly as measured by total 
 score at 
W13; 
• Change from baseline in symptoms of acromegaly as measured by individual 
 score 
at W13; 
• Change from baseline in 
 score at W13; 
• Change from baseline in 
 at W13; 
• Change from baseline in investigator assessed symptoms of acromegaly at W13; 
• Change from baseline in PGI-S scores at W13; 
• PGI-I scores at W13; 
• Plasma concentrations of CRN00808. 
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. 


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STATISTICAL CONSIDERATIONS 
Sample Size Calculation 
Approximately 45 subjects are planned to be enrolled in the study. At least 30 subjects from 
Groups 1 and 2 will be enrolled, i.e., a cap of N=15 is set for the sum of the number of subjects 
in Group 3 to 5. 
The primary objective of this study is to evaluate efficacy (IGF-1 levels) in subjects who are 
partial responders to somatostatin analogue based treatment regimens. As such, the sample 
size is chosen to provide sufficient clinical experience to evaluate IGF-1 changes descriptively 
and is not formally powered for hypothesis testing. Summary statistics for the primary endpoint 
will be provided. 
Analysis Datasets 
Safety Analysis Set comprises all subjects who received at least one dose of the study 
medication. The Safety Analysis Set will be used for all safety analyses and for some of the 
secondary efficacy endpoints.  
Efficacy Analysis Set comprises all subjects from Groups 1 and 2 who received at least one dose 
of the study medication. The Efficacy Analysis Set will be used for the evaluation of the primary 
efficacy endpoint and for some of the secondary efficacy endpoints. 
Per Protocol Analysis Set (PP) comprises all subjects from the Efficacy Analysis Set having no 
major protocol deviation affecting treatment efficacy. The PP analysis set will be used for 
supportive efficacy analyses. 
Efficacy Evaluation 
For the primary endpoint, change from baseline (mean of Screening values) in IGF-1 level at 
W13, descriptive statistics (n, mean, SD, 90% CI of mean, min, max, median) will be presented 
on the Efficacy Analysis Set and on the PP Analysis Set. 
For all other efficacy endpoints descriptive statistics will be performed on the Efficacy Analysis 
Set. In addition, efficacy data from Groups 3, 4 and 5 will also be summarized. 
Safety Evaluation 
Safety endpoints will be summarized with descriptive statistics and shift tables where 
applicable. 
PK Evaluation 
Plasma concentration will be summarized by baseline status (controlled or partially controlled) 
and overall using descriptive statistics. 
 
 
 


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Table of Contents 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .............................................................................. 3 
CONTACT LIST ................................................................................................................................. 4 
PROTOCOL SYNOPSIS ...................................................................................................................... 7 
List of Tables ................................................................................................................................. 20 
List of Figures ................................................................................................................................ 20 
List of Abbreviations and Acronyms ............................................................................................. 21 
1 
INTRODUCTION ..................................................................................................................... 26 
1.1 
Rationale ........................................................................................................................ 26 
1.1.1 
Justification of Dose and Dose Regimen ............................................................................. 27 
2 
STUDY OBJECTIVES ................................................................................................................ 28 
3 
INVESTIGATIONAL PLAN ........................................................................................................ 29 
3.1 
Overall Study Design ...................................................................................................... 29 
3.2 
Study Population ............................................................................................................ 33 
3.2.1 
Inclusion Criteria ................................................................................................................. 34 
3.2.2 
Exclusion Criteria ................................................................................................................. 35 
3.2.3 
Withdrawal, Removal, and Replacement of Subjects ......................................................... 37 
3.2.4 
Follow-Up for Drug Discontinuation/Subject Withdrawal from the Study ......................... 39 
3.2.5 
Discontinuation of the Study .............................................................................................. 40 
4 
TREATMENT PROCEDURES .................................................................................................... 41 
4.1 
CRN00808 (Investigational Medicinal Product) ............................................................. 41 
4.2 
Packaging and Labeling .................................................................................................. 41 
4.3 
Treatment Assignment and Blinding .............................................................................. 41 
4.4 
Method of Administration ............................................................................................. 41 
4.4.1 
CRN00808 Dosing and Administration ................................................................................ 41 
4.4.2 
Background Medication ...................................................................................................... 42 
4.5 
Study Drug Supply, Storage and Tracking ...................................................................... 42 
4.6 
Drug Accountability and Treatment Compliance ........................................................... 43 
4.7 
Medical History and Prior/Concomitant Medications ................................................... 43 
4.7.1 
Permitted Concomitant Medications .................................................................................. 44 
4.7.2 
Prohibited Concomitant Medications ................................................................................. 44 


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4.8 
Contraception ................................................................................................................. 45 
5 
STUDY PROCEDURES .............................................................................................................. 46 
5.1 
Screening Period (V1a, V1b, V2) .................................................................................... 46 
5.1.1 
Screening Failures ............................................................................................................... 47 
5.1.2 
Re-screening ........................................................................................................................ 47 
5.2 
Treatment Period ........................................................................................................... 48 
5.3 
Follow-up Period ............................................................................................................ 50 
5.4 
Unscheduled visits .......................................................................................................... 51 
6 
SAFETY ANALYSIS ................................................................................................................... 56 
6.1 
Safety Assessments ........................................................................................................ 56 
6.1.1 
Adverse Events .................................................................................................................... 56 
6.1.2 
Serious Adverse Events ....................................................................................................... 59 
6.1.3 
Physical Examination ........................................................................................................... 60 
6.1.4 
Vital Signs ............................................................................................................................ 60 
6.1.5 
ECG Assessment .................................................................................................................. 60 
6.1.6 
Outpatient 24-hour Holter .................................................................................................. 61 
6.1.7 
Cardiovascular Safety Monitoring ....................................................................................... 61 
6.1.8 
Laboratory Assessments ..................................................................................................... 62 
6.1.9 
Gall bladder Ultrasound ...................................................................................................... 64 
6.1.10 
Magnetic Resonance Imaging (MRI) ................................................................................... 64 
6.1.11 
Investigator Assessed Symptoms of Acromegaly ............................................................... 64 
6.1.12 
 Patient Reported Outcome Questionnaire ................. 65 
6.1.13 
 .................................................... 65 
6.1.14 
Patient Global Impression of Severity and Improvement ................................................... 66 
7 
STATISTICAL ANALYSIS ........................................................................................................... 67 
7.1 
Study Endpoints ............................................................................................................. 67 
7.2 
Statistical Methods and Analyses .................................................................................. 68 
7.2.1 
Determination of Sample Size ............................................................................................. 68 
7.2.2 
Analysis Datasets................................................................................................................. 68 
7.2.3 
Demographic and Baseline Characteristics ......................................................................... 68 
7.2.4 
Treatment Assignment and Study Medication ................................................................... 68 


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7.2.5 
Efficacy Analysis .................................................................................................................. 68 
7.2.6 
Safety Analysis .................................................................................................................... 69 
7.2.7 
Interim Analysis ................................................................................................................... 69 
8 
DATA MANAGEMENT ............................................................................................................ 70 
8.1 
Data Handling ................................................................................................................. 70 
8.1.1 
Source Documents .............................................................................................................. 70 
8.1.2 
Coding Dictionaries ............................................................................................................. 70 
8.2 
Data Management and Quality Control ......................................................................... 70 
8.3 
Database lock ................................................................................................................. 71 
9 
STUDY MANAGEMENT/PROCEDURES AND INSTRUCTIONS .................................................. 72 
9.1 
Safety Related Procedures ............................................................................................. 72 
9.1.1 
Rapid Notification on Serious Adverse Events .................................................................... 72 
9.1.2 
Rapid Notification on Pregnancies ...................................................................................... 72 
9.1.3 
Overdose ............................................................................................................................. 73 
9.1.4 
Emergency Procedure for Un-blinding................................................................................ 73 
9.1.5 
Central IGF-1 Reader ........................................................................................................... 73 
9.2 
Regulatory Issues, Ethics and Good Clinical Practice ..................................................... 73 
9.2.1 
Regulatory Guidelines and Ethical Considerations ............................................................. 73 
9.2.2 
Institutional Review Board/Independent Ethics Committee .............................................. 74 
9.2.3 
Informed Consent ............................................................................................................... 74 
9.2.4 
Sponsor ............................................................................................................................... 74 
9.2.5 
Principal Investigator .......................................................................................................... 74 
9.3 
Administrative Procedures ............................................................................................. 75 
9.3.1 
Protocol Amendment and Protocol Deviations .................................................................. 75 
9.3.2 
Monitoring Procedures ....................................................................................................... 75 
9.3.3 
Record Retention ................................................................................................................ 76 
9.3.4 
Quality Control and Quality Assurance ............................................................................... 76 
9.3.5 
Financing and Insurance ..................................................................................................... 76 
9.3.6 
Publication Policy/Disclosure of Data ................................................................................. 77 
10 
REFERENCES ....................................................................................................................... 78 
Appendix 1 - World Medical Association Declaration of Helsinki ................................................ 79 


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Appendix 2 - Medications Associated with Torsades De Pointes ................................................. 85 
 
 
List of Tables 
Table 1 - Overall Visit Schedule..................................................................................................... 52 
Table 2 - Classification of Adverse Events by Intensity ................................................................. 57 
Table 3 - Classification of Adverse Events by Relationship to Investigational Medicinal Product 57 
Table 4 - Adverse Event Outcome ................................................................................................ 58 
 
 
List of Figures 
Figure 1 - Screening Period ........................................................................................................... 29 
Figure 2 - Overall Study Design ..................................................................................................... 30 
 
 
 


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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 thyroxine 
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 
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 
mL 
Milliliter 
MCH  
Mean Corpuscular Hemoglobin  
MCHC  
Mean Corpuscular Hemoglobin Concentration 
MCV  
Mean Corpuscular Volume 
mg 
Milligram 
min 
Minutes 
MM 
Medical Monitor 
MNAR 
Missing not at random  


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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  
SST3 
Somatostatin receptor 3 
SST5 
Somatostatin receptor 5 


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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 efficacy of CRN00808 in acromegaly subjects treated with somatostatin analogue based 
treatment regimens. 
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: 1) octreotide LAR 
or lanreotide depot; 2) combination treatment of SSA (i.e., octreotide LAR or lanreotide depot) 
and a dopamine agonist (bromocriptine or cabergoline); 3) combination treatment of SSA 
(i.e., octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline); 
4) pasireotide LAR; or 5) combination treatment of SSA (i.e., octreotide LAR or lanreotide depot) 
and pegvisomant 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 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 
and/or attempting to return subjects to a biochemically controlled state. Subjects will be 
switched from their depot to a 
 starting dose of CRN00808. Because some subjects who 
are partial responders at the study entry or those who were on previous combination therapy, 
may require higher doses of the study drug, the protocol allows for dose up-titration to doses of 
 in a sequential manner. The 
 dose will only be administered to 
subjects who are tolerating the 
 dose and do not achieve IGF-1 ≤ULN. The dose titration 
design allows the dose of CRN00808 to be increased (if necessary) as the plasma concentrations 
of octreotide, lanreotide or pasireotide taper down. It is expected that by the end of the titration 
period, the concentrations of octreotide, lanreotide or pasireotide will be undetectable or too 
low to contribute to efficacy. The protocol also allows for a study drug dose reduction in the 
event that a dose is not tolerated in the judgment of the investigator. This 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 evaluate the efficacy of CRN00808 in acromegaly subjects treated with somatostatin 
analogue based treatment regimens; 
• 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 is an open label dose blinded exploratory study designed to evaluate the safety, PK and 
efficacy of CRN00808 in subjects with acromegaly that are treated with somatostatin analogue 
based treatment regimens. The study will consist of the following periods:  
• Screening (up to 6 weeks); 
• Treatment Period (up to 13 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 45 subjects on stable doses of SSA based pharmacotherapy for the treatment of 
acromegaly will be recruited for this clinical trial.  
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, lanreotide depot or pasireotide LAR. 
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, the Screening IGF-1 measurements 
(performed by the study central laboratory) must fall into the ranges specified for one of the 
following groups: 


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• Group 1: Partial responders on a stable treatment of octreotide LAR or lanreotide depot 
(at least one Screening IGF-1 value must be >ULN, and the V2 value must be ≤2.5×ULN); 
• Group 2: Partial responders on a stable combination treatment of SSA (i.e., octreotide 
LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (at least 
one Screening IGF-1 value must be >ULN, and the V2 value must be ≤2.5×ULN); 
• Group 3: Complete responders on a stable combination treatment of SSA (i.e., octreotide 
LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (mean 
of Screening IGF-1 values must be ≤ULN); 
• Group 4: Complete responders on a stable dose of pasireotide LAR (mean of Screening 
IGF-1 values must be ≤ULN); 
• Group 5: Complete responders on a stable combination treatment of SSA (i.e., octreotide 
LAR or lanreotide depot) and pegvisomant (mean of Screening IGF-1 values 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.  
For additional details on screening procedures, refer to Section 5.1 and Table 1. 
 
TREATMENT 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, when the last dose of standard 
acromegaly treatment was administered. Subjects enrolling into the Treatment Period will not 
continue their 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, V12/W10, and 
V14/W13 the study drug is to be administered at the study center, also under fasting conditions. 
During the entire Treatment Period, the subjects are expected to swallow four capsules (Size 2) 
with water every day.    
During the V6/W4 and V9/W7, the dose may be titrated up in a blinded fashion, provided the 
preceding IGF-1 values collected in V4/W2, and in V7/W5, respectively, are >0.9×ULN and the 
current dose is tolerated by the subject. At V12/W10, the dose may be titrated up in a blinded 
fashion, provided the preceding IGF-1 value collected in V10/W8 is >ULN and the current dose is 
tolerated by the subject. 
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 


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tolerability at V5/W3, V6/W4, V8/W6, V9/W7, V11/W9 and V12/W10. If tolerability is confirmed 
and the IGF-1 reader has determined that IGF-1 has not met adequate suppression criteria, a 
blinded blister card containing the appropriate higher dose will be assigned at the V6/W4, V9/W7 
and/or V12/W10. Dose increases in 
 increments will be allowed only at the V6/W4 (from 
 V9/W7 (from 
) and V12/W10 (from 
 
). 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, V9/W7 and V12/W10, 
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 a 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 blister 
cards taking into account information from the investigator and from the central IGF-1 reader. 
Subjects 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. 
Dose Decreases During Treatment Period  
At any point during the Treatment 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, V9/W7 and/or V12/W10) if IGF-1 control is inadequate while taking 
 per day and the subject is tolerating the 
 dose well. If in the judgement of the 
investigator, the subject is eligible for a re-challenge at the higher dose at an up-titration visit, 
subjects who have been dose reduced from 
 may re-challenge at 
 
 respectively.  Subjects whose dose is reduced from 
 per day will not be allowed 
to re-challenge with the 
 dose.   
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 blister card containing the new dose. 
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. 


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Criteria for Resumption of Standard Acromegaly Treatment  
At any time during the Treatment Period, if the subject is experiencing a significant worsening of 
symptoms associated with acromegaly, and in the Investigator’s opinion would not benefit from 
continuing in the study, standard acromegaly treatment should be resumed. Subjects meeting 
these criteria will be discontinued from the study and an early termination visit will be scheduled, 
prior to resuming standard pharmacotherapy whenever possible. 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). 
During the Follow-up Period, 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 V16 performed prior to resumption of 
standard acromegaly treatment whenever possible. These subjects will be considered study 
completers. 
3.2 Study Population 
Approximately 45 male and female subjects with a confirmed acromegaly diagnosis who fall into 
one of the five groups are planned to be enrolled in this study.  
• Group 1: Partial responders on a stable treatment of octreotide LAR or lanreotide depot 
(at least one Screening IGF-1 value must be >ULN, and the V2 value must be ≤2.5×ULN); 
• Group 2: Partial responders on a stable combination treatment of SSA (i.e., octreotide 
LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (at least 
one Screening IGF-1 value must be >ULN, and the V2 value must be ≤2.5×ULN); 
• Group 3: Complete responders on a stable combination treatment of SSA (i.e., octreotide 
LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (mean 
of Screening IGF-1 values must be ≤ULN); 
• Group 4: Complete responders on a stable dose of pasireotide LAR (mean of Screening 
IGF-1 values must be ≤ULN); 
• Group 5: Complete responders on a stable combination treatment of SSA (i.e., octreotide 
LAR or lanreotide depot) and pegvisomant (mean of Screening IGF-1 values must be 
≤ULN). 
Groups 1 and 2 will contribute at least 30 of the approximately 45 subjects enrolled. 
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, who meet the protocol defined criteria (see Section 3.2) 
for a partial or complete responder to somatostatin analogue based therapy. A stable 
dose is defined as no changes in acromegaly medication doses in 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 
sperm for the duration of the study and until at least 3 months after the last dose of the 
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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 
subjects in Group 3, 4, or 5 who have undergone pituitary radiation therapy at any time 
prior to the study entry. A history of radiation therapy is not a restriction for subjects in 
Group 1 or 2. If a subject in Group 3, 4, or 5 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; 
6. Based on Holter monitor performed during the Screening Period: symptomatic 
bradycardia (i.e., bradycardia associated with significant dizziness, lightheadedness, or 


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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 of CYP3A4 or inhibitors of 
CYP3A4 (see Protocol Section 4.7.2); 
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 are complete responders (both Screening IGF-1 values ≤ULN) to octreotide 
LAR or lanreotide depot monotherapy; 
17. Subjects taking octreotide LAR at a dose higher than 40 mg, or lanreotide depot at a dose 
higher than 120 mg, or pasireotide LAR higher than 60 mg; 
18. Subjects who usually take octreotide LAR, lanreotide depot or pasireotide LAR 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% 
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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 CRN00808-02; 
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 
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, 


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if subjects meet criteria for resumption of standard acromegaly treatment or if they require 
initiation of a prohibited concomitant medication 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 4.7.2); 
k. Any 
supraventricular 
tachyarrhythmia 
associated 
with 
symptoms 
of 
hemodynamic response. 
4. Indication of drug-induced liver injury: 


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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, 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. 
Groups 1 and 2 will contribute at least 30 subjects. 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.  
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. 


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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 PVC blisters and stored at 
 
. 
4.2 Packaging and Labeling  
Capsules (
, and matching placebo) will be supplied in blisters containing 36 capsules 
each.  
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.  
4.3 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. 
4.4 Method of Administration  
4.4.1 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 four 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. 


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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. 
4.4.2 Background Medication 
Subjects will receive their final pre-trial acromegaly medications (octreotide LAR, lanreotide 
depot, pasireotide LAR, dopamine agonist or pegvisomant) for use during the Screening Period. 
At V1b, the subject will receive the final injection of the somatostatin agonist (octreotide LAR, 
lanreotide depot, or pasireotide LAR) approximately 4 weeks prior to entry into the Treatment 
Period of the study (V3). For subjects previously treated with adjunctive dopamine agonist or 
pegvisomant, the last dose of the adjunctive medication will be administered at V2. 
4.5 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.    
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 
 
, 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. 


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4.6 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. 
4.7 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.  
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 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 drug 
treatment period, 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; 


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• Not to start any over-the-counter medication, homeopathic preparations, or herbal 
supplements, except as instructed or approved by the investigator. 
4.7.1 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. 
4.7.2 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, 
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. 


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4.8 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 
contraceptions; 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 
estrogen-containing 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, lanreotide depot or pasireotide 
LAR, 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 
(anytime); 
• 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/pasireotide plasma sample (V1b before the last deport 
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);  
• Patient Global Impression of Severity (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 source document.  
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 
CRN00808-02 study. 
Subjects who have screen failed study CRN00808-02 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 CRN00808-03. Informed consent for CRN00808-03 is required 
to be obtained prior to initiating any new CRN00808-03 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, V12/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 four 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, V7, and V10 for which the visit window is +4 days and V14 for 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;  
• Patient Global Impression of Severity; 
• 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), V10 (W8/D50), V12 
(W10/D64), V13 (W11/D71) and V14 (W13/D90-91) 
• Symptom directed physical examination. Ring size should be measured on V14; 
• Vital signs;  
• 12-lead ECG (in triplicate, ONLY at V4, V7, V10, V13 and V14);  
• Urine pregnancy test (ONLY at V6, V9, V12 and V14); 
• Assessments of routine safety, hematology and biochemistry parameters – V6, V9, V12, 
and V14 to be drawn fasting. Additionally, assessment of HbA1c and lipids at V9 and V14 
only; 
• 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), sample set 6: at V13 (1-15 hours 
post dose), sample set 7: at V14/D90-91 (1-8 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); sample 12: at V12 (prior to dosing); sample 13: 
at V13 (1-15 hours post dose); sample 14: at V14 on the last day of dosing in W13 (prior 
to dosing).  
• Measurement of 
levels will be done only for sample 4, sample 7, sample 10, 
sample 13 and sample 14; 
• PK plasma sample (pre-dose and 2 hours (+/- 15 min) post-dose at V6, V9 and V12; 1-15 
hours post-dose at V4, V7, V10, and V13; 1-8 hours post-dose at V14);  
• Assessment of hormones (fT3, fT4, thyroid antibody, TSH, cortisol, ACTH, LH, FSH and 
prolactin - ONLY at V14);  
• Gall bladder ultrasound (ONLY at V14); 
• Residual octreotide/lanreotide/pasireotide plasma sample (at V9 and V14 ONLY);  
• 
questionnaires, only at V14;  
• Study drug dispense: V6: TITRATION 3-week-supply (3 cards; one card/week), 
V9: TITRATION 3-week-supply (3 cards; one card/week), V12: TITRATION 4-week-supply 
(4 cards; one card/week);  
• Study drug return and accountability; 
• AE assessment, including changes in symptoms of acromegaly;  
• Patient Global Impression of Severity; 
• Patient Global Impression of Improvement (ONLY at V14); 
• 
 (daily beginning the day after V13 through V14 ONLY); 
• Concomitant medications; 


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• Confirmation of tolerability for potential dose up-titration (V6, V9 and V12 only); 
• Dose titration decision (ONLY at V6, V9 and V12); 
• Study drug administration at the study center (V6, V9, V12, and V14 and ONLY).  
V5 (W3/D15), V8 (W6/D36), V11 (W9/D57) – Phone Call Assessment 
• AE assessment, including changes in symptoms of acromegaly; 
• Patient Global Impression of Severity; 
• Concomitant medications; 
• Confirmation of tolerability for potential dose up-titration (V5, V8 and V11 only). 
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 8: 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;  
• 
 questionnaires, ONLY at V16;  
• AE assessment, including changes in symptoms of acromegaly;  


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• Patient Global Impression of Severity;  
• Patient Global Impression of Improvement (ONLY at V16); 
• 
 (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. 
 
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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Table 1 - Overall Visit Schedule 
STUDY PROCEDURES a 
SCREENING 
PERIOD b 
TREATMENT PERIOD 
FOLLOW-UP  
PERIOD c 
STUDY WEEKS 
W-6 to D0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W13 
W15 
W17 
STUDY DAYS 
- 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D90-91 
D105 
D11
9 
STUDY VISITS 
V1a 
V1b 
V2 
V3d 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16e 
VISIT WINDOW (DAYS) 
b 
- 
+4 
Phone 
±2 
±2 
+4 b 
Phone 
±2 
±2 
+4 b  
Phone 
±2 
±2 
±2 
- 
±2 
±2 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility verification 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including acromegaly history 
information) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination (including weight and 
ring size) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Symptom directed physical examination 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X v 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs f 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
24-hour outpatient Holter monitor completed 
and verified g 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG h 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
Pregnancy test i 
X (s) 
 
 
X (u) 
 
 
X (u) 
 
 
X (u) 
 
 
X (u) 
 
X (u) 
 
X (u) 
HBV, HCV and HIV testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (including urinalysis) j 
X 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotype blood sample k 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Head MRI l 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum GH (integrated) m 
 
X1 
X2 
 
X3 
 
 
X4 
 
 
X5 
 
 
X6 
X7 
 
X8 
Serum IGF-1/
 n 
 
X1 
X2 
X3 
X4 
 
X6 
X7 
 
X9 
X10 
 
X12 
X13 
X14 
X15 
X16 
Injection of pre-trial pharmacotherapy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X U 
Hormone levels (fT3, fT4, thyroid antibody, 
TSH, cortisol, ACTH, LH, FSH and prolactin) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Gall bladder ultrasound completed o 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetic (PK) plasma sample p 
 
 
 
 
X  
 
X  
X  
 
X  
X  
 
X 
X 
X  
X 
X 
Residual octreotide/lanreotide/pasireotide 
plasma sample 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X  
 
 


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STUDY PROCEDURES a 
SCREENING 
PERIOD b 
TREATMENT PERIOD 
FOLLOW-UP  
PERIOD c 
STUDY WEEKS 
W-6 to D0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W13 
W15 
W17 
STUDY DAYS 
- 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D90-91 
D105 
D11
9 
STUDY VISITS 
V1a 
V1b 
V2 
V3d 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16e 
VISIT WINDOW (DAYS) 
b 
- 
+4 
Phone 
±2 
±2 
+4 b 
Phone 
±2 
±2 
+4 b  
Phone 
±2 
±2 
±2 
- 
±2 
±2 
Baseline investigator assessed symptoms of 
acromegaly q 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life questionnaires 
 
 w 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Study drug dosing on site r 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Study drug dispense 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X  
 
 
 
 
Return and accountability of study drug s 
 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
Adverse event monitoring (including 
investigator assessed changes in symptoms of 
acromegaly) q 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Global Impression of Severity (PGI-S) y 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess compliance with completion of 
 x 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Patient Global Impression of Improvement 
(PGI-I) y 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Prior and concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirmation of tolerability for potential dose 
up-titration 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
Potential dose up-titration t 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Visits at the Study Center: V1a/1b, V3, V6, V9, V12, V14, V16 
Phone Call Visits: V5, V8, V11 
Visits at Either the Study Center or Subject’s Home/Suitable Alternate Location: V2, V4, V7, V10, V13, V15 
a All study assessments will be conducted at approximately the same time of day, unless otherwise specified. 
b The Screening Period will consist of 2-3 visits over 4-6 weeks. V1b will occur 0-2 weeks after the initial screening visit V1a. V2 will occur 1-2 weeks after V1b.  
See Figure 1. V7 and V10 must be at least 7 days after V6 and V9, respectively. 
c During the Follow-up Period, subjects are expected to be off all acromegaly treatment, including CRN00808. During this period, the subjects will be allowed to 
complete the study and resume a standard acromegaly treatment if the subject experiences significant worsening of acromegaly symptoms and the most recent 
IGF-1 value is >ULN. Such subjects should have all the V16 assessments performed prior to the resumption of standard acromegaly treatment whenever possible. 
d 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. 
e Final visit for subjects who have completed the study. In case of early termination, V16 assessments will be performed. 


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f Blood pressure, pulse rate, respiratory rate, and body temperature. All measurements are to be taken at rest. 
g 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. 
h 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, V13, V14 and V16 only. When possible, 
the ECGs should be performed while fasting approximately 2 hours after the study drug dosing. 
i 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. 
j Samples for clinical laboratory tests including hematology, biochemistry, and urinalysis will be obtained after overnight fast except at Screening, V4, V7, V10, 
V13, and V15 which can be drawn fasting or non-fasting. HbA1c will be drawn at V1a, V3, V9, V14, and V16/ET only. Fasting lipid profile will be drawn at V3, V9, 
V14 and V16/ET only. 
k Blood sample for genotyping will be analyzed and will be collected for the determination of the UGT1A1 genotype. Subjects may opt out of this testing. 
l 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. 
m 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), sample set 6: at V13 
(collected 1-15 hours post study drug dose), sample set 7: at V14/D90-91 (1-8 hours post dose), Follow-up Period: sample set 8: at V16 or early termination 
(anytime).   
n 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); sample 12: at V12 (prior to dosing); sample 13: at V13 (1-15 hours post study drug dose); sample 14: at V14 on the last day of dosing in W13 (prior 
to dosing). Follow-up Period: sample 15: at V15 (anytime); sample 16: at V16 (anytime). Note: Sample 5, sample 8, and sample 11 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), 13 (V13), 14 (V14) and 16 (V16). 
o 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 
at V14. 
p PK sample should be collected at the following time-points: pre-dose and 2 hours (+/- 15 min) post-dose at V6, V9 and V12; 1-15 hours post-dose at V4, V7, 
V10, and V13; 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. 
q Acromegaly symptoms will be assessed by investigator site staff as described in Section 6.1.11. 
r 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, V12, 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. 
s 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. 
t At V6/W4, V9/W7 and V12/W10 the dose may be up-titrated up in a blinded fashion (see Section 3.1). 


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u As clinically indicated in the judgement of the investigator. 
v Ring size should be measured at the V14 during symptom directed physical examination. 
w 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. 
x 
 at home on a daily basis beginning the day after V1b through V3; daily beginning the day after V13 
through V14, and daily beginning the day after V15 through V16. Please see Section 6.1.12. 
y PGI-S and PGI-I 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 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, V12, V13, 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, V13, 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 <500msec (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 pointe). 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 4.7.2); 
• 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, V13, 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) 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 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, 13, 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/pasireotide plasma sample 
Blood samples to evaluate plasma concentrations of octreotide, lanreotide, or pasireotide will be 
collected during the Screening and Treatment Period, as indicated in Table 1. Measurement of 
octreotide and lanreotide concentration will be done by a central bioanalytical laboratory using 
validated methods. Measurement of pasireotide concentration will be done, if necessary. 
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 V14 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 complete 
 at home 
periodically throughout the study and results will be entered into the EDC. Subjects will complete 
 daily beginning the day after V1b through V3; daily beginning the day after V13 through 
V14; and daily beginning the day after V15 through V16.  
 should be completed at home approximately the same time of day as consistently as 
possible.  Site staff will review subject compliance with 
completion at each study visit as 
indicated in Table 1.  Responses to the 
 will not be reconciled with Adverse Event data. 
 
 
 
 
 
 
 
 
6.1.13
 
 assessments will be performed at V3, V14 and V16. The 
questionnaires will be completed by the subject following standardized instructions at scheduled 
study visits and results recorded by site personnel in EDC. Quality of life questionnaires should 
be completed at the beginning of specified visits prior to other study procedures. 


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6.1.14 Patient Global Impression of Severity and Improvement 
The Patient Global Impression of Severity (PGI-S) is a single question regarding overall current 
acromegaly symptom severity that will be completed by the subject at all study visits and results 
recorded by site personnel in the EDC. The Patient Global Impression of Improvement (PGI-I) is a 
single question regarding overall acromegaly symptom change compared to before study start 
that will be completed by the subject at visits designated in Table 1 and results recorded by site 
personnel in the EDC. PGI-S and PGI-I should be completed after Quality of Life questionnaires 
and before any other study procedures. 
 
 
 


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7 STATISTICAL ANALYSIS 
7.1 Study Endpoints 
EFFICACY ENDPOINTS 
Primary endpoint: 
The primary endpoint is the change from baseline (mean of Screening values) in IGF-1 level at 
W13. 
Key Secondary endpoints: 
• Proportion of subjects with the mean of their last two consecutive IGF-1 measurements 
≤ULN;   
• Proportion of subjects with the mean of their last two consecutive IGF-1 measurements 
≤1.5×ULN;  
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; 
• Change from baseline in serum GH levels measured at W13; 
• Change from baseline in serum 
levels measured at W13; 
• Increase in serum GH, IGF-1, and 
 levels 3+ weeks after withdrawal of CRN00808; 
• Change from baseline in symptoms of acromegaly as measured by total 
score at W13; 
• Change from baseline in symptoms of acromegaly as measured by individual 
 score at 
W13; 
• Change from baseline in 
 score at W13; 
• Change from baseline in 
at W13; 
• Change from baseline in investigator assessed symptoms of acromegaly at W13; 
• Change from baseline in PGI-S scores at W13; 
• PGI-I scores at W13; 
• Plasma concentrations of CRN00808. 
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; 


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• 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 
Approximately 45 subjects are planned to be enrolled in the study. At least 30 subjects from 
Groups 1 and 2 will be enrolled, i.e., a cap of N=15 is set for the sum of the number of subjects in 
Group 3 to 5. 
The primary objective of this study is to evaluate efficacy (IGF-1 levels) in subjects who are partial 
responders to somatostatin analogue based treatment regimens. As such, the sample size is 
chosen to provide sufficient clinical experience to evaluate IGF-1 changes descriptively and is not 
formally powered for hypothesis testing. Summary statistics for the primary endpoint will be 
provided.  
7.2.2 Analysis Datasets 
Safety Analysis Set comprises all subjects who received at least one dose of the study medication. 
The Safety Analysis Set will be used for all safety analyses and for some of the secondary efficacy 
endpoints.  
Efficacy Analysis Set comprises all subjects from Groups 1 and 2 who received at least one dose 
of the study medication. The Efficacy Analysis Set will be used for the evaluation of the primary 
efficacy endpoint and for some of the secondary efficacy endpoints. 
Per Protocol Analysis Set (PP) comprises all subjects from the Efficacy Analysis Set 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 
Not applicable. As this is an open label study, it is not deemed feasible to employ blinding 
methods among the five groups. After the initial starting dose, further dose increases/decreases 
are blinded to the investigator and subject. 
7.2.5 Efficacy Analysis 
7.2.5.1 Analysis of Primary Endpoint 
For the primary endpoint, change from baseline (mean of Screening values) in IGF-1 level at W13, 
descriptive statistics (n, mean, SD, 90% CI of mean, min, max, median) will be presented on the 
Efficacy Analysis Set and on the PP Analysis Set.  


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7.2.5.2 Analysis of Secondary and Exploratory Endpoints 
All quantitative endpoints will be summarized using descriptive statistics, as described for the 
primary endpoint. Results will be provided for all groups combined, for groups 1 and 2 combined 
(the Efficacy Analysis Set), and for each of the five groups separately. All proportional endpoints 
will be similarly summarized using counts and percentages.  
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. 
 
 
 
 


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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.  


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A formal quality control (QC) will be conducted prior to database lock.  
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 Treatment 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 blister cards 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’ study drug dose 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 
applicable local regulatory guidelines and Directive of the European Parliament, guidelines set 


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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. 
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. 


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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, 
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, 


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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).  
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. 


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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.  
 


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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: CRN00808-03  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 07 June 2019 
CRN00808 
CONFIDENTIAL 
Page 83 of 88 
 
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: CRN00808-03  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 07 June 2019 
CRN00808 
CONFIDENTIAL 
Page 84 of 88 
 
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: CRN00808-03  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 07 June 2019 
CRN00808 
CONFIDENTIAL 
Page 85 of 88 
 
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 


Study code: CRN00808-03  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 07 June 2019 
CRN00808 
CONFIDENTIAL 
Page 86 of 88 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Erythromycin 
E.E.S., Robimycin, EMycin, 
Erymax, Ery-Tab, Eryc 
Ranbaxy, Erypar, Eryped, 
Erythrocin Stearate 
Filmtab, Erythrocot, E-
Base, Erythroped, Ilosone, 
MY-E, Pediamycin, 
Abboticin, Abboticin-ES, 
Erycin, PCE Dispertab, 
Stiemycine, Acnasol, 
Tiloryth 
Antibiotic 
Bacterial infection, 
increase GI motility 
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 


Study code: CRN00808-03  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 07 June 2019 
CRN00808 
CONFIDENTIAL 
Page 87 of 88 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Levomepromazine 
(methotrimeprazine) 
(only on non-US market) 
Nosinan, Nozinan, 
Levoprome 
Antipsychotic 
Schizophrenia 
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 


Study code: CRN00808-03  
 
CLINICAL STUDY PROTOCOL 
Study Sponsor: Crinetics Pharmaceuticals, Inc. 
 
Version 3.0, 07 June 2019 
CRN00808 
CONFIDENTIAL 
Page 88 of 88 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Sparfloxacin (removed 
from market) 
Zagam 
Antibiotic 
Bacterial infection 
Sulpiride (only on non-US 
market) 
Dogmatil, Dolmatil, 
Eglonyl, Espiride, Modal, 
Sulpor 
Antipsychotic, atypical 
Schizophrenia 
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 CRN00808-03 (ACROBAT EDGE) 
 
An open label exploratory study to evaluate the safety, pharmacokinetics and 
efficacy of CRN00808 in patients with acromegaly treated with somatostatin 
analogue based treatment regimens 
(ACROBAT EDGE) 
 
Investigational Product: 
CRN00808 
US IND Number: 
137912 
ClinicalTrials.gov Identifier: 
NCT03789656 
EudraCT Number: 
2018-002230-20 
Protocol Version and Date: 
Version 3.0, 07 June 2019 
Phase: 
Phase 2 
Methodology: 
Single arm, Open-Label 
Sponsor: 
Crinetics Pharmaceuticals, Inc. 
10222 Barnes Canyon Road, Building #2 
San Diego, CA 92121 
Analysis Plan Date: 
01 October 2020 
Analysis Plan Version: 
Final Version 1  
 
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   
01 October 2020
CRN00808-03 (ACROBAT EDGE) 
Page 2
 
Confidential and Proprietary 
APPROVAL PAGE 
 
Statistical Analysis Plan for Protocol CRN00808-03 (ACROBAT EDGE) 
Analysis Plan Date:  
01 October 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   
01 October 2020
CRN00808-03 (ACROBAT EDGE) 
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 ........................................................................................13 
2.2.3. 
Study Drug .................................................................................................13 
2.2.4. 
Treatment Assignment, Blinding, and Randomization Methodology .......13 
2.2.5. 
Study Procedures .......................................................................................13 
2.3. 
Study Endpoints .....................................................................................................14 
2.3.1. 
Primary Efficacy Endpoint ........................................................................14 
2.3.2. 
Secondary Efficacy Endpoints ...................................................................14 
2.3.2.1. 
Proportion of Subjects with IGF-1 ≤ 1.0 × ULN at Week 13/EoT ...14 
2.3.2.2. 
Proportion of Subjects with IGF-1 ≤ 1.5 × ULN at Week 13/EoT ...14 
2.3.3. 
Exploratory Efficacy Endpoints .................................................................14 
2.3.3.1. 
Biomarkers ........................................................................................14 
2.3.3.2. 
Patient and Investigator Reported Outcomes Endpoints ..................16 
2.3.3.3. 
Pharmacokinetics (PK) .....................................................................19 
2.3.4. 
Safety Endpoints ........................................................................................19 
3. 
Sample Size Justification .................................................................................. 20 
4. 
General Statistical Methods .............................................................................. 21 
4.1. 
Reporting Conventions ..........................................................................................21 
4.2. 
Computing Environment ........................................................................................21 
4.3. 
Partial Dates ...........................................................................................................22 
4.4. 
Data Conventions ...................................................................................................23 
4.5. 
Standard Calculations ............................................................................................23 
4.6. 
Treatments..............................................................................................................24 
4.7. 
Visits ......................................................................................................................24 
4.7.1. 
Windows ................................................................................................................24 
4.7.2. 
Repeat or Unscheduled Assessments .....................................................................26 
4.7.3. 
Definition of Baseline(s) ........................................................................................26 
4.7.4. 
Definition of End of Treatment (EoT) ...................................................................26 
5. 
Analysis Sets .................................................................................................... 27 
6. 
Examination of Subgroups ............................................................................... 28 
7. 
Study Population .............................................................................................. 29 
7.1. 
Subject Disposition ................................................................................................29 


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Confidential and Proprietary 
7.2. 
Demographics and Baseline Characteristics ..........................................................29 
7.3. 
Baseline Acromegaly Disease Characteristics .......................................................30 
7.4. 
Acromegaly Symptoms at Study Entry..................................................................30 
7.5. 
General Medical History ........................................................................................30 
7.6. 
Protocol Deviations ................................................................................................31 
7.7. 
Pretreatment, Prior, and New Concomitant Medications or Non-Pharmacological 
Treatments..............................................................................................................31 
8. 
Efficacy Analyses ............................................................................................. 32 
8.1. 
Adjustments for Covariates....................................................................................32 
8.2. 
Handling of Dropouts or Missing Data ..................................................................32 
8.2.1. 
Responder Endpoints .................................................................................32 
8.2.2. 
Biomarker Endpoints .................................................................................32 
8.2.3. 
Patient or Investigator Reported Outcomes ...............................................32 
8.3. 
Interim Analyses and Data Monitoring..................................................................32 
8.3.1. 
Interim Analysis .........................................................................................32 
8.4. 
Multicenter Studies ................................................................................................33 
8.5. 
Use of an “Efficacy Subset” of Patients ................................................................33 
8.6. 
Multiple Comparisons/Multiplicity .......................................................................33 
8.7. 
Primary Efficacy Analysis .....................................................................................33 
8.7.1. 
Additional Analyses of the Primary Endpoint ...........................................33 
8.8. 
Secondary Efficacy Analyses ................................................................................33 
8.8.1. 
Proportion of Subjects with IGF-1 ≤ 1.0 × ULN at Week 13/EoT ............33 
8.8.2. 
Proportion of Subjects with IGF-1 ≤ 1.5 × ULN at Week 13/EoT ............34 
8.9. 
Exploratory Efficacy Analyses ..............................................................................34 
8.9.1. 
Biomarker Endpoint Analyses ...................................................................34 
8.9.1.1. 
IGF-1 .................................................................................................34 
8.9.1.2. 
GH .....................................................................................................35 
8.9.1.3. 
35 
8.9.2. 
Patient and Investigator Reported Outcome Endpoint Analyses ...............35 
8.9.2.1. 
 
 ......................................................................................35 
8.9.2.2. 
Investigator Assessed Symptoms of Acromegaly.............................35 
8.9.2.3. 
 .........................................................................................35 
8.9.2.4. 
 ...........................................................................................36 
8.9.2.5. 
Patient Global Impression .................................................................36 
8.9.3. 
Pharmacokinetic (PK) Analyses ................................................................36 
9. 
Safety Analyses ................................................................................................ 37 
9.1. 
Extent of Exposure .................................................................................................37 
9.2. 
Adverse Events ......................................................................................................37 
9.3. 
Clinical Laboratory Evaluations ............................................................................39 


Statistical Analysis Plan   
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CRN00808-03 (ACROBAT EDGE) 
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Confidential and Proprietary 
9.3.1. 
Serum Chemistry, Hematology, and HbA1c .............................................39 
9.3.2. 
Shifts in CTCAE Grade .............................................................................39 
9.3.3. 
Shifts in Normal Range ..............................................................................40 
9.3.4. 
Hormones ...................................................................................................40 
9.3.5. 
Genotyping .................................................................................................40 
9.4. 
Vital Signs ..............................................................................................................40 
9.5. 
Ring Size, Weight and BMI ...................................................................................40 
9.6. 
12-Lead Electrocardiograms (ECGs) .....................................................................40 
9.7. 
Gall Bladder Ultrasound ........................................................................................41 
9.8. 
Other Safety Assessments ......................................................................................41 
10. 
Changes to Protocol Planned Analyses ............................................................ 42 
 


Statistical Analysis Plan   
01 October 2020
CRN00808-03 (ACROBAT EDGE) 
Page 6
 
Confidential and Proprietary 
LIST OF TABLES 
Table 1: 
Treatment Period Visit Windows Excluding PGI-S ........................................25 
Table 2: 
Treatment Period Visit Windows PGI-S Only.................................................25 
Table 3: 
Follow Up Visit Windows ...............................................................................26 
 
LIST OF FIGURES 
Figure 1: 
Screening Period ..............................................................................................11 
Figure 2: 
Overall Study Design .......................................................................................12 
 


Statistical Analysis Plan   
01 October 2020
CRN00808-03 (ACROBAT EDGE) 
Page 7
 
Confidential and Proprietary 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
ACTH 
adrenocorticotropic hormone 
 
 
AE 
adverse event 
ANCOVA 
analysis of covariance 
 
 
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 
 
 
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   
01 October 2020
CRN00808-03 (ACROBAT EDGE) 
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 
PGI 
Physician Global Impression 
PGI-I 
Physician Global Impression of Improvement 


Statistical Analysis Plan   
01 October 2020
CRN00808-03 (ACROBAT EDGE) 
Page 9
 
Confidential and Proprietary 
Abbreviation 
Term 
PGI-S 
Physician Global Impression of Severity 
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 
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 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
VAS 
Visual Analogue Scale 
vs 
versus 
WHO 
World Health Organization 
 


Statistical Analysis Plan   
01 October 2020
CRN00808-03 (ACROBAT EDGE) 
Page 10
 
Confidential and Proprietary 
1. 
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of Study 
CRN00808-03 (ACROBAT EDGE) 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 Error! Reference source not found., 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 treated with somatostatin 
analogue based treatment regimens; 
• 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 is an open label dose blinded exploratory study designed to evaluate the safety, PK and 
efficacy of CRN00808 in subjects with acromegaly that are treated with somatostatin analogue 
based treatment regimens. The study will consist of the following periods: 
• Screening Period (up to 6 weeks); 
• Treatment Period (TP; up to 13 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 
 
See study protocol for complete details. There was a COVID-19 Emergency Amendment to the 
protocol to specifically address changes to study visit schedule and assessments, changes in 
subject withdrawal criteria, changes to provision of study drug and study supplies, and IGF-1 
measurements and titration. 
 


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2.2.2. 
Study Population 
Approximately 45 subjects on stable doses of SSA based pharmacotherapy for the treatment of 
acromegaly will be recruited for this clinical trial. In order to be eligible to enter the Treatment 
Period, the Screening IGF-1 measurements (performed by the study central laboratory) must fall 
into the ranges specified for one of the following groups: 
• Group 1: Partial responders on a stable treatment of Octreotide LAR or Lanreotide depot 
(at least one Screening IGF-1 value must be >ULN, and the V2 value must be 
≤2.5×ULN); 
• Group 2: Partial responders on a stable combination treatment of SSA (i.e., Octreotide 
LAR or Lanreotide depot) and a dopamine agonist (Bromocriptine or Cabergoline) (at 
least one Screening IGF-1 value must be >ULN, and the V2 value must be ≤2.5×ULN); 
• Group 3: Complete responders on a stable combination treatment of SSA (i.e., 
Octreotide LAR or Lanreotide depot) and a dopamine agonist (Bromocriptine or 
Cabergoline) (mean of Screening IGF-1 values must be ≤ULN);  
• Group 4: Complete responders on a stable dose of Pasireotide LAR (mean of Screening 
IGF-1 values must be ≤ULN); 
• Group 5: Complete responders on a stable combination treatment of SSA (i.e., 
Octreotide LAR or Lanreotide depot) and Pegvisomant (mean of Screening IGF-1 values 
must be ≤ULN). 
2.2.3. 
Study Drug 
Study drug consists of CRN00808 or placebo. Placebo was only used for dose-blinding the dose 
after the first potential up-titration visit and not as a comparator. 
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 
 
 capsules [
 Size 2]) in order to maintain blinding during dose up-titration. 
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.  
The study drug dose is blinded after the first potential up-titration visit and capsules are identical 
for the study drug and placebo. All instances of unblinding of study drug dose 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. 


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2.3. 
Study Endpoints 
2.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in IGF-1 levels between Baseline and Week 13 / 
End of Treatment (EoT).  The Baseline value will be defined as the mean of the IGF-1 prior to 
first dose of study drug.  If a subject discontinues prior to Week 13, the last on treatment 
assessment will be used for the Week 13/EoT. Data from the central lab, i.e. the source data will 
be used for analyses. 
See Section 4.7 for definition of visits and Section 8.2 for handling of missing data.  
2.3.2. 
Secondary Efficacy Endpoints  
The secondary endpoints are: 
2.3.2.1. 
Proportion of Subjects with IGF-1 ≤ 1.0 × ULN at Week 13/EoT  
The secondary endpoint is the proportion of subjects who maintain IGF-1 response, defined as 
the last assessment prior to end of treatment with IGF-1≤ 1.0 × ULN meet responder criteria.  
Prior determining response, the IGF-1 value in units of ULN will be rounded to two significant 
figures. This endpoint will be limited to those subjects in Groups 3, 4, and 5 who start the study 
with ≤ 1.0 × ULN.  For subjects that complete treatment, the Week 13 will be used for each 
subject.  For subjects who do not complete treatment, the last on treatment assessment will be 
used for each subject.  If the IGF-1 value is missing, the subject will be counted as a non-
responder.  
2.3.2.2. 
Proportion of Subjects with IGF-1 ≤ 1.5 × ULN at Week 13/EoT  
The same responder analysis as specified above in Section 2.3.2.1, but where responder is 
defined as the last assessment prior to end of treatment with IGF-1 ≤ 1.5 × ULN meet responder 
criteria.   For subjects that complete treatment, the Week 13 will be used for each subject.  For 
subjects who do not complete treatment, the last on treatment assessment will be used for each 
subject.  If the IGF-1 value is missing, the subject will be counted as a non-responder.  
2.3.3. 
Exploratory Efficacy Endpoints  
The following exploratory efficacy endpoints will be evaluated: 
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 evaluated:  
• Change between each post-baseline timepoint (on treatment and follow up) and Baseline. 
Baseline is defined as the mean of all IGF-1 assessments prior to first dose of study drug.  
The change between each post-baseline value and Baseline value will be calculated for 
each subject. 
• Change from end of CRN00808 treatment to 2 and 4 weeks after withdrawal of 
CRN00808.  End of CRN00808 treatment is defined as the Week 13/Visit 14 visit, 


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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.   
Other definitions of response include:  
• Response based on percent change from baseline will be defined as percent change from 
baseline less than or equal to 15%, while a non-responder will be defined as percent 
change from baseline greater than 15%.  
o The same responder definition, but using 20% instead of 15%. 
• Response based on percent change from Week 13/EoT will be defined as percent change 
from end of CRN00808 treatment greater than 15%, while a non-responder will be 
defined as percent change from baseline less than or equal to 15%. 
o The same responder definition, but using 20% instead of 15%. 
Data from the central lab, i.e. the source data will be used for analyses. 
2.3.3.1.2. GH 
The proportion of subjects who meet GH responder criteria, defined as the mean the three-serum 
integrated GH < 5 ng/mL, rounded to two significant figures.  For subjects that complete 
treatment, the mean of the three values obtained at Week 13 will be calculated for subject.  For 
subjects who do not complete treatment, the mean of the last two consecutive on treatment 
assessments will be calculated for each subject.  If any of the three values are missing, the 
available values will be used.  If all three GH values are missing, the subject will be counted as a 
non-responder. 
The same responder analysis will be done, where responder is defined as the mean of the three-
serum integrated GH < 2.5 ng/mL, and rounded to two significant figures.   
The following change in GH levels will be evaluated:  
• Change between Week 13/EoT and Baseline.  Baseline is defined as the mean of all 
available integrated values prior to the first dose of study drug (Visit 1b, Visit 2). For 
subjects who complete treatment, the Week 13 value will be defined as the mean of the 
integrated GH values at Week 13.  For subjects who do not complete treatment, the mean 
of the integrated GH values at the last on treatment assessments will be used.  If any of 
the integrated values are missing, the available values will be used.  The change between 
the calculated Week 13/EoT value and Baseline value will be calculated for each subject.  
• Change between each post-baseline timepoint including EoT (on treatment and follow 
up) and Baseline. Baseline is defined as the mean of all available integrated values prior 
to the first dose of study drug (Visit 1b, Visit 2).   At each visit, the mean of the 
integrated GH values will be used.  If any of the integrated values are missing, the 
available value(s) will be used.  The change between each post-baseline value and 
Baseline value will be calculated for each subject. 


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• Change from end of CRN00808 treatment to 4 weeks after withdrawal of CRN00808.  
End of CRN00808 treatment is defined as the Week 13/Visit 14 visit, therefore, 4 weeks 
after withdrawal are defined as the Week 17/Visit 16.  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 be calculated using SI units and conventional 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 change endpoints specified above for IGF-1 (Section 2.3.3.1.1) will also be calculated for 
.   
Data from the central lab, i.e. the source data will be used for analyses. 
2.3.3.2. 
Patient and Investigator Reported Outcomes Endpoints 
2.3.3.2.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Change between Week 13 and Baseline.  The Baseline value will be defined as the mean 
of the available scores on the 7 days prior to first dose of study drug.  The Week 13 value 
will be defined as the mean of the available scores 7 days prior to their last dose, 
inclusive of the date of last dose.  If any of the 7 days are missing, the available, non-


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missing values will be used to calculate the mean. The change between the calculated 
Week 13 value and calculated Baseline value will be derived for each subject. 
• Change from end of CRN00808 treatment to 4 weeks after withdrawal of CRN00808.  
End of CRN00808 is defined as the Week 13/Visit 14 visit, 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. 
• Change between the Week 17 follow up timepoint and Baseline. The Baseline value will 
be defined as the mean of the available scores on the 7 days prior to first dose of study 
drug.  The Week 17 value will be defined as the mean of the available scores 7 days prior 
to the visit. The change between follow up value and Baseline value will be calculated for 
each subject. 
• Change between the Week 17 follow up timepoint and Screening. The Week 17 value 
will be defined as the mean of the available scores 7 days prior to the visit.  The 
Screening value will be defined as the mean of the available scores between Screening 
Visit 1b and Screening Visit 2. The change between follow up value and Screening value 
will be calculated for each subject. 
A minimum of 4 days should be available to calculate a mean.   
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 Week 13 (Visit 14) will be 
calculated for each subject (range, -3 to 3).  
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. 
 
 
 
 
 
 
 
 
 
 


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• Change between Week 13/EoT and Baseline.  Baseline is defined as the assessments 
prior to first dose of study drug.  For subjects who complete treatment, the Week 13 value 
will be used.  For subjects who do not complete treatment, the last on treatment 
assessment will be used.  The change between the Week 13/EoT value and Baseline 
value will be calculated for each subject. 
• Change between each post-baseline timepoint including EoT (on treatment and follow 
up) and Baseline. Baseline is defined as the Day 1 (Visit 3) value.  The value at each visit 
will be used for each post-baseline timepoint. The change between each post-baseline 
value and Baseline value will be calculated for each subject. 
• Change between the Week 17 follow up timepoint and end of CRN00808 treatment. For 
subjects who complete treatment, the Week 13 value will be used.  For subjects who do 
not complete treatment, the last on treatment assessment will be used. The value at each 
follow up visit will be used. The change between each follow up value and Week 13 
value will be calculated for each subject.  
2.3.3.2.4. 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
    
2.3.3.2.5. Patient Global Impression 
The Patient Global Impression of Severity (PGI-S) is a single question regarding overall current 
acromegaly symptom severity scored as none (Score=0), mild (Score=1), moderate (Score=2), 
and severe (Score=3).  The Patient Global Impression of Change (PGI-I) is a single question 


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regarding overall acromegaly symptom change compared to before study start scored as very 
much improved (Score=-3), much improved (Score=-2), minimally improved (Score=-1), no 
change (Score=0), minimally worse (Score=1), much worse (Score=2), and very much worse 
(Score=3). 
The PGI-S change will be calculated as specified above for IGF-1 (Section Error! Reference 
source not found.). Baseline will be defined as the last value prior to first dose of study drug.  
The PGI-I scores at Week 13/EoT and follow up Week 17 (Visit 16) will also be presented. 
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 and Lanreotide is planned to be measured for each subject 
throughout the study.  Because of the small sample size, measurement of Pasireotide 
concentration will not be performed. Values less than the limit of quantitation (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 group emergent 
adverse events (TEAEs). 
 


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3. 
SAMPLE SIZE JUSTIFICATION 
Approximately 45 subjects are planned to be enrolled in the study. At least 30 subjects from 
Groups 1 and 2 will be enrolled, i.e., a cap of N=15 is set for the sum of the number of subjects 
in Group 3 to 5. 
The primary objective of this study is to evaluate efficacy (IGF-1 levels) in subjects who are 
partial responders to somatostatin analogue based treatment regimens. As such, the sample size 
is chosen to provide sufficient clinical experience to evaluate IGF-1 changes descriptively and is 
not formally powered for hypothesis testing. Summary statistics for the primary endpoint will be 
provided. 
 


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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.  
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 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 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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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. 
Variables with a non-normal distribution that impacts the interpretation or validity of the planned 
analysis may have a data transformation applied (e.g., ln, log10).  
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: 


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temp (degrees Celsius) = 5 / 9 × (temp [degrees Fahrenheit] – 32) 
• 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 groups:  
• Group 1 
• Group 2 
• Group 3 
• Group 4 
• Group 5 
• Total 
Group 1 is equivalent to the Efficacy Analysis Set and will be noted as such in applicable 
summary tables. 
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) 
, Paltusotine (CRN00808) 
, and Total. 
4.7. 
Visits 
4.7.1. 
Windows   
Each visit will be denoted by its visit “Week”. 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 and Table 2 for on treatment assessments and 
Table 3 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.  Summaries of Screening visits will use the nominal, scheduled visit from the eCRF.  


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Table 1: 
Treatment Period Visit Windows Excluding PGI-S 
Target Scheduled Visit 
Target 
Study 
Day a 
Analysis Window Study Day a 
Low 
High 
Baselineb 
1 
See Section Error! Reference source not found. 
Week 2 
8 
2 
15 
Week 4 
22 
16 
24 
Week 5 
29 
25 
36 
Week 7 
43 
37 
45 
Week 8 
50 
46 
57 
Week 10 
64 
58 
68 
Week 11 
71 
69 
78 
Week 13 
91 
79 
95 
a Study day will be calculated from first dose of CRN00808.  
b Baseline is defined in Section 4.7.3. 
Table 2: 
Treatment Period Visit Windows PGI-S Only 
Target Scheduled Visit 
Target 
Study 
Day a 
Analysis Window Study Day a 
Low 
High 
Baselineb 
1 
See Section Error! Reference source not found. 
Week 2 
8 
2 
11 
Week 3  
15 
12 
18 
Week 4 
22 
19 
25 
Week 5 
29 
26 
32 
Week 6  
36 
33 
39 
Week 7 
43 
40 
46 
Week 8 
50 
47 
53 
Week 9  
57 
54 
60 
Week 10 
64 
61 
67 
Week 11 
71 
69 
78 
Week 13 
91 
79 
95 
a Study day will be calculated from first dose of CRN00808.  
b Baseline is defined in Section 4.7.3. 
 


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Table 3: 
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   
The IGF-1 results were evaluated for anomalous values.  Values determined to be anomalous 
were re-assayed.  Appendix 1 describes the decision tree for which re-tested values are included 
in analyses. 
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, Baseline is defined as the mean of all available values prior to the first 
dose of study drug (Visit 1b, Visit 2, Visit 3).  For GH, 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, 
Baseline will be defined as the mean of the available scores on the 7 days prior to first dose of 
study drug.  For baseline characteristics, safety assessments and other efficacy assessments, 
Baseline is as the last non-missing value prior to the first dose of study drug. 
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 dose of study drug may also be considered in 
the calculation of baseline observations. 
4.7.4. 
Definition of End of Treatment (EoT) 
The End of Treatment value is defined as the last on treatment assessment.  In many cases the 
V16/ET CRF is to be populated, however, in cases where that is not possible, the last value 
obtained on treatment will be determined. 
 


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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 Efficacy Analysis Set will include all subjects in Group 1 who received at least one dose 
of study drug. The Efficacy Analysis Set will be the primary analysis population used for all 
efficacy analyses.   
• The Full Analysis Set will include all subjects (all groups) who received at least one dose of 
the study drug. The Full Analysis Set will be the secondary analysis population used for all 
efficacy analyses.  
• The Completers Analysis Set will include all Full Analysis Set subjects who complete 13 
weeks of treatment.  The Completers Analysis Set will be the tertiary analysis population 
used for all efficacy analyses. The Completers Analysis Set will be used for supportive 
efficacy analyses if it differs from the Full Analysis Set by more than 5 subjects total. 
• The Per Protocol (PP) Analysis Set will include all subjects from the Full Analysis Set 
having no major protocol deviations affecting treatment efficacy. The PP Analysis Set will be 
used for supportive efficacy analyses if it differs from the Full Analysis Set by more than 
5 subjects total.  
• The Safety Analysis Set is equivalent to the Full Analysis Set. The Safety Analysis Set will 
be used for all safety analyses. 


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6. 
EXAMINATION OF SUBGROUPS 
Subgroups will be defined based on Baseline values, unless otherwise specified. Frequencies of 
categorizations for the below characteristics will be summarized by group and total. 
General baseline subgroups of interest are as follows: 
• Age categories:  <65 vs ≥65 years 
• Sex:  Male vs Female 
• Race:  White vs All Other Races (Black or African American, Asian, Native Hawaiian or 
Other Pacific Islander, American Indian or Alaska Native) 
• Geographic Region:  North America (USA) vs Europe (United Kingdom, Germany, 
Hungary, Romania, Slovakia, Italy, Poland, Serbia) vs Rest of World (Brazil, Australia, 
New Zealand) 
Efficacy baseline subgroups of interest are as follows: 
• Duration (months) of acromegaly from informed consent: <Median vs ≥Median  
• Group 1 only: Lanreotide vs Octreotide pretrial acromegaly treatment 
• Duration (months) of pre-trial acromegaly treatment: <Median vs ≥Median  
• Prior pituitary surgery: Yes vs No 
Where the median is specified as the cut point, the median of the specified group at Baseline will 
be used. 
The primary, secondary, and select exploratory efficacy endpoints will be analyzed for the Group 
1 Lanreotide vs Octreotide subgroup using the Efficacy Analysis Set.  During the CSR 
preparation, additional subgroup analyses may be performed. Those analyses will be considered 
as ad-hoc analyses and will be presented and discussed in the CSR. 
Subgroup analyses related to COVID-19 may be considered after review of blinded data.  Any 
analyses will be documented in the CSR. 


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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 dosed with reasons for screen failure, the number treated in the TP, the 
number in each Analysis Set, the number who withdraw from the study prior to completing the 
treatment 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. 
The number and percentage of subjects enrolled by geographical region and study site will be 
summarized by group and for all subjects for the Full Analysis Set.   
By-subject data listings of all the above study disposition data including 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 
Demographic variables will include the following: 
• Age at informed consent including the subgroups defined in Section 6. 
• Sex 
• Race  
• Ethnicity 
Other baseline characteristics, from 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 
Frequencies of categorizations for the above characteristics as defined in Section 6 will also be 
summarized. 
Demographics and baseline characteristics will be presented by group and total for the Full and 
Completers Analysis Sets. The PP Analysis Set may be presented if it differs from the Full 
Analysis Set by more than 5 subjects total. 
No inferential statistical comparisons will be performed. 
All demographic and baseline characteristics data will be presented in by-subject data listings. 


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7.3. 
Baseline Acromegaly Disease Characteristics 
The following disease characteristics will be summarized: 
• Duration (months) since diagnosis (from informed consent) 
• 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 treatments administered at Visit 1b (SSA) or prior to Visit 3 
(dopamine agonist or GH receptor blocker): Octreotide LAR, Lanreotide depot, 
Pasireotide LAR, Bromocriptine, Cabergoline, Pegvisomant 
o Doses pre-trial acromegaly treatments administered at Visit 1b (SSA) or prior to 
Visit 3 (dopamine agonist or GH receptor blocker) recorded on the Concomitant 
Medications eCRF.  Octreotide LAR, Lanreotide depot, and Pasireotide LAR 
doses will be summarized as monthly dose, Cabergoline as weekly, and 
Bromocriptine and Pegvisomant as weekly.  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.  
Frequencies of categorizations for the above characteristics as defined in Section 6 will also be 
summarized. 
Baseline disease characteristics will be presented by group and total for the Full Analysis Set and 
Completers Analysis Sets. The PP Analysis Set may be presented if it differs from the Full 
Analysis Set by more than 5 subjects total. 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 
The number and percentage of subject with each acromegaly symptom at study entry and the 
most bothersome symptom will presented by group and total for Full Analysis Set.  In addition, 
summaries by grade will be presented for each symptom and the most bothersome symptom. 
Acromegaly symptoms at study entry will be presented in a by-subject data listing. 
7.5. 
General Medical History 
Medical history will be summarized by SOC, PT, and group using the Full Analysis Set. 
Summaries will be ordered by descending order of total incidence of SOC and PT within each 
SOC. 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. 
General medical history will be presented in a by-subject data listing. 


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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.  
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 dose information. 
Important protocol deviations include, but are not limited to  
• Subjects who entered the study, even though they did not satisfy the entry criteria.  
• Subjects who received 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 group using the Full 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.  
Pretreatment medications and non-pharmacological treatments will only be listed. Prior and new 
concomitant medications will be summarized for each treatment by WHO ATC level 2, WHO 
ATC level 4, and preferred name using the Full Analysis Set. Prior and new concomitant 
medications treatments will also be summarized separately. These summaries will present the 
number and percentage of subjects using each medication/treatment. Subjects may have more 
than one medication/treatment per ATC level and preferred name. At each level of subject 
summarization, a subject is counted once if he/she reported one or more medications/treatments 
at that level. Each summary will be ordered by descending order of the total incidence of ATC 
level and preferred name within each ATC level.  A separate table for all medications with an 
indication of acromegaly will be presented. 


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8. 
EFFICACY ANALYSES  
All efficacy analyses will use the Efficacy or the Full Analysis Sets. Select analyses will also be 
repeated using the Completers Analysis Set. If the total number of subjects in the Full and PP 
Analysis Set differ by more than 5 subjects, efficacy analyses may be repeated for the PP 
Analysis Set for relevant primary, secondary, and select exploratory efficacy endpoints.  
Statistical analysis of all efficacy endpoints will be considered nominal and descriptive. 
All efficacy endpoints, recorded and derived, will be presented in by-subject data listings.  
8.1. 
Adjustments for Covariates 
Not Applicable.  
8.2. 
Handling of Dropouts or Missing Data 
The following methods will be implemented to address missing data for relevant primary, 
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.  
Sensitivity analyses will use “observed cases,” where subjects who do not provide an assessment 
at the specified time point for the defining of response will not be included. That is, for the 
percentage of responders, the subject will not be included in the numerator or the denominator.  
8.2.2. 
Biomarker Endpoints 
As described within each endpoint definition in Section 2.3, subjects who do not complete 
treatment will have their last on treatment assessment imputed for the Week 13/EoT value for the 
purposes of continuous summaries of IGF-1 and GH.  Additional analyses will be conducted 
using observed cases only.  
8.2.3. 
Patient or Investigator Reported Outcomes 
Missing data will not be imputed for patient or investigator reported outcomes. 
8.3. 
Interim Analyses and Data Monitoring 
8.3.1. 
Interim Analysis  
No interim analyses are planned for this study.  Note however, this is an open-label, exploratory 
study and there may be ongoing review of data during study conduct. 


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8.4. 
Multicenter Studies 
The number and percentage of subjects randomized by geographical region and study site will be 
summarized by group and for all subjects.  No other summaries or analyses by site or region will 
be performed. 
8.5. 
Use of an “Efficacy Subset” of Patients 
Not Applicable. 
8.6. 
Multiple Comparisons/Multiplicity 
Not Applicable. 
8.7. 
Primary Efficacy Analysis 
The primary efficacy analysis will test the following hypothesis: 
• H0:  The median IGF-1 change from Baseline to Week 13 is equal to zero. 
• H1:  The median IGF-1 change from Baseline to Week 13 is different than zero.  
The primary efficacy analyses, using the Efficacy Analysis Set, will evaluate change from 
Baseline to Week 13, at alpha level of 0.05, using Wilcoxon Signed Rank test. Descriptive 
statistics (Section 4.1) of values and change from Baseline by group and total will be 
presented including 95% CI for the arithmetic mean and geometric mean with associated 
95% CI.   
8.7.1. 
Additional Analyses of the Primary Endpoint 
The primary endpoint will be analyzed for the Group 1 Lanreotide vs Octreotide subgroup 
using the Efficacy Analysis Set. 
Sensitivity analyses using observed cases will be presented. 
Sensitivity analyses using the Full, PP, and Completers Analysis Sets will be presented. 
8.8. 
Secondary Efficacy Analyses 
Secondary efficacy endpoints are described in Section 2.3.2. 
8.8.1. 
Proportion of Subjects with IGF-1 ≤ 1.0 × ULN at Week 13/EoT 
The secondary efficacy analysis will test the following hypothesis: 
• H0:  The proportion of IGF-1 responders at Week 13/EoT is equal to 0.50. 
• H1:  The proportion of IGF-1 responders at Week 13/EoT is different than 0.50.  
The number and percentage, with associated two-sided exact (Clopper-Pearson) 95% CIs, of 
subjects in each category (response, nonresponse) will be presented by group and total for the 
Full Analysis Set, limited to Groups 3, 4 and 5 only, including a nominal p-value from an 
exact binomial test.  
Sensitivity analyses using the PP and Completers Analysis Sets will be presented. 


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8.8.2. 
Proportion of Subjects with IGF-1 ≤ 1.5 × ULN at Week 13/EoT 
The secondary efficacy analysis will test the following hypothesis: 
• H0:  The proportion of IGF-1 responders at Week 13/EoT is equal to 0.50. 
• H1:  The proportion of IGF-1 responders at Week 13/EoT is different than 0.50.  
The number and percentage, with associated two-sided exact (Clopper-Pearson) 95% CIs, of 
subjects in each category (response, nonresponse) will be presented by group and total for the 
Full Analysis Set, including a nominal p-value from an exact binomial test. 
This endpoint will also be analyzed for the Group 1 Lanreotide vs Octreotide subgroup using 
the Efficacy Analysis Set. 
Sensitivity analyses using the PP and Completers Analysis Sets will be presented. 
8.9. 
Exploratory Efficacy Analyses 
Exploratory efficacy endpoints are described in Section 2.3.3.  
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 and analyzed in the 
same manner specified for the primary endpoint (Section 8.7) for the Full, PP, and 
Completers Analysis Sets.  Changes in IGF-1 levels will also be analyzed for the Group 1 
Lanreotide vs Octreotide subgroup using the Efficacy Analysis Set. 
Additional analyses of IGF-1 rate of change will be evaluated using a general linear mixed 
effects model to evaluate the slope for the Full Analysis Set. Rate of change will be evaluated 
from Baseline to end of CRN00808 treatment and separately from end of CRN00808 
treatment to last assessment. The model will fit a random intercept and slope for each subject 
and will include fixed effects for group, time, and group × time interaction. Time will be 
expressed in weeks as a continuous variable and will include all assessments. An 
unstructured covariance structure will be used to model the within-subject errors. If the 
computational algorithm fails to converge, the following structures will be executed:  
heterogeneous Toeplitz, Toeplitz, heterogeneous First-Order Autoregressive [AR (1)], AR 
(1), heterogeneous compound symmetry (HCS), and compound symmetry (CS). The 
covariance structure converging to the best fit, as determined by Akaike’s information 
criterion (AIC), will be used. The Kenward and Roger method will be used to calculate the 
denominator degrees of freedom for the test of fixed effects. Estimates of the slope will be 
presented by group along with corresponding 95% CIs.  
As doses are allowed to be titrated, if sufficient data exist, a dose response analysis may be 
conducted evaluating the change between the following weeks: Week 4 (prior to any dose 
titration), Week 7 (after 1st potential dose titration), and Week 10 (2nd potential dose titration) 
for the Full Analysis Set. 
Response rates based on percent change from baseline and percent change from end of 
CRN00808 treatment will be presented using the same methods specified for the IGF-1 


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secondary endpoints (Sections 8.8.1 and 8.8.2) for the Full and Completer Analysis Sets. 
Response rates will also be analyzed for the Group 1 Lanreotide vs Octreotide subgroup using 
the Efficacy Analysis Set. 
8.9.1.2. 
GH 
The proportion of subjects who achieve a serum GH<5.0 ng/mL, and separately GH<2.5 
ng/mL, at Week 13 will be analyzed using the same methods specified in Section Error! 
Reference source not found.. for the Full, PP, and Completers Analysis Sets. GH response 
rates will also be analyzed for the Group 1 Lanreotide vs Octreotide subgroup using the 
Efficacy Analysis Set. 
Changes in serum GH as specified in Section 2.3.3.1.2 will be presented and analyzed in the 
same manner specified for the primary endpoint (Section 8.7) for the Full, PP, and 
Completers Analysis Sets. Changes in serum GH will also be analyzed for the Group 1 
Lanreotide vs Octreotide subgroup using the Efficacy Analysis Set. 
The same dose response analysis specified for IGF-1 (Section 8.9.1.1) may be conducted for GH 
for the Full Analysis Set.  
8.9.1.3. 
 
Changes in 
 levels as specified in Section 2.3.3.1.3 will presented and analyzed in the 
same manner specified for the primary endpoint (Section 8.7). 
8.9.2. 
Patient and Investigator Reported Outcome Endpoint Analyses 
8.9.2.1. 
Patient Assessed Symptoms of Acromegaly: 
 
 
 
 
 
  
 
 
8.9.2.2. 
Investigator Assessed Symptoms of Acromegaly 
The number and percentage of subjects with each symptom present study entry is presented in 
Section 7.4. The number of and percentage of subjects whose symptom reduced in 
severity/grade, resolved, increased in severity/grade, or new occurrence will be presented at each 
visit by group and total for the Full Analysis Set.  
The same summary will be presented for the most bothersome symptom specified at study entry. 


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8.9.2.3. 
 
 
 
 
 
 
 
   
 
 
8.9.2.4. 
 
 
 
 
 
 
 
 
 
8.9.2.5. 
Patient Global Impression 
The number and percentage of subjects with each PGI-S score for each scheduled visit and the 
change in PGI-S scores will be presented by group and total for the Full Analysis Set and for the 
Group 1 Lanreotide vs Octreotide subgroup using the Efficacy Analysis Set.   
In addition, responder analyses will be presented for the Full Analysis Set, where a responder is 
defined as PGI-S / PGI-I Score of very much improved or much improved and a non-responder 
as all other responses.   
8.9.3. 
Pharmacokinetic (PK) Analyses 
Plasma CRN00808 concentrations and elapsed time from the last CRN00808 dose taken will be 
listed. A summary of concentrations by CRN00808 dose for each timepoint will be presented. In 
addition, the percent change in CRN00808 concentration from end of CRN00808 treatment 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.   
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.   
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 – 72 capsules [the dispensed overage]) / 
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 summary will be presented by group 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 
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 total 
incidence of SOC and PT within each SOC. Summaries of the following types will be presented: 


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• 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 PT.  
• 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 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.  
• 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. 
• Subject incidence of serious TEAEs by MedDRA SOC and PT.  
• 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”. 


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All of the above tables will be repeated only for MedDRA PT, excluding MedDRA SOC. 
The following listings will be presented by group 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.  
All clinical laboratory data will be presented in by-subject data listings.  
9.3.1. 
Serum Chemistry, Hematology, and HbA1c 
Quantitative serum chemistry, hematology, and HbA1c results for each scheduled visit, baseline 
through Week 17, and changes from Baseline will be summarized by group and total.   
9.3.2. 
Shifts in CTCAE Grade 
Quantitative laboratory tests will be assigned grades based on National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 5, where applicable. Shifts in 
CTCAE grade from Baseline to worst on-treatment value, worst follow-up value, and worst on-
study post- Baseline value will be presented by group and total. Denominators for percentages 
will be the number of subjects with non-missing data at the specific visit and Baseline. 
In addition, for each laboratory test the number and percent of subjects with a lab value with 
CTCAE grade ≥3 and the number and percent of subjects with a CTCAE shift of ≥2 grades will 
be presented.  Listings will be presented for any subject with a post- Baseline CTCAE grade 3 or 
4 laboratory value. Normal ranges provided by the central laboratory will be presented in a 
separate 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. 


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9.3.3. 
Shifts in Normal Range 
In addition, for laboratory tests that cannot be graded via CTCAE, shift tables (i.e., low-normal-
high at baseline versus low-normal-high at post-baseline visit in a 3-by-3 contingency table) 
from Baseline to worst on-treatment value, worst follow-up value, and worst on-study post- 
Baseline value will be presented by group and total.  Denominators for percentages will be the 
number of subjects with non-missing data at the specific visit and baseline. 
9.3.4. 
Hormones 
Hormone levels will be summarized at Baseline and Week 13 by group and total.  In addition, 
change and percent change from Baseline will be presented. 
9.3.5. 
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 systolic and diastolic pressure (mmHg), pulse rate (beats/min), 
respiratory rate (breaths/min), and body temperature (C) will be presented in a data listing. 
Summaries of vital sign parameter results for each scheduled visit, baseline through Week 17, 
and changes from Baseline will be summarized by group and total.  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 summarized at Baseline and each post- 
baseline visit through Week 17 by group and total.  In addition, change and percent change from 
Baseline will be presented. 
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. For 
summary purposes 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 summarized from Baseline 
through Week 17 by group and total. In addition, change from baseline will be presented.  
A categorical summary of the following abnormal QTcF values will be presented:  >450 msec, 
>480 msec, and >500 msec. Change summaries will also be presented for measurements that 
represent a change of >30 msec and >60 msec. Categorical analyses will be presented from 
Baseline through Week 17 by group and total.  


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A separate listing for those subjects with any QTcF >450 msec or a QTcF change from 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 
in the listing.  
The investigator interpretation results are collected as normal, abnormal not clinically 
significant, and abnormal clinically significant. Subjects whose interpretation shifts from normal 
to abnormal clinically significant or not clinically significant 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 
The number and percentage of subjects with gallstones absent or present at Baseline and Week 
13 will be presented by group and total.  Any changes from Baseline to Week 13 will also be 
summarized as Newly Appeared and No Longer Present. Similar summaries will be presented 
for gall bladder sludge. 
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 
The Efficacy Analysis Set was modified to include on Group 1 subjects, excluding Group 2.  
Group 1 subjects may differ from Group 2 in terms of IGF-1/GH responses to switching from 
respective pre-trial medication regimens to paltusotine monotherapy.  For this reason, the safety 
and efficacy profile should be considered separately by group.    
The secondary endpoint of proportion of subjects with IGF-1 ≤ 1.0 × ULN at Week 13/EoT was 
clarified to only include subjects who start the study with IGF-1 ≤ 1.0 × ULN, i.e. limited to 
Groups 3, 4, and 5. 
For both secondary endpoints of proportion of subjects with IGF-1 ≤ 1.0 × ULN at Week 13/EoT 
and proportion of subjects with IGF-1 ≤ 1.5 × ULN at Week 13/EoT, these were clarified to only 
use Week 13/EoT assessments and not use the mean of last two consecutive assessments.  The 
mean of last two consecutive assessments (Week 11 and Week 13) will not be used as subjects 
who titrate to the full dose (
), may not be stabilized at the full dose by Week 11. 
For endpoints which specified at Week 13, it was clarified the Week 13 value would be used for 
subject who complete treatment or End of Treatment value would be used for subjects who do 
not complete treatment. 
The protocol specifies 90% CIs of the mean will be presented, instead the SAP includes 95% 
CIs. 
To assess the protocol specified endpoint of the amount of increase in IGF-1 or GH levels 3 or 
more weeks after withdrawal of CRN00808, the change from end of CRN00808 treatment will 
be used (Sections Error! Reference source not found. and 2.3.3.1.2 respectively). 
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. 
Additional exploratory efficacy endpoints were added. 
 
 


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APPENDIX 1. DECISION TREE FOR INCLUDING RE-TESTED IGF-1 
VALUES