An Open Label, Randomized, Phase 2 Study to Assess the Safety, Tolerability, and Efficacy of IONIS-GHR-LRx, an Antisense Inhibitor of the Growth Hormone Receptor, Administered Monthly as Monotherapy in Patients With Acromegaly
Phase: PHASE2
Conditions: Acromegaly
Sponsor: Ionis Pharmaceuticals, Inc.

 
 
An Open Label, Randomized, Phase 2 Study to Assess the Safety, Tolerability, and Efficacy of 
IONIS-GHR-LRx, an Antisense Inhibitor of the Growth Hormone Receptor, Administered 
Monthly as Monotherapy in Patients With Acromegaly   
 
NCT04522180 
 
30 August 2022 

 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
ISIS 766720-CS5 
 
An Open Label, Randomized, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of IONIS GHR-LRX, an Antisense 
Inhibitor of the Growth Hormone Receptor, Administered Monthly 
as Monotherapy in Patients with Acromegaly 
 
Protocol Amendment 3 – 13 December 2021 
 
EudraCT No:  2020-000675-20 
 
Trial Sponsor 
Ionis Pharmaceuticals 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone:  760 931 9200 
Fax:  760 603 3564 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
2 
ISIS 766720-CS5 
Amendment 3  
 
EudraCT No:  2020-000675-20 
 
Clinical Phase:  2 
 
An Open Label, Randomized, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of IONIS GHR-LRX, an Antisense 
Inhibitor of the Growth Hormone Receptor, Administered Monthly 
as Monotherapy in Patients with Acromegaly 
 
 
 
 
Protocol History: 
Original Protocol: 
25 February 2020 
Amendment 1: 
31 July 2020  
Amendment 2: 
7 July 2021  
 
 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Carlsbad, CA  92010 
 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. that must not be disclosed to anyone 
other than the recipient study staff and members of the independent ethics committee, institutional review board, or 
authorized regulatory agencies.  This information cannot be used for any purpose other than the evaluation or 
conduct of the clinical investigation without the prior written consent of Ionis Pharmaceuticals, Inc. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
3 
Protocol Signature Page 
 
Protocol Number: 
ISIS 766720-CS5 
Protocol Title: 
An Open Label, Randomized, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of IONIS GHR-LRX, an Antisense Inhibitor of 
the Growth Hormone Receptor, Administered Monthly as Monotherapy in 
Patients with Acromegaly  
Amendment:  
Amendment 3 
Date:  
 
13 December 2021 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “An 
Open Label, Randomized, Phase 2 Study to Assess the Safety, Tolerability, and Efficacy of 
IONIS GHR-LRX, an Antisense Inhibitor of the Growth Hormone Receptor, Administered 
Monthly as Monotherapy in Patients with Acromegaly” dated 13 December 2021, and agree to 
conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
4 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT .........................................................................................................9 
PROTOCOL SYNOPSIS ..............................................................................................................11 
STUDY DESIGN AND TREATMENT SCHEMA ......................................................................21 
STUDY GLOSSARY ....................................................................................................................22 
1. 
OBJECTIVES AND ENDPOINTS ............................................................................25 
1.1. 
Objectives ...................................................................................................................25 
1.1.1. 
Primary Objectives .....................................................................................................25 
1.1.2. 
Secondary Objective ...................................................................................................25 
1.1.3. 
Additional/Exploratory Objectives .............................................................................25 
1.1.3.1. 
Pharmacokinetic (PK) Objectives ...............................................................................25 
1.2. 
Study Endpoints ..........................................................................................................25 
1.2.1. 
Primary Endpoint ........................................................................................................25 
1.2.2. 
Secondary Endpoints ..................................................................................................26 
1.2.3. 
Additional/Exploratory Endpoints ..............................................................................26 
1.2.3.1. 
Pharmacokinetic (PK)/Pharmacodynamics (PD) Exploratory Endpoints ..................26 
2. 
BACKGROUND AND RATIONALE .......................................................................27 
2.1. 
Overview of Disease ...................................................................................................27 
2.2. 
Therapeutic Rationale .................................................................................................27 
2.3. 
ISIS 766720 ................................................................................................................28 
 
 
 
 
2.3.3. 
Preclinical Experience ................................................................................................30 
2.3.4. 
Clinical Experience .....................................................................................................31 
2.4. 
Rationale for Dose and Schedule of Administration ..................................................32 
2.5. 
Benefit-Risk Assessment ............................................................................................32 
2.5.1. 
Benefit Assessment .....................................................................................................32 
2.5.2. 
Risk Assessment .........................................................................................................32 
2.5.3. 
Risk Assessment – GHR Inhibition ............................................................................33 
2.5.4. 
Risk Assessment – Antisense .....................................................................................33 
2.5.5. 
Risk Assessment – COVID-19 ...................................................................................33 
3. 
EXPERIMENTAL PLAN ..........................................................................................33 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
5 
3.1. 
Study Design ...............................................................................................................33 
3.2. 
Number of Study Centers ...........................................................................................33 
3.3. 
Number of Patients .....................................................................................................33 
3.4. 
Overall Study Duration and Follow-up ......................................................................34 
3.4.1. 
Screening ....................................................................................................................34 
3.4.2. 
Treatment ....................................................................................................................34 
3.4.3. 
Post-Treatment ............................................................................................................34 
4. 
PATIENT ENROLLMENT ........................................................................................34 
4.1. 
Screening ....................................................................................................................34 
4.2. 
Randomization ............................................................................................................35 
4.3. 
Replacement of Patients .............................................................................................35 
5. 
PATIENT ELIGIBILITY ...........................................................................................35 
5.1. 
Inclusion Criteria ........................................................................................................35 
5.2. 
Exclusion Criteria .......................................................................................................36 
6. 
STUDY PROCEDURES ............................................................................................38 
6.1. 
Study Schedule ...........................................................................................................38 
6.1.1. 
Screening ....................................................................................................................38 
6.1.2. 
Treatment Period ........................................................................................................39 
6.1.3. 
Post-Treatment Period ................................................................................................40 
6.2. 
Study/Laboratory Assessments ...................................................................................41 
6.2.1. 
Clinical Laboratory Assessments ...............................................................................41 
6.2.2. 
Oral Glucose Tolerance Test and Growth Hormone Response during OGTT ...........41 
6.2.3. 
Assessments for Acromegaly .....................................................................................42 
6.2.3.1. 
Acromegaly Quality of Life Questionnaire ................................................................42 
6.2.3.2. 
Acromegaly Symptoms and Treatment Score Questionnaire-Monotherapy ..............43 
6.2.3.3. 
EQ-5D .........................................................................................................................43 
6.2.3.4. 
36-Item Short Form Survey ........................................................................................43 
6.2.3.5. 
Ring Size Assessment .................................................................................................43 
6.2.4. 
MRI .............................................................................................................................43 
6.2.5. 
Echocardiography .......................................................................................................43 
6.3. 
Restriction on the Lifestyle of Patients .......................................................................44 
6.3.1. 
Contraception Requirements ......................................................................................44 
6.3.2. 
Other Requirements ....................................................................................................45 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
6 
7. 
STUDY DRUG ...........................................................................................................45 
7.1. 
Study Drug Description ..............................................................................................45 
 
 
7.2. 
Packaging and Labeling ..............................................................................................45 
7.3. 
Study Drug Accountability .........................................................................................45 
8. 
TREATMENT OF PATIENTS ..................................................................................45 
 
 
8.2. 
Other Protocol-Required Drugs ..................................................................................46 
8.3. 
Other Protocol-Required Treatment Procedures ........................................................46 
8.4. 
Treatment Precautions ................................................................................................46 
8.5. 
Safety Monitoring Rules .............................................................................................46 
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests ..................................................47 
8.5.1.1. 
Dose Adjustment Guidelines for Liver Monitoring ....................................................48 
8.5.2. 
Safety Monitoring Rules for Platelet Count Results...................................................48 
8.5.3. 
Safety Monitoring for Minor Bleeding Events ...........................................................48 
8.5.4. 
Safety Monitoring Rules for Renal Function Test Results .........................................48 
8.6. 
Stopping Rules ............................................................................................................49 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations .........................................................49 
8.6.2. 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules 
for Renal Function Test Results .................................................................................49 
8.6.3. 
Stopping Rule for Platelet Count Results ...................................................................49 
8.7. 
Adjustment of Dose and/or Treatment Schedule ........................................................52 
8.8. 
Discontinuation of Study Drug/Treatment .................................................................52 
8.9. 
Withdrawal of Patients from the Study Procedures ....................................................53 
8.10. 
Concomitant Therapy and Procedures ........................................................................53 
8.10.1. 
Concomitant Therapy .................................................................................................53 
8.10.2. 
Concomitant Procedures .............................................................................................54 
8.11. 
Treatment Compliance ................................................................................................54 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .....................54 
9.1. 
Sponsor Review of Safety Information ......................................................................54 
9.2. 
Regulatory Requirements ...........................................................................................55 
9.3. 
Definitions ..................................................................................................................55 
9.3.1. 
Adverse Event .............................................................................................................55 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
7 
9.3.2. 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction ............56 
9.3.3. 
Serious Adverse Event (SAE) ....................................................................................56 
9.3.4. 
Adverse Event of Special Interest ...............................................................................57 
9.4. 
Monitoring and Recording Adverse Events ...............................................................57 
9.4.1. 
Serious Adverse Events ..............................................................................................57 
9.4.2. 
Non-Serious Adverse Events ......................................................................................58 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) .........................................58 
9.4.3.1. 
Relationship to the Study Drug...................................................................................58 
9.4.3.2. 
Severity .......................................................................................................................58 
9.4.3.3. 
Action Taken with Study Drug ...................................................................................59 
9.4.3.4. 
Treatment Given for Adverse Event ...........................................................................59 
9.4.3.5. 
Outcome of the Adverse Event ...................................................................................59 
9.4.3.6. 
Follow-up of Adverse Event .......................................................................................60 
9.5. 
Procedures for Handling Special Situations ...............................................................60 
9.5.1. 
Abnormalities of Laboratory Tests .............................................................................60 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................60 
9.5.3. 
Dosing Errors ..............................................................................................................61 
9.5.4. 
Contraception and Pregnancy .....................................................................................61 
10. 
STATISTICAL CONSIDERATIONS .......................................................................62 
10.1. 
Stratification, Subsets, and Covariates .......................................................................62 
10.2. 
Sample Size Considerations .......................................................................................62 
10.3. 
Populations .................................................................................................................62 
10.4. 
Definition of Baseline .................................................................................................63 
10.5. 
Interim Analysis ..........................................................................................................63 
10.6. 
Planned Methods of Analysis .....................................................................................63 
10.6.1. 
Demographic and Baseline Characteristics ................................................................63 
10.6.2. 
Safety Analysis ...........................................................................................................63 
10.6.3. 
Efficacy Analysis ........................................................................................................64 
10.6.4. 
Pharmacokinetic Analysis ..........................................................................................64 
10.6.5. 
Additional Analyses ....................................................................................................64 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ...........................................65 
11.1. 
Informed Consent .......................................................................................................65 
11.2. 
Ethical Conduct of the Study ......................................................................................65 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
8 
11.3. 
Independent Ethics Committee/Institutional Review Board ......................................65 
11.4. 
Patient Confidentiality ................................................................................................66 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..............................................66 
12.1. 
Protocol Amendments ................................................................................................66 
12.2. 
Study Termination ......................................................................................................66 
12.3. 
Study Documentation and Storage .............................................................................67 
12.4. 
Study Monitoring ........................................................................................................67 
12.5. 
Language .....................................................................................................................68 
12.6. 
Compensation for Injury .............................................................................................68 
13. 
REFERENCES ...........................................................................................................69 
14. 
APPENDICES ............................................................................................................71 
APPENDIX A. SCHEDULE OF PROCEDURES .....................................................................72 
APPENDIX B. LIST OF LABORATORY ANALYTES ..........................................................80 
APPENDIX C. PK SAMPLING SCHEDULE ...........................................................................82 
APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING TO 
LABORATORY ABNORMALITIES ..............................................................84 
 
 
LIST OF TABLES 
Table 1: 
Sampling Schedule:  Day of Oral Glucose Tolerance Test and GH Response 
During OGTT .............................................................................................................42 
Table 2: 
ISIS 766720 Characteristics .......................................................................................45 
Table 3: 
ISIS 766720 Dosing Information ................................................................................46 
Table 4: 
Actions in Patients with Low Platelet Count ..............................................................51 
 
 
LIST OF FIGURES 
Figure 1: 
Design of GalNAc Conjugated Chimeric 2ʹ-MOE Phosphorothioate 
Oligonucleotides (MOE-Gapmer) ..............................................................................30 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 766720-CS5 
Protocol Title: 
An Open Label, Randomized, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of IONIS GHR-LRX, an Antisense Inhibitor 
of the Growth Hormone Receptor, Administered Monthly as 
Monotherapy in Patients with Acromegaly 
Amendment Number: 
3 
Amendment Date: 
13 December 2021 
 
The primary purpose of this amendment is to update the patient randomization and clarify 
enrollment of treatment dose groups.  Because some participating countries did not 
have regulatory approval for all dose levels, the Sponsor has decided to provide all sites the 
opportunity to enroll patients in their region at an approved dose level.  To facilitate this, patients 
will continue to be randomized through the IVR system; however, it may not necessarily be 
equally in a 1:1:1 manner.  Additionally, the Sponsor decided to assess the safety and efficacy of 
the higher dose levels prior to deciding to conduct the 80-mg treatment group.   
Additionally, Protocol Section 8.5.3 was updated to provide clarification to contact the Sponsor 
Medical Monitor prior to any modifications in safety monitoring. 
These updates do not change the safety and efficacy objectives of the trial.  
Also, administrative clarifications and corrections for typographical errors have been made 
throughout the protocol to improve the overall clarity of the original protocol; however, these 
changes do not impact subject safety, exposure, or the overall study design. 
The following modifications to Protocol ISIS 766720-CS5 have been made.  Changes to the 
protocol language are bolded and underlined.  The table below provides a list of changes to the 
protocol: 
Protocol Section 
Description of Change 
Protocol Synopsis:  
Number of Patients 
Approximately 40 patients are planned to be randomized in the study.  
Thirty-six (36) patients (12 in each treatment group) in the per protocol 
set (PPS) are needed to complete the Treatment Period and the primary 
efficacy endpoint.  Patients will be randomized equally (1:1:1) to 1 of 
the 3 treatment groups (80 mg, 120 mg, 160 mg).  Patients will be 
enrolled to either the 120 mg or the 160 mg groups initially.  After 
review of the safety and efficacy data in approximately 50% of the 
patients, the 80 mg group may be enrolled.  If the 80 mg treatment 
group is not conducted, approximately 30 patients will be 
randomized. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
10 
Protocol Section 
Description of Change 
Protocol Synopsis:  
Statistical Considerations  
Eligible patients will be stratified based on screening serum IGF-1 level 
(> 2.5× ULN vs. ≤ 2.5 × ULN age and sex adjusted by the central lab) 
and then patients will be randomized to 1 of 3 one of the treatment 
groups (ISIS 766720 80 mg, 120 mg or 160 mg). in a 1:1:1 ratio. 
Protocol Section 3.3 
Number of Patients 
Thirty-six (36) patients (12 in each treatment group) in  the per protocol 
set (PPS) are needed to complete the Treatment Period and the primary 
efficacy endpoint.  If the 80 mg treatment group is not conducted, 
approximately 30 patients will be randomized. 
Protocol Section 4.2 
Randomization 
Eligible patients will be stratified based on screening IGF-1 levels 
(≤ 2.5 × ULN or > 2.5 × ULN age and sex adjusted by central lab) and 
then patients will be randomized equally (1:1:1) to 1 of the 3 one of the 
ISIS 766720 dose treatment groups (80 mg, 120 mg, 160 mg).  The 
Sponsor or Designee will prepare the randomization list.  Patients will 
be enrolled to either the 120 mg or the 160 mg groups initially.  
After review of the safety and efficacy data in approximately 50% of 
the patients, the 80 mg group may be enrolled.    
Protocol Section 8.5.3 
Safety Monitoring for Minor Bleeding Events Minor bleeding events are 
those that do not fulfill the criteria for major bleeding (MB) or clinically 
relevant, non-major bleeding events (which are defined in Section 8.6.3). 
If a minor bleeding event occurs, additional testing of coagulation 
parameters (activated partial thromboplastin time [aPTT], prothrombin 
time [PT], INR) and platelet count should may be performed after 
consultation with the Sponsor Medical Monitor or Designee. 
Protocol Section 9.3.3 
Serious Adverse Event 
The terms "severe" and "serious" are not synonymous.  Severity refers to 
the intensity of an AE (e.g., rated as mild, moderate, or severe, or 
according to National Cancer Institute Common Terminology Criteria 
for Adverse Events [NCI CTCAE]; OR Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials; the event itself may be of relatively minor 
medical significance [such as severe headache without any further 
findings]). 
Protocol Section 10.2 
Sample Size Considerations 
Approximately 40 patients are planned to be randomized in the study.  
If the 80 mg treatment group is not conducted, approximately 
30 patients will be randomized.   
 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
11 
PROTOCOL SYNOPSIS 
Protocol Title 
An Open Label Randomized, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of IONIS GHR-LRX, an Antisense Inhibitor 
of the Growth Hormone Receptor, Administered Monthly as 
Monotherapy in Patients with Acromegaly 
Study Phase 
2 
Indication 
Acromegaly  
Primary Objectives 
To evaluate the safety and tolerability of ISIS 766720 subcutaneous 
(SC) injection as a monotherapy in patients with acromegaly. 
To evaluate the efficacy of ISIS 766720 SC injection on serum 
insulin-like growth factor-1 (IGF-1) as a monotherapy in patients 
with acromegaly.   
Secondary Objective 
To evaluate the effect of ISIS 766720 SC to normalize serum IGF-1 
levels. 
Study Design 
This will be a Phase 2, randomized, open label multi-center study. 
Number of Patients 
Approximately 40 patients are planned to be randomized in the study.  
Thirty-six (36) patients (12 in each treatment group) in the per 
protocol set (PPS) are needed to complete the Treatment Period and 
the primary efficacy endpoint.  
 
 
 
 
 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
12 
PROTOCOL SYNOPSIS CONTINUED 
Study Population 
Inclusion Criteria 
1. 
Must have given written informed consent (signed and dated) 
and any authorizations required by local law and be able to 
comply with all study requirements 
2. 
Males or females with a documented diagnosis of Acromegaly* 
who are 18 to 75 years old (inclusive) at the time of informed 
consent 
* Defined as a previous diagnosis of GH-secreting adenoma by 
surgical pathology; or the presence of a pituitary adenoma 
identified on magnetic resonance imaging (MRI) or computed 
tomography (CT) Scan (if MRI is contraindicated) and serum 
IGF-1 levels above the upper limit of normal (ULN) for age 
and sex at time of diagnosis (serum IGF-1 level and imaging at 
diagnosis will be collected in the case report forms [CRF]) 
3. 
Have had pituitary surgery (e.g. transsphenoidal) unless there 
was a contraindication to surgery and are either acromegaly 
medical treatment naïve, or who had not taken any other 
acromegaly medications prior to the screening visit as outlined 
below:  
bromocriptine:  2 weeks  
cabergoline:  4 weeks  
quinagolide:  4 weeks  
octreotide daily injection (SC) or oral formulation:  4 weeks  
pegvisomant:  4 weeks  
octreotide LAR:  3 months  
pasireotide LAR:  4 months  
lanreotide (all formulations):  3 months 
4. 
At Screening, serum IGF-1 (performed at central lab) between 
1.3 to 5 × ULN, inclusive, adjusted for age and sex.  IGF-1 can 
be repeated once and averaged to determine eligibility if the 
initial result is between 1.1–1.3 × ULN, or between 
5-5.3 = × ULN 
5. 
Females must be non-pregnant and non-lactating, and either: 
a. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy)  
b. post-menopausal (defined as 12 months of spontaneous 
amenorrhea in females > 55 years of age or, in females 
≤ 55 years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and follicle-stimulating hormone 
(FSH) levels in the postmenopausal range for the laboratory 
involved) 
c. abstinent (defined in Section 6.3.1) or  
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
13 
PROTOCOL SYNOPSIS CONTINUED 
Study Population Continued 
Inclusion Criteria Continued 
d. Women of childbearing potential (WOCBP) should agree to 
taking all precaution to avoid pregnancy during the Trial 
Period (including Post-Treatment), including agreeing to 
receive pregnancy testing before each monthly dose, using 
1 highly effective method of birth control (Section 6.3.1) from 
the time of signing the informed consent form (ICF) until 
14 weeks after the last dose of ISIS 766720 administration  
Males must be either: 
e. surgically sterile 
f. abstinent (defined in Section 6.3.1) or 
g. if engaged in sexual relations with a female of child-bearing 
potential, the patient must be using a highly effective 
contraceptive method (refer to Section 6.3.1) from the time of 
signing the ICF until 14 weeks after the last dose of 
ISIS 766720 
6. 
Willing to refrain from strenuous exercise/activity (for example 
heavy lifting, weight training, intense aerobics classes etc.) for at 
least 24 hours prior to study visits 
7. 
Willing to refrain from alcohol or tobacco use for 8 hours prior 
to study visits 
Exclusion Criteria 
1. 
Clinically significant (CS) abnormalities in medical history 
according to Investigator judgement (e.g., previous acute 
coronary syndrome within 6 months of Screening, major 
non-pituitary surgery within 2 months of Screening) or from 
Screening physical examination (PE) 
2. 
Patients who received surgery for pituitary adenoma within the 
last 3 months before the trial, and/or planning to receive surgery 
during the trial 
3. 
Patients who received radiotherapy for pituitary adenoma within 
the last 2 years before the trial, and/or planning to receive 
radiotherapy during the trial 
4. 
Patients with a pituitary tumor that, per Investigator judgment, is 
worsening (e.g., either growing, or at risk of compressing or 
abutting the optic chiasm or other vital structures) as assessed by 
pituitary/sellar MRI protocol at Screening or within 3 months of 
Screening.  CT scan is allowed if MRI is contraindicated. 
5. 
Evidence of decompensated cardiac function per medical 
judgement and/or New York Heart Association (NYHA) 
Class 3 or 4 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
14 
PROTOCOL SYNOPSIS CONTINUED 
Study Population Continued 
Exclusion Criteria Continued 
6. 
Clinical evidence of symptomatic hyperprolactinemia that would 
necessitate treatment  
7. 
Symptomatic cholelithiasis, and/or choledocholithiasis 
8. 
Intentionally left blank 
9. 
Patient with history of hypoglycemia unawareness (who have 
had > 3 severe episodes in the past 6 months) or documented 
reactive hypoglycemia 
10. Screening laboratory results as follows, or any other CS 
abnormalities in Screening laboratory values that would render a 
patient unsuitable for inclusion (abnormalities may be retested 
for eligibility purposes) 
a. UPCR ≥ 500 mg/g.  In the event of urine protein/creatinine 
ratio (UPCR) above this threshold eligibility may be 
confirmed by a quantitative total urine protein measurement 
of < 1000 mg/24 hr 
b. Positive test (including trace) for blood on urinalysis.  In the 
event of a positive test eligibility may be confirmed with urine 
microscopy showing ≤ 5 red blood cells per high power field  
c. alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) > 1.5 × ULN; alkaline phosphatase (ALP) > 3 × ULN; 
Total bilirubin ≥ 1.5 × ULN.  Patients with Gilbert’s 
syndrome may have total bilirubin ≥ 1.5 × ULN if only the 
indirect bilirubin is elevated > ULN and the ALT/AST is not 
greater than the ULN. 
d. eGFR < 45 mL/min/1.73 m2 as determined by the Chronic 
Kidney Disease-Epidemiological Collaboration (CKD-EPI) 
equation for creatinine clearance OR serum creatinine 
> 1.8 mg/dL in males and > 1.5 mg/dL in females 
e. Platelet count < 125,000 mm3 
f. Abnormal thyroid function tests must be discussed with the 
Sponsor Medical Monitor or Designee 
g. HbA1c > 10% 
h. Abnormal morning cortisol test demonstrating symptomatic 
adrenal insufficiency based on investigator judgement   
11. Active infection requiring systemic antiviral or antimicrobial 
therapy that will not be completed prior to Study Day 1 
12. Unwillingness to comply with study procedures, including 
follow-up, as specified by this protocol, or unwillingness to 
cooperate fully with the Investigator 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
15 
PROTOCOL SYNOPSIS CONTINUED 
Study Population Continued 
Exclusion Criteria Continued 
13. Active infection with human immunodeficiency virus (HIV), 
hepatitis C (HCV) or hepatitis B (HBV) diagnosed by initial 
serology testing and confirmed with RNA testing, or prior 
treatment for HCV.  Patients at Screening who test positive by 
serology, but negative by RNA may be allowed in consultation 
with the Sponsor Medical Monitor or Designee 
14. Malignancy within 5 years, except for basal or squamous cell 
carcinoma of the skin, carcinoma in situ of the cervix, follicular 
Stage 1 or papillary thyroid cancer that has been successfully 
treated; patients that have been treated with curative intent and 
which have no recurrence within 5 years may also be eligible if 
approved by the Sponsor Medical Monitor or Designee 
15. Treatment with another investigational drug, biological agent, or 
device within 1 month of Screening, or 5 half-lives of 
investigational agent, whichever is longer 
16. Treatment with any non-ION- or ISIS-oligonucleotide (including 
small interfering ribonucleic acid [siRNA]) at any time or prior 
treatment with an ION- or ISIS-oligonucleotide within 9 months 
of Screening.  Patients that have previously received only a 
single-dose of an ION- or ISIS-oligonucleotide as part of a 
clinical study may be included as long as duration ≥ 4 months 
has elapsed since dosing.  This exclusion does not apply to 
vaccines (neither mRNA nor viral vector vaccines) 
17. History of bleeding diathesis or coagulopathy 
18. Recent history of, or current drug or alcohol abuse that could 
affect study compliance per Investigator judgment 
19. Patients may not have chronic systemic use of weight loss 
medications (except GLP-1 agonist or SGLT2 inhibitors) or 
participate in weight loss programs within 2 months before 
Screening.  Patients taking GLP-1 agonist or SGLT2 inhibitors 
indicated for weight loss maybe allowed with prior consultation 
with the Sponsor Medical Monitor or Designee 
20. Patients on anti-diabetes medications must be on a stable dose 
and regimen for ≥ 3 months prior to Screening.  Patients taking 
insulin can be allowed with prior consultation with the Sponsor 
Medical Monitor or Designee 
21. Patients on estrogen containing medications must be on a stable 
dose and regimen for ≥ 3 months prior to Screening 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
16 
PROTCOL SYNOPSIS CONTINUED 
Study Population Continued 
Exclusion Criteria Continued 
22. Patients on glucocorticoid replacement used for adrenal 
insufficiency must be on a stable dose and regimen (increases 
used to prevent adrenal crisis is permitted) for ≥ 3 months prior 
to Screening  
23. Use of oral anticoagulants, unless the dose has been stable for 
4 weeks prior to the first dose of ISIS 766720 and regular clinical 
monitoring is performed during the trial 
24. Blood donation of 50 to 499 mL within 30 days of Screening or 
of > 499 mL within 60 days of Screening and during the trial 
25. Have any other conditions, which, in the opinion of the 
Investigator and Sponsor would make the patient unsuitable for 
inclusion, or could interfere with the patient participating in or 
completing the Study 
All ISIS 766720 injections will be SC administered in the clinic 
during the first 17 weeks of the Treatment Period.  Home health is an 
option at select visits.   
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
17 
PROTCOL SYNOPSIS CONTINUED 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
18 
PROTCOL SYNOPSIS CONTINUED 
Study Visit Schedule and 
Procedures 
Detailed information regarding the study procedures is outlined in 
Section 6 of protocol. 
The study for an individual patient will generally consist of the 
following periods: 
• 
A ≤ 6-week Screening Assessment Period 
• 
A 73-week Treatment Period: ISIS 766720 will be administered 
as a once monthly SC injection (except during Month 1 where a 
booster dose is administered on Day 15).  The primary endpoint 
will be evaluated at 6 months (Week 27) 
• 
A 14-week Post-Treatment Evaluation Period  
Laboratory and other study procedures will be performed to assess 
eligibility during the Screening Periods.   
In the Treatment Period patients will be randomized to a treatment 
group.   
Safety and tolerability will be assessed biweekly in the first 17 weeks 
and monthly after Week 17.  A primary endpoint visit will occur at 
Week 27 (6 months).  Efficacy, exploratory endpoints and plasma PK 
assessments will be conducted periodically during the Treatment 
Period.  During the Post-Treatment Period, safety, exploratory and 
PK will be assessed for 14 weeks.  The 2-hour OGTT and GH 
response assessments will be performed (3×) during the study (see 
Section 6.2.2 for details).  An MRI (3×) and Echocardiogram (2×) 
will be done.  See Appendix A. 
Assessment of acromegaly clinical symptoms, patient reported 
outcome, and ring size measurement will be monitored during the 
Treatment Period and the Post-Treatment Period. 
All safety data including adverse events (AEs) and concomitant 
medications will be reviewed by the Sponsor’s Medical Monitor or 
Designee on an ongoing basis throughout the trial. 
Dose adjustments may be allowed after 17 weeks of treatment and 
only after consultation with Sponsor Medical Monitor (or Designee).   
If initiation of other acromegaly medication(s) is clinically indicated, 
according to the Investigator judgement, the patient will discontinue 
ISIS 766720 and enter the Post-Treatment Period.  In order to allow 
the drug to reach therapeutic steady-state concentrations, it is 
recommended to wait until after Week 17 before initiating other 
acromegaly medications. 
All patients will complete the 14-week Post-Treatment Period after 
their last dose.   
Primary Endpoint 
The primary efficacy endpoint is the percent change in IGF-1 from 
Baseline to Week 27. 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
19 
PROTCOL SYNOPSIS CONTINUED 
Secondary Endpoints 
The secondary efficacy endpoints include: 
• 
Patients who achieve normalized IGF-1 levels to within 
1.2 times gender and age limits at Day 183 (Week 27) 
• 
Patients who achieve normalized IGF-1 levels to within 
1.0 times gender and age limits at Day 183 (Week 27) 
• 
Change from Baseline in serum IGF-1 over time 
• 
Percent change from Baseline in serum IGF-1 over time 
Safety Endpoints 
The safety endpoints include incidence and severity of 
treatment-emergent adverse events (TEAE), use of concomitant 
medications, results of laboratory assessments, electrocardiogram 
(ECG), and vital signs. 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
20 
PROTCOL SYNOPSIS CONTINUED 
Statistical Considerations 
An interim analysis may be conducted when approximately 50% of 
patients complete the primary efficacy assessment. 
Sponsor 
Ionis Pharmaceuticals 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
22 
STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
AcroQoL 
Acromegaly Quality of Life Questionnaire 
AE 
adverse event(s) 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ALS 
acid labile subunit 
aPTT 
activated partial thromboplastin time 
ASGPR 
asialoglycoprotein receptor 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase (SGOT) 
ASTS-M 
Acromegaly Symptom and Treatment Score 
Questionnaire-Monotherapy 
AUCt 
area under the plasma concentration-time curve from time zero 
to time t 
βhCG 
beta-subunit of human chorionic gonadotropin (pregnancy test) 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CKD-EPI 
Chronic Kidney Disease-Epidemiological Collaboration  
Cmax  
maximum concentration 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRNMB 
clinically relevant non-major bleeding  
CRP 
C-reactive protein 
CS 
clinically significant 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
dL 
Deciliter 
EBV 
Epstein-Barr Virus 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ECHO 
echocardiogram 
EQ5D 
Euro QOL 
ETTX 
early termination from treatment 
ETPT 
early termination from post-treatment 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
GHBP 
growth hormone binding protein 
GH 
growth hormone 
GHR 
growth hormone receptor  
GHR-LRx 
ISIS 766720 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
23 
HbA1c 
glycated hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
hs-CRP 
CRP measured by high sensitivity assay 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IGF-1 
insulin-like growth factor-1 
IGFBP3 
insulin-like growth factor binding protein 3 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISIS 766720 
antisense inhibitor of GHR 
MB 
major bleeding 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically significant 
NOAEL 
no-observed-adverse-effect-level 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
on study 
The patient is ‘on study’ from signing of the informed consent 
until their last study visit 
OGTT 
oral glucose tolerance test 
PD 
pharmacodynamic(s) 
PE 
physical examination 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PPS 
per protocol set 
PT 
prothrombin time 
PTWk5 
Post-Treatment Week 5 
QoL 
quality of life 
RNA 
ribonucleic acid 
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the 
RNA strand in RNA/DNA hybrids 
SAE 
serious adverse event 
SF36 
36-item Short Form Survey  
siRNA 
small interfering ribonucleic acid 
SC 
subcutaneous(ly) 
Study Day 1 
defined as the first day ISIS 766720 product is administered to 
the patient 
Study Drug 
ISIS 766720 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
24 
SRL 
somatostatin receptor ligands 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximal concentration 
ULN 
upper limit of normal 
UPCR 
urine protein/creatinine ratio 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
25 
1. 
OBJECTIVES AND ENDPOINTS 
1.1. 
Objectives 
1.1.1. 
Primary Objectives 
To evaluate the safety and tolerability of ISIS 766720 subcutaneous (SC) injection as a 
monotherapy in patients with acromegaly.   
To evaluate the efficacy of ISIS 766720 SC injection on serum insulin-like growth factor-1 
(IGF-1) as a monotherapy in patients with acromegaly.   
1.1.2. 
Secondary Objective 
To evaluate the effect of ISIS 766720 SC to normalize serum IGF-1 levels. 
1.2. 
Study Endpoints 
1.2.1. 
Primary Endpoint 
The primary efficacy endpoint is the percent change in IGF-1 from Baseline to Week 27. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
26 
1.2.2. 
Secondary Endpoints 
The secondary efficacy endpoints include: 
• Patients who achieve normalized IGF-1 levels to within 1.2 times gender and age 
limits at Day 183 (Week 27) 
• Patients who achieve normalized IGF-1 levels to within 1.0 times gender and age 
limits at Day 183 (Week 27) 
• Change from Baseline in serum IGF-1 over time 
• Percent change from Baseline in serum IGF-1 over time 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
27 
2. 
BACKGROUND AND RATIONALE 
2.1. 
Overview of Disease 
Acromegaly is a chronic disorder caused by GH hypersecretion, most commonly secondary to a 
GH secreting pituitary adenoma (Katznelson et al. 2014).  Growth hormone circulates and 
through binding and activation of growth hormone receptor (GHR), it stimulates production of 
IGF-1.  Circulating IGF-1 is mostly made in the liver (Liu et al. 2000); IGF-1 in large part 
mediates the somatic and metabolic effects of GH.  Hypersecretion of GH leads to excess 
production of IGF-1 (Katznelson et al. 2014).  High levels of circulating GH and IGF-1, lead to 
multisystem diseases due to somatic overgrowth and metabolic dysregulation, causing multiple 
comorbidities (e.g., type 2 diabetes, cardiomyopathy, and respiratory complications), premature 
mortality, physical disfigurement (e.g., enlarged facial features, hands, and feet, and painful 
arthritis), and decreased quality of life (QoL) (Melmed 2006; Giustina et al. 2020).  Growth 
hormone hypersecretion worsens insulin resistance, producing impaired glucose tolerance and 
diabetes mellitus in 15-38% of patients (Katznelson et al. 2014).  The incidence of acromegaly is 
approximately 3 cases per 1 million persons per year, and the prevalence is about 60 per million 
(Melmed 2006).  The therapeutic goal for acromegaly includes normalization of biochemical 
variables (GH and IGF-1), reversal of mass effects of the tumor, improvement in signs, 
symptoms and comorbidities of the disease and minimization of long-term mortality risk.  
Treatment goals include assessment and management of the comorbidities, such as aggressive 
control of lipid abnormalities and type 2 diabetes (Katznelson et al. 2011; Katznelson et al. 
2014). 
Surgical removal of the pituitary tumor is the primary treatment for GH secreting adenoma.  
However, if the biochemical and clinical evaluation after surgery reveals persistent disease, or if 
surgery is not an option for the patient, then medical therapy is necessary.  Current medical 
treatments include dopamine agonists, somatostatin receptor ligands (SRLs), and GHR 
antagonist (pegvisomant, or Somavert).  According to societal guideline for acromegaly, 
(Katznelson et al. 2014), Somavert is recommended as a potential first line medication prior to 
combination therapy to treat persistent disease with or without surgery.  In Phase 4 post-market 
observational studies, Somavert can normalize ~63% of the patients not previously controlled, 
however with the side effects of increased transaminases, and low incidence of adenoma growth 
(van der Lely et al. 2012; Tritos et al. 2017).  In a retrospective analysis, Somavert monotherapy, 
administered either as primary medical therapy or as adjunctive therapy according to local 
practice, led to IGF-1 normalization in > 75% of patients (Tritos et al. 2017).  As currently 
available medications are limited by incomplete efficacy and side effects that can include 
hyperglycemia, gastrointestinal upset, gallbladder disease, injection site reaction, or liver enzyme 
elevations, more safe and effective medical therapies are still needed. 
2.2. 
Therapeutic Rationale 
Since acromegaly is due to excessive GH and IGF-1 action, the goal is to suppress this pathway.  
As a matter of fact, normalization of circulating IGF-1 is a surrogate endpoint for the treatment 
of acromegaly.  Inhibition of GH signaling results in suppression of IGF-1 secretion (Rowland et 
al. 2005).  This can be achieved by suppressing the action of GHR.  Clinical evidence that this 
mechanism lowers IGF-1 levels comes from studies conducted with Somavert (pegvisomant) and 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
28 
ATL1103.  Somavert is a human GHR antagonist that competes with endogenous GH for 
binding to its receptor and blocks production of IGF-1, and can normalize IGF-1 in ~63% of 
patients.  However, Somavert dosing regimen is inconvenient for patients as it requires daily 
administration by SC injection and it may also cause elevations in circulating GH levels and in 
liver transaminases (Melmed 2006).  Additionally, clinical evidence of a reduction in IGF-1 
levels by GH inhibition is supported by studies conducted with the antisense drug ATL1103 (an 
antisense inhibitor of GHR) in which ATL1103, by reducing GHR, reduced serum IGF-1 levels 
by 26% after 13 weeks of dosing (Trainer et al. 2018). 
 
 
In addition, since mature GHR is cleaved to produce the 
circulating GHBP which binds to circulating GH and prolongs its half-life (Fisker 2006), 
The known potential risks to study participants associated with ISIS 766720 are described in the 
Guidance to the Investigator section of the ISIS 766720 Investigator’s Brochure. 
2.3. 
ISIS 766720 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
29 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
30 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
31 
2.3.4. 
Clinical Experience 
Detailed information concerning the clinical studies conducted with ISIS 766720 can be found in 
the Investigator’s Brochure.  A summary is included below. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
32 
2.5. 
Benefit-Risk Assessment 
Detailed information concerning the benefit-risk assessment of ISIS 766720 can be found in the 
Investigator’s Brochure.   
2.5.1. 
Benefit Assessment 
The benefits of ISIS 766720 are unknown at this time. 

33 
3. 
EXPERIMENTAL PLAN 
3.1. 
Study Design 
This will be a Phase 2, randomized, open label multi-center study. 
3.2. 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3. 
Number of Patients 
Approximately 40 patients are planned to be randomized in the study.  Thirty-six (36) patients 
(12 in each treatment group) in the per protocol set (PPS) are needed to complete the Treatment 
Period and the primary efficacy endpoint.  
 
   

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
34 
3.4. 
Overall Study Duration and Follow-up 
The study for an individual patient will generally consist of the following periods: 
• A ≤ 6-week Screening Assessment Period 
• A 73-week Treatment Period:  ISIS 766720 will be administered as a once-monthly 
SC injection (except during Month 1 where a booster dose is administered on 
Day 15).  The primary endpoint will be evaluated at 6 months (Week 27) 
• A 14-week Post-Treatment Evaluation Period  
Patients may be required to attend additional visits for monitoring of AEs or abnormal 
investigation results.  The frequency of additional monitoring will be determined by the Sponsor 
Medical Monitor or Designee in consultation with the Investigator. 
3.4.1. 
Screening 
Patient eligibility for the study will be determined within 42 days prior to study entry.  Sponsor 
Medical Monitor or Designee review is required for patients to enter the Treatment Period. 
3.4.2. 
Treatment 
Eligible patients will report to the Study Center for ISIS 766720 administration per Schedule of 
Procedures in Appendix A.  ISIS 766720 will be dosed monthly (in addition, a booster dose of 
ISIS 766720 is administered on Day 15).  Please refer to Section 6.1.2 and Appendix A for 
detailed instructions regarding treatment requirements.   
3.4.3. 
Post-Treatment 
Patients are to return to the Study Center for follow-up visits for 14 weeks after last injection of 
ISIS 766720 per Schedule of Procedures in Appendix A.  Any patient who receives at least 
1 dose of ISIS 766720 will be required to complete the Post-Treatment Period.  The final study 
visit will be 14 weeks after the last injection (PTWk15).   
4. 
PATIENT ENROLLMENT 
4.1. 
Screening 
Before patients may be enrolled into the study, the Sponsor or Designee requires a copy of the 
Study Center’s written independent ethics committee/institutional review board (IEC/IRB) 
approval of the protocol, informed consent form (ICF), and all other patient information and/or 
recruitment material. 
Patients or their legally acceptable representatives must sign the consent form before any 
screening tests or assessments are performed.  At the time of consent, the patient will be 
considered enrolled into the study and will be assigned a unique screening number before any 
study procedures, including Screening procedures, are performed.  At the time of randomization, 
patients will be assigned a unique patient identification number.  This number will be used to 
identify the patient throughout the trial and must be used on all study documentation related to 
that patient.  The screening number and patient identification number must remain constant 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
35 
throughout the entire trial.  In the event the patient is re-consented and re-screened the patient 
must be given a new screening number.  Screening numbers and patient identification numbers, 
once assigned, will not be re-used. 
4.2. 
Randomization 
Patients will be randomized after all Screening assessments have been completed, after the 
Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2, and after 
review by the Sponsor Medical Monitor or Designee.  No patient may begin treatment prior to 
randomization and assignment of a unique patient identification number. 
4.3. 
Replacement of Patients 
Patients who withdraw from the study will not be replaced. 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria at 
the time point specified in the individual eligibility criterion listed. 
5.1. 
Inclusion Criteria 
1. Must have given written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements 
2. Males or females with a documented diagnosis of Acromegaly* who are 18 to 75 years 
old (inclusive) at the time of informed consent 
* Defined as a previous diagnosis of GH-secreting adenoma by surgical pathology; or the 
presence of a pituitary adenoma identified on magnetic resonance imaging (MRI) or 
computed tomography (CT) Scan (if MRI is contraindicated) and serum IGF-1 levels 
above the upper limit of normal (ULN) for age and sex at time of diagnosis (serum 
IGF-1 level and imaging at diagnosis will be collected in the case report forms [CRF]). 
3. Have had pituitary surgery (e.g. transsphenoidal) unless there was a contraindication to 
surgery and are either acromegaly medical treatment naïve, or who had not taken any 
other acromegaly medications prior to the screening visit as outlined below:  
bromocriptine:  2 weeks  
cabergoline:  4 weeks  
quinagolide:  4 weeks  
octreotide daily injection (SC) or oral formulation:  4 weeks  
pegvisomant:  4 weeks  

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
36 
octreotide LAR:  3 months  
pasireotide LAR:  4 months  
lanreotide (all formulations):  3 months 
4. At Screening, serum IGF-1 (performed at central lab) between 1.3 to 5 × ULN, inclusive, 
adjusted for age and sex.  IGF-1 can be repeated once and averaged to determine 
eligibility if the initial result is between 1.1–1.3 × ULN, or between 5–5.3 × ULN  
5. Females must be non-pregnant and non-lactating, and either: 
a. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy)  
b. post-menopausal (defined as 12 months of spontaneous amenorrhea in females 
> 55 years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea 
without an alternative medical cause and follicle-stimulating hormone (FSH) levels in 
the postmenopausal range for the laboratory involved) 
c. abstinent (defined in Section 6.3.1) or  
d. Women of childbearing potential (WOCBP) should agree to taking all precaution to 
avoid pregnancy during the Trial Period (including Post-Treatment), including 
agreeing to receive pregnancy testing before each monthly dose, using 1 highly 
effective method of birth control (Section 6.3.1) from the time of signing the (ICF) 
until 14 weeks after the last dose of ISIS 766720 administration  
Males must be either: 
e. surgically sterile 
f. abstinent (defined in Section 6.3.1) or 
g. if engaged in sexual relations with a female of child-bearing potential, the patient 
must be using a highly effective contraceptive method (refer to Section 6.3.1) from 
the time of signing the ICF until 14 weeks after the last dose of ISIS 766720 
6. Willing to refrain from strenuous exercise/activity (for example heavy lifting, weight 
training, intense aerobics classes etc.) for at least 24 hours prior to study visits 
7. Willing to refrain from alcohol or tobacco use for 8 hours prior to study visits 
5.2. 
Exclusion Criteria 
1. Clinically significant (CS) abnormalities in medical history according to Investigator 
judgement (e.g., previous acute coronary syndrome within 6 months of Screening, major 
non-pituitary surgery within 2 months of Screening) or from Screening physical 
examination (PE) 
2. Patients who received surgery for pituitary adenoma within the last 3 months before the 
trial, and/or planning to receive surgery during the trial 
3. Patients who received radiotherapy for pituitary adenoma within the last 2 years before 
the trial, and/or planning to receive radiotherapy during the trial 
4. Patients with a pituitary tumor that, per Investigator judgment, is worsening (e.g., either 
growing, or at risk of compressing or abutting the optic chiasm or other vital structures) 
as assessed by pituitary/sellar MRI protocol at Screening or within 3 months of 
Screening.  CT scan is allowed if MRI is contraindicated 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
37 
5. Evidence of decompensated cardiac function per medical judgement and/or New York 
Heart Association (NYHA) Class 3 or 4 
6. Clinical evidence of symptomatic hyperprolactinemia that would necessitate treatment  
7. Symptomatic cholelithiasis, and/or choledocholithiasis 
8. Intentionally left blank  
9. Patients with history of hypoglycemia unawareness (who have had > 3 severe episodes in 
the past 6 months) or documented reactive hypoglycemia 
10. Screening laboratory results as follows, or any other CS abnormalities in Screening 
laboratory values that would render a patient unsuitable for inclusion (abnormalities may 
be retested for eligibility purposes) 
a. UPCR ≥ 500 mg/g.  In the event of urine protein/creatinine ratio (UPCR) above this 
threshold eligibility may be confirmed by a quantitative total urine protein 
measurement of < 1000 mg/24 hr 
b. Positive test (including trace) for blood on urinalysis.  In the event of a positive test 
eligibility may be confirmed with urine microscopy showing ≤ 5 red blood cells per 
high power field  
c. alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 × ULN; 
alkaline phosphatase (ALP) > 3 × ULN; Total bilirubin ≥ 1.5 × ULN.  Patients with 
Gilbert’s syndrome may have total bilirubin ≥ 1.5 × ULN if only the indirect bilirubin 
is elevated > ULN and the ALT/AST is not greater than the ULN. 
d. eGFR < 45 mL/min/1.73 m2 as determined by the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) equation for creatinine clearance OR 
serum creatinine > 1.8 mg/dL in males and > 1.5 mg/dL in females 
e. Platelet count < 125,000 mm3 
f. Abnormal thyroid function tests must be discussed with the Sponsor Medical Monitor 
or Designee 
g. HbA1c > 10% 
h. Abnormal morning cortisol test demonstrating symptomatic adrenal insufficiency 
based on Investigator judgement   
11. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
12. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
13. Active infection with human immunodeficiency virus (HIV), hepatitis C (HCV) or 
hepatitis B (HBV) diagnosed by initial serology testing and confirmed with RNA testing, 
or prior treatment for HCV.  Patients at Screening who test positive by serology, but 
negative by RNA may be allowed in consultation with the Sponsor Medical Monitor or 
Designee 
14. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin, 
carcinoma in situ of the cervix, follicular Stage 1 or papillary thyroid cancer that has been 
successfully treated; patients that have been treated with curative intent and which have 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
38 
no recurrence within 5 years may also be eligible if approved by the Sponsor Medical 
Monitor or Designee 
15. Treatment with another investigational drug, biological agent, or device within 1 month 
of Screening, or 5 half-lives of investigational agent, whichever is longer 
16. Treatment with any non-ION- or ISIS-oligonucleotide (including small interfering 
ribonucleic acid [siRNA]) at any time or prior treatment with an ION- or 
ISIS-oligonucleotide within 9 months of Screening.  Patients that have previously 
received only a single-dose of an ION- or ISIS-oligonucleotide as part of a clinical study 
may be included as long as duration ≥ 4 months has elapsed since dosing. This exclusion 
does not apply to vaccines (neither mRNA nor viral vector vaccines) 
17. History of bleeding diathesis or coagulopathy 
18. Recent history of, or current drug or alcohol abuse that could affect study compliance per 
Investigator judgment 
19. Patients may not have chronic systemic use of weight loss medications (except GLP-1 
agonist or SGLT2 inhibitors) or participate in weight loss programs within 2 months 
before Screening.  Patients taking GLP-1 agonist or SGLT2 inhibitors indicated for 
weight loss may be allowed with prior consultation with the Sponsor Medical Monitor or 
Designee 
20. Patients on anti-diabetes medications must be on a stable dose and regimen for 
≥ 3 months prior to Screening.  Patients taking insulin can be allowed with prior 
consultation with the Sponsor Medical Monitor or Designee 
21. Patients on estrogen containing medications must be on a stable dose and regimen for 
≥ 3 months prior to Screening  
22. Patients on glucocorticoid replacement used for adrenal insufficiency must be on a stable 
dose and regimen (increases used to prevent adrenal crisis is permitted) for ≥ 3 months 
prior to Screening  
23. Use of oral anticoagulants, unless the dose has been stable for 4 weeks prior to the first 
dose of ISIS 766720 and regular clinical monitoring is performed during the trial 
24. Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL within 
60 days of Screening and during the trial 
25. Have any other conditions, which, in the opinion of the Investigator and Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the patient participating 
in or completing the Study 
6. 
STUDY PROCEDURES 
6.1. 
Study Schedule 
All required study procedures are outlined in Appendix A, Appendix B, and Appendix C. 
6.1.1. 
Screening 
Written informed consent for the study will be obtained prior to the performance of any 
study-related procedures including screening procedures.  Race and ethnicity data will be 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
39 
collected as part of the demographic information for all screened patients during the Screening 
Period.  Up to a 6-week Screening Period is provided for completing screening assessments and 
determining patient eligibility for the study. 
During the 6 weeks, site will need to gather disease history relating to acromegaly and pituitary 
adenoma, and the results of the most recent MRI.  MRI of the sellar will need to be performed 
before randomization if there is no prior MRI within the last 3 months prior to Screening.  If the 
MRI is contraindicated, then a CT Scan may be performed.  In addition, an echocardiogram will 
be conducted, if there is no prior echocardiogram within the last 3 months prior to Screening. 
Individuals may be disqualified if the result of any laboratory test is outside the range specified 
in the eligibility criteria (Section 5.1 and 5.2) or, if no range is specified, is abnormal and CS as 
judged by the Investigator or the Sponsor Medical Monitor or Designee.  During the Screening 
Period, screening results may be retested (Home Health Care Visit Option can be used) for 
assessment after discussion with the Sponsor Medical Monitor or Designee for eligibility 
purposes.   
IGF-1 can be repeated once and averaged to determine eligibility if the initial result is between 
1.1–1.3 × ULN, or between 5–5.3 × ULN. 
Sponsor Medical Monitor or Designee review of eligibility is required for patients to enter the 
Treatment Period.  Qualified patients will be randomized and proceed to the Treatment Period 
Week 1, Day 1 Assessments. 
Screen failed patients may be re-screened 1 more time after the Investigator feels the reason for 
screen failure has resolved. 
6.1.2. 
Treatment Period 
During the 1.5-year study, each patient will receive up to 20 SC doses of ISIS 766720 with a 
planned monthly interval between each dose except for a booster dose at Day 15 (WK 3).  All 
patients will have bi-weekly visits beginning at Day 1 (WK 1) through Day 113 (WK 17).  After 
that visits occur monthly through Day 505 (WK 73) with an additional visit on Day 183 (WK 27) 
for primary endpoint assessments.  Of the 24 required study visits, 14 selected study visits may 
be performed outside of the clinic by a Sponsor selected Home Health Care professional 
(See Appendix A).  Home health visits are optional and would be arranged by study center staff 
if requested by the patient.  In consultation with the Sponsor, a Home Health Care visit may be 
conducted for a study visit day that was intended to be an in-clinic visit.  It is preferable that the 
entire visit is conducted, however the following assessments may be omitted:  ECG, body 
weight, physical exam, ring size, and OGTT.  If a visit cannot be performed in the clinic or by 
Home Health, patient contact (e.g., phone, text, email or video) is required by site personnel to 
assess any adverse events or changes in concomitant medications.  Any assessments not 
completed at the Home Health Care visit should be attempted at the next clinic visit. 
Safety, efficacy, PK and exploratory assessments will be performed per Appendix A, 
Appendix B, and Appendix C throughout the Treatment Period on ISIS 766720 administration 
days.  At each visit, patients should arrive fasting at least 8 hours for safety and clinical 
laboratory evaluations; vital signs, blood pressure (BP) assessments, AEs and concomitant 
medication usage will be assessed during each visit.   

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
40 
A 2-hour OGTT and GH response procedure will be conducted pre-dose on Day 1 and pre-dose 
on Day 183 (WK 27) and Day 505 (WK 73).  The pre-dose-Day 1 OGTT and GH response 
procedure may be conducted between Day -41 and pre-dose Day 1.  To decrease the study 
burden on potential patients, it is suggested that this procedure is done after the patient has 
completed and qualified based on all other screening procedures.  The OGTT and GH Response 
procedure can be conducted in the clinic or as arranged by a Home Health Care professional.  
The patient must fast 10-hours prior to OGTT and GH Response assessment.   
Quality of life assessments and general health assessments including ASTS-M, AcroQOL, 
EQ5-D, and SF-36 questionnaires will be assessed along with ring size assessment periodically 
throughout the study.  See Section 6.2.3 for a description of the study procedures.  Study 
required procedures at study visits are listed in the Schedule of Procedures in Appendix A, 
Appendix B, and Appendix C.  Patient will be requested to complete AcroQoL, ASTS-M, 
EQ5-D, and SF-36 and ring size assessments prior to all other procedures and dosing 
(see Section 6.2).   
All blood samples should be drawn prior to ISIS 766720 administration (exceptions are the 
post-dose samples for PK sampling at Day 1 and Day 113).   
An MRI (3×) and Echocardiogram (2×) will be done.  See Appendix A for timing of procedure. 
During each visit, the study staff should attempt to complete all the study procedures prior to 
ISIS 766720 administration as outlined in the Appendix A, however, if a procedure is conducted 
after ISIS 766720 administration it will be considered a deviation that does not impact the 
evaluation of efficacy. 
All safety data including AEs and concomitant medications will be reviewed by the Sponsor’s 
Medical Monitor or Designee on an ongoing basis throughout the trial.  Early termination 
patients from the Treatment Period will be requested to enter the 14-week Post-Treatment 
Period.  The first visit to complete is an “early termination from treatment” visit entitled ETTX.  
The ETTX visit should be completed as soon as possible after the decision is made, preferably 
4 weeks after the last dose.  The remainder of the Post-Treatment visits should then follow the 
schedule which are in intervals relative to the patients last dose (Appendix A).  All patients 
receiving at least 1 dose of study medication are required to enter the Post-Treatment Period for 
continuing safety evaluations.  Please contact your CRA at the time of early termination to 
review the schedule. 
6.1.3. 
Post-Treatment Period 
After completing the 73 weeks of the Treatment Period, including patients who discontinue early 
from the Treatment Period, patients will return for Post-Treatment follow-up evaluations 
(Appendix A).  All patients will be followed for 14 weeks, the last visit is Post-Treatment 
Week 15 (PTWk15) occurring 99 days after the last dose.  Note:  the visits are scheduled in 
intervals relative to the patient’s last dose, for example Post-Treatment Week 5 (PTWk5) is 
28 days after the last dose.   
Safety and clinical laboratory evaluations as well as PD markers, including those for PK/PD 
analysis, will be performed as indicated in the Appendix A, Appendix B, and Appendix C.  
Safety and efficacy data, including any AEs and concomitant medications will be recorded and 
reviewed by the Sponsor’s Medical Monitor or Designee.   

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
41 
The AcroQoL, ASTS-M, EQ5-D, and SF-36 and ring size assessment will be conducted 
periodically in the Post-Treatment Period.  
Early termination patients from the Post-Treatment Period (ETPT) will be required to complete 
the ETPT Study procedures (Appendix A).   
6.2. 
Study/Laboratory Assessments  
6.2.1. 
Clinical Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B.  Blood chemistry should be taken after fasting for at least 8 hours 
(at least 10 hours for OGTT).  During this time the patient should ensure that they consume 
sufficient water in order to not become dehydrated. 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to 
clumping, hemolysis or quantity not sufficient) or missing, a repeat blood specimen should be 
re-drawn as soon as possible (ideally within 7 days) either in clinic or by home health or local 
laboratory.  The next dose of ISIS 766720 may not be administered until a result not meeting a 
stopping rule is available.  See Section 8.5 for more guidance.  Platelet results must meet the 
timeframe requirements in Section 8.5.2. 
At any time, the Sponsor Medical Monitor or designee may request both a local and central 
laboratory collection in parallel to assess patient safety.  
6.2.2. 
Oral Glucose Tolerance Test and Growth Hormone Response during OGTT 
Patients will undergo OGTT and GH response procedures during the study per Appendix A.  For 
each OGTT procedure, patients should be fasting for 10 hours before the test (only water is 
permitted).  It is preferable to collect blood samples for OGTT through indwelling catheter, but it 
is not mandatory.  (See Appendix A and Table 1).  After an indwelling catheter (if used) is 
inserted at T-5 minutes, a 5-minute period is allowed to remove any effects linked to the stress 
induced by venipuncture.  Blood sampling will begin before the glucose solution is consumed at 
Time 0.  The glucose anhydrous solution (75 grams in a 300-mL solution) will be consumed 
within a 5-minute period, after which blood samples will be drawn during the test every 
30 minutes from the start time of glucose ingestion during the 2 hours of the OGTT as outlined 
in Table 1.  Patients may drink water during the OGTT but must refrain from eating or drinking 
any other fluids except water and must refrain from smoking until the fasting period is completed 
(after the 120-minute blood draw).  During the Treatment Period, the OGTT should be 
completed before ISIS 766720 is administered.   

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
42 
Table 1: 
Sampling Schedule:  Day of Oral Glucose Tolerance Test and GH Response 
During OGTT 
Intervention 
Time (Minutes) 
OGTT and GH Response Sampling 
 
-5 
Catheter Insertion (if used)  
T0 = 75 grams 
Glucose Ingestion 
0 
Prior to Glucose ingestion 
Glucose, Insulin, C-peptide, Growth Hormone 
30  
Glucose, Insulin, C-peptide, Growth Hormone 
60 
Glucose, Insulin, C-peptide, Growth Hormone 
90 
Glucose, Insulin, C-peptide, Growth Hormone 
120# 
Glucose, Insulin, C-peptide, Growth Hormone 
# After the 120-min blood draw, the fasting period is completed 
 
6.2.3. 
Assessments for Acromegaly 
There are up to 5 procedures that will be conducted that assess signs, symptoms and QoL for an 
acromegaly patient.  For purposes of this clinical trial and consistency across visits, it is 
requested that these assessments for acromegaly be: 
1. Conducted at the beginning of the study visit (prior to other study procedures and drug 
administration) 
2. Conducted sequentially in this order:  1) AcroQoL; 2) ASTS-M; 3) EQ-5D; 4) SF-36; 
5) Ring Size Assessment.  All QOL and health assessment questionnaires will be a paper 
assessment filled out by patients and the results are entered into eCRF by site staff 
3. It may take approximately 40 minutes to complete all 5 assessments 
Prior to filling out the QOL and health assessment questionnaires, the patient should sit quietly in 
a room without distraction, and be reminded of the following; i) the purpose of the 
questionnaires, ii) to complete the questionnaire honestly, and iii) they should be aware that there 
are no wrong answers, iv) it is important to answer all questions. 
Note:  the order of completion of assessments relative to ISIS 766720 administration is a 
recommended best practice but not a requirement, and therefore will not constitute a deviation if 
not strictly followed. 
6.2.3.1. 
Acromegaly Quality of Life Questionnaire  
To assess the health-related QoL affected by acromegaly, patients will complete the AcroQoL 
questionnaire during the Treatment and Post-Treatment Periods (per Appendix A).  AcroQoL is 
a 22-question survey to quantify the self-perceived impact of acromegaly in patients’ life.  
It contains 2 scales that evaluate physical (8 questions) and psychological aspects related to the 
appearance and personal relations (7 items each) (Webb et al. 2002).  This questionnaire will 
take about 10 minutes to be completed.   

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
43 
6.2.3.2. 
Acromegaly Symptoms and Treatment Score Questionnaire-Monotherapy  
Patients will be asked to complete the ASTS-M to monitor symptoms relating to acromegaly and 
its treatments.  Each question is answered on a scale of 0 to 4 from no symptom to very severe.  
The questions address acromegaly-specific symptoms (e.g., headache, perspiration, paresthesia) 
and treatments (burden of ISIS 766720).  This questionnaire will take about 5 minutes to 
complete.   
6.2.3.3. 
EQ-5D 
Patients will be asked to complete the EQ5D which is a standardized instrument for measuring 
health outcome.  It measures 5 health dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety depression.  It is used as a quantitative measure of health outcome 
that reflects the patient’s own judgement.  Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems and extreme problems.  The patient is asked to 
indicate his/her health state by ticking the box next to the most appropriate statement in each of 
the 5 dimensions.  This questionnaire will take about 10 minutes to complete. 
6.2.3.4. 
36-Item Short Form Survey  
Patients will be asked to complete the SF-36 which is a set of generic, coherent, and easily 
administered QoL measures.  It measures 8 health concepts: physical functioning, bodily pain, 
role limitations due to physical health problems, role limitations due to personal or emotional 
problems, emotional well-being, social functioning, energy/fatigue, and general health 
perceptions.  It also includes a single item that provides an indication of perceived change in 
health.  Each section has different instructions on how to answer the questions.  This 
questionnaire will take about 10 minutes to be completed.   
6.2.3.5. 
Ring Size Assessment 
Finger size is an objective measure of soft tissue swelling and overgrowth and can be used to 
monitor the response to treatment.  Measurement should be taken prior to any intravenous 
cannulation.  Ring size is assessed using the study provided ring sizer widget and the 4th finger of 
the non-dominant hand.  The ring size to record is the one with the tightest fit.  If the finger is too 
large to be measured by the ring sizer then use the 5th finger (and make a note of this).  The same 
finger will be used throughout the trial (Barts Endocrine 2009).  The ring size assessment should 
be completed by the same staff member at each visit if possible. 
6.2.4. 
MRI 
MRI of the sellar region will be conducted for all patients for whom MRI is not contraindicated, 
e.g., patients having metal implants.  If the MRI is contraindicated, then a CT scan may be 
performed.  See Appendix A for timing of procedure. 
6.2.5. 
Echocardiography 
Echocardiography for assessment of left and right ventricular function be conducted at times 
indicated in Appendix A.  For the purpose of assessment of treatment-emergent changes, all 
echocardiograms will be evaluated by an independent central reader. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
44 
6.3. 
Restriction on the Lifestyle of Patients 
6.3.1. 
Contraception Requirements 
All male patients and WOCBP must refrain from sperm/egg donation and practice highly 
effective contraception from the time of signing the ICF until 14 weeks after their last dose of 
study treatment.   
Male patients engaged in sexual relations with a female of child-bearing potential must use 
highly effective contraception from the time of signing the informed consent until 14 weeks after 
the patient’s last dose of study treatment.  If the patient’s s non-pregnant female partner is using 
a highly effective contraception method throughout the duration of the study, the requirement for 
contraception for the male patient is considered fulfilled.   
For the purposes of this study, WOCBP are defined as any female who has experienced 
menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age 
or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal range for the 
laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post hysterectomy 
For the purposes of the study, highly effective contraception is defined as follows: 
For male patients: 
• a vasectomy with negative semen analysis at Follow-up 
• sexual abstinence† 
• Male patients with partners that are pregnant must use condoms to ensure that the 
fetus is not exposed to the ISIS 766720 
For female patients of childbearing potential: 
• surgical sterilization (e.g., bilateral tubal occlusion), hormonal contraception 
associated with inhibition of ovulation (combined [estrogen and progestogen 
containing] or progestogen-only), intrauterine device (IUD), intrauterine 
hormone-release system (IUS), a vasectomized partner or sexual abstinence† 
† Note:  Abstinence is only acceptable as true abstinence, refraining from heterosexual 
intercourse throughout the duration of study participation.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence 
for the duration of a trial and withdrawal are not acceptable methods of contraception. 
 
Note:  A female condom and a male condom should not be used together as friction 
between the 2 can result in either or both products failing. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
47 
stopping rules based upon re-test may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified Designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  If any of the stopping criteria described 
in Section 8.6 are met, the patient will be permanently discontinued from further treatment with 
ISIS 766720, evaluated fully as outlined below and in consultation with the Sponsor Medical 
Monitor (or appropriately qualified Designee), and will be followed up in accordance with 
Section 8.8 of the Protocol.   
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 × ULN or the greater of 2 × baseline 
value or 3 × ULN if the baseline value was > ULN at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional, confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 × ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 × ULN or 
the greater of 2 × baseline value or 3 × ULN if the baseline value was > ULN should have their 
liver chemistry tests (ALT, AST, ALP, international normalized ratio [INR], and total bilirubin) 
retested at least once-weekly until ALT and AST levels become ≤ 1.5 × ULN or < 1.5 × baseline 
value if the baseline value was > ULN. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 × ULN or the greater of 2 × baseline value or 3 × ULN if the baseline value was 
> ULN, the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (hepatitis A virus [HAV] immunoglobulin M [IgM], hepatitis 
B surface antigen [HBsAg], HCV antibody, cytomegalovirus [CMV] IgM, and Epstein-
Barr Virus [EBV] antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor or Designee.  Repetition of the above evaluations should be considered 
if a patient’s ALT and/or AST levels reach 5 × ULN. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
48 
8.5.1.1. 
Dose Adjustment Guidelines for Liver Monitoring 
Patients with a confirmed ALT or AST ≥ 3 × ULN but ≤ 5 × ULN without an alternative 
explanation, with normal bilirubin levels, and who have not met other stopping rules, may have 
their ISIS 766720 adjusted downward in consultation with the Sponsor Medical Monitor or 
Designee. 
Dose adjustment will not be allowed for patients with confirmed elevations > 5 × ULN.  These 
patients will follow steps outlined in Section 8.6 Stopping Rules.   
8.5.2. 
Safety Monitoring Rules for Platelet Count Results 
An evaluable platelet count is required prior to each dose during the Treatment Period.  
Treatment should be held if there is no evaluable platelet count within the 2 weeks (+7 days) up 
to Week 17 and within 4 weeks (+7 days) after Week 17 prior to the scheduled dose.  Any 
unreportable platelet count result must be rechecked and determined not to have met a stopping 
rule before dosing can continue.  Central laboratory is preferred; however, a local laboratory may 
be utilized to ensure a platelet value is available prior to dosing. 
If a patient’s absolute platelet count is ≥ 75,000/mm3 to ≤ 100,000/mm3, then the patient’s 
platelet counts should be monitored weekly.  In case of platelet count below 75,000/mm3, the 
platelet monitoring rule defined in Stopping Rules (Section 8.6.3) should be followed. 
In the event of a platelet count < 75,000/mm3, additional laboratory investigations may be 
conducted in consultation with Sponsor Medical Monitor or Designee. 
8.5.3. 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding (MB) or 
clinically relevant, non-major bleeding events (which are defined in Section 8.6.3).  If a minor 
bleeding event occurs, additional testing of coagulation parameters (activated partial 
thromboplastin time [aPTT], prothrombin time [PT], INR) and platelet count may be performed 
after consultation with the Sponsor Medical Monitor or Designee. 
8.5.4. 
Safety Monitoring Rules for Renal Function Test Results 
If a patient’s results meet Criteria 1 or 2 below, please confirm the results and initiate weekly 
monitoring if confirmed.  If the event of a persistent elevation is observed over 2 consecutive 
weeks, then go to Section 8.6.2. 
1. Serum creatinine increase that fulfills all of the following:  ≥ 0.3 mg/dL (26.5 μmol/L) 
and ≥ 40% above baseline creatinine values and > ULN (refer to definition of baseline in 
Section 8.6) 
2. Proteinuria, UPCR > 750 mg/g for baseline > 200 mg/g, or 4 × baseline for baseline 
< 200 mg/g that is confirmed by repeated UPCR or by a quantitative total urine protein 
measurement of > 1.0 g/24 hr 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
49 
8.6. 
Stopping Rules  
For the purposes of the stopping rules baseline is defined as:  the average of pre-dose values 
(unless otherwise specified). 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor (or appropriately 
qualified Designee), dosing of a patient with ISIS 766720 will be stopped permanently; values 
that are not confirmed due to failure to retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 × ULN, which is confirmed 
2. ALT or AST > 5 × ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 × ULN or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was > ULN, which is confirmed and total bilirubin > 2 × ULN or INR > 1.5 
4. ALT or AST > 3 × ULN or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was > ULN with the new appearance (i.e., onset coincides with the changes in 
hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or concomitant eosinophilia (> ULN)  
8.6.2. 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules for 
Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for either of the 
2 criteria below, dosing of a patient with ISIS 766720 will be suspended temporarily: 
1. Serum creatinine increase that fulfills all of the following:  ≥ 0.3 mg/dL (26.5 μmol/L) 
and ≥ 40% above baseline creatinine values and > ULN (refer to definition of baseline in 
Section 8.6) 
2. Proteinuria, UPCR > 750 mg/g for baseline > 200 mg/g, or 4 × baseline for baseline 
< 200 mg/g that is confirmed by repeated UPCR or by a quantitative total urine protein 
measurement of > 1.0 g/24 hour 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or Designee. 
8.6.3. 
Stopping Rule for Platelet Count Results 
In the event of any platelet count less than 50,000/mm3, dosing of the patient with ISIS 766720 
will be stopped permanently.  Platelet count will be monitored at least twice weekly until 
3 successive values > 75,000/mm3 then weekly until 3 values > 100,000/mm3 (Table 4). 
Administration of steroids is recommended for patients whose platelet count is less than 
25,000/mm3.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) 
recommend Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; 
Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or methylprednisolone 30 mg/kg/day for 
7 days.   

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
50 
Note:  Patient may require continuation with oral steroids after methylprednisolone treatment is 
stopped. 
In the event of a platelet count ˂ 75,000/mm3 and > 50,000/mm3, and in the absence of MB or 
clinically relevant non-major bleeding (CRNMB) (defined below; (Schulman and Kearon 2005; 
Buller et al. 2007) , dosing with ISIS 766720 should be suspended temporarily until the platelet 
count has recovered to > 100,000/mm3.  The suitability of the patient for continued dosing will 
be determined by the Investigator in consultation with the Sponsor Medical Monitor or Designee 
and will be based on factors such as the original rate of decline in the patient’s platelet count, 
whether any bleeding events were experienced, and the speed of recovery of platelet count after 
interruption of dosing.  If dosing is reinitiated, platelet count must be measured weekly until the 
end-of-study.   
If, after reintroduction of ISIS 766720, the platelet count falls below 75,000/mm3, further dosing 
of the patient with ISIS 766720 will be stopped permanently.   
Definition of Major Bleeding Events (Schulman and Kearon 2005): 
1. Fatal bleeding, and/or 
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome 
3. Clinically overt bleeding leading to transfusion of ≥ 2 units of packed red blood cells or 
whole blood or a fall in hemoglobin of 2.0 mg/dL (1.24 mmol/L) or more within 24 hours 
Definition of Clinically Relevant Non-Major Bleeding Events (Buller et al. 2007): 
Clinically relevant CRNMB is defined as overt bleeding not meeting the criteria for MB but that 
resulted, for example, in medical examination, intervention, or had clinical consequences for a 
patient. 
Definition of Minor Bleeding Events: 
Minor bleeding events are those that do not fulfill the criteria for MB or CRNMB (defined 
above). 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
51 
Table 4: 
Actions in Patients with Low Platelet Count 
Platelet Count 
Drug Dose 
Monitoring 
> 100,000/mm3  
No action 
Monitor per Schedule of Procedures every 2 weeks 
(+7 days) up to Week 17 and every 4 weeks 
(+7 days) after Week 17  
≥ 75,000 to 
≤ 100,000/mm3 
No action 
Monitor every week until 3 successive values 
> 100,000/mm3 
≥ 50,000 to 
< 75,000/mm3 
Pause dosing 
When platelet count returns 
to > 100,000/mm3 restart 
dosing only if approved by 
Sponsor Medical Monitor 
or Designee 
Monitor at least twice weekly until 3 successive 
values > 75,000/mm3 then weekly until 3 values 
> 100,000/mm3. 
If redosing then continue to monitor weekly for the 
remainder of the Treatment Period.  If not redosing 
then subsequent monitoring should be per the 
Schedule of Procedures. 
Consider discontinuation of antiplatelet agents/ 
non-steroidal anti-inflammatory drug 
(NSAIDS)/anticoagulant medication while platelet 
count < 75,000/mm3. 
≥ 25,000 to 
< 50,000/mm3 
Permanently discontinue 
ISIS 766720 
Monitor twice weekly until 3 successive values 
> 75,000/mm3 then weekly until 3 values 
> 100,000/mm3.  Subsequent monitoring should be 
per the Schedule of Procedures. 
Discontinue antiplatelet agents/NSAIDS/ 
anticoagulant medication while platelet count 
˂ 75,000/mm3 if possible. 
˂ 25,000/mm3 
Permanently discontinue 
ISIS 766720 
Monitor daily until 3 successive values show 
improvement then monitor twice weekly until 
3 successive values > 75,000/mm3 then weekly until 
3 values > 100,000/mm3.  Subsequent monitoring 
should be per the Schedule of Procedures. 
Steroids recommended* 
Consider need for hospitalization and referral to 
hematologist 
Discontinue antiplatelet agents/ NSAIDS/ 
anticoagulant medication while platelet count 
˂ 75,000/mm3 if possible 
* Recovery in platelet count may be accelerated by administration of high-dose steroids.  Treatment guidelines for 
immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 4 days every 
2-4 weeks for 1-4 cycles; Prednis(ol)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or methylprednisolone 
30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after methylprednisolone). 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
52 
8.7. 
Adjustment of Dose and/or Treatment Schedule 
ISIS 766720 dose adjustments and interruptions will be allowed for safety, tolerability or 
efficacy.  Dose adjustments for efficacy (no higher than a 200 mg dose) may be made after 
Week 17 IGF-1 results are available.  It is recommended to maintain an adjusted dose for 
efficacy for 3 months prior to further adjustment.  Any dose adjustment requires consultation 
with the Sponsor Medical Monitor or Designee.   
Patients may have their dose interrupted in response to AEs after consultation with Sponsor 
Medical Monitor or Designee.   
8.8. 
Discontinuation of Study Drug/Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of 
ISIS 766720 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Sections 8.6.1 to 8.6.3 
• The patient meets any of the following Exclusion Criteria (see Section 5.2) after 
discussion with the Sponsor Medical Monitor (or appropriately qualified Designee) 
− Patient needing pituitary surgery or radiation during Treatment Period 
− Patient with a pituitary tumor that is worsening (e.g., either growing, or at risk of 
compressing or abutting the optic chiasm or other vital structures) as assessed by 
pituitary/sellar MRI protocol 
− Treatment with any other acromegaly medications 
The reason for discontinuation of ISIS 766720 must be recorded in the electronic Case Report 
Form (eCRF) and source documentation. 
Patients who discontinue ISIS 766720 should complete early termination from treatment visit 
(ETTX) and then enter the Post-Treatment Period) unless consent is withdrawn.  Minimally, 
every effort should be made to complete the ETTX (see Appendix A, Section 6.1.2). 
If the patient declines or is unable to participate in the above, the Investigator should clarify what 
type of follow-up the patient is agreeable to:  in person, by phone/mail, through family/friends, 
via correspondence/communication with other physicians, and/or from review of the medical 
records.  Wherever possible, these patients should continue to be followed up via the agreed 
means to collect information on AEs, concomitant medications and survival status.  At the very 
least, the patient’s status at the end of the protocol defined study period should be ascertained 
and documented wherever possible.  The agreed means of follow-up will be documented in the 
patient records and the Sponsor notified. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
53 
8.9. 
Withdrawal of Patients from the Study Procedures 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the study Procedures might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the eCRF. 
Any patient who withdraws consent, in writing or via verbal communication (documented by 
study site personnel) to participate in the study will be removed from further treatment and study 
observation immediately upon date of request.  These patients should be encouraged to complete 
the ETTX visit procedures at the time of withdrawal if patient is in the Treatment Period, or the 
ETPT visit if patient is in the Post-Treatment Period (Appendix A).  If the patient declines or is 
unable to participate in the above, the Investigator should clarify what type of follow-up the 
patient is agreeable to:  in person, by phone/mail, through family/friends, via correspondence/ 
communication with other physicians, and/or from review of the medical records.  Wherever 
possible these patients should continue to be followed up via the agreed means to collect 
information on AEs, concomitant medications and survival status.  At the very least, the patient’s 
status at the end of the protocol defined study period should be ascertained and documented 
wherever possible.  The agreed means of follow-up will be documented in the patient records 
and notified to the Sponsor. 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the Post-Treatment Period and early termination study procedures.   
8.10. 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
eCRF.  Adverse events related to administration of these therapies or procedures must also be 
documented on the appropriate eCRF. 
8.10.1. 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between signing 
of informed consent and last visit (PTWk15/ETPT).   
Allowed Concomitant Therapy 
Any other medications deemed necessary by the Investigator are allowed except those listed in 
the disallowed concomitant therapy. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
54 
In the Post-Treatment Period, approved acromegaly medication may be added for patients with 
elevated IGF-1 (≥ 1.3) levels in consultation with the Investigator and Sponsor Medical Monitor 
or Designee.   
Disallowed Concomitant Therapy 
The following medications or interventions cannot be started during the Treatment Period: other 
approved or investigational medications for acromegaly (e.g., bromocriptine, cabergoline, 
pasireotide, quinagolide, octreotide (all formulations), pegvisomant, pasireotide, lanreotide (all 
formulations), dopamine agonist).  If modification of acromegaly medication is considered, the 
recommendation is to wait until after Week 17 to allow ISIS 766720 to reach steady-state 
therapeutic concentrations and to ensure patient is on a maximal dose of ISIS 766720 per 
Section 8.7 prior to initiation of other acromegaly medications.   
Use of anti-obesity agents or weight loss programs are not allowed prior to Week 27.  Initiation 
of anti-obesity agents or weight loss programs after Week 27 may be considered after 
consultation with the Sponsor Medical Monitor or Designee 
It is preferred for patients to maintain stable regimens of estrogen containing medications, 
antidiabetic medications and glucocorticoids throughout the study, however, changes to a stable 
regimen allowed at Screening may only be considered after consultation with the Sponsor 
Medical Monitor or Designee. 
Any investigational therapeutic drug or device including other marketed agents at experimental 
dosages/utilities that are being tested—patient will be withdrawn. 
8.10.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of informed consent and the last visit (PTWk15)  
Surgery and radiotherapy for pituitary adenoma during the trial is not allowed (see Section 5.2) 
and patients who undergo these procedures during the study will be early terminated from the 
Treatment Period and enter the Post-Treatment Period.   
8.11. 
Treatment Compliance 
There is not a patient diary for this trial. 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING  
9.1. 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor or Designee in 
accordance with the applicable Ionis and/or Designee SOPs throughout the conduct of the 
clinical trial. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
55 
9.2. 
Regulatory Requirements 
The Sponsor or Designee is responsible for regulatory submissions and reporting to the 
Investigators of serious adverse events (SAEs) including suspected unexpected serious adverse 
reactions (SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A 
and ICH GCP.  Country-specific regulatory requirements will be followed in accordance with 
local country regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.   
In addition to the Investigator’s assessment of relatedness, the Sponsor or Designee will evaluate 
the available information and perform an independent assessment of all reported SAEs and 
determine if there is a reasonable possibility that ISIS 766720 is causally related to a reported 
SAE.  While the Sponsor may upgrade an Investigator’s decision it is not permissible to 
downgrade the Investigator’s opinion for the purposes of determining whether the SAE meets the 
definition of a SUSAR. 
For the purpose of regulatory reporting of SUSARs, no SAE associated with use of ISIS 766720 
is considered expected for this study population. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An adverse event (AE) can be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 
medicinal (investigational) product, whether or not the AE is considered related to the medicinal 
(investigational) product. 
An AE can therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
• Recurrence of an intermittent medical condition (e.g., headache) not present at 
Baseline 
• Any deterioration in a laboratory value or other clinical test (e.g., electrocardiogram 
[ECG], X-ray) that is associated with symptoms or leads to a change in study 
treatment or concomitant treatment or discontinuation from ISIS 766720 
Adverse events that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as biopsies). 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
56 
9.3.2. 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction 
Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not have been established, ADR is defined as follows: 
All noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reactions. 
The phrase "responses to a medicinal product" means that a causal relationship between the 
medicinal product and the AE has been determined by the Sponsor as at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
Suspected Unexpected Adverse Drug Reaction  
A suspected unexpected ADR is any ADR, the nature or severity of which is not consistent with 
the applicable product information, e.g., Investigator's Brochure for an unapproved medicinal 
(investigational) product. 
A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction. 
9.3.3. 
Serious Adverse Event (SAE) 
A SAE is any AE that in the view of either the Investigator or Sponsor, meets any of the 
following criteria: 
• Results in death 
• Is life threatening: that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate risk 
of death.  It does not include an AE or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization is defined as an admission of greater than 24 hours to a medical 
facility and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• Results in a congenital anomaly or birth defect in the offspring of the patient (whether 
the patient is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do 
not require hospitalization may also be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent 1 of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
57 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of an AE 
(e.g., rated as mild, moderate, or severe, or according to National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE]; the event itself may be of relatively 
minor medical significance [such as severe headache without any further findings]). 
Severity and seriousness need to be independently assessed for each AE recorded on the eCRF. 
9.3.4. 
Adverse Event of Special Interest  
Adverse events of special interest (AESI), including both serious or non-serious events, is 1 of 
scientific and medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor could be appropriate. 
For the purpose of this study, severe reductions in platelet count < 50,000/mm3 accompanied by 
a major MB event or CRNMB event, or platelet count of < 25,000/mm3 independent of an MB or 
CRNMB event are considered as AEs of special interest and is subject to 15-day expediting 
reporting by the Sponsor to the regulatory agencies.   
Investigators should report AEs that met the AESI criteria to the Sponsor immediately, and no 
more than 24 hours of the Investigator's first knowledge of the event. 
9.4. 
 Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible.  Before a 
diagnosis is confirmed, all symptoms should be reported as separate AEs. 
9.4.1. 
Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs, and any 
case of platelet count < 50,000/mm3 (regardless of their relationship to ISIS 766720) should be 
reported to the Sponsor or Designee within 24 hrs of the Study Center’s first knowledge of the 
event.  The collection of SAEs will begin after the patient signs the ICF and stops at the end of 
the patient’s Follow-up Period which is defined as Early Termination Post-Treatment (ETPT) or 
Post-Treatment Week 15 (PTWK15) visit.  When the Investigator is reporting by telephone, it is 
important to speak to someone in person vs. leaving a message.  The Initial Serious Adverse 
Event Form should be completed, and a copy should be emailed or faxed to the Sponsor or 
Designee. 
Detailed information should be actively sought and included on follow-up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed 
until resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
58 
9.4.2. 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the ICF and will stop at the 
end of the patient’s Follow-up Period, which is defined as PTWk15/ETPT visit, or the last visit 
when patient withdraws consent.  The Investigator will monitor each patient closely and record 
all observed or volunteered AEs on the Adverse Event Case Report Form. 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event CRF: 
9.4.3.1. 
Relationship to the Study Drug 
The event’s relationship to ISIS 766720 is characterized by 1 of the following: 
• Related:  There is clear evidence that the event is related to the use of ISIS 766720, 
e.g., confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and ISIS 766720 administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely 
(e.g., concomitant medications or ongoing medical conditions) or the temporal 
relationship to ISIS 766720 administration and/or exposure suggests that a causal 
relationship is unlikely (For reporting purposes, Unlikely/Remote will be grouped 
together with Not Related) 
• Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator 
believes no relationship exists between the event and ISIS 766720 
9.4.3.2. 
Severity 
The severity of AEs and SAEs relating to laboratory tests and AEs at the injection site will be 
graded based on criteria from the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0, November 2017 (refer to Appendix D).  Any AE not listed in Appendix D will be 
graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s 
usual daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
59 
9.4.3.3. 
Action Taken with Study Drug 
Action taken with ISIS 766720 due to the event is characterized by 1 of the following. 
• None:  No changes were made to ISIS 766720 administration and dose 
• Not Applicable:  SAE/AE was reported during Screening Period prior to 
ISIS 766720 administration 
• Permanently Discontinued:  ISIS 766720 was discontinued and not restarted 
• Temporarily Interrupted, Re-started – Same Dose:  Dosing and/or dosing 
frequency was temporarily interrupted/changed or delayed due to the AE and 
restarted at the same dose 
• Reduced Dose:  Dosing was reduced, temporarily interrupted or delayed due to the 
AE and restarted at the next lower dose or reduced dosing frequency 
9.4.3.4. 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form.  Treatment should also be recorded on the concomitant 
treatment or ancillary procedures eCRF, as appropriate. 
9.4.3.5. 
Outcome of the Adverse Event 
If the event is a non-serious AE, then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF 
the SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should 
be entered as the SAE resolution date) 
• Recovered with Sequelae:  The signs/symptoms of the reported SAE have improved 
but not completely resolved, and a new baseline for the patient is established since 
full recovery is not expected 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
• Unknown:  The outcome of the reported SAE is not available, e.g., patient is lost to 
follow-up 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
60 
9.4.3.6. 
Follow-up of Adverse Event 
Investigator Follow-Up 
During the Study Period, the Investigator should follow each AE until the event has resolved to 
baseline grade or better, the event is assessed as stable, the patient is lost to follow-up, or the 
patient withdraws consent.  Every effort should be made to follow all SAEs considered to be 
related to ISIS 766720 or related to study procedures until a final outcome can be reported. 
Resolution of AE (with dates) should be documented on the Adverse Event eCRF and in the 
patient’s medical record to facilitate source data verification.   
Investigator should follow-up, or support the Sponsor’s effort to follow up with all pregnancies 
reported during the study from either the study patient or the female partner of male study patient 
until pregnancy outcome is available.   
Sponsor Follow-Up 
For SAEs, AESI and pregnancy cases in patients who has completed or terminated study, the 
Sponsor or a Designee should follow-up by telephone, fax, email, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge summaries, 
consultant reports, autopsy reports) in order to perform an independent medical assessment of the 
reported case. 
9.5. 
Procedures for Handling Special Situations 
9.5.1. 
Abnormalities of Laboratory Tests 
Clinically significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor or Designee.  Laboratory abnormalities deemed not clinically significant (NCS) 
by the Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported 
as AEs by the Investigator should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the patient’s 
consent to participate in the study 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
61 
• The condition that required the prescheduled or elective procedure or routinely 
scheduled treatment was present before and did not worsen or progress in the opinion 
of the Investigator between the patient’s consent to participate in the study and the 
timing of the procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3. 
Dosing Errors 
ISIS 766720 errors (including overdose, underdose, and administration error) should be 
documented as Protocol Deviations.  A brief description should be provided in the deviation, 
including whether the patient was symptomatic (list symptoms) or asymptomatic, and the event 
accidental or intentional. 
Dosing details should be captured on the Dosing CRF.  If the patient takes a dose of ISIS 766720 
that exceeds protocol specifications and the patient is symptomatic, then the symptom(s) should 
be documented as an AE and be reported per Section 9.4. 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied.  An overdose or incorrect administration of study treatment is not itself an AE, but 
it may result in an AE.  All AEs associated with an overdose or incorrect administration of 
ISIS 766720 should be recorded on the Adverse Event eCRF.  If the associated AE fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event). 
Should an overdose occur, the Investigator or Designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or Designee within 
24 hours. 
9.5.4. 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a female patient becomes pregnant or a pregnancy is suspected, or if a male patient believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
Designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported by designating as ‘Follow-up’ on the 
Pregnancy Forms and reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility.   
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with ISIS 766720.  However, the patient will be encouraged to 
complete the Post-Treatment follow-up portion of the study to the extent that study procedures 
do not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
62 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records to obtain additional 
information relevant to the normality of the newborn(s).  A longer follow-up may be required if 
the newborn child experiences a medical condition.  Follow-up will be performed to the extent 
permitted by the applicable regulations and privacy considerations; e.g., pregnancy ICF may be 
required. 
Male patients:  The progress of the pregnancy of a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
follow-up with the mother and may request access to the mother and infant’s medical 
records to obtain additional information relevant to the pregnancy progress and outcome.  A 
longer follow-up may be required if a newborn-child experiences a medical condition.  
Follow-up will be performed to the extent permitted by the applicable regulations and privacy 
considerations; e.g., partner ICF may be required. 
10.3. 
Populations 
Safety Set:  All patients who are randomized and receive at least 1 dose of ISIS 766720. 
Full Analysis Set (FAS):  All randomized patients who receive at least 1 dose of ISIS 766720 
and have at least 1 post-baseline efficacy or PD assessment. 
Per Protocol Set (PPS):  All FAS patients who complete at least 6 of the 8 doses of ISIS 766720 
with the first 27 Weeks administered and have no significant protocol deviations that would be 
expected to impact efficacy. 
PK Set:  All patients who are randomized and receive at least 1 dose of ISIS 766720 and have at 
least 1 evaluable PK sample. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
63 
10.4. 
Definition of Baseline 
Unless otherwise specified, baseline is defined as the last non-missing value prior to the first 
administration of ISIS 766720. 
10.5. 
Interim Analysis  
An interim analysis may be conducted when approximately 50% of patients complete the 
primary efficacy assessment.   
10.6. 
Planned Methods of Analysis 
Descriptive summary statistics including n, mean, median, standard deviation, interquartile range 
(25th percentile, 75th percentile), and range (minimum, maximum) for continuous variables, and 
counts and percentages for categorical variables will be used to summarize most data.  Where 
appropriate, p-values will be reported.  All statistical tests will be conducted using 2-sided tests 
with 5% type I error rates unless otherwise stated. 
The efficacy endpoints will be assessed on the FAS and PPS with the latter being the basis for 
the primary efficacy analysis.  The safety analyses will be performed on the Safety Set.  
Pharmacokinetic analysis will be conducted in the PK Set. 
10.6.1. 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
treatment group.  Patient randomization and disposition will be summarized by treatment group.  
All patients enrolled will be included in the summary of patient disposition. 
10.6.2. 
Safety Analysis 
Treatment duration and amount of ISIS 766720 received will be summarized by treatment group 
and total.  The TEAEs and serious TEAEs will be summarized for each treatment group and total 
using the Medical Dictionary for Regulatory Activities (MedDRA™) coding system, by system 
organ class, preferred term, relationship to ISIS 766720, and severity.  Tables and/or narratives 
of treatment-emergent deaths, serious and significant AEs, including early withdrawals due to 
AEs, will also be provided. 
Laboratory tests including chemistry panel, complete blood count with differential, coagulation 
panel, complement etc., will be summarized by study visits for each treatment group and total.  
These safety variables will also be presented as change and percent change from Baseline over 
time after ISIS 766720 administration, as appropriate.  Vital sign, calculated BMI, and ECG 
measures will be summarized by treatment group and total.  Concomitant medications will be 
coded using WHO Drug dictionary and summarized as well.   
Echocardiograms will be assessed by an independent central reader.  Change from baseline will 
be summarized for the following parameters, that may include left ventricular mass (LVM), 
LVM index (LVMi), LV ejection fraction, LV posterior wall thickness (LVPWT), peak velocity 
ratio (E/A), interventricular septum thickness (IVST) and isovolumic relaxation time (IVRT) 
whenever possible.  

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
64 
10.6.3. 
Efficacy Analysis 
The primary analysis will be the comparison of percent change from Baseline to Week 27 in 
serum IGF-1.  The null hypothesis of no percentage change in serum IGF-I levels from Baseline 
to Week 27 will be tested for each treatment group in the PPS.  The data will be analyzed using a 
one-sample t-test with an alpha level of 5%.  Ninety-five percent (95%) confidence interval of 
estimated percent reduction within treatment group will also be provided.  In the case data 
departs substantially from normality, the nonparametric test will be employed instead.  The 
primary analysis will take place after all patients complete Treatment Period and the database has 
been locked.   
The primary efficacy endpoint will also be assessed, as a secondary analysis, in the FAS.   
Additional secondary efficacy analyses are: 
• change and percent change from Baseline to each schedule post-baseline visit in 
serum IGF-1 by the ISIS 766720 treatment groups in the PPS and FAS.  The data will 
be analyzed in a similar way to the primary analysis 
• proportion of patients achieve normalized IGF-1 levels to within 1.2 times of gender 
and aged limits within each ISIS766720 treatment groups will be assessed by an exact 
binomial test in the PPS and FAS.   
• proportion of patients achieve normalized IGF-1 levels to within 1.0 times of gender 
and aged limits within each ISIS 766720 treatment groups will be assessed by an 
exact binomial test in the PPS and FAS 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
65 
Further details will be described in the Statistical Analysis Plan (SAP).   
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1. 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor or Designee. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific screening 
procedures or ISIS 766720 are administered.  The patient must be given sufficient time to 
consider whether to participate in the study.   
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the ICF 
should be signed and personally dated by the patient and by the person who conducted the 
informed consent discussion (not necessarily an Investigator).  The original signed ICF should be 
retained in the Study Master File and in any other locations required by institutional policy, and a 
copy of the signed consent form should be provided to the patient. 
11.2. 
Ethical Conduct of the Study 
All applicable regulations and guidelines of current Good Clinical Practice (GCP) as well as the 
demands of national drug and data protection laws and other applicable regulatory requirements 
must be followed.   
11.3. 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed ICF, other written patient information, and any proposed 
advertising material must be submitted to the IEC/IRB for written approval.  A copy of the 
written approval of the protocol and ICF must be received by the Sponsor before recruitment of 
patients into the study and shipment of ISIS 766720.  A copy of the written approval of any other 
items/materials that must be approved by the Study Center or IEC/IRB must also be received by 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
66 
the Sponsor before recruitment of patients into the study and shipment of ISIS 766720.  The 
Investigator’s Brochure must be submitted to the IEC/IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with 
ICH GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of SAEs occurring at 
the Study Center and other AE reports received from the Sponsor or Designee, in accordance 
with local procedures. 
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor. 
11.4. 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the CRFs or 
other documents submitted to the Sponsor, patients should be identified by initials (if permitted 
by local law) and a patient identification number only.  Documents that are not for submission to 
the Sponsor (e.g., signed ICFs) should be kept in strict confidence by the Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1. 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IEC/IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor. 
12.2. 
Study Termination 
The Sponsor reserves the right to terminate the study.  The Investigator reserves the right to 
terminate their participation in the study, according to the terms of the site contract.  The 
Investigator/Sponsor should notify the IEC/IRB in writing of the trial’s completion or early 
termination. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
67 
12.3. 
Study Documentation and Storage 
An eCRF utilizing an Electronic Data Capture application will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, imaging, and correspondence.  In this study, eCRF may not be 
used as source documents. 
The Investigator and Study Center staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor and/or applicable regulatory authorities.  Elements should include: 
• Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation and all correspondence to and from the IEC/IRB 
and the Sponsor 
• If drug supplies are maintained at the Study Center, proof of receipt, ISIS 766720 
Product Accountability Record, Return of ISIS 766720 Product for Destruction, final 
ISIS 766720 product reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4. 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor or Designee is responsible for inspecting the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research.  
The monitor should have access to patient medical records and other study-related records 
needed to verify the entries on the CRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
68 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department (or Designees).  
Inspection of Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review 
of study-related records will occur to evaluate the trial conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor or Designee.  During this review, patient data will be 
checked for consistency, omissions, and any apparent discrepancies.  In addition, the data will be 
reviewed for adherence to the protocol and GCP.  To resolve any questions arising from the 
clinical data management review process, data queries and/or Study Center notifications will be 
sent to the Study Center for completion and return to Sponsor or Designee. 
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the Principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5. 
Language 
Case report forms must be completed in English.  Generic names and trade names are acceptable 
for concomitant medications.  Combination medications should be recorded using their trade 
name. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6. 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
13 December 2021 
69 
13. 
REFERENCES
Altmann K-H, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: From 
nuclease resistance to biological efficacy in animals. CHIMIA Int J Chem 1996; 50: 168‑176. 
Barts Endocrine 2009. E-Protocols Acromegaly and Growth Hormone. 
http://www.bartsendocrinology.co.uk/resources/ACROMEGALY+AND+GH+PROTOCOLS+$ 
5Bfinal$5D.pdf. 
Buller HR, Cohen AT, Davidson B, et al. Idraparinux versus standard therapy for venous 
thromboembolic disease. N Engl J Med 2007; 357: 1094-1104. 
Crooke ST, Baker BF, Kwoh TJ, et al. Integrated safety assessment of 2'-o-methoxyethyl 
chimeric antisense oligonucleotides in nonhuman primates and healthy human volunteers. Mol 
Ther 2016; 24: 1771‑1782. 
Crooke ST, Baker BF, Xia S, et al. Integrated Assessment of the Clinical Performance of 
GalNAc3-Conjugated 2'-O-Methoxyethyl Chimeric Antisense Oligonucleotides: I. Human 
Volunteer Experience. Nucleic Acid Ther 2019; 29: 16-32. 
Fisker S. Physiology and pathophysiology of growth hormone-binding protein: methodological 
and clinical aspects. Growth Horm IGF Res 2006; 16: 1-28. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha 
phosphorothioate 2'-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across 
species. Drug Metab Dispos 2003; 31: 1419-1428. 
Giustina A, Barkan A, Beckers A, et al. A Consensus on the Diagnosis and Treatment of 
Acromegaly Comorbidities: An Update. J Clin Endocrinol Metab 2020; 105:  
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased 
immune stimulation in mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, et al. Sequence-dependent hydrolysis of RNA using modified 
oligonucleotide splints and RNase H. FEBS Lett 1987; 215: 327-330. 
Katznelson L, Atkinson JL, Cook DM, et al. American Association of Clinical Endocrinologists 
medical guidelines for clinical practice for the diagnosis and treatment of acromegaly--2011 
update. Endocr Pract 2011; 17 Suppl 4: 1‑44. 
Katznelson L, Laws ER, Jr., Melmed S, et al. Acromegaly: an endocrine society clinical practice 
guideline. J Clin Endocrinol Metab 2014; 99: 3933-3951. 
Kwoh J. 2008 Chapter 13: An Overview of the Clinical Safety Experience of First- and Second-
Generation Antisense Oligonucleotides. in S. T.  Crooke (ed.), Antisense Drug Technology: 
Principles, Strategies, and Applications (Boca Raton). 
Liu JL, Yakar S, and LeRoith D. Conditional knockout of mouse insulin-like growth factor-1 
gene using the Cre/loxP system. Proc Soc Exp Biol Med 2000; 223: 344-351. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of 
antisense oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 
274: 1715-1722. 
Melmed S. Medical progress: Acromegaly. N Engl J Med 2006; 355: 2558-2573. 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
70 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2'-modified oligonucleotides containing 
2'-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Prakash TP, Graham MJ, Yu J, et al. Targeted delivery of antisense oligonucleotides to 
hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. 
Nucleic Acids Res 2014; 42: 8796-8807. 
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and 
management of primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Rowland JE, Lichanska AM, Kerr LM, et al. In vivo analysis of growth hormone receptor 
signaling domains and their associated transcripts. Mol Cell Biol 2005; 25: 66-77. 
Schulman S and Kearon C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694. 
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and 
expression. Physiol Rev 1995; 75: 591-609. 
Trainer PJ, Newell-Price JDC, Ayuk J, et al. A randomised, open-label, parallel group phase 2 
study of antisense oligonucleotide therapy in acromegaly. Eur J Endocrinol 2018; 179: 97-108. 
Tritos NA, Chanson P, Jimenez C, et al. Effectiveness of first-line pegvisomant monotherapy in 
acromegaly: an ACROSTUDY analysis. Eur J Endocrinol 2017; 176: 213-220. 
van der Lely AJ, Biller BM, Brue T, et al. Long-term safety of pegvisomant in patients with 
acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J Clin Endocrinol Metab 
2012; 97: 1589-1597. 
Wang Y, Yu RZ, Henry S, et al. Pharmacokinetics and Clinical Pharmacology Considerations of 
GalNAc3-Conjugated Antisense Oligonucleotides. Expert Opin Drug Metab Toxicol 2019; 15: 
475-485. 
Webb SM, Prieto L, Badia X, et al. Acromegaly Quality of Life Questionnaire (ACROQOL) a 
new health-related quality of life questionnaire for patients with acromegaly: development and 
psychometric properties. Clin Endocrinol (Oxf) 2002; 57: 251-258. 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
71 
14. 
APPENDICES 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
72 
APPENDIX A. SCHEDULE OF PROCEDURES 
 
Treatment Period   
Post-Treatment Period  
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
73 
Appendix A.  Schedule of Procedures – Treatment Period  
Study Period 
Screen1 
Treatment Period2 
Study Week 
-6 to -1 
1 
3 
5 
7 
9 
11 13 15 17 
21 
25 
27 
29 
33 
37 
41 
45 
49 
53 
57 
61 
65 
69 
73 
Study Day 
-42 to -1 1 
15 29 43 57 71 85 99 113 141 169 183 197 225 253 281 309 337 365 393 421 449 477 505 
Visit Window ± Day 
0 
 
3 
5 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
Home Health Care Visit Option16  
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI/CT of sellar  
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
 
 
 
 
X3 
Echocardiogram 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
AcroQoL 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ASTS-M 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
EQ-5D 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
SF-36 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Ring Size Measurement 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Body Weight and Height4 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam6 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ECG (12-Lead)  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
74 
Appendix A.  Schedule of Procedures – Treatment Period Continued 
Study Period 
Screen1 
Treatment Period2 
Study Week 
-6 to -1 
1 
3 
5 
7 
9 
11 13 15 17 
21 
25 
27 
29 
33 
37 
41 
45 
49 
53 
57 
61 
65 
69 
73 
Study Day 
-42 to -1 1 
15 29 43 57 71 85 99 113 141 169 183 197 225 253 281 309 337 365 393 421 449 477 505 
Visit Window ± Day 
0 
 
3 
5 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
Home Health Care Visit Option16  
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Screening FSH7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panel (Fasting)8, 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Partial PD Panel:  GH, IGF-1, 
GHBP8 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Full PD Panel8 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
hs-CRP 
 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Coagulation Panel 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pituitary Axis10, Thyroid Panel 
X 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Bone Biomarker 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Lipid panel8 
X 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Cardiac Biomarkers 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Screening HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glycemic Panel (Including 
HbA1c)8 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
2 hr. OGTT and GH Response 
Assessment11, 12 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Archived Serum Sample13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
75 
Appendix A.  Schedule of Procedures – Treatment Period Continued 
Study Period 
Screen1 
Treatment Period2 
Study Week 
-6 to -1 
1 
3 
5 
7 
9 
11 13 15 17 
21 
25 
27 
29 
33 
37 
41 
45 
49 
53 
57 
61 
65 
69 
73 
Study Day 
-42 to -1 1 
15 29 43 57 71 85 99 113 141 169 183 197 225 253 281 309 337 365 393 421 449 477 505 
Visit Window ± Day 
0 
 
3 
5 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
Home Health Care Visit Option16  
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Immunogenicity Testing14 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
PK Blood Sampling14 
 
X15 
X 
X 
 
X 
 
X 
 
X15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ISIS 766720Administration  
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Contact  
 
If a visit cannot be conducted, patient contact (e.g., phone, text, email or video) is required by site personnel to assess Adverse Events and 
Concomitant Medications 
ALL STUDY PROCEDURES ARE CONDUCTED PRIOR TO THE ISIS 766720 INJECTION, EXCEPT PK DAY 1 & DAY 113. 
1 
During the Screening Period, screening results may be retested using the Home Health Care Visit Option for assessment after discussion with the Sponsor Medical Monitor or 
Designee for eligibility purposes 
2 
If a patient terminates early from the Treatment Period, an early termination visit from treatment (ETTX) is required as soon as possible, preferably 4 weeks after the last dose.  
After ETTX visit, patient should continue in Post-Treatment Period, following the schedule in intervals relative to patient’s last dose 
3 
Prior MRI/CT and/or echocardiogram (ECHO) performed within the last 3 months of screening visit can be used.  The window to conduct the MRI at Day 365 (WK53) and 
Day 505 (WK 73) and ECHO at Day 505 (Week 73) is ± 2 weeks 
4 
Height collected at Screening only 
5 
BP, heart rate (HR), RR, temperature 
6 
Full PE to be given at Screening and abbreviated physical exam to be given during Treatment as indicated to assess changes from Screening 
7 
A pregnancy test is required at Screening for all female patients who are of childbearing potential regardless of age.  Serum at Screening, and dipstick is acceptable after 
Screening.  FSH is required to confirm menopause for women ≤ 55 years who have 12 months of spontaneous amenorrhea with no alternative medical cause, and who are not 
surgically sterile.  For patients requiring confirmation of menopause at Screening per protocol, a pregnancy test and FSH are required at Screening, however, once menopause 
status is confirmed, a pregnancy test is not required in subsequent visits.  If patient is surgically sterile, no pregnancy test or FSH is required 
8 
Fasting is not required at Screening Visit.  For all other visits, fasted samples should be taken after fasting for 8 hours.  During this time the patient can drink water and they 
should ensure that they consume enough water to not become dehydrated   
9 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or missing, the test must be repeated 
and a result not meeting stopping rule must be obtained prior to next dose.  Platelets require a valid result from the prior platelet test within 21 days up to week 17 and within 
35 days after week 17 (per Section 8.5.2). In consultation with the medical monitor or designee, a local lab and central lab should be drawn and evaluated prior to dosing (per 
Section 6.2.1) 
10 A morning cortisol sample is required, and the sample should be drawn prior to 9:00 AM.  For patients on stable glucocorticoid therapy, the cortisol sample may be taken at 
any time 
11 Patient should fast for 10 hours prior to OGTT.  OGTT Sample Time Schedule: 0, 30, 60, 90, 120 mins.  After the 120-min blood draw, the fasting period is completed.  See 
Section 6.2.2 procedure details 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
76 
Appendix A.  Schedule of Procedures – Treatment Period Continued 
Legend Continued 
12 The pre-dose Day 1 OGTT may by conducted during the Screening Period between Day -41 and pre-dose Day 1.  To decrease the study burden on potential patients, it is 
suggested that this procedure is done after the patient has completed and qualified for all other screening procedures.  The procedure can be conducted in the clinic or by a 
Home Health Care professional.  The window for completing Day 183 and Day 505 OGTT is ± 30 days 
13 Stored at -70 (± 10) °C for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine and/or chemokine levels, measurement of additional 
markers of kidney function, measurement of antibodies, etc.) 
14 Unless otherwise specified, all PK and immunogenicity samples must be collected pre-dose 
15 Pre-dose, 1, 2, 4 hours.  See Appendix C 
16 Home health may be used at these visits if applicable.  In consultation with the Sponsor, a Home Health Care visit may be conducted for a study day visit that was intended to 
be a clinic visit; it is preferable that the entire visit is conducted, however the following assessments may be omitted: ECG, body weight, physical exam, ring size, and OGTT. 
Any assessments not completed at the Home Health Care visit should be attempted at the next clinic visit.  A confirmation of ISIS 766720 dosing by the Home Health Provider 
should be obtained and documented in source within 48 hrs 
 
 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
77 
Appendix A. Schedule of Procedures – Post-Treatment Period 
Study Period 
Post-Treatment Period (14 Weeks) 
 
Study Week (Wk) from Last Dose 
PTWk5 
PTWk9 
PTWk15 
ETTX1, 2 
ETPT1, 2 
Study Day from Last Dose 
PTD292 
PTD572 
PTD992 
NA 
NA 
Study Day from Day 1 
533 
561 
604 
NA 
NA 
Visit Window ± 
7 
7 
7 
NA 
NA 
Home Health Care Visit Option3 
X 
X 
 
 
MRI/CT of sellar 
 
 
 
X13 
 
Echocardiogram 
 
 
 
X14 
 
AcroQoL 
X 
X 
X 
ASTS-M 
X 
X 
X 
EQ-5D 
 
 
X 
X 
X 
SF-36 
 
 
X 
X 
X 
Ring Size Measurement 
 
 
X 
X 
X 
Body Weight  
X 
X 
X 
Vital Signs4 
X 
X 
X 
X 
X 
Physical Exam5 
X 
X 
X 
ECG (12-Lead)   
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
Pregnancy Test6 
X 
X 
X 
X 
X 
Chemistry Panel (Fasting)7, 8 
X 
X 
X 
X 
X 
Hematology8 
X 
X 
X 
X 
X 
Partial PD Panel: GH, IGF-1, GHBP7 
X 
X 
 
 
Full PD Panel7 
X 
X 
X 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
78 
Appendix A. Schedule of Procedures – Post-Treatment Period Continued 
Study Period 
Post-Treatment Period (14 Weeks) 
 
Study Week (Wk) from Last Dose 
PTWk5 
PTWk9 
PTWk15 
ETTX1, 2 
ETPT1, 2 
Study Day from Last Dose 
PTD292 
PTD572 
PTD992 
NA 
NA 
Study Day from Day 1 
533 
561 
604 
NA 
NA 
Visit Window ± 
7 
7 
7 
NA 
NA 
Home Health Care Visit Option3 
X 
X 
 
 
hs-CRP 
X 
X 
 
Coagulation Panel 
X 
X 
X 
Pituitary Axis9, Thyroid panel and 
Bone Biomarker, Cardiac Biomarker 
X 
X 
X 
Lipid panel7 
 
 
X 
X 
X 
Glycemic Panel7 
 
 
X 
X 
 
2 hr. OGTT and GH response 
Assessment10 
 
 
 
X11 
 
Archived Serum Sample12 
X 
X 
X 
X 
X 
Immunogenicity Testing 
X 
X 
X 
X 
X 
PK Blood Sampling 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
Patient Contact  
If a visit cannot be conducted, patient contact (e.g., phone, text, email or video) is required by site personnel to assess 
Adverse Events and Concomitant Medications 
1 The PTWK5 visit does not need to be completed if the ETTX is completed 4 weeks after the last dose.  After ETTX visit, patient should continue in Post-
Treatment Period, following the schedule in intervals relative to patient’s last dose.   
2 A Patient terminating from the Post-Treatment Period should complete the ETPT  
3 Home health may be used at these visits if applicable for the participating site/country 
4 BP, heart rate (HR), RR, temperature 
5 Abbreviated physical exam to be given during Post-Treatment Period  
6 Dipstick pregnancy test acceptable.  If surgically sterile or menopause confirmed at Screening, a pregnancy test is not required in subsequent visits 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
79 
Appendix A. Schedule of Procedures – Post-Treatment Period Continued 
Legend Continued 
7 Fasted samples should be taken after fasting for 8 hours.  During this time the patient can drink water and they should ensure that they consume sufficient 
water to not become dehydrated   
8 If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) the test must be 
repeated.  In consultation with the Sponsor Medical Monitor or designee, a local lab and central lab should be drawn and evaluated (per Section 6.2.1) 
9 A morning cortisol sample is required, and the sample should be drawn prior to 9:00 AM.  Not required for patients on stable glucocorticoid therapy 
10 Patient should fast for 10 hours prior to OGTT.  OGTT Sample Time Schedule: 0, 30, 60, 90, 120 mins.  After the 120-min blood draw, the fasting period is 
completed.  See Section 6.2.2 for complete details of the procedure 
11  ETTX OGTT assessment may be completed in the clinic or by a Home Health Care Professional within ± 14 Days.  If the patient had completed an OGTT in 
within the previous 2 months, then the OGTT does not need to be done 
12  Stored at -70(± 10) °C for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine and/or chemokine levels, measurement of 
additional markers of kidney function, measurement of antibodies, etc.) 
13  An MRI should be conducted at ETTX for patients who early terminate from the trial after and including Wk 25 but before Wk 53.  If the ETTX visit is after 
Week 53, a third MRI is not required.  The window to conduct the ETTX MRI is ± 2 weeks 
14  An ECHO should be conducted at ETTX for patients who early terminate from the trial after and including Wk 25 but before Wk 73.  The window to conduct 
the ETTX ECHO is ± 2 weeks 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
80 
APPENDIX B. LIST OF LABORATORY ANALYTES 
 
 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
81 
Appendix B. List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of ISIS 766720 or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Cholesterol 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
ALP 
• 
Creatine kinase 
• 
GGT 
• 
Lipase  
 
Pituitary Axis 
• 
Morning Cortisol (before 
9:00 AM) 
• 
ACTH 
• 
Prolactin 
• 
SHBG 
• 
Testosterone 
• 
FSH (females only) 
• 
LH 
Screening Tests 
• 
HBsAg 
• 
Hepatitis C antibody 
• 
HIV antibody 
• 
Serum βhCG 
• 
FSH (females only)1 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
PD Panel (*Partial PD Panel)  
• 
IGF-1*5 
• 
GH* 
• 
GHBP* 
• 
ALS  
• 
IGFBP3 
 
Glycemic Panel 
• 
HbA1c 
• 
Glucose 
• 
Glycated albumin  
 
OGTT Plasma Assessments 
• 
Glucose 
• 
Insulin 
• 
c-peptide  
• 
GH 
 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells (WBC) 
• 
WBC Differential (% and 
absolute) 
− 
Neutrophils 
− 
Eosinophils 
− 
Basophils   
− 
Lymphocytes 
− 
Monocytes 
 
Thyroid Panel 
• 
TSH 
• 
Free T4 
• 
Total T3 
 
Bone Biomarkers4 
• 
Urinary N-telopeptide 
crosslink (NTX) 
• 
Bone specific alk phos 
• 
Amino terminal 
propeptide of Type 1 
procollagen (PINP) 
 
Pharmacokinetics2 
• 
ISIS 766720 levels in 
plasma 
 
Immunogenicity2 
Anti-ISIS 766720 
antibodies 
Inflammatory 
• 
hs-CRP4  
 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
UPCR 
• 
UACR 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic examination3 
 
Lipid Panel 
• 
Total Cholesterol 
• 
LDL cholesterol 
• 
HDL cholesterol 
• 
Triglycerides 
• 
VLDL 
• 
Lp(a) 
 
Cardiac Biomarkers4 
• 
Cardiac troponin I 
• 
NT-proBNP 
 
1 
Only to confirm post-menopausal state at Screening, if required 
2 
Plasma PK and immunogenicity samples may also be used for profiling of drug binding proteins, bioanalytical method 
validation purposes, stability assessments, metabolite assessments, or to assess other actions of ISIS 766720 with plasma 
constituents 
3 
Will be performed on abnormal findings unless otherwise specified 
4  May be analyzed 
5  IGF-1 results will be available from Week 17 visit and every three months or more frequently per PI judgement in 
consultation with Sponsor Medical Monitor or Designee 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
82 
APPENDIX C. PK SAMPLING SCHEDULE  
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
83 
Appendix C. PK Sampling Schedule  
 
Treatment Period 
Treatment Period 
Wk 
1 
Wk 
3 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 
17 
Wk 
21 
Wk 
25 
Wk 
27 
Wk 
29 
Wk 
33 
Wk 
37 
Wk 
41 
Wk 
45 
Wk 
49 
Wk 
53 
Wk 
76 
Wk 
61 
Wk 
65 
Wk 
69 
Wk 
73 
D 
1 
D 
15 
D 
29 
D 
57 
D 
85 
D 
113 
D 
141 
D 
169 
D 
183 
D 
197 
D 
225 
D 
253 
D 
281 
D 
309 
D 
337 
D 
365 
D 
393 
D 
421 
D 
449 
D 
477 
D 
505 
Blood: 
Pre-
dose, 1, 
2, 4 hr, 
Post-SC 
Injection 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose, 1, 
2, 4 hr, 
Post-SC 
Injection 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Any-
time 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Blood: 
Pre-
dose 
Note:  If 4-hour PK sampling is not possible a protocol deviation can be entered 
Wk = week 
D = day 
 
Post-Treatment Period 
Post-Treatment Period 
Early Termination from 
Treatment 
Early Termination from 
Post-Treatment 
PTWk5 
PTWk9 
PTWk15 
D533 
D561 
D604 
ETTX 
ETPT 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
Blood: 
Anytime 
PTWk = post-treatment week 
D = day from Day 1 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
84 
APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING 
TO LABORATORY ABNORMALITIES 
 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
85 
Appendix D. Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for AEs relating to lab test abnormalities and AEs at the 
injection site are based upon the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0, November 2017.  Grading used is determined by Investigator Judgement.   
 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
86 
 
 

ISIS 766720-CS5 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
13 December 2021 
 
87 
 

Version: 1
Version Date: 16 Dec 2021
Title: 766720 CS5 Amendment 3 An Open Label, Randomized, Phase 2 Study to Assess
the Safety, Tolerability, and Efficacy of IONIS GHR-LRX, an Antisense Inhibitor of
the Growth Hormone Receptor, Administered Monthly as Monotherapy in Patients
Protocol

 
 
 
 
Statistical Analysis Plan 
 
 
ISIS 766720-CS5 
 
An Open-Label, Randomized, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of IONIS GHR-LRX, an Antisense 
Inhibitor of the Growth Hormone Receptor, Administered Monthly 
as Monotherapy in Patients with Acromegaly 
 
 
Date:  30 August 2022 
 
Version:  2.0 
 
 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
2 
SIGNATURES 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court, Carlsbad, CA 92010 
Compound Name: 766720 
Protocol: 
766720-CS5 
Study Title:   
An Open-Label, Randomized, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of IONIS GHR-LRX, an Antisense Inhibitor of the 
Growth Hormone Receptor, Administered Monthly as Monotherapy in 
Patients with Acromegaly 
Issue Date:   
13 December 2021 (Protocol Amendment 3 – ROW) 
 20 December 2021 (Protocol Amendment 4 – Russia) 
 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
3 
TABLE OF CONTENTS 
SIGNATURES .................................................................................................................................2 
LIST OF TABLES ...........................................................................................................................4 
SUMMARY OF CHANGES ...........................................................................................................5 
ABBREVIATIONS .........................................................................................................................7 
1. 
INTRODUCTION ........................................................................................................8 
1.1. 
Study Overview ............................................................................................................8 
1.2. 
Objectives .....................................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Additional/Exploratory Objectives .............................................................................10 
1.3. 
Endpoints ....................................................................................................................10 
1.3.1. 
Primary Endpoint ........................................................................................................10 
1.3.2. 
Secondary Endpoints ..................................................................................................10 
1.3.3. 
Safety Endpoints .........................................................................................................10 
1.3.4. 
Additional/Exploratory Endpoint(s) ...........................................................................11 
2. 
PROCEDURES ..........................................................................................................11 
2.1. 
General Overview of Procedures ................................................................................11 
2.2. 
Randomization & Treatment Allocation ....................................................................12 
2.3. 
Conduct .......................................................................................................................12 
2.4. 
Data Monitoring ..........................................................................................................12 
2.4.1. 
Safety Data Monitoring ..............................................................................................12 
2.5. 
Data Management .......................................................................................................12 
2.5.1. 
Case Report Form Data ..............................................................................................12 
2.5.2. 
Laboratory Data ..........................................................................................................13 
2.5.3. 
Pharmacokinetics (PK) Data .......................................................................................13 
3. 
ANALYTICAL PLAN ...............................................................................................13 
3.1. 
Statistical Design Summary ........................................................................................13 
3.2. 
General Overview of Analyses ...................................................................................13 
3.2.1. 
Statistical Methods ......................................................................................................13 
3.2.2. 
Subject Population Analyzed ......................................................................................15 
3.2.3. 
Handling of Missing Data ...........................................................................................15 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
4 
3.2.4. 
Disposition of Subjects ...............................................................................................15 
3.2.5. 
Demographic and Baseline Characteristics ................................................................15 
3.2.6. 
Scoring of Questionnaires and Ring Size Assessment ...............................................16 
3.2.7. 
Stratification, Subsets, and Covariates .......................................................................21 
3.3. 
Primary Analysis ........................................................................................................22 
3.3.1. 
Primary Endpoint Definition ......................................................................................22 
3.3.2. 
Analysis of Primary Endpoint ....................................................................................22 
3.3.3. 
Sample Size Consideration .........................................................................................22 
3.3.4. 
Planned Interim Analysis ............................................................................................22 
3.3.5. 
Incomplete or Missing Data........................................................................................22 
3.4. 
Secondary Analyses ....................................................................................................23 
3.4.1. 
Secondary Endpoint Definitions .................................................................................23 
3.4.2. 
Analysis of Secondary Endpoints ...............................................................................23 
3.5. 
Exploratory Analyses ..................................................................................................23 
3.6. 
Pharmacokinetic Analysis ..........................................................................................24 
3.6.1. 
Plasma Concentration Data of Total Full-Length Oligonucleotides ..........................24 
3.6.2. 
Plasma Pharmacokinetic Parameters ..........................................................................25 
3.6.3. 
Pharmacokinetic/Pharmacodynamic Exposure-Response Analysis ...........................25 
3.6.4. 
Immunogenicity (IM) Analysis ..................................................................................26 
3.7. 
Safety Analyses ..........................................................................................................26 
3.7.1. 
Exposure .....................................................................................................................26 
3.7.2. 
Adverse Events ...........................................................................................................27 
3.7.3. 
Vital Signs Measurements ..........................................................................................29 
3.7.4. 
Laboratory Measurements ..........................................................................................29 
3.7.5. 
12-Lead Electrocardiograms (ECG) ...........................................................................30 
3.7.6. 
Acromegaly Past Medications and Concomitant Medications ...................................31 
3.7.7. 
Echocardiograms ........................................................................................................31 
4. 
REFERENCES ...........................................................................................................32 
 
LIST OF TABLES 
Table 1: 
The AcroQoL Questionnaire ......................................................................................17 
Table 2: 
The ASTS-M Questionnaire .......................................................................................19 
Table 3: 
The Abbreviated Item Content for the SF-36 Health Survey Domain Scales ............21 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
6 
Section 
Title 
Change/Rationale 
Section 3.7 
Safety Analyses 
Updated the summary groups for safety analysis:  
The results are summarized by the maximum ISIS 766720 dose 
received through the study and overall.    
Section 3.7.2 
Adverse Events 
Updated imputation rules for missing dates of adverse events. 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
7 
ABBREVIATIONS 
In addition to the study glossary provided in the protocol, here are additional abbreviations 
provided for the study SAP. 
Abbreviation 
Definition 
AUC 
area under curve 
IAUC 
incremental AUC 
 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
8 
1. 
INTRODUCTION 
This document provides a description of the study organization, study procedures, and the plan 
for the statistical analysis of the study data.  Section 1 discusses study design, objectives, and 
endpoints; Section 2 provides the study procedures; Section 3 provides the detailed plan for the 
statistical analyses. 
The purpose of this plan is to provide specific guidelines from which the analysis will proceed.  
Any deviations from these guidelines will be documented in the clinical study report (CSR). 
Within this document, the terms ‘patient’ and ‘subject’ are both used to describe the individual 
who enrolls in this study. 
1.1. 
Study Overview 
This is a Phase 2, randomized, open label multi-center study.    
All eligible patients will be randomized to one of the 3 treatment groups 
 
stratified by screening serum IGF-1 level (> 2.5 ULN vs. ≤ 2.5 ULN age and sex 
adjusted by the central lab).  ISIS766720 will be administered as a once monthly SC injection 
(except during Month 1 where a booster dose is administered on Day 15) during a 73-week 
Treatment Period).  At the end of Treatment Period, patients will enter a 14-week Post-treatment 
(PT) Evaluation Period.   
The Study Design and Treatment Schema are depicted as follows: 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
9 
 
 
1.2. 
Objectives 
1.2.1. 
Primary Objectives 
• To evaluate the safety and tolerability of ISIS 766720 subcutaneous (SC) injection as 
a monotherapy in patients with acromegaly. 
• To evaluate the efficacy of ISIS 766720 SC injection on serum insulin-like growth 
factor-1 (IGF-1) as a monotherapy in patients with acromegaly. 
1.2.2. 
Secondary Objectives 
To evaluate the effect of ISIS 766720 SC to normalize serum IGF-1 levels. 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
10 
1.3. 
Endpoints 
1.3.1. 
Primary Endpoint 
The primary efficacy endpoint is the percent change in IGF-1 from Baseline to Week 27.   
1.3.2. 
Secondary Endpoints 
The following secondary endpoints will be analyzed for efficacy:   
• Patients who achieve normalized IGF-1 levels to within 1.2 times gender and age 
limits at Day 183 (Week 27). 
• Patients who achieve normalized IGF-1 levels to within 1.0 times gender and age 
limits at Day 183 (Week 27). 
• Change from Baseline in serum IGF-1 over time. 
• Percent change from Baseline in serum IGF-1 over time. 
1.3.3. 
Safety Endpoints  
Safety endpoints which will include: 
• Adverse events 
• Vital signs and weight 
• Physical Exams 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
11 
• Laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• Echocardiogram 
• Electrocardiograms (ECGs) 
• Use of concomitant medications 
2. 
PROCEDURES 
2.1. 
General Overview of Procedures 
Ionis Pharmaceuticals, Inc. (or designee) will review all study data including source documents, 
CRFs, and laboratory reports.  The study site will enter patient source data into the case report 
form.  Some laboratory data will be transferred electronically from Endocrine Lab, Ludwig-
Maximulians-University (LMU) Munich via Medpace Reference Laboratories (MRL), and from 
Pharmaceutical Product Development (PPD) Inc. (plasma concentration data) to Ionis 
Pharmaceuticals, Inc. 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
12 
2.2. 
Randomization & Treatment Allocation 
Patients will be randomized after all screening assessments have been completed and after the 
Investigator has verified that they are eligible per criteria in protocol Sections 5.1 and 5.2.  No 
subject may begin treatment prior to randomization and assignment of a unique subject 
identification number.   
Eligible patients will be randomized to receive a planned monthly ISIS 766720 SC injection as 
outlined in protocol Section 3.4.2.   
The Sponsor or designee will prepare the randomization list and utilize an automated IRT 
(Interactive Response Technology) system for randomization assignment. 
2.3. 
Conduct 
The study will be conducted in accordance with current Good Clinical Practice (GCP) and 
International Conference on Harmonization (ICH) guidelines, the World Medical Association 
Declaration of Helsinki guidelines, the Food and Drug Administration (FDA) Code of Federal 
Regulations, and all other local regulatory requirements. 
2.4. 
Data Monitoring 
2.4.1. 
Safety Data Monitoring 
Ionis Pharmaceuticals, Inc. (or designee) is responsible for processing all reported adverse events 
(AEs).  All serious adverse events (SAEs), reported to Ionis Pharmaceuticals, Inc. (or designee), 
will be reviewed according to standard operating procedures.  The medical monitor will review 
all AEs and SAEs on an ongoing basis throughout the study.  Ionis Pharmaceuticals, Inc. (or 
designee) will prepare and submit safety reports to the health authorities worldwide in 
accordance with local requirements.  If it becomes necessary to communicate new safety 
information, Ionis Pharmaceuticals, Inc. (or designee) will also prepare a safety notification letter 
and transmit it to all applicable study sites. 
2.5. 
Data Management 
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this Study.  
2.5.1. 
Case Report Form Data 
BioClinica, Inc. is responsible for creating the EDC data entry screens, database and edit checks 
using definitions developed by Ionis Pharmaceuticals, Inc.  Ionis Pharmaceuticals, Inc. is 
responsible for the review, data management querying and locking of the database. 
Data are single-entered into the EDC system by the investigator site staff.  Programmed edit 
checks (computer logic that checks the validity of the data entered and also prompts for missing 
data that is expected to be entered) are run and automatic queries are generated.  Ionis 
Pharmaceuticals, Inc. reviews all data for accuracy and validity and generates additional queries 
in the EDC system when necessary.  The data is corrected or an explanation concerning the 
query is provided in the EDC system.  After all data is entered, source data verified, reviewed 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
14 
will be assessed on the FAS and PPS with the latter being the basis for the primary efficacy 
analysis.  The safety analyses will be performed on the Safety Set.  Pharmacokinetic analysis 
will be conducted in the PK Set. 
For the continuous outcomes, the data will be analyzed using one-sample t-test to evaluate the 
estimate percent changes are different than zero.  For the categorical outcomes, the data will be 
analyzed by using one-sample binomial Exact test (Clopper and Pearson 1934) to evaluate 
whether the estimate proportions are deviated from zero.  The normality assumption for one-
sample t-test model will be assessed by the Shapiro-Wilk test.  In the case of data departs 
substantially from normality, the nonparametric Wilcoxon signed rank test will be applied 
instead.  All statistical tests will be conducted using 2-sided tests with 5% Type I error rate 
unless otherwise stated.  Where appropriate, P-values will also be provided as an indicator to 
summarize how much deviation from zero within each treatment group based on the statistical 
tests. 
Additional summary of between treatment group comparison may be provided.  Treatment group 
and the stratification factor are included as the independent variables in the statistical model 
while comparing among treatment groups.  For the continuous endpoints, the ANCOVA or 
ANOVA model will be applied depending on the independent variables or van Elteren test if the 
data departs substantially from normality.  For the dichotomous endpoints, logistic regression 
will be used instead.  
Additional subject listings included case report form (CRF) data and derived outcomes from the 
data may be presented.   
Baseline definition: 
Due to the variance of IGF-1 between Screening and Day 1, baseline of IGF-1 is defined as the 
average value of Screening and Day 1 prior to the first administration of ISIS 766720.  Multiple 
results with the same visit label will be averaged first, and baseline IGF-1 will be calculated as 
IGF-1 at Screening plus IGF-1 at Day 1 divide by 2.  
For other endpoints, baseline is defined as the last non-missing value prior to the first 
administration of ISIS 766720. 
Analytical visits: 
In general, all post-baseline data will be summarized using the visit labels provided in the data.  
Multiple results with the same visit label will be averaged for the continuous variables, and the 
worst result will be used for the categorical variables.  Results with visit labels as “Unscheduled” 
will not be included in the by-visit summary tables and figures except for determining baseline 
and the incidence of abnormality lab summary including AST, ALT, platelet and renal but will 
be presented in data listings.   
For patients who had last dose prior to treatment termination, PD results greater than 3 weeks 
after the last dose (the date of last dose + 21 days) up to treatment termination will not be 
included in the by-visit summary tables and figures.  Also, for patients who started other 
acromegaly medications in the post-treatment period, PD results after the start date of 
acromegaly medication will not be included in the by-visit summary tables and figures. 
Other situations, such as required additional confirmation, will be described separately in the 
related endpoint analysis approach.  

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
15 
3.2.2. 
Subject Population Analyzed 
The following analysis populations are defined for this study: 
• Safety Set:  All patients who are randomized and received at least 1 dose of 
ISIS 766720.   
• Full Analysis Set (FAS):  All randomized patients who received at least 1 dose of 
ISIS 766720- and have at least 1 post-baseline efficacy or PD assessment.  
• Per Protocol Set (PPS):  All FAS patients who complete at least 6 of the 8 doses of 
ISIS 766720 within the first 27 weeks administered and have no significant protocol 
deviations that would be expected to impact efficacy.  
• PK Set:  All randomized patients who receive at least 1 dose of ISIS 766720 and have 
at least one evaluable PK sample. 
In addition to the above analysis sets, it is recognized that some data displays will be provided 
for "All Screened", "Screening Failures" and "All Randomized" subjects but no data analysis is 
planned to be executed in these populations.   
Summary of related COVID-19 public health emergency incidence will be described in detail in 
the corresponding sections.  
3.2.3. 
Handling of Missing Data 
Missing values will not be imputed.  Patients with missing data for a scheduled assessment time 
point were excluded from the summary for that time point.  
Summary of missing visits for key study parameters will be summarized.  Number of patients 
with missing data and missing data related to COVID-19 public health emergency may be 
provided.   
3.2.4. 
Disposition of Subjects 
The number of patients screened, the number of patients screen failures, the number and 
percentage of patients enrolled, the number and percentage of patients completed the study 
treatment, the number and percentage of patients who discontinued from treatment early and 
reason, the number and percentage of patients completed post-treatment follow-up, and who 
discontinued from post-treatment follow-up and reason will be summarized.   
A by-patient listing will also be provided. 
Additional listing will be provided to describe the screen failure, treatment/post-treatment 
follow-up termination incidences related COVID-19 public health emergency.   
3.2.5. 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
safety population.  The summary includes age, gender, ethnicity, race, weight, height, and body 
mass index (BMI).  Other disease characteristics related assessments, such as serum IGF-1, will 
be summarized in the summary tables separately.  

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
16 
For summarizing race, if multiple races are recorded in the database, then ‘Multiple Race’ is 
used in the summary table.  The listing will display the specific race values.   
BMI will be computed using the formula: BMI = (weight in kilograms) / [screening height in 
cm/100]2 
All protocol deviations will be listed and be summarized.  Additional summary table by 
deviation type and classification will be provided to illustrate the protocol deviations related 
COVID-19 public health emergency.   
3.2.6. 
Scoring of Questionnaires and Ring Size Assessment 
Acromegaly Quality of Life Questionnaire (AcroQoL) 
AcroQoL is a specific questionnaire designed to evaluate Health Related Quality of Life 
(HRQoL) in patients with acromegaly.  It comprises 22 items (Table 1), which are spread across 
2 dimensions: physical (8 items) and psychological (14 items).  There is a further breakdown of 
the psychological dimension into 2 sub-dimensions (each comprising 7 items): one evaluates 
appearance and the other evaluates the impact of the disease on the patient’s personal 
relationships. 
 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
17 
Table 1: 
The AcroQoL Questionnaire 
 
AcroQoL dimension 
Questions included in each dimension 
Physical 
1, 3, 9, 13, 14, 15, 19, 22 
Psychological 
2, 4, 5, 6, 7, 8, 10, 11, 12, 16, 17, 18, 20, 21 
 
Sub-dimensions (of the 
psychological dimension) 
Questions included in each sub-dimension 
Appearance 
2, 4, 7, 11, 12, 16, 17 
Personal relations 
5, 6, 8, 10, 18, 20, 21 
 
Each of the 22 items of the AcroQoL is answered in a 1 to 5 Likert scale measuring either the 
frequency of occurrence (always, most of the time, sometimes, rarely, or never) or the degree of 
agreement with the items (completely agree, moderately agree, neither agree nor disagree, 
moderately disagree, completely disagree).  Answers to each of the items are rated on a scale of 
1 to 5: 1 corresponds to the response category “Always” or “Completely agree”, depending on 
the item type, and 5 is equivalent to the response category “Never” or “Completely disagree”.  
This means that the lower the score the greater the impact on HRQoL. 
The scores for each dimension or sub-dimension are the sum of the item responses given for each 
dimension / sub-dimension.  Consequently, the score for the physical dimension can range from 
8 to 40 points, the psychological dimension from 14 to 70 points, and each of the sub-dimensions 
(appearance and personal relationships) from 7 to 35 points.  All these scores are interpreted by 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
18 
taking the lowest score as corresponding to the worst imaginable HRQoL, and the highest score 
as corresponding to the best imaginable HRQoL, as expressed through the specific scales of this 
questionnaire. In addition, a global score can be calculated by the sum of the responses to the 
22 items, which can range from 22 points (worst HRQoL) to 110 points (best HRQoL). 
To simplify interpreting questionnaire scores, the raw scores can be standardized on a scale 
running from 0 (worst HRQoL) to 100 (best HRQoL), by using the following formula: 
 
𝑌= [
(X) −min
(max − min )] × 100 
Here Y is the re-calculated score, and X is the sum of all the item responses within the dimension 
or global score (min. is the minimum possible score in the study dimension, and max. is the 
maximum possible score in the study dimension). 
For example, to standardize the global score (Y), substitute X for the sum of the scores of the 
22 items, min for 22 and max for 110 (being the two extreme values); thus, scores range from 
0 (worst HRQoL) to 100 points (best HRQoL). 
 
Global score  𝑌= [
(𝑋)−22
(110−22)] × 100 
To interpret each of the questionnaire scores, all of the items should be answered.  However, for 
most HRQoL questionnaires a score is considered calculable if the percentage of un-answered 
questions does not exceed 25% of the items used to obtain the score.  In such cases, one assumes 
that the scoring of the missing item or items is equivalent to the average score obtained in the 
rest of the items that make up the calculation of the score.  In the case of AcroQoL, scores can be 
interpreted for each of the dimensions if the number of unanswered items does not exceed 2 in 
the physical dimension, 1 in the appearance and personal relationships sub-dimensions, or 3 in 
the psychological dimension.  To get a global score, the maximum number of unanswered 
questions permissible is 5.  The standardized scores of each dimension and global score will be 
tabulated.   

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
19 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
ISIS 766720-CS5 
20 
Euro QoL-5 Dimensions (EQ-5D) 
The EQ-5D is the most widely used generic PRO instrument internally (Kind 2005) and 
recommended by NICE for evidence submitted to its technology appraisal process (NICE 2013).  
The EQ-5D is comprised of 6 questions. The first 5 questions address the following quality of 
life dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety /depression.  
The last question is represented by a 20-cm vertical visual analogue scale (VAS), scored from 
0 to 100 asking the patient to “mark your own health state today” (Brooks 1996).  A new version 
of the instrument, the five level EQ-5D was developed to improve sensitivity and to standardize 
the language used across dimensions (Herdman et al. 2011) and the study utilizes this latest 
instrument.   
The EQ-5D comprises the same five questions/dimensions but increases the available response 
options (‘levels’) from three to five (no; slight; moderate; severe; extreme problems/unable to).  
Short Form 36 (SF-36) 
The SF-36 is a multi-purpose health survey with 36 questions and very popular instrument for 
evaluating health-related quality of life (QoL).  The questionnaire measures functional health and 
well-being from the patient’s point of view.  The 35 questionnaire are aggregated into  eight 
multi-item health domains: physical functioning (PF), role physical (RP), bodily pain (BP), 
general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental 
health (MH) (based on classification shown in Table 3).  The 8 domains, in turn, can be 
aggregated into two summary domains tapping physical and mental health: a physical component 
summery (PCS, including PF, RP, GH and BP) and a mental component summary (MCS, 
including MH, RE, SF, and VT).  The SF-36 V2 health Survey form will be used for this study 
and the norm-based score for each domain will be calculated using Optum’s SF36v2/SF-12v2 
scoring software.  Higher scores are associated with a better QOL.  The change and percentage 
change from Baseline will be tabulated at the scheduled visits.  

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
21 
Table 3: 
The Abbreviated Item Content for the SF-36 Health Survey Domain Scales 
 
 
Ring Size Assessment 
Per protocol, ring size is assessed using the study provided ring sizer widget and the fourth finger 
of the non-dominant hand.  The ring size to record is the one with the tightest fit.  If the finger is 
too large to be measured by the ring sizer then use the fifth finger (and make a note of this).  The 
same finger will be used throughout the trial.  The ring size circumference (mm) will be 
calculated as: 
ring size circumference = ring size *3.14159 
Only subjects with post-treatment values using the identical finger as the one used for baseline 
value will be included in the change and percent change from Baseline analysis. 
3.2.7. 
Stratification, Subsets, and Covariates 
Eligible Patients will be stratified on Screening serum IGF-1 level (> 2.5 ULN vs. ≤ 2.5 ULN 
age and sex adjusted by the central lab).   
The following covariates may be used for further exploration in subgroups or as covariates: 
• Age group (< 65 years vs. ≥ 65 years) 
• Race (Caucasian vs non-Caucasian) 
• Gender 
• Serum IGF-1 level status (>2.5 ULN vs. ≤ 2.5 ULN) 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
22 
Additional baseline demographic and disease characteristics may also be considered as 
covariates.  
3.3. 
Primary Analysis 
3.3.1. 
Primary Endpoint Definition 
The primary endpoint is percent change from Baseline to Week 27 in IGF-1 within each 
ISIS 766720 treated group and overall.  
3.3.2. 
Analysis of Primary Endpoint 
The analysis of the study primary endpoint will be conducted in the PPS.  The results will be 
summarized by the ISIS 766720 dose received at randomization and overall.  In addition, 
because most of patients will have dose escalation after primary endpoint of Week 27, the results 
will also be summarized by the maximum ISIS 766720 dose received through the study and 
overall. 
Subset analysis will be conducted among uncontrolled population (IGF-1 > 1.3 × ULN at Day 1) 
and high-strata IGF-1 population (IGF-1 > 2.5 × ULN at Screening), separately.  The data will be 
analyzed using one-sample t-test to detect the reduction of IGF-1 significant different than zero 
at Week 27.  The normality assumption for one-sample t-test model will be assessed by the 
Shapiro-Wilk test.  In the case of data departs substantially from normality, the nonparametric 
Wilcoxon signed rank test will be applied instead.   Additional summary in FAS will be 
provided.  
3.3.3. 
Sample Size Consideration 
Approximately 40 patients are planned to be randomized in the study while considering an 
estimated 10% overall drop-out rate.  Based on the assumption of expected IGF-1 reduction of 
27.5% from Baseline with SD of 30% per treatment group, the minimum sample size of 
12 evaluable patients per treatment group will provide 80% power to detect the difference 
between the null hypothesis of no change and the expected reduction using a 2-sided one-sample 
t-test with a significant level of 5%.   
3.3.4. 
Planned Interim Analysis 
An interim analysis may be conducted when approximately 50% patients complete the primary 
efficacy endpoint assessment.  Additional summaries may be performed to coincide with study 
milestones, like publication or regulatory interaction.  
3.3.5. 
Incomplete or Missing Data 
In general, missing IGF-1 for a scheduled assessment will not be imputed.  Patients with missing 
data for a scheduled assessment time point will be excluded from the summary for that time 
point. 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
23 
3.4. 
Secondary Analyses 
3.4.1. 
Secondary Endpoint Definitions 
Normalized IGF-1 level is defined as the ratio of the serum IGF-1 level and patient’s upper limit 
of normal (ULN).  The ULN will be varied among patients due to gender and age.  Patients 
whose calculated ratios at scheduled visits are less than or equal to 1.2 or 1.0 will be deemed as 
achieving normalized IGH-1 at that scheduled visit.  
For change from Baseline, non-missing IGF-1 measures over time will be compared to their 
baseline.    
Patients without IGF-1 measure at a scheduled visit will not be imputed for that scheduled visit. 
3.4.2. 
Analysis of Secondary Endpoints 
The analysis population will be conducted in both FAS and PPS.  The results will be summarized 
by the ISIS 766720 dose received at randomization and overall.  In addition, the results will also 
be summarized by the maximum ISIS 766720 dose received through the study and overall. 
Subset analysis will be conducted among uncontrolled population (IGF-1 > 1.3 × ULN at Day 1) 
and high-strata IGF-1 population (IGF-1 > 2.5 × ULN at Screening), separately.     
Proportion of subject incidence of achieving within 1.2 times, achieving 1.0 times of ULN over 
time will be summarized at each scheduled visit respectively.  The estimated proportion with 
95% confidence interval will be provided.  
Absolute, change and percent change from Baseline to each scheduled post-baseline visit in 
IGF-1 over time will be summarized at each scheduled visit.   

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
24 
3.6. 
Pharmacokinetic Analysis 
3.6.1. 
Plasma Concentration Data of Total Full-Length Oligonucleotides 
Pharmacokinetic (PK) analysis will be conducted in the PK Population.  For all patients, plasma 
concentrations of ISIS 766720 (total full-length ASO, reported as ISIS 766720-eq.), along with 
the scheduled (nominal) and actual samples times (i.e., time from SC dosing) and actual dose 
will be listed (when applicable) for each patient by dose cohort, nominal dose, patient ID, patient 
immunogenicity (IM) status, IM onset (if applicable) as defined in Section 3.6.4, and day.  In 
addition, percent differences between scheduled and actual sampling times will be listed for all 
patients.  Percent differences between actual administered dose and nominal dose will also be 
listed.   

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
25 
Plasma concentrations below the lower limit of quantification (LLOQ) will be presented as 
“BLQ”.  For the purpose of calculating descriptive statistics (n, mean, SD, SE, %CV, geometric 
mean, geometric %CV, median, minimum, and maximum) for plasma concentrations, all BLQ 
values will be set to zero.  Mean plasma concentrations that are BLQ will be presented as BLQ, 
and the SD, SE, %CV, geometric mean, and geometric %CV will be reported as not applicable.  
Summary statistics of ISIS 766720-eq. plasma concentrations will be tabulated by nominal dose, 
nominal day, and scheduled time point.   
ISIS 766720-eq. plasma trough (pre-dose) and post-treatment concentration versus time (actual) 
for each individual patient, as well as the mean (± SD or SE) and/or median plasma trough 
concentrations over time (scheduled), will be presented graphically on linear and 
semilogarithmic scales without and with stratification by patient immunogenicity status as 
applicable (see Section 3.6.4). 
At the discretion of the pharmacokineticist and/or biostatistician, samples may be excluded from 
the summary descriptive statistics and mean and median plots if there are large deviations 
between scheduled and actual sampling times, or large deviations between actual dose and 
nominal dose. 
3.6.2. 
Plasma Pharmacokinetic Parameters 
Non-compartmental pharmacokinetic analysis of ISIS 766720-eq. will be carried out on each 
individual patient data set where post-treatment profiles are collected using Phoenix WinNonlin 
Version 8.0 or higher (Pharsight Corporation, Mountain View, CA).  Plasma pharmacokinetic 
parameters in each patient (when applicable) will be determined.  For calculation of PK 
parameters, all BLQ values will be set to zero.  The following plasma PK parameters will be 
calculated (when applicable and not necessarily limited to) based on actual sampling times:   
1. Cmax:  the maximum observed ISIS 766720 concentration in plasma will be determined 
on Nominal Day 1 and Nominal Day 113.   
2. Tmax: the time at which Cmax occurs will be determined on Nominal Day 1 and Nominal 
Day 113.   
3. t1/2λz:  apparent terminal elimination half-life will be calculated from the equation, 
t1/2λz = 0.693/λz, where λz is the rate constant associated with the apparent terminal 
elimination phase.  A minimum of three data points in the elimination phase will be used 
to define z and the correlation of determination values (r2 adjusted) has to be at or 
greater than 0.8 for the estimate to be accepted. This parameter may be calculated 
following the last dose if applicable. 
Plasma pharmacokinetic parameters will be summarized using descriptive statistics (n, mean, 
SD, %CV, geometric mean, geometric %CV, median, minimum, and maximum) by nominal 
dose and day.    
3.6.3. 
Pharmacokinetic/Pharmacodynamic Exposure-Response Analysis 
Exposure-response correlations may be explored graphically between plasma exposure (i.e., 
Ctrough) and selected PD measures (e.g., serum IGF-1, GH, and GHBP levels) if applicable.   

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
26 
Population PK and PKPD analysis may be performed using the PK and PD data from this study 
and/or combined with other ISIS 766720 clinical PK data later in the development timeline. 
3.6.4. 
Immunogenicity (IM) Analysis 
Immunogenicity (IM) analyses will be conducted in the ‘Safety Set’.  Samples collected for IM 
assessment at selected time points will be analyzed for anti-ISIS 766720 antibodies (i.e., anti-
drug antibodies; ADA).  Samples will be designated ‘IM positive’ based on both positive 
screening and confirmation assay results (i.e., confirmed positive result), otherwise they will be 
deemed ‘IM negative’.  Study subjects will be given ‘positive’ subject IM status if they have at 
least one confirmed positive sample at any time during the Treatment or Post-treatment 
Evaluation Periods.  Study subjects will be given ‘negative’ subject IM status if all evaluated IM 
sample results during the Treatment and Post-treatment Evaluation Periods are negative and they 
have at least one evaluable IM result post-dose.  Otherwise, study subjects will be given 
‘unknown’ subject IM status. 
Sample IM status (screen positive/negative, confirmed positive/negative or not evaluable, and 
when applicable, titer of anti-ISIS 766720 antibodies) before, during, and after treatment with 
ISIS 766720 will be listed by the ISIS 766720 dose received (80 mg, 120 mg or 160 mg).  
Subject IM status (positive/negative or unknown) for all evaluable patients, along with the study 
day associated with the first positive IM status emerged (Tfirst, i.e., onset of ADA development), 
the last positive IM status observed (Tlast) and max and/or end of treatment titer will be listed by 
treatment and dose. 
Additionally, the sample and patient IM incidence (number) and incidence rate (percent) will be 
summarized as the total number and percent of evaluated patients with antibody negative, 
positive, and unknown status by the ISIS 766720 dose received (80 mg, 120 mg or 160 mg).  
Furthermore, onset, and peak titer of the ADA response, if applicable, will be summarized as 
median, interquartile range (25th percentile, 75th percentile), and range (minimum, maximum). 
Other immunogenicity data analysis may be conducted at the discretion of the 
pharmacokineticist and/or statistician.  Potential relationships between immunogenicity results 
(e.g., IM status) and selected efficacy (e.g., %change in serum IGF-1, GH, and GHBP levels), 
safety, and pharmacokinetic measures (e.g., Ctrough) may be evaluated in an exploratory manner 
either in this report and/or combined with other ISIS 766720 clinical PK data later in the 
development timeline. 
3.7. 
Safety Analyses 
The safety analysis will be conducted on the Safety Set.  The results are summarized by the 
maximum ISIS 766720 dose received through the study and by overall.    
3.7.1. 
Exposure 
The time on study will be defined as the total number of days a subject is known to be followed 
on study calculated as follows:  
Time on study = Last date on study – Date of first dose + 1, 
where the last date on study is defined as the date of the latest visit with evaluation for a given 
subject. Visits with refused or unable to contact are not visits with evaluation 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
27 
3.7.2. 
Adverse Events 
The incidence of adverse events (AEs) will be summarized by Medical Dictionary for 
Regulatory Activities (MedDRA) Version 22.0 (or higher) preferred term (PT) and system organ 
class (SOC) for: 
• Any treatment emergent adverse events (TEAEs). 
• Related TEAEs. Related is defined as “Related”, “Possible”, or missing relationship 
to Study Drug.  
• Any TEAEs by severity.  At each severity level of subject summarization, a subject is 
classified according to the highest severity if the subject reported one or more events.  
AEs with missing severity will be categorized as “Missing” for this summary. 
• Serious TEAEs. 
• TEAEs leading to permanent Study Drug discontinued. 
Serious and non-serious AEs that lead to study discontinuation or investigational drug 
discontinuation will be listed separately.  Non-TEAE will be included and be noted in the subject 
AE listing. 
To determine the AE as treatment-emergent or not, if there is no “Formlink” link, and the AE 
(start date/time) occurs after the subject’s first dosing date/time, then the AE is treatment-
emergent.  Otherwise, if the AE (start date/time) occurs prior to the subject’s first dosing 
date/time, then the AE is not treatment-emergent.  
In addition, if there is a “Formlink” link between two AE records, then we compare them 
pairwise, and consider two cases, where we compare the AE severity (mild/moderate/severe) and 
seriousness (Yes/No) between the two records in the pair.  We chronologically order the 
2 records (by AE start date) and refer to the “first” and “second” AE.   
Case 1:  The first AE record in the pair occurs before first dosing, and the second AE 
record occurs after first dosing. 
If the AE severity or seriousness of the second record is worse than that of the first 
record, then only the second AE is deemed as a TEAE.  Otherwise, neither record is 
considered as TEAE. 
Case 2:  Both AE records in the pair occur after first dosing. 
Only the worst AE will be deemed as one TEAE. 
All TEAEs identified based on the rules above will be summarized in the event number analysis.    

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
28 
Missing Date for Adverse Events 
For AEs, the following imputation rules will be applied to impute missing date under 
conservative principles. 
Missing or partial start dates:  
If year, month and day are all missing then assign the date of first administration of Study Drug 
• If month and day are missing and year is: 
o the same as the year of the first administration of Study Drug then assign the month-
day of first Study Drug  
o earlier than the year of the first administration of Study Drug then assign 
December 31 
o after the year of the first administration of Study Drug then assign January 1 
• If only day is missing and month-year is: 
o the same as the month-year of the first administration of Study Drug then assign 
the day of first Study Drug  
o earlier than the month-year of the first administration of Study Drug then assign the 
last day of the month 
o after the month-year of the first administration of Study Drug then assign the first 
day of the month 
Imputation will be performed for the end date only if the day or month is missing (i.e., year is 
present) for a stop date as follows: 
• If month and day are missing and year is 
o the same as the year of the last dose of Study Drug then assign the month-day of 
the last dose of Study Drug  
o otherwise, assign December 31 
• If only day is missing then assign the last day of the month 
If the imputed start date is later than the imputed end date then set the imputed start date to the 
imputed end date. 
Local Cutaneous Reactions at the Injection Site 
Local cutaneous reaction at injection site (LCRIS) is defined as (A) moderate or severe adverse 
events with the PTs Injection site erythema, Injection site swelling, Injection site pruritus, or 
Injection site pain that started on the day of injection, persisted for at least two days or ongoing; 
or (B) any AE at the Study Drug injection site, regardless of severity, that leads to 
discontinuation of Study Drug, where AE at the Study Drug injection site is the principal reason 
for discontinuation. 
Percentage of injections leading to LCRIS will be calculated as follows for each subject: 
(A/B)*100, where A = number of injections with an LCRIS, and B = total number of injections.  
Doses that are split across multiple injections are counted as a single injection. 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
ISIS 766720-CS5 
29 
LCRIS will be summarized using the MedDRA coding system, by SOC/PT.  Percentage of the 
injections leading to LCRIS at injection site will also be summarized.  
LCRIS will be listed by preferred term. 
Flu-like Reactions 
Flu-like reactions are defined as adverse events with PTs including either (A) Influenza like 
illness or (B) Pyrexia or Feeling hot or Body temperature increased, plus at least two of the 
following symptoms with the PTs:  Chills, Myalgia, or Arthralgia, starting on day of injection or 
the next day.  
Percentage of injections leading to flu-like reactions will be summarized using the descriptive 
statistics. 
Percentage of injections leading to flu-like reactions will be calculated as follows for each 
subject: (A/B)*100, where A = number of injections leading to flu-like reactions, and B = total 
number of injections. 
FLRs will be summarized using the MedDRA coding system, by SOC/PT.  Percentage of the 
injections leading to FLRs at injection site will also be summarized.  
FLRs will be listed by preferred term. 
AE of Special Interest (AESI) 
Per protocol, severe reductions in platelet count < 50,000/mm3 accompanied by a clinically 
relevant bleeding event or platelet count of < 25,000/mm3 independent of a clinically relevant 
bleeding event are considered as AESI.  The AEs meeting the AESI criteria will be captured in 
the AE CRF page with a check box to indicate.  
AESI will be summarized using the MedDRA coding system, by SOC/PT.  A listing of AESI 
will also be generated. 
3.7.3. 
Vital Signs Measurements 
Vital signs will include heart rate, respiratory rate, body temperature, calculated BMI, and 
systolic and diastolic blood pressure.  Vital signs will be summarized for vital sign values as well 
as the change and percent change from Baseline at each post-baseline visit. 
3.7.4. 
Laboratory Measurements 
Bone biomarkers, pituitary axis, thyroid panel, inflammatory, lipid panel, chemistry, 
hematology, coagulation, cardiac biomarkers and urinalysis (result, change and percent change 
from Baseline) will be summarized at each post-baseline visit.  Listing of laboratory assessments 
in Chemistry, Hematology and urinalysis will be provided.  Local laboratory data will also be 
provided in the listings separately.  
For Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST), the number and 
percent of subjects falling in each of the following categories will be tabulated:  
•
ALT/AST > 3 × ULN, confirmed
•
ALT/AST > 5 × ULN, confirmed

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
 
ISIS 766720-CS5 
 
30 
For Total Bilirubin (BILI), the number and percent of subjects falling in each of the following 
categories will be tabulated: 
• BILI > 1 × ULN, confirmed 
A confirmed value is based on a consecutive lab value performed on a different day to, but 
within 7 days of, the initial value.  If the repeated value is in the same or worse category, then the 
initial value is considered confirmed.  If the consecutive value is in a better category, then the 
initial value is confirmed using the consecutive value category.  If values that are not confirmed 
due to failure to retest or missing lab values, then the initial value is presumed confirmed.  
If there are multiple results on the same day (no matter from the same lab vendor or different lab 
vendors), then the worst value will be utilized in the analysis. 
The number and percentage of patients falling in each of the following categories (using 
available central and local laboratory assessments) based on post-baseline assessments will be 
provided: 
• Confirmed Platelet count 100,000/mm3 to lower limit of normal (based on central lab) 
• Confirmed Platelet count 75,000 to < 100,000/mm3   
• Confirmed Platelet count 50,000 to < 75,000/mm3   
• Confirmed Platelet count 25,000 to < 50,000/mm3    
• Confirmed Platelet count < 25,000/mm3    
• Confirmed ≥ 30% Platelet count decrease from Baseline; further classifying by the 
lower limit of normal (Above or below) 
Additional analysis to explore the possible thrombocytopenia incidence can also be found in 
AESI described in Section 3.7.1.   
Subjects with more than one confirmed value will be counted exactly once under the worst 
confirmed category. 
3.7.5. 
12-Lead Electrocardiograms (ECG) 
Safety 12 lead ECG will be performed at the visits indicated in the protocol Schedule of 
Procedures.   
The ECG data will include ventricular rate (VR), PR interval, QRS duration, QT, and corrected 
QT intervals, and overall interpretation.  
For the continuous variables above, descriptive statistics (n, mean, standard error, standard 
deviation, median, 25th percentile, 75th percentile, minimum and maximum) of the results at each 
study visit, as well as the change and percent change from Baseline to each study visit, will be 
presented in summary tables; for the categorical responses to overall interpretation, the results at 
each visit will be summarized by counts and percentages.  In addition, patients reported QT 
interval > 500 msec and QT interval increase more than 60 msec from Baseline will be 
summarized at each visit.  All the ECG data collected will be listed.  

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
ISIS 766720-CS5 
31 
3.7.6. 
Acromegaly Past Medications and Concomitant Medications 
Acromegaly Past Medications and concomitant medications will be coded using WHO Drug 
dictionary (version March 2019) and summarized by ATC class and generic name. 
3.7.7. 
Echocardiograms 
Change from Baseline will be summarized for the following parameters, that may include left 
ventricular mass (LVM), LVM index (LVMi), LV ejection fraction, LV posterior wall thickness 
(LVPWT), peak velocity ratio (E/A), interventricular septum thickness (IVST) and isovolumic 
relaxation time (IVRT) whenever possible. 

Ionis Pharmaceuticals, Inc. 
CONFIDENTIAL 
Version 2.0, 30 August 2022 
Statistical Analysis Plan 
ISIS 766720-CS5 
32 
4. 
REFERENCES
Brooks, R. 1996. “EuroQol: The Current State of Play.” Health Policy 37: 53–72. 
Clopper, C J, and E S Pearson. 1934. “The Use of Confidence or Fiducial Limits Illustrated in the Case of 
the Binomial.” Biometrika 26 (4): 404. 
Herdman, M., C. Gudex, A. Lloyd, M. Janssen, P. Kind, D. Parkin, G. Bonsel, and X. Badia. 2011. 
“Development and Preliminary Testing of the New Five-Level Version of EQ-5D (EQ-5D-5L).” Qual 
Life Res 20: 1727–36. 
Kind, Paul. 2005. “EQ-5D Concepts and Methods: A Developmental History,” 201–20. 
NICE. 2013. “Guide to the Methods of Technology Appraisal 2013.” 

Version: 1
Version Date: 14 Sep 2022
Title: 766720-CS5 Statistical Analysis Plan V2.0