Conditions: Acromegaly
Keywords: Acromegaly, IONIS-GHR-LRx
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 43
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess the safety, tolerability, and efficacy of IONIS-GHR-LRx in up to 60 participants with acromegaly.

Detailed description:
This short-term study assessed changes in serum insulin-like growth factor 1 (IGF-1) over a 16-week treatment period in a participant population diagnosed with acromegaly being treated with long-acting somatostatin receptor ligands (SRL).

Arms:
arm 1: Participants received placebo by subcutaneous injection (SC) once every 4 weeks for 16 weeks. arm 2: Participants received IONIS GHR-LRx, 60 milligrams (mg), SC, once every 4 weeks for 16 weeks. arm 3: Participants received IONIS GHR-LRx, 80 mg, SC, once every 4 weeks for 16 weeks. arm 4: Participants received IONIS GHR-LRx, 120 mg, SC, once every 4 weeks for 16 weeks. arm 5: Participants received IONIS GHR-LRx, 160 mg, SC, once every 4 weeks for 16 weeks.

Interventions: intervention 1: IONIS-GHR-LRx intervention 2: Placebo
Intervention descriptions: intervention 1: IONIS GHR-LRx administered subcutaneously. intervention 2: Placebo administered subcutaneously.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of ISIS 766720 (IONIS-GHR-LRx, an Antisense 
Inhibitor of the Growth Hormone Receptor) Administered Once Every 28 
Days for 16 Weeks in Patients With Acromegaly Being Treated With Long- 
acting Somatostatin Receptor Ligands (SRL) 
NCT03548415 
18-May-2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of ISIS 766720 (IONIS-GHR-LRx, an Antisense 
Inhibitor of the Growth Hormone Receptor) Administered Once Every 28 
Days for 16 Weeks in Patients With Acromegaly Being Treated With Long- 
acting Somatostatin Receptor Ligands (SRL) 
 
 
NCT03548415 
 
 
Clinical Study Protocol Version 4.0: 18-May-2020 
Official Title: 
NCT Number: 
Document Dates: 


1 of 84 
 
Clinical Study Report 
CONFIDENTIAL 
Ionis Pharmaceuticals, Inc. 
Study Number: ISIS 766720-CS2 
 
 
1 March 2022 
16. Appendices 
 
 
 
1. 
STUDY INFORMATION 
1.1. 
Protocol and Protocol Amendments 
The protocol was amended 4 times. The latest version of the protocol (Protocol Amendment 4) 
is provided along with the change summary for the revision. 
 
Protocol Version 
Date 
Document Provided 
Original 
25 January 2018 
None 
Protocol Amendment 1 
22 June 2018 
None 
Protocol Amendment 2 
10 August 2018 
None 
Protocol Amendment 3 
14 May 2019 
None 
Protocol Amendment 4 
18 May 2020 
Protocol and change summary 


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IONIS PHARMACEUTICALS, INC. 
 
ISIS 766720-CS2 
A Double Blind, Placebo-Controlled, Phase 2 Study to Assess the 
Safety, Tolerability, and Efficacy of ISIS 766720 (IONIS GHR-LRX, 
an Antisense Inhibitor of the Growth Hormone Receptor) 
Administered Once Every 28 Days for 16 Weeks in Patients with 
Acromegaly Being Treated with Long-acting Somatostatin Receptor 
Ligands (SRL) 
 
Protocol Amendment 4 – 18 May 2020 
 
EudraCT No: 2017-004259-22 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
Fax: 
 
Key Sponsor Contact: 
 
2855 Gazelle Court 
Carlsbad, CA 92010 
,


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MD, PhD 
 
ISIS 766720-CS2 
Protocol Amendment 4 
Licensee Protocol Number 766720-CS2 
EudraCT No: 2017-004259-22 
Clinical Phase: 2 
A Double Blind, Placebo-Controlled, Phase 2 Study to Assess the 
Safety, Tolerability, and Efficacy of ISIS 766720 (IONIS GHR-LRX, 
an Antisense Inhibitor of the Growth Hormone Receptor) 
Administered Once Every 28 Days for 16 Weeks in Patients with 
Acromegaly Being Treated with Long-acting Somatostatin Receptor 
Ligands (SRL) 
 
Protocol History: 
Original Protocol: 
25 January 2018 
Amendment 1: 
11 May 2018 
Amendment 2: 
21 June 2018 
Amendment 3 
1 May 2019 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
Carlsbad, CA 92010 
 
 
See electronic signature and date attached at end of 
document 
 
 
 
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 
. 


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Protocol Signature Page 
 
 
Protocol Number: 
ISIS 766720-CS2 
Protocol Title: 
A Double Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of ISIS 766720 (IONIS GHR-LRX, an Antisense 
Inhibitor of the Growth Hormone Receptor) Administered Once Every 
28 Days for 16 Weeks in Patients with Acromegaly Being Treated with 
Long-acting Somatostatin Receptor Ligands (SRL) 
Amendment: 
Amendment 4 
Date: 
18 May 2020 
 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “A 
Double Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability, and Efficacy 
of ISIS 766720 (IONIS GHR-LRX, an Antisense Inhibitor of the Growth Hormone Receptor) 
Administered Once Every 28 Days for 16 Weeks in Patients with Acromegaly Being Treated 
with Long-acting Somatostatin Receptor Ligands (SRL),” dated 18 May 2020, 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 (E6). 
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) 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................. 4 
TABLE OF TABLES ....................................................................................................................... 8 
TABLE OF FIGURES ...................................................................................................................... 8 
PROTOCOL AMENDMENT .......................................................................................................... 9 
PROTOCOL SYNOPSIS ............................................................................................................... 13 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................... 19 
STUDY GLOSSARY .................................................................................................................... 20 
1. 
OBJECTIVES ............................................................................................................. 22 
1.1. 
Primary Objectives ...................................................................................................... 22 
1.2. 
Secondary Objective ................................................................................................... 22 
1.3. 
Tertiary Objectives ...................................................................................................... 22 
1.4. 
Exploratory Objectives................................................................................................ 22 
2. 
BACKGROUND AND RATIONALE ....................................................................... 22 
2.1. 
Overview of Disease ................................................................................................... 22 
2.2. 
Therapeutic Rationale ................................................................................................. 23 
2.3. 
ISIS 766720 ................................................................................................................ 24 
2.3.1. 
Mechanism of Action .................................................................................................. 24 
2.3.2. 
Chemistry .................................................................................................................... 24 
2.3.3. 
Preclinical Experience ................................................................................................. 25 
2.3.4. 
Clinical Experience ..................................................................................................... 26 
2.4. 
Rationale for Dose and Schedule of Administration ................................................... 26 
2.5. 
Risk Assessment ......................................................................................................... 27 
2.5.1. 
Risk Assessment ......................................................................................................... 27 
3. 
EXPERIMENTAL PLAN ........................................................................................... 28 
3.1. 
Study Design ............................................................................................................... 28 
3.2. 
Number of Study Centers ............................................................................................ 28 
3.3. 
Number of Patients ...................................................................................................... 28 
3.4. 
Overall Study Duration and Follow-up ....................................................................... 28 
3.4.1. 
Screening ..................................................................................................................... 29 
3.4.2. 
Treatment .................................................................................................................... 29 
3.4.3. 
Post-Treatment ............................................................................................................ 29 


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3.5. 
End-of-Study ............................................................................................................... 29 
3.6. 
Data and Safety Monitoring Board ............................................................................. 29 
4. 
PATIENT ENROLLMENT ........................................................................................ 29 
4.1. 
Screening ..................................................................................................................... 29 
4.2. 
Randomization ............................................................................................................ 30 
4.3. 
Replacement of Patients .............................................................................................. 30 
4.4. 
Unblinding of Treatment Assignment .......................................................................... 30 
5. 
PATIENT ELIGIBILITY ............................................................................................ 31 
5.1. 
Inclusion Criteria......................................................................................................... 31 
5.2. 
Exclusion Criteria ....................................................................................................... 32 
6. 
STUDY PROCEDURES ............................................................................................ 34 
6.1. 
Study Schedule ............................................................................................................ 34 
6.1.1. 
Screening ..................................................................................................................... 34 
6.1.2. 
Baseline and Treatment Period ................................................................................... 35 
6.1.3. 
Post-Treatment Period ................................................................................................ 36 
6.2. 
Study Assessments ....................................................................................................... 37 
6.2.1. 
Clinical Laboratory Assessments ................................................................................ 37 
6.2.2. 
Oral Glucose Tolerance Test (OGTT) ........................................................................ 37 
6.2.3. 
Assessments for Acromegaly ...................................................................................... 38 
6.2.3.1. 
Acromegaly Quality of Life Questionnaire (AcroQoL) .............................................. 38 
6.2.3.2. 
Acromegaly Symptoms and Treatment Score Questionnaire (ASTS) ........................ 38 
6.2.3.3. 
Ring Size Assessment .................................................................................................. 38 
6.3. 
Restriction on the Lifestyle of Patients ....................................................................... 39 
6.3.1. 
Contraception Requirements ....................................................................................... 39 
6.3.2. 
Other Requirements .................................................................................................... 40 
7. 
STUDY DRUG ........................................................................................................... 40 
7.1. 
ISIS 766720 or Placebo............................................................................................... 40 
7.2. 
Packaging and Labeling .............................................................................................. 40 
7.3. 
Study Drug Accountability .......................................................................................... 40 
8. 
TREATMENT OF PATIENTS .................................................................................. 40 
8.1. 
Study Drug Administration ......................................................................................... 40 
8.2. 
Other Protocol-Required Drugs .................................................................................. 41 


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8.3. 
Other Protocol-Required Treatment Procedures ......................................................... 41 
8.4. 
Treatment Precautions ................................................................................................. 41 
8.5. 
Safety Monitoring Rules ............................................................................................. 41 
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests ................................................... 42 
8.5.1.1. 
Dose Adjustments Guidelines for Liver Monitoring ................................................... 43 
8.5.2. 
Safety Monitoring Rules for Platelet Count Results ................................................... 43 
8.5.3. 
Safety Monitoring for Minor Bleeding Events ........................................................... 44 
8.5.4. 
Safety Monitoring Rules for Renal Function Test Results ......................................... 45 
8.6. 
Stopping Rules ............................................................................................................ 45 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations ......................................................... 45 
8.6.2. 
Temporary Stopping Rules for Renal Function Test Results ...................................... 45 
8.6.3. 
Stopping Rule for Platelet Count Results ................................................................... 46 
8.7. 
Adjustment of Dose and/or Treatment Schedule ........................................................ 47 
8.8. 
Discontinuation of Study Drug .................................................................................... 48 
8.9. 
Withdrawal of Patients from the Study Procedures .................................................... 48 
8.10. 
Concomitant Therapy and Procedures ........................................................................ 49 
8.10.1. 
Concomitant Therapy .................................................................................................. 49 
8.10.2. 
Concomitant Procedures ............................................................................................. 50 
8.11. 
Treatment Compliance ................................................................................................ 50 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 50 
9.1. 
Sponsor Review of Safety Information ....................................................................... 50 
9.2. 
Regulatory Requirements ............................................................................................. 50 
9.3. 
Definitions ................................................................................................................... 51 
9.3.1. 
Adverse Event ............................................................................................................. 51 
9.3.2. 
Adverse Drug Reaction and Unexpected Suspected Adverse Drug Reaction ............ 51 
9.3.3. 
Serious Adverse Event (SAE) ..................................................................................... 52 
9.3.3.1. 
Adverse Events of Special Interest (AESI) ................................................................. 52 
9.4. 
Monitoring and Recording Adverse Events ................................................................ 53 
9.4.1. 
Serious Adverse Events .............................................................................................. 53 
9.4.2. 
Non-Serious Adverse Events ...................................................................................... 53 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) ......................................... 53 
9.4.3.1. 
Relationship to the Study Drug ................................................................................... 53 


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9.4.3.2. 
Severity ....................................................................................................................... 54 
9.4.3.3. 
Action Taken with Study Drug ................................................................................... 54 
9.4.3.4. 
Treatment Given for Adverse Event ........................................................................... 54 
9.4.3.5. 
Outcome of the Adverse Event ................................................................................... 55 
9.4.3.6. 
Follow-up of Adverse Event ....................................................................................... 55 
9.5. 
Procedures for Handling Special Situations ................................................................ 56 
9.5.1. 
Abnormalities of Laboratory Tests ............................................................................. 56 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................. 56 
9.5.3. 
Dosing Errors .............................................................................................................. 56 
9.5.4. 
Contraception and Pregnancy ..................................................................................... 57 
10. 
STATISTICAL CONSIDERATIONS ........................................................................ 58 
10.1. 
Study Endpoints, Subsets, and Covariates .................................................................. 58 
10.1.1. 
Primary Efficacy Endpoint .......................................................................................... 58 
10.1.2. 
Secondary Efficacy Endpoints .................................................................................... 58 
10.1.3. 
Tertiary and Pharmacodynamic Endpoints ................................................................. 58 
10.1.4. 
Exploratory Endpoints ................................................................................................ 58 
10.1.5. 
Safety Endpoints ......................................................................................................... 59 
10.2. 
Sample Size Considerations ........................................................................................ 59 
10.3. 
Populations .................................................................................................................. 59 
10.4. 
Definition of Baseline ................................................................................................. 59 
10.5. 
Interim Analysis .......................................................................................................... 59 
10.6. 
Planned Methods of Analysis ..................................................................................... 60 
10.6.1. 
Demographic and Baseline Characteristics ................................................................. 60 
10.6.2. 
Safety Analysis ........................................................................................................... 60 
10.6.3. 
Efficacy Analysis ........................................................................................................ 60 
10.6.4. 
Pharmacokinetic Analysis ............................................................................................ 61 
10.6.5. 
Additional Analyses .................................................................................................... 62 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS.............................................. 62 
11.1. 
Informed Consent ........................................................................................................ 62 
11.2. 
Ethical Conduct of the Study ....................................................................................... 62 
11.3. 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) .................. 63 
11.4. 
Patient Confidentiality................................................................................................. 63 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ............................................... 63 
12.1. 
Protocol Amendments ................................................................................................. 63 
12.2. 
Study Termination ....................................................................................................... 64 
12.3. 
Study Documentation and Storage .............................................................................. 64 
12.4. 
Study Monitoring ........................................................................................................ 64 
12.5. 
Language ..................................................................................................................... 65 
12.6. 
Compensation for Injury ............................................................................................. 65 
13. 
REFERENCES ............................................................................................................ 66 
14. 
APPENDICES ............................................................................................................ 68 
APPENDIX A. SCHEDULE OF PROCEDURES ...................................................................... 69 
APPENDIX B. LIST OF LABORATORY ANALYTES ........................................................... 75 
APPENDIX C. PK SAMPLING SCHEDULE ........................................................................... 77 
APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING TO 
LABORATORY ABNORMALITIES ....................................................................... 79 
 
 
 
TABLE OF TABLES 
Table 1 
Sampling Schedule: Day of Oral Glucose Tolerance Test (OGTT) .......................... 37 
Table 2 
Study Drug Characteristics .......................................................................................... 40 
Table 3 
Study Drug Dosing Information .................................................................................. 41 
Table 4 
Additional Labs to be Performed in the Event of a Platelet Count 
< 75,000/mm3 ...................................................................................................................................................................... 44 
Table 5 
Actions in Patients with Low Platelet Count .............................................................. 47 
TABLE OF FIGURES 
Figure 1 
Design of GalNAc Conjugated Chimeric 2ʹ-MOE Phosphorothioate 
Oligonucleotides (MOE-Gapmer)............................................................................... 25 


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PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 766720-CS2 
Protocol Title: 
A Double Blind, Placebo-Controlled, Phase 2 Study to 
Assess the Safety, Tolerability, and Efficacy of ISIS 766720 
(IONIS GHR-LRX, an Antisense Inhibitor of the Growth Hormone 
Receptor) Administered Once Every 28 Days for 16 Weeks in 
Patients with Acromegaly Being Treated with Long-acting 
Somatostatin Receptor Ligands (SRL) 
Amendment Number: 
4 
Amendment Date: 
18 May 2020 
 
 
The main purposes of this amendment are to: (1) update several requirements for patient 
eligibility for the study based on available safety data to date, (2) formalize the procedures added 
to the protocol based on the guidance given in the May 1, 2020 Memo to Investigators entitled 
“ISIS 766720-CS2: Coronavirus COVID-19 Guidance – Follow-Up”, and (3) update the 
protocol to reflect the decision to conduct Cohort D. 
1. 
Patient Eligibility Updates: 
a. Three (3) entry criteria have been revised that were originally exclusionary until 
experience with ISIS 766720 in the acromegaly population was obtained which is now 
available and includes the acceptable safety profile observed from two ongoing clinical 
trials including 39 patients from Cohorts A, B, C and D as well as 31 patients in the 
Open-Label Trial ISIS 766720-CS3 (up to 9 months) to date. 
• The safety data demonstrate a lack of hypoglycemia, therefore, insulin is now 
permitted at screening and during the study. Exclusion Criteria #19 and #20 have 
been revised to reflect this. Section 8.10.1 Concomitant Therapy has been updated to 
reflect this change. 
• The safety data demonstrate no adverse effect on the hypothalamic-pituitary-adrenal 
axis (HPA) as ACTH and cortisol levels remained within normal limits pre- and post- 
dosing, therefore, two exclusion criteria have been revised: 
i. A morning blood cortisol level of < 10 mcg/dL was initially considered 
exclusionary in order to ensure that patients did not have suppression of HPA axis 
until sufficient data to assess the effects of ISIS 766720 on the HPA axis in 
acromegaly patients was available. Further, morning cortisol levels are variable 
and cannot establish the presence or absence of adrenal insufficiency with 
certainty – for example, many clinicians consider a value of cortisol < 7-8 mcg/dL 
as indicative of adrenal insufficiency. Most clinicians assess adrenal 
insufficiency based on cortisol levels coupled with clinical judgement that 
evaluates signs and symptoms and may use a cosyntropin suppression test (if 
available). Taken together, Exclusion Criteria #10h has been changed to remove 


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the specific numeric cut-off value for a morning blood cortisol level of 
<10 mcg/dL and replaced with the exclusion of a patient if an abnormal morning 
cortisol test is consistent with symptomatic adrenal insufficiency based on 
Investigator judgement. 
ii. 
Patients on glucocorticoid replacement therapy are now permitted. Exclusion 
Criteria #19 has been revised to reflect this. Section 8.10.1 Concomitant Therapy 
has been updated to reflect this change and specifies that changes in a stable 
regimen of glucocorticoid replacement therapy may be considered during the 
study in consultation with the Sponsor Medical Monitor or designee. 
b. The protocol contraceptive requirements for male patients has been revised to clarify 
the requirements for a male patient with a non-pregnant female partner. Inclusion 
Criteria #5d and Section 6.3.1 Contraception Requirements are revised accordingly. 
2. Procedures added based on Memo to Investigators dated May 1, 2020 
The changes will allow for additional visits and procedures to be conducted via home health 
visits when in-clinic visits are affected due to local precautions and restrictions related to 
COVID-19 Pandemic (or other circumstances) that may limit the patient’s ability to go to the 
clinic. Specifically, the following has been added to Section 6 Study Procedures and 
Appendix A Schedule of Procedures: 
• The option to conduct a Home Health Care visit in place of a clinic visit. This can be 
accommodated in consultation with the Sponsor 
• A Patient Contact Option (e.g., phone, text, email or video) was added to assess 
adverse events and changes in concomitant medications if a visit cannot be performed 
3. 
Based on the safety and efficacy observed in lower dose levels, the decision to conduct 
Cohort D was communicated to sites in September 2019. The protocol has been revised to 
remove the reference that Cohort D “may be conducted” (not included in the list of changes 
below). 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact the subject safety, exposure, or the overall study design. 
A list of changes to the protocol are BOLDED and underlined below: 


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Protocol Section 
Description of Change 
Rationale 
PROTOCOL 
SYNOPSIS and 
Section 5 
Inclusion 
Criteria, 
Section 6.3.1 
Inclusion Criteria 
5d. 
Males must be surgically sterile, abstinent or, if engaged in sexual relations 
with a female of child-bearing potential, the patient or the patient’s non- 
pregnant female partner must be using 1 highly effective contraceptive 
method (refer to Section 6.3.1) from the time of signing the informed consent 
form until 14 weeks after the last dose of Study Drug. 
6.3.1 
Contraception Requirements 
The update removed the 
protocol mandated 
contraception requirement 
for patient’s female partner 
and added that female 
partner use of a highly 
contraceptive method as an 
alternative option to meet a 
male patient’s 
contraception requirement. 
All male patients and WOCBP must refrain from sperm/egg donation and 
practice highly effective contraception from the time of signing the informed 
consent form until 14 weeks after their last dose of study treatment. 
Male patients engaged in sexual relations with a female of child-bearing 
potential must also encourage their female partner to use contraception from 
the time of signing the informed consent until 14 weeks after the patient’s last 
dose of study treatment. 
If the male patient’s non-pregnant female partner is using a highly 
effective contraception method, from the time of signing the informed 
consent form until 14 weeks after their last dose of study treatment, the 
male patient’s contraception requirement is considered fulfilled. 
Synopsis: Study 
Population 
Section 5.2 
Exclusion 
Criteria 
Exclusion Criteria 
10h. Morning (prior to 9 AM) blood cortisol < 10 mcg/d: (280 nmol/L) 
Abnormal morning cortisol test consistent with symptomatic 
adrenal insufficiency based on Investigator judgement 
19. Patients may not have insulin, chronic systemic use of glucocorticoids, 
weight loss medications or participate in weight loss programs within 
2 months before randomization and during study participation. 
Patients on glucocorticoid replacement therapy 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. 
See rationale in the Patient 
Eligibility updates detailed 
above for changes in 
Exclusion Criteria 
20. Patients on anti-diabetes medications must be on a stable dose and 
regimen for ≥ 3 months prior to screening and throughout the trial. 
Patients taking GLP-1 agonists or insulin can be allowed with prior 
consultation with the Sponsor Medical Monitor. 


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Protocol Section 
Description of Change 
Rationale 
Section 6.1.2 
Baseline and 
Treatment Period 
Section 6.1.3 
Post-Treatment 
Period 
Additional text was added: 
In consultation with the Sponsor, a Home Health Care visit may be 
conducted for a study visit that was intended to be a clinic visit. A 
confirmation of Study Drug dosing by the Home Health Provider should 
be obtained and documented in source within 48 hours. It is preferable 
that the entire visit is conducted, however, the following assessments may 
be omitted from the Home Health Care visit: ECG, body weight, 
physical exam, ring size, and OGTT. Any assessments not performed at 
the Home Health Care visit should be attempted at the next clinic visit. 
Added to allow flexibility 
for Home Health Care visits 
to be conducted to decrease 
patient burden due to 
Covid-19 related 
restrictions or other 
circumstances that arise 
during the study that will 
require Sponsor 
consultation 
If a visit cannot be performed, patient contact (e.g. phone, text or video) 
is required by site personnel to assess any adverse events or changes in 
concomitant medications. 
Section 6.2.1 
Clinical 
Laboratory 
Assessments 
Appendix A 
Footnote 9 
Additional text added: 
At any time, the Sponsor Medical Monitor or designee may request both 
a central and local lab collection in parallel to assess patient safety. 
To reduce patient burden 
for possible unscheduled 
visits due to safety 
follow-up, local lab 
collections in parallel with 
central lab collection was 
added 
Section 8.10.1: 
Concomitant 
Therapy 
Disallowed Concomitant Therapy: 
The following medications or interventions cannot be started during the trial: 
other approved or investigational medications for acromegaly (e.g., 
pasireotide, dopamine agonist or pegvisomant), insulin, anti-obesity agents or 
weight loss programs, and chronic systemic use of glucocorticoids. 
Section updated to allow 
insulin use as concomitant 
medication. 
Appendix A 
A schedule item for Patient Contact Option was added: 
If a visit cannot be performed, patient contact is required by site 
personnel to assess Adverse Events and Concomitant Medications 
An additional footnote was added: 
B 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. These assessments should be attempted at the next 
clinic visit if not performed at the Home Health Care visit. A 
confirmation of ISIS 766720 dosing by the Home Health Provider 
should be obtained and documented in source within 48 hours 
Footnote 20 – removed as Home Health Care is covered in Footnote B 
now 
20. Home Health Care Option can be used for retesting only 
Added to allow flexibility 
for Home Health Care visits 
to be conducted to decrease 
patient burden due to 
Covid-19 related 
restrictions or other 
circumstances that arise 
during the study that will 
require Sponsor 
consultation 


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PROTOCOL SYNOPSIS 
 
Protocol Title 
A Double Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability, and Efficacy of 
ISIS 766720 (IONIS GHR-LRX an Antisense Inhibitor of the Growth Hormone Receptor) 
Administered Once Every 28 Days for 16 Weeks in Patients with Acromegaly Being Treated with 
Long-acting Somatostatin Receptor Ligands (SRL) 
Study Phase 
2 
Indication 
Acromegaly 
Primary Objectives 
To evaluate the efficacy of ISIS 766720 subcutaneous injection on serum insulin-like growth factor 1 
(IGF-1) vs. placebo as an add-on therapy to long acting somatostatin receptor ligands (SRL) octreotide 
or lanreotide. 
To evaluate the safety and tolerability of ISIS 766720 subcutaneous injection vs. placebo on add-on 
therapy of SRL. 
Secondary Objective 
To evaluate the effect of ISIS 766720 to normalize serum IGF-1 levels. 
Tertiary Objectives 
To evaluate the effects of ISIS 766720 subcutaneous injection on growth hormone (GH) over time. 
To evaluate the effects of ISIS 766720 subcutaneous injection on the following pharmacodynamic 
endpoints: fasting plasma growth hormone binding protein (GHBP), acid labile subunit (ALS), insulin 
growth factor binding protein 3 (IGFBP3). 
Exploratory Objectives 
To evaluate the effects of ISIS 766720 subcutaneous injection on the following glycemic parameters: 
HbA1c, fasting plasma glucose, glycated albumin as well as glucose, insulin and C-peptide during 
2-hour oral glucose tolerance test (OGTT). 
To evaluate the effects of ISIS 766720 subcutaneous injection on the clinical endpoints using 
acromegaly quality of life questionnaire (AcroQoL), acromegaly symptoms and treatment score 
questionnaire (ASTS) and ring size measurement. 
To evaluate PK exposure over time and potential PK/PD correlation on relevant biomarkers. 
Study Design 
This is a randomized, double blind, placebo-controlled, multi-center study of ISIS 766720 or placebo 
as add-on to SRL 
Number of Patients 
Approximately 60 patients are planned to be randomized in this study. The needed evaluable patients 
per cohort and their corresponding randomization ratio (ISIS 766720 vs. placebo) are listed as follows: 
Study Population 
The Sponsor Medical Monitor may be consulted if any questions arise regarding the inclusion or 
exclusion criteria. 
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 documented diagnosis of Acromegaly*. Aged 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 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 for age and sex at time of diagnosis (serum IGF-1 level and MRI at diagnosis 
will be collected in the CRF). 
Cohort 
Number of 
Patients 
Randomization 
Ratio 
A 
15 
2:1 
B 
15 
2:1 
C 
12 
5:1 
D 
12 
5:1 


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Study Population 
Continued 
Inclusion Criteria Continued 
3. Patients must be on stable maximum or maximally tolerated dose of SRL (lanreotide Autogel or 
octreotide LAR, per treating physician judgment) every 28 days* for a minimum of 3 months 
prior to screening and will be required to continue their stable dose of SRL throughout the study. 
In accordance with US approved prescribing information, the maximal dose recommended per 
the package insert for lanreotide Autogel is 120 mg every 28 days and for octreotide LAR is 
40 mg every 28 days (the reason for the maximally tolerated dose of SRL will be collected in the 
CRF). SRL dose should not exceed the maximum dose as approved in the local region (as 
indicated in the SRL label). Prior use of other medications for treating acromegaly (pasireotide, 
dopamine agonist or pegvisomant) is allowed but not within 6 weeks of screening 
*Patients who are on a stable monthly dosing regimen, but not exactly every 28 days will be 
considered for inclusion to this study. Patients who are on a stable regimen, that is not monthly 
e.g., every 3 weeks or every 6 weeks are excluded. 
4. At Screening, serum IGF-1 (performed at central lab) between 1.3 to 5 × ULN, inclusive, 
adjusted for age and sex 
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 FSH levels in the postmenopausal range for the laboratory 
involved); 
c. 
abstinent 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 informed consent form until 14 weeks 
after the last dose of Study Drug administration 
Males must be surgically sterile, abstinent or, if engaged in sexual relations with a female 
of child-bearing potential, the patient must be using 1 highly effective contraceptive 
method (refer to Section 6.3.1) from the time of signing the informed consent form until 
14 weeks after the last dose of Study Drug 
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 abnormalities in medical history (e.g., previous acute coronary syndrome 
within 6 months of screening, major non-pituitary surgery within 3 months of screening) or from 
screening physical examination 
2. Patients who received surgery for pituitary adenoma within the last 6 months before the trial, 
and/or planning to receive surgery during the trial 
3. Patients who received radiotherapy for pituitary adenoma within the last 3 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 or CT scan protocol at screening or within 6 months of screening 
5. Evidence of decompensated cardiac function per medical judgement and/or NYHA class 3 or 4 


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Study Population 
Continued 
Exclusion Criteria Continued 
6. Clinical evidence of symptomatic hyperprolactinemia that would necessitate treatment 
7. Symptomatic cholelithiasis, and/or choledocholithiasis 
8. Have a diagnosis of Gilbert’s disease 
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 clinically-significant abnormalities in 
screening laboratory values that would render a patient unsuitable for inclusion. (abnormalities 
may be retested for eligibility purposes) 
a. 
Urine protein/creatinine (P/C) ratio ≥ 500 mg/g. In the event of P/C ratio 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. 
ALT or AST > 1.2 × ULN, bilirubin > ULN; alkaline phosphatase > 3 × ULN 
d. 
eGFR < 45 mL/min/1.73m2 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 < LLN 
f. 
Abnormal thyroid function tests must be approved by the Sponsor Medical Monitor 
g. 
HbA1c > 10% 
h. 
 Abnormal morning cortisol test consistent with 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. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or 
chronic hepatitis B 
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 with a history of other malignancies 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 
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 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 a duration ≥ 4 month has elapsed since dosing 
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 


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Study Population 
Continued 
Exclusion Criteria Continued 
19. Patients may not have chronic systemic use of glucocorticoids, weight loss medications or 
participate in weight loss programs within 2 months before randomization and during study 
participation. Patients on glucocorticoid replacement therapy 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 
20. Patients on anti-diabetes medications must be on a stable dose and regimen for ≥ 3 months prior 
to screening and throughout the trial. Patients taking GLP-1 agonists or insulin can be allowed 
with prior consultation with the Sponsor Medical Monitor 
21. Patients on estrogen containing medications must be on a stable dose and regimen for ≥ 3 months 
prior to screening and throughout the trial 
22. Use of oral anticoagulants, unless the dose has been stable for 4 weeks prior to the first dose of 
Study Drug and regular clinical monitoring is performed during the trial 
23. 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 
24. 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 
Treatment Groups 
There will be up to 4 treatment groups: 
Cohort A: ISIS 766720 60 mg or placebo (2:1) + SRL every 28 days. In addition, a booster dose of 
Study Drug is administered on Day 15. 
Cohort B: ISIS 766720 80 mg or placebo (2:1) + SRL every 28 days. In addition, a booster dose of 
Study Drug is administered on Day 15. 
Cohort C: ISIS 766720 120 mg or placebo (5:1) + SRL every 28 days. In addition, a booster dose 
of Study Drug is administered on Day 15. 
Cohort D: ISIS 766720 160 mg or placebo (5:1) + SRL every 28 days. In addition, a booster dose 
of Study Drug is administered on Day 15. 
Study Drug Dosage 
and Administration 
ISIS 766720 (100 mg/mL) and placebo will be supplied in vials of 0.8 mL. Study Drug (ISIS 766720 
or placebo) injection volumes will be 0.6 and 0.8 mL for Cohort A (60 mg) and Cohort B (80 mg) 
respectively. For Cohort C the total injection volume will be 1.2 mL (120 mg) and for Cohort D the 
total injection volume will be 1.6 mL (160 mg). The administration of Study Drug for Cohort C and 
D may be delivered as a single injection or 2 non-contiguous injections (If 2 non-contiguous 
injections, volumes such as, 0.6 mL × 2 for 120 mg and 0.8 mL × 2 160 mg, may be used). All Study 
Drug injections will be subcutaneously administered in the clinic. 
The patient’s stable SRL regimen will continue throughout study participation and ideally 
administered on the same day as the Study Drug. If the SRL cannot be administered in the Clinic, the 
administration of SRL relative to Study Drug should be consistent (e.g., 1-3 days after the Study 
Drug administration during the Treatment Period) throughout the trial. The date and time of each 
SRL dose will be documented by the patient in a SRL dosing diary and provided to the study center 
staff at subsequent visits. 
Rationale for Dose 
and Schedule Selection 
The dose levels of 60 mg/q28 days and 80 mg/q28 days were selected based on the safety, 
pharmacokinetic, and pharmacodynamic data from ISIS 766720 Phase 1 study in healthy volunteers. 
The Phase 1 study evaluated ISIS 766720 doses of 40 mg, 60 mg, and 80 mg administered as single 
doses and 10 mg, 20 mg and 30 mg administered as 4 doses over a 2-week period that were found to 
be generally well-tolerated and induced significant reductions in GHBP, a biomarker of GHR 
inhibition. The safety data obtained in the Phase 1 study (ISIS 766720-CS1) as well as the clinical 
experience with several other 2ʹ-MOE modified ASOs (Sewell et al. 2002; Chi et al. 2005; Kastelein 
et al. 2006) and GalNAc conjugated ASOs (Viney et al. 2016; Graham et al. 2017) supports the 
dosing regimen planned for this Phase 2 study. 


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Rationale for Dose 
and Schedule Selection 
Continued 
The every 28-day dosing regimen (Day 1, 29, 57, 85 and 112) is supported by the long plasma half- 
life of this compound (approximately 2-3 weeks) and significant GHBP reductions observed after 
single doses of 60 mg and 80 mg in the Phase 1 study. With every 28-day dosing regimen, steady- 
state concentrations are expected to be reached approximately after 4-5 doses. Therefore, a booster 
dose, administered 2 weeks after the first dose (Day 15), is included to achieve steady-state 
concentrations earlier in the Treatment Period to allow assessment of efficacy with the proposed 
dosing period (after steady-state concentrations are achieved. 
The range of dosing proposed for the present study will provide the equivalent drug exposure of 
30 mg and 40 mg administered weekly for the first 4 weeks and 15 mg and 20 mg administered 
weekly for the remaining 12 weeks respectively for Cohort A (60 mg) and Cohort B (80 mg). The 
highest dose selected for this study, 80 mg every 28 days (e.g., 20 mg per week), is predicted to 
decrease growth hormone receptor expression aiming for at least 50% reduction in serum IGF-1 
levels in acromegaly patients. 
The dose level of 120 mg/q28 day, and potentially 160 mg/q28 day, have been added to assess the 
safety and efficacy of higher doses of ISIS 766720. Based on all available data from the nonclinical 
toxicology program, the no-observed-adverse-effect-level (NOAEL) for ISIS 766720 in the monkey 
was determined to be 30 mg/kg based on the weekly study for 16 weeks and the monthly dosing 
regimen study for 9 months. This provides a therapeutic margin of up to 35-fold for an approximate 
2.3 mg/kg/month (160 mg/month) clinical dose based on plasma AUC (extrapolated from the 
Phase 1, 80 mg data). 
Each patient will receive 6 SC injections of Study Drug in the clinic during the 16-week Treatment 
Period on Days 1, 15, 29, 57, 85 and 112. The 16-week treatment duration of the trial is supported by 
the ISIS 766720 nonclinical 16-week toxicology studies (See Investigators Brochure) and by 
previous long-term weekly clinical dosing studies with several other 2′-MOE-modified ASOs. 
The SRL dosing regimen will be every 28 days and can be administered in the clinic on Days 1, 29, 
57, 85 and 112 during the Treatment Period and will continue monthly during the Post-Treatment 
Period. If the SRL cannot be administered in the Clinic, the administration of SRL relative to Study 
Drug should be consistent (e.g., same number of days [1 to 3 days] post Study Drug administration) 
throughout the trial. The date and time of each SRL dose administered outside of the clinic will be 
documented by the patient in a SRL dosing diary and provided to the study center staff at subsequent 
visits. 
Study Visit Schedule 
and Procedures 
Detailed information regarding the study procedures is outlined in Section 6, Appendix A, 
Appendix B, and Appendix C. 
The study for an individual patient will generally consist of the following periods: 
• 
A ≤ 9-week Screening Assessment Period 
• 
A 16-week Treatment Period during which Study Drug will be administered as a once-every- 
28 days SC injection (except during Month 1 where a booster dose is administered on Day 15) 
• 
A 14-week Post-Treatment Evaluation Period 
Once in the Post-Treatment Period, patients who meet eligibility requirements for the open-label 
extension (OLE) study may elect to enroll in the OLE study and will need to sign the IRB/IEC 
approved informed consent. Patients not participating in the OLE study will enter the 14-week Post- 
Treatment Evaluation Period. 
Laboratory and other study procedures will be performed to assess eligibility during the Screening 
Periods. Safety and tolerability will be assessed biweekly while efficacy, exploratory and plasma PK 
assessments will be conducted periodically during the Treatment Period of the study. During the 
Post-Treatment Period, safety, exploratory and PK will be assessed for 14 weeks. (Schedule of 
Events in Appendix A and Appendix B). 
A 2-hour OGTT will be performed (3×) during the study (see Appendix A for details). 
Assessment of acromegaly clinical symptoms, patient reported outcome, and ring size measurement 
will be monitored during the Treatment Period and Post-Treatment Period. 


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Safety and 
Tolerability 
Evaluations 
The safety and tolerability of ISIS 766720 will be assessed by determining the incidence, severity, 
dose-relationship of adverse effects and changes in laboratory, ECG, and physical exam evaluations. 
Safety results in patients dosed with ISIS 766720 will be compared with those from patients dosed 
with placebo. The safety and tolerability profile of the Study Drug (including liver, renal function, 
platelet, hypoglycemia and hyperglycemia,) will be monitored regularly during the Treatment Period 
and at scheduled visits in the Post-Treatment Period. 
Efficacy Evaluations 
Assessment of the effects of ISIS 766720 on serum IGF-1 percent change from Baseline to 28 days 
after the last dose (Study Visit PTWk5) 
Pharmacokinetic 
Evaluations 
The plasma pharmacokinetics of ISIS 766720 (as total full-length ASO, from fully conjugated to 
unconjugated ISIS 766720) will be assessed throughout treatment and Post-Treatment Periods. 
Plasma PK sample collection time points are detailed in Appendix C. 
Assessment of the effects of ISIS 766720 on serum IGF-1, GH, GHBP, ALS, IGFBP3, as well as 
glycemic parameters (both fasting and during OGTT) will be measured over time during the 
Treatment Period and Post-Treatment Period. 
Statistical 
Considerations 
Based on prior clinical trial experience with pegvisomant, it is estimated that the standard deviation 
of the percent change from Baseline serum IGF-1 is approximately 20%. In the Per Protocol Set, 
with at least 10 planned patients in the pooled placebo group and 10 patients in ISIS 766720 dose 
group, there will be at least 90% power to detect a 45% difference in mean percent change from 
Baseline serum IGF-1 between each of the ISIS 766720 dose groups and the pooled placebo group at 
an alpha level of 0.05. 
Eligible patients will be stratified based on screening serum IGF-1 levels (> 2.5 × ULN vs. ≤ 2.5 × 
ULN age and sex adjusted by the central lab). Cohort A and Cohort B are enrolled in parallel and 
patients will be randomized to 1 of 2 dose cohorts in a 1:1 ratio (Cohort A or Cohort B). Once 
Cohort A and B enrollment is completed, Cohort C will begin enrollment. Cohort D will be 
conducted based on the safety and efficacy observed in the lower dose cohorts. Upon randomization 
to Cohort A or Cohort B patients will be further randomized in a 2:1 ratio to receive either 
ISIS 766720 or placebo. For Cohort C and Cohort D, the randomization will be in a 5:1 ratio to 
receive either ISIS 766720 or placebo respectively. 
An interim analysis may be conducted when at least 6 patients in the higher strata (> 2.5 ×x ULN 
serum IGF-1) or at least 6 patients in the lower strata (≤ 2.5 × ULN serum IGF-1) complete the Week 
11 assessments (2 weeks after Day 57 [i.e., 3 month] dose). Additional interim analysis may also be 
conducted once each cohort completes the Post-Treatment Week 5 assessments. 
Sponsor 
Ionis Pharmaceuticals Inc. 


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TREATMENT PERIOD 
Dosing at Day 1, 15, 29, 57, 85, 112 
END-OF-STUDY 
PROCEDURES 
Day 211 (PTWk15) 
or Early termination from 
Post-Treatment (ETPT) 
 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
POST-TREATMENT 
(PT) EVALUATIONS 
Days 113 to 210 
EARLY 
TREATMENT 
TERMINATION 
(ETTX) 
SCREEN 
-63 to -1 days before Baseline 
(Day 1) 


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STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
AcroQoL 
acromegaly quality of life questionnaire 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase (SGOT) 
ASTS 
acromegaly symptom and treatment score questionnaire 
AUCt 
area under the plasma concentration-time curve from time zero to time t 
Bb 
complement factor Bb (activated complement split product) 
βhCG 
beta-subunit of human chorionic gonadotropin (pregnancy test) 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C5a 
complement factor C5a (activated complement split product) 
Cmax 
maximum concentration 
CBC 
complete blood count 
CMV 
cytomegalovirus 
CRF 
case report form 
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 
ETPT 
early termination visit from post-treatment 
ETTX 
early termination from treatment 
FAS 
full analysis set 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
GHBP 
growth hormone binding protein 
GHR 
growth hormone receptor 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
hsCRP 
CRP measured by high sensitivity assay 


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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 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRATM 
Medical Dictionary for Regulatory Activities 
MPV 
mean platelet volume 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically-significant 
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 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PPS 
Per Protocol Set 
PT 
prothrombin time 
QoL 
quality of life 
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the RNA strand in 
RNA/DNA hybrids 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
siRNA 
small interfering ribonucleic acid 
SC 
subcutaneous(ly) 
Study Day 1 
defined as the first day Study Drug product is administered to the patient 
Study Drug 
ISIS 766720 or placebo 
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 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 


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1. 
OBJECTIVES 
1.1. 
Primary Objectives 
To evaluate the efficacy of ISIS 766720 subcutaneous (SC) injection on serum insulin-like 
growth factor 1 (serum IGF-1) vs. placebo as an add-on therapy to long acting somatostatin 
receptor ligands (SRL) octreotide or lanreotide. 
To evaluate the safety and tolerability of ISIS 766720 SC injection vs. placebo as add-on therapy 
to SRL. 
 
1.2. 
Secondary Objective 
To evaluate the effect of ISIS 766720 to normalize serum IGF-1 levels. 
 
1.3. 
Tertiary Objectives 
To evaluate the effects of ISIS 766720 SC injection on GH over time. 
To evaluate the effects of ISIS 766720 SC injection on the following pharmacodynamic 
endpoints: fasting plasma GHBP, ALS, IGFBP3. 
 
1.4. 
Exploratory Objectives 
To evaluate the effects of ISIS 766720 SC injection on the following glycemic parameters: 
HbA1c, fasting plasma glucose, glycated albumin as well as glucose, insulin and C-peptide 
during 2-hour oral glucose tolerance test. 
To evaluate the effects of ISIS 766720 SC injection on the clinical endpoints using AcroQoL, 
acromegaly sign and symptom treatment score questionnaire (ASTS) and ring size measurement. 
To evaluate pharmacokinetic (PK) exposure over time and potential PK/PD correlation on 
relevant biomarkers. 
 
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 (Melmed 2006). 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 


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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). 
Surgical removal of the pituitary tumor is the primary treatment for growth hormone 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, 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). 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 
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. 2015). 
As a GalNAc conjugated 2ʹ-MOE-gapmer, ISIS 766720 has the potential to be efficacious in 
treating acromegaly by specifically reducing hepatic expression of GHR and subsequent 
lowering serum IGF-1 levels. In addition, since mature GHR is cleaved to produce the 
circulating growth hormone binding protein (GHBP) which binds to circulating GH and prolongs 
its half-life (Fisker 2006), ISIS 766720 has the potential to decrease circulating GHBP therefore 
increase GH clearance. Indeed, while preclinical mouse and primate studies with GHR antisense 
inhibitor demonstrated reduction in hepatic GHR ribonucleic acid (RNA), hepatic GHR protein 
as well as plasma IGF-1 levels, circulating GH was not increased by ASO treatment unlike 
comparative mouse studies with Somavert which caused elevations in circulating GH levels. 
Finally, due to its estimated half-life of 2 to 3 weeks, ISIS 766720 is expected to have a superior 
duration of action, decreased treatment burden, thereby contributing to the potential of 


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ISIS 766720 having an enhanced pharmacological benefit and tolerability relative to available 
acromegaly treatments. 
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 
2.3.1. 
Mechanism of Action 
ISIS 766720 is an antisense oligonucleotide (ASO) drug targeting GHR RNA. It is covalently 
bonded to triantennary N-acetyl galactosamine (GalNAc), a high-affinity ligand for the 
hepatocyte-specific asialoglycoprotein receptor (ASGPR) to form an ASO-GalNAc conjugate. 
This GalNAc-conjugate approach results in enhanced ASO delivery to hepatocytes vs. 
non-parenchymal cells in the liver and increases ASO potency by ≥ 10-fold in mice (Prakash et 
al. 2014) compared to unconjugated ASOs. The ASO portion is complementary to base-pair 
positions 154678-154697 within Intron 2 of the GHR RNA and binds to the RNA by Watson and 
Crick base pairing. The hybridization (binding) of ISIS 766720 to the cognate RNA results in 
the ribonuclease H1 (a non-specific endonuclease that catalyzes the cleavage of RNA via a 
hydrolytic mechanism) (RNase H1)-mediated degradation of the GHR RNA, thus preventing 
production of GHR protein and its cleavage product GHBP. Since GHBP is in circulation, its 
level can be used as a biomarker for GHR protein reduction by the ASO. 
 
2.3.2. 
Chemistry 
Chemically, ISIS 766720 is a synthetic oligonucleotide covalently linked to a ligand antisense 
conjugate (LICA). The oligonucleotide portion of the drug consists of 20 nucleotides (i.e., a 
20-mer). Of the nineteen (19) internucleotide linkages, fifteen (15) are 3ʹ-O to 5ʹ-O 
phosphorothioate bonds, and 4 are 3ʹ-O to 5ʹ-O phosphodiesters. The nucleotide sequence of 
ISIS 766720 is complementary to a 20-nucleotide stretch within Intron 2 of the GHR RNA 
genomic sequence (NC_000005.10) and binds to the RNA by Watson-Crick base pairing. 
Structurally, the oligonucleotide has 4 regions. Two (2) of them, the 5 nucleotides at the 5′ end 
and the 5 nucleotides at the 3′ end, are composed of 2ʹ-O-(2-methoxyethyl) (MOE)-modified 
ribonucleotides, as per Figure 1 below. 
These MOE-modified nucleotides confer (1) increased affinity to the target RNA (Altmann et al. 
1996; McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby 
increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high-dose 
toxicities thereby resulting in an improved safety profile compared to first generation antisense 
drugs containing phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000). 
The third region, the central portion of the oligonucleotide, is composed of 
10 oligodeoxynucleotides. This chimeric design is called a MOE-Gapmer, and ISIS 766720 
employs this chimeric structure to enable use of the RNase H1-mechanism for antisense activity. 
This is because while the 2ʹ-MOE modification confers increased stability and affinity, it does 
not support RNase H1-catalyzed cleavage of RNA hybridized to 2ʹ-MOE-modified nucleotides 
(McKay et al. 1999). This is caused by conformational changes induced in the heteroduplex by 
2ʹ-alkoxy:RNA hybrids that are not recognized by RNase H1 enzyme (Inoue et al. 1987; Monia 
et al. 1993). By limiting the 2′-O-(2-methoxyethyl) (2′-MOE) modification to nucleotides 


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flanking the phosphorothioate oligodeoxynucleotide core, the beneficial attributes of the 2′-MOE 
chemistry are preserved while also retaining RNase H1 recognition. 
A fourth region, comprised of a tri-antennary cluster of N-acetyl galactosamine (GalNAc) sugars, 
is linked to the 5ʹ end of ISIS 766720 via a phosphodiester linkage. The GalNAc cluster is a 
high affinity ligand for the asialoglycoprotein receptor (ASGPR), a receptor expressed primarily 
on the surface of liver hepatocytes (Stockert 1995). The GalNAc3 cluster enhances delivery of 
ISIS 766720 to liver hepatocytes over other cell types and enhances potency. After 
internalization into cells, the GalNAc cluster is metabolized to release ‘free ASO’ inside the cell 
(Prakash et al. 2014). The internucleosidic linkages are a mixture of phosphorothioate and 
phosphodiester. The phosphorothioate linkages are introduced into the DNA gap region and at 
both ends of the oligonucleotide to protect it from nuclease mediated metabolism. The mixed 
backbone design reduces the total number of phosphorothioate linkages which reduces 
non-specific interactions with proteins and further enhances potency and therapeutic index of 
GalNAc conjugated ASOs. 
 
2′-MOE wing 
2′-Deoxy gap 
2′-MOE wing 
(RNase H active) 
5’- THA-AHo 
sCsCsAoCoCs 
TsTsTsGsGsGsTsGsAsAs 
ToAoGsCsA 
THA = GalNAc cluster 
AH= Amino hexyl linker 
2′-MOE = 2′-O-(2-methoxyethyl) 
2′-Deoxy = DNA 
s = phosphorothioate diester linkage 
o = phosphate diester linkage 
Figure 1 
Design of GalNAc Conjugated Chimeric 2ʹ-MOE Phosphorothioate 
Oligonucleotides (MOE-Gapmer) 
The sequence of ISIS 766720 is shown. 
 
 
2.3.3. 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with ISIS 766720 can be 
found in the Investigator’s Brochure. A summary is included below. 
The pharmacologic effects of ASOs designed to reduce hepatic GHR messenger ribonucleic acid 
(mRNA) expression and reduce serum IGF-1 protein expression were examined in mice and in 
non-human primates. ISIS 766720 exhibits full complementarity to the human and nonhuman 
primate GHR RNA sequence. ISIS 766720 is pharmacologically active in cynomolgus monkeys, 
as shown by reductions in hepatic GHR mRNA as well as IGF-1 plasma protein levels with 


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treatment. The cynomolgus monkey is accepted as a relevant preclinical safety model for 
oligonucleotide-based therapeutics and the anticipated pharmacologic activity of ISIS 766720 in 
this species. Since the human GHR transcript is not expressed in rodents, a mouse-specific 
inhibitor of GHR RNA expression (ISIS 807403) was included in the mouse 16-week and 
6-month repeat-dose studies to evaluate the potential effects associated with exaggerated 
pharmacology in mice. 
General repeat-dose toxicology studies were conducted with ISIS 766720 in the mouse and 
monkey for 6-month and 9-month of treatment, respectively. Pharmacokinetic data confirmed 
continuous and generally dose-dependent exposure to ISIS 766720. The most noteworthy 
findings observed in mice and monkeys following ISIS 766720 treatment were, in general, non- 
specific class effects that are typical for a 2′-MOE ASO. The intended pharmacologic effect of 
dose-dependent reduction in liver GHR mRNA levels was achieved in both mice and monkeys, 
with subsequent decreases in serum IGF-1 levels, but there were no toxicologically relevant 
findings considered to be related to the pharmacologic inhibition of GHR expression in either 
species. 
 
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. 
The safety and tolerability of ISIS 766720 was evaluated in a total of 36 healthy subjects in a 
double-blinded, placebo-controlled, dose-escalation Phase 1 study ISIS 766720-CS1. Of these 
36 subjects, 27 received ISIS 766720 (9 in the single-dose cohorts and 18 in the multiple-dose 
cohorts), and 9 received placebo. ISIS 766720 was well-tolerated at doses up to 80 mg 
administered as a single-dose and 120 mg total dose (30 mg administered as 4 doses over 
2 weeks). There were no SAEs and all reported AEs were mild in severity. There were no 
dose-dependent clinically meaningful trends in laboratory assessments. 
Since GHBP is a fragment of GHR released into the circulation, reducing GHR expression with 
ISIS 766720 is expected to lower the circulating GHBP, thus making GHBP a useful biomarker 
for the activity of ISIS 766720 in healthy volunteers. Indeed, GHBP is decreased in a 
dose-dependent manner to a mean reduction of approximately 60% observed 15 days after a 
single-dose of 80 mg ISIS 766720. The effect of ISIS 766720 on IGF-1 will be evaluated in the 
current study in the relevant patient population. 
 
2.4. 
Rationale for Dose and Schedule of Administration 
The dose levels of 60 mg/q28 days and 80 mg/q28 days were selected based on the safety, PK, 
and pharmacodynamic data from ISIS 766720 Phase 1 study in healthy volunteers. The Phase 1 
study evaluated ISIS 766720 doses of 40 mg, 60 mg, and 80 mg administered as single doses and 
10 mg, 20 mg and 30 mg administered as 4 doses over a 2-week period that were found to be 
generally well-tolerated and induced significant reductions in GHBP, a potential biomarker of 
GHR inhibition. The safety data obtained in the Phase 1 study (ISIS 766720-CS1) as well as the 
clinical experience with several other 2ʹ-MOE modified ASOs (Sewell et al. 2002; Chi et al. 
2005; Kastelein et al. 2006) and GalNAc-conjugated ASOs (Viney et al. 2016; Graham et al. 
2017) supports the dosing regimen planned for this Phase 2 study. 


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The every 28-day dosing regimen (Days 1, 29, 57, 85 and 112) is supported by the long plasma 
half-life of this compound (approximately 2-3 weeks) and significant GHBP reductions observed 
after single doses of 60 mg and 80 mg. With a once-every-28-day dosing regimen, steady-state 
concentrations are expected to be reached approximately after 4-5 doses. Therefore, a booster 
dose, administered 2 weeks after the first dose (Day 15), is included to achieve steady-state 
concentrations earlier in the Treatment Period to allow assessment of efficacy after steady-state 
concentrations are achieved. 
The range of dosing proposed for the present study will provide the equivalent drug exposure of 
30 mg and 40 mg administered weekly for the first 4 weeks and 15 mg and 20 mg administered 
weekly for the remaining 12 weeks; respectively for Cohort A (60 mg) and Cohort B (80 mg). 
The highest dose selected for this study, 80 mg every 28 days (e.g., 20 mg per week), could 
decrease hepatic GHR expression resulting in at least a 50% reduction in serum IGF-1 levels in 
acromegaly patients. 
The dose level of 120 mg/q28 day, and potentially 160 mg/q28 day, have been added to assess 
the safety and efficacy of higher doses of ISIS 766720. Based on all available data from the 
nonclinical toxicology program, the no-observed-adverse-effect-level (NOAEL) for ISIS 766720 
in the monkey was determined to be 30 mg/kg based on the weekly study for 16 weeks and the 
monthly study for 9 months. This provides a therapeutic margin of up to 35-fold for an 
approximate 2.3 mg/kg/month (160 mg/month) clinical dose based on plasma AUC (extrapolated 
from the Phase 1, 80 mg data). 
Each patient will receive 6 SC injections in the clinic during the 16-week Treatment Period on 
Days 1, 15, 29, 57, 85 and 112. 
The 16-week treatment duration of the trial is supported by the ISIS 766720 nonclinical 16-week 
toxicology studies (See Investigators Brochure) and by previous long-term weekly clinical 
dosing studies with several other 2ʹ-MOE-modified ASOs. 
The SRL dosing regimen will be every 28 days and can be administered in the clinic on Days 1, 
29, 57, 85, and 112 during the Treatment Period and will continue monthly during the Post- 
Treatment Period. If the SRL cannot be administered in the Clinic, the administration of SRL 
relative to Study Drug should be consistent (e.g., same number of days [1-3 days] post-Study 
Drug administration) throughout the trial. The date and time of each SRL dose administered 
outside of the clinic will be documented by the patient in a SRL dosing diary and provided to the 
study center staff at subsequent visits. See Section 6.1.2 for SRL dosing information. 
In addition to the experience of ISIS 766720, this dose range is supported by the preclinical and 
clinical safety experience of several other 2ʹ-MOE-modified ASOs that have been safely 
administered intravenously and SC in multiple clinical studies at doses up to 1000 mg (Kwoh 
2008; Crooke et al. 2016) and for treatment durations that exceed 24 months. 
 
2.5. 
Risk Assessment 
2.5.1. 
Risk Assessment 
Given the short duration of the study, the risks associated with GHR reduction are not anticipated 
in this trial. 


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3. 
EXPERIMENTAL PLAN 
3.1. 
Study Design 
This is a double blind, placebo-controlled, Phase 2 study to assess the safety, tolerability, and 
efficacy of ISIS 766720 administered once every 4 weeks for 16 weeks to patients with 
acromegaly uncontrolled (IGF-1 level between 1.3 × to 5 × ULN) on select long-acting SRL. 
Patients will be stratified by the screening IGF-1 level (IGF-1 > 2.5 × ULN or ≤ 2.5 × ULN age 
and sex adjusted by central lab). 
 
3.2. 
Number of Study Centers 
This study will be conducted at multiple centers worldwide at approximately 40 sites. 
 
3.3. 
Number of Patients 
Approximately 60 patients are planned to be randomized in this study. The number of evaluable 
patients per cohort and their corresponding randomization ratio (ISIS 766720 vs. Placebo) are 
listed as follows: 
 
Cohort 
Number of Patients 
Randomization Ratio 
A 
15 
2:1 
B 
15 
2:1 
C 
12 
5:1 
D 
12 
5:1 
 
 
3.4. 
Overall Study Duration and Follow-up 
The study for an individual patient will generally consist of the following periods: 
• A ≤ 9-week Screening Assessment Period 
• A 16-week Treatment Period during which Study Drug will be administered as a once 
every 4-week SC injection (except during Month 1 where a booster dose is 
administered on Day 15) 
• A 14-week Post-Treatment Evaluation Period 
Once in the Post-Treatment Period, patients who meet eligibility requirements for the open-label 
extension (OLE) study may elect to enroll in the OLE study and will need to sign the IRB/IEC 
approved informed consent. Patients not participating in the OLE study will enter the 14-week 
Post-Treatment Evaluation Period. 
Patients may be required to attend additional visits for monitoring of adverse events (AE) or 
abnormal investigation results. The frequency of additional monitoring will be determined by 
the Study Medical Monitor in consultation with the Investigator. 


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3.4.1. 
Screening 
Patient eligibility for the study will be determined within 63 days prior to study entry. Sponsor 
Medical Monitor or designee approval is required for patients to enter the Treatment Period. 
 
3.4.2. 
Treatment 
Eligible patients will report to the Study Center for Study Drug administration per schedule of 
procedures in Appendix A. Study Drug and SRL will be dosed in clinic every 28 days (in 
addition, a booster dose of Study Drug is administered on Day 15) while additional visits to 
collect safety assessments (Day 43, Day 71 and Day 99) could be completed either in clinic or by 
home health care visit. If the SRL cannot be administered in the Clinic, the administration of 
SRL relative to Study Drug should be consistent (e.g., same number of days (1 to 3 days) post- 
Study Drug administration) throughout the trial with date and time documented by the patient in 
a dosing diary. The treatment duration is 16 weeks. See Section 6.1.2 for timing of SRL dosing. 
3.4.3. 
Post-Treatment 
Patients are to return to the Study Center for follow-up visits for 14 weeks after last injection per 
schedule of procedures in Appendix B. Any patient who receives at least 1 dose of Study Drug 
(ISIS 766720 or placebo) will be required to complete the Post-Treatment Period. The final 
study visit will be 14 weeks after the last injection (PTWk15). 
 
3.5. 
End-of-Study 
The End-of-Study is defined as last patient, last visit when all patients complete the last visit of 
the Post-Treatment Period. 
3.6. 
Data and Safety Monitoring Board 
This trial will not have a Data and Safety Monitoring Board. 
 
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, 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 
throughout the entire trial. In the event the patient is re-consented and re-screened the patient 


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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 
approval by Sponsor Medical Monitor. No patient may begin treatment prior to randomization 
and assignment of a unique patient identification number. 
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 to 1 of 2 dose cohorts 
in a 1:1 ratio (Cohort A or Cohort B). Within each dose cohort, patients will be further 
randomized to receive ISIS 766720 or placebo in a 2:1 ratio. 
Eligible patients for Cohorts C and D will be stratified based on screening IGF-1 levels 
(≤ 2.5 × ULN or > 2.5 × ULN, age and sex adjusted by central lab). Patients will be randomized 
to receive ISIS 766720 or placebo in a 5:1 ratio. 
After enrollment in Cohort A and B is completed, Cohort C will begin enrollment. Cohort D 
will be conducted based on the safety and efficacy results of the lower-dose cohorts 
 
4.3. 
Replacement of Patients 
Patients who withdraw from the study will not be replaced. 
 
4.4. 
Unblinding of Treatment Assignment 
The Sponsor and representatives, and all patients, and Study Center personnel related to the 
study, will be blinded throughout the study. However, if a patient has suffered a related Serious 
Adverse Event (SAE) (as defined in Section 9.3.3), and/or when knowledge of the treatment 
assignment will impact the clinical management of the patient, the Investigator will have the 
ability to unblind the treatment assignment for that patient using the automated IRT (Interactive 
Response Technology) system. The Sponsor or designee will be informed of the unblinding of a 
patient within 24 hours. An unblinded randomization schema will be maintained securely at the 
Sponsor’s designated vendor. In addition, all suspected unexpected serious adverse reactions 
(SUSARs) will be unblinded by the Sponsor or designee for the purpose of regulatory reporting 
(see Section 9.2). 
Every reasonable attempt should be made to complete the early termination study procedures and 
observations (see Appendix A and Appendix B) prior to unblinding if needed, as knowledge of 
the treatment arm could influence patient assessment. 
In addition, the Ionis Drug Safety Oversight committee, chaired by the Chief Medical Officer, 
will also have the ability to request for unblinding the treatment assignment if needed for safety 
and data interpretation. 


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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. 
The Sponsor Medical Monitor may be consulted if any questions arise regarding the inclusion or 
exclusion criteria. 
 
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 documented diagnosis of Acromegaly*. Aged 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 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 for age and sex at time of diagnosis (serum IGF-1 
level and MRI at diagnosis will be collected in the CRF) 
3. Patients must be on stable maximum or maximally tolerated dose of SRL (lanreotide 
Autogel or octreotide LAR, per treating physician judgment) every 28 days* for a 
minimum of 3 months prior to screening and will be required to continue their stable dose 
of SRL throughout the study. In accordance with US approved prescribing information, 
the maximal dose recommended per the package insert for lanreotide Autogel is 120 mg 
every 28 days and for octreotide LAR is 40 mg every 28 days (the reason for the 
maximally tolerated dose of SRL will be collected in the CRF). SRL dose should not 
exceed the maximum dose as approved in the local region (as indicated in the SRL label). 
Prior use of other medications for treating acromegaly (pasireotide, dopamine agonist or 
pegvisomant) is allowed but not within 6 weeks of screening 
* Patients who are on a stable monthly dosing regimen, but not exactly every 28 days 
will be considered for inclusion to this study. Patients who are on a stable regimen 
that is not monthly e.g., every 3 weeks or every 6 weeks are excluded. 
4. At screening, serum IGF-1 (performed at central lab) between 1.3 to 5 × ULN, inclusive, 
adjusted for age and sex 
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 FSH levels in the postmenopausal range for 
the laboratory involved) 
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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 until 14 weeks after the last dose of Study Drug 
administration 
Males must be surgically sterile, abstinent or, if engaged in sexual relations with a 
female of childbearing potential, the patient must be using 1 highly effective 
contraceptive method (refer to Section 6.3.1) from the time of signing the informed 
consent form until 14 weeks after the last dose of Study Drug. 
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 abnormalities in medical history (e.g., previous acute coronary 
syndrome within 6 months of screening, major non-pituitary surgery within 3 months of 
screening) or from screening physical examination 
2. Patients who received surgery for pituitary adenoma within the last 6 months before the 
trial, and/or planning to receive surgery during the trial 
3. Patients who received radiotherapy for pituitary adenoma within the last 3 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 or CT scan protocol at screening or within 6 months 
of screening 
5. Evidence of decompensated cardiac function per medical judgement and/or NYHA 
class 3 or 4 
6. Clinical evidence of symptomatic hyperprolactinemia that would necessitate treatment 
7. Symptomatic cholelithiasis, and/or choledocholithiasis 
8. Have a diagnosis of Gilbert’s disease 
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 clinically-significant abnormalities 
in screening laboratory values that would render a patient unsuitable for inclusion. 
(abnormalities may be retested for eligibility purposes) 
a. Urine protein/creatinine (P/C) ratio ≥ 500 mg/g. In the event of P/C ratio above this 
threshold eligibility may be confirmed by a quantitative total urine protein 
measurement of < 1000 mg/24 hr 


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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. ALT or AST > 1.2 × ULN, bilirubin > ULN; alkaline phosphatase (ALP) > 3 × ULN 
d. eGFR < 45 mL/min/1.73m2 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 < LLN 
f. Abnormal thyroid function tests must be approved by the Sponsor Medical Monitor 
g. HbA1c > 10% 
h.  Abnormal morning cortisol test consistent with 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. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
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 with a history of other malignancies 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 
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 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 a duration 
≥ 4 month has elapsed since dosing 
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 glucocorticoids, weight loss medications 
or participate in weight loss programs within 2 months before randomization and during 
study participation. Patients on glucocorticoid replacement therapy 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 


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20. Patients on anti-diabetes medications must be on a stable dose and regimen for 
≥ 3 months prior to screening and throughout the trial. Patients taking GLP-1 agonists or 
insulin can be allowed with prior consultation Sponsor Medical Monitor 
21. Patients on estrogen containing medications must be on a stable dose and regimen for 
≥ 3 months prior to screening and throughout the trial 
22. Use of oral anticoagulants, unless the dose has been stable for 4 weeks prior to the first 
dose of Study Drug and regular clinical monitoring is performed during the trial 
23. 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 
24. 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 
collected as part of the demographic information for all screened patients during the Screening 
Period. Up to a 9-week Screening Period is provided for completing screening assessments and 
determining patient eligibility for the study. 
During the 9 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 6 months prior to screening. If MRI 
is contraindicated, then a computed tomography (CT) scan is acceptable. 
Individuals may be disqualified if the result of any laboratory test is outside the range specified 
in the eligibility criteria (Sections 5.1 and 5.2) or, if no range is specified, is abnormal and 
clinically-significant (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 by the Sponsor Medical Monitor or Designee for 
eligibility purposes. 
The IGF-1 screening (and repeat IGF-1, if needed) blood sample must be drawn up to 3 days 
prior to or on the day of SRL administration. 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 approval is required for patients to enter the Treatment 
Period after eligibility is reviewed. Qualified patients will be stratified and randomized and 
proceed to the Treatment Period Week 1, Day 1 Assessments. 


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Screening failed patients may be re-screened 1 more time after the Investigator feels the reason 
for screening failure has resolved. 
 
6.1.2. 
Baseline and Treatment Period 
All randomized patients will return to the clinic for Study Drug on Day 1, Day 15 (Study Drug 
administration only), Day 29, Day 57, Day 85 and Day 112. All Study Drug administration 
occurs at the beginning of a study week with the exception that the last Study Drug 
administration is conducted at the END of the Study Week – Week 16, Day 112. The patient’s 
stable SRL regimen will continue throughout study participation and the administration of SRL 
relative to Study Drug must be consistent throughout the trial. Therefore, plan to align all SRL 
injections to be either i) the same day as the Study Drug administration, or ii) up to 3 days after 
the Study Drug administration. The IGF-1 blood sample must be taken prior to Study Drug 
administration. 
If the SRL cannot be administered in the Clinic, the date and time of each SRL dose will be 
documented by the patient in a SRL dosing diary and provided to the study center staff at 
subsequent visits. 
Safety, efficacy, PK and exploratory assessments will be performed per Appendix A, 
Appendix B, and Appendix C throughout the Treatment Period on Study Drug administration 
days and on Day 43, Day 71 and Day 99. The study procedures required on Day 43, Day 71 and 
Day 99 may be performed outside the clinic by a Sponsor selected Home Health Care 
professional. In consultation with the Sponsor, a Home Health Care visit may be conducted for a 
study visit that was intended to be a clinic visit. A confirmation of Study Drug dosing by the 
Home Health Provider should be obtained and documented in source within 48 hours. It is 
preferable that the entire visit is conducted, however, the following assessments may be omitted 
from the Home Health Care visit: ECG, body weight, physical exam, ring size, and OGTT. Any 
assessments not performed at the Home Health Care visit should be attempted at the next clinic 
visit. 
If a visit cannot be performed, patient contact (e.g., phone, text or video) is required by site 
personnel to assess any adverse events or changes in concomitant medications. 
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 usage will be 
assessed during each visit. 
A 2-hour Oral Glucose Tolerance Test (OGTT) will be conducted on Study Day 1 pre-dose and 
Day 57. The Day 1 OGTT can be conducted between Day -7 and Day-1. Acromegaly symptom 
and treatment score (ASTS) questionnaire and quality of life via AcroQoL questionnaire will be 
assessed along with ring size assessment periodically throughout the study. See Section 6.2 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 and ring size assessments prior to all 
other procedures and dosing (see Section 6.2). All blood samples should be drawn prior to Study 
Drug administration (exceptions are the post-dose samples for PK sampling). 


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During each visit, the study staff should attempt to complete all the study procedures prior to 
Study Drug administration as outlined in the Appendix A , however, if a procedure is conducted 
after Study Drug 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 2 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 16 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 3 Visit (PTWK3) 
is 14 days after the last dose and 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 
analysis, will be performed as indicated in the Appendix A, Appendix B and Appendix C. 
Patients will continue their SRL therapy, Safety and efficacy data, including any AEs and 
concomitant medications will be recorded and reviewed by the Sponsor’s Medical Monitor or 
designee. The Investigator after consultation with the Sponsor Medical Monitor or designee may 
conduct an MRI (or CT when MRI is contraindicated) in the Post-Treatment Period if clinically 
indicated. A 2-hour OGTT will be conducted at the PTWk5 visit. The AcroQoL, ASTS, and 
ring size assessment will be conducted periodically in the Post-Treatment Period. 
In consultation with the Sponsor, a Home Health Care visit may be conducted for a study 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 from the Home Health Care visit: ECG, body weight, 
physical exam, ring size, and OGTT. Any assessments not performed at the Home Health Care 
visit should be attempted at the next clinic visit. 
If a visit cannot be performed, patient contact (e.g., phone, text or video) is required by site 
personnel to assess any adverse events or changes in concomitant medications. 
Once in the Post-Treatment Period, patients who meet eligibility requirements for the open-label 
extension (OLE) study may elect to enroll in the OLE study and will need to sign the IRB/IEC 
approved informed consent. Patients not participating in the OLE study will enter the 14-week 
Post-Treatment Evaluation Period. 
Early termination patients from the Post-Treatment Period will be required to complete the ETPT 
Study procedures (Appendix A). 


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6.2. 
Study 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 
lab. The next dose of Study Drug may not be administered until a result not meeting a stopping 
rule is available. 
At any time, the Sponsor Medical Monitor or designee may request both a central and local lab 
collection in parallel to assess patient safety. 
 
6.2.2. 
Oral Glucose Tolerance Test (OGTT) 
Patients will undergo 3 OGTT procedures during the Treatment Period (X2) and Post-Treatment 
Period (X1) per Appendix A. For each OGTT procedure, patients should begin fasting for 
10 hours the evening 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 is inserted and a 5-minute period is allowed to remove 
any effects linked to the stress induced by venipuncture. Blood sampling will begin at 
Time 0-before the glucose solution is consumed. The glucose 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 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 
Study Drug is administered. 
Table 1 
Sampling Schedule: Day of Oral Glucose Tolerance Test (OGTT) 
 
Intervention 
Time (Minutes) 
OGTT Sampling 
Study Day 
D1*, 57, 141 
-5 
Catheter Insertion (if used) 
T0 = 75 grams Glucose 
Ingestion 
0 
Prior to Glucose 
ingestion 
Glucose, Insulin, C-peptide 
30 
Glucose, Insulin, C-peptide 
60 
Glucose, Insulin, C-peptide 
90 
Glucose, Insulin, C-peptide 
120# 
Glucose, Insulin, C-peptide 
* Day 1 OGTT: The Day 1 OGTT can be conducted between Day-7 and Day-1. The procedure can be conducted in 
the clinic or as arranged by a Home Health Care professional 
# After the 120-min blood draw, the fasting period is completed 


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6.2.3. 
Assessments for Acromegaly 
There are up to 3 procedures that will be conducted that assess signs, symptoms and quality of 
life (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) Acromegaly Symptoms and 
Treatment Score Questionnaire (ASTS); 3) Ring Size Assessment. AcroQoL and ASTS 
will be a paper assessment filled out by patients and the results are entered into eCRF by 
site staff 
3. It may take approximately 20 minutes to complete all 3 assessments 
Prior to filling out the AcroQoL and ASTS 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, iii) they should be aware that there are no wrong 
answers, and iv) it is important to answer all questions. 
Note: Deviations from the order of completion or relation of completion to Study Drug 
administration will not be considered a significant deviation that will impact efficacy. 
6.2.3.1. 
Acromegaly Quality of Life Questionnaire (AcroQoL) 
To assess the health-related quality of life 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. 
6.2.3.2. 
Acromegaly Symptoms and Treatment Score Questionnaire (ASTS) 
Patients will be asked to complete the assessment to monitor symptoms relating to the 
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 Study Drug and effectiveness of SRL). This 
questionnaire will take about 5 minutes to complete. Patients should leave Question #5 blank for 
Day 1 and Post-Treatment days 127, 141, 155, 183, 211, and ETPT. 
6.2.3.3. 
Ring Size Assessment 
Finger size is an objective measure of soft tissue swelling and over growth 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 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 (Barts Endocrine 2009). If possible, the 
same study personnel should conduct the ring size assessment at each clinic visit. 


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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 informed consent form until 14 weeks after 
their last dose of study treatment. 
If the male patient’s non-pregnant female partner is using a highly effective contraception 
method, from the time of signing the informed consent form until 14 weeks after their last dose 
of study treatment, the male patient’s contraception requirement 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: 
• Highly effective male contraception includes: a vasectomy with negative semen 
analysis at Follow-up, sexual abstinence†, non-pregnant female partner uses 1 highly 
effective contraceptive methods (defined below) 
• Male patients with partners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the Study Drug 
• For female partners of male patients, contraception should be encouraged 
Female patients of childbearing potential: 
• Using 1 highly effective method of contraception: 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. 


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6.3.2. 
Other Requirements 
Patients must refrain from strenuous exercise/activity (for example heavy lifting, weight training, 
intense aerobics classes, etc.) for at least 24 hours prior to each study visit and also be willing to 
refrain from alcohol or tobacco use for 8 hours prior to study visits and/or laboratory sampling. 
All patients will be required to fast for at least 8 hours before laboratory sampling and for at least 
10 hours before OGTT. 
 
7. 
STUDY DRUG 
7.1. 
ISIS 766720 or Placebo 
The characteristics of the Study Drug (ISIS 766720 or placebo) are listed in Table 2. 
The Study Drug is contained in 2 mL stoppered glass vials. The Study Drug and its storage and 
preparation instructions will be provided by the Sponsor or Designee. The Study Drug must be 
stored securely at 2-8 °Celsius and be protected from light. 
Table 2 
Study Drug Characteristics 
 
Study Drug 
ISIS 766720 
Placebo 
Strength 
100 mg/ mL 
Not Applicable 
Volume/Formulation 
0.8 mL solution per vial 
0.8 mL solution per vial 
Route of Administration 
subcutaneous 
subcutaneous 
 
 
7.2. 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged ISIS 766720 and placebo labeled in 
accordance with specific country regulatory requirements. 
 
7.3. 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of Study 
Drug (ISIS 766720 or placebo) supplies provided by the Sponsor according to Sponsor 
instruction and in accordance with institutional policy. 
 
8. 
TREATMENT OF PATIENTS 
8.1. 
Study Drug Administration 
During Treatment Period, Study Drug will be administered subcutaneously during clinic visits by 
study nurse or by Home Health professional outside of clinic per schedule of procedure in 
Appendix A. Study Drug (ISIS 766720 or placebo) injection volumes will be 0.6 and 0.8 mL for 
Cohort A (60 mg) and Cohort B (80 mg) respectively. For Cohort C the total injection volume 
will be 1.2 mL (120 mg) and for Cohort D the total injection volume will be 1.6 mL (160 mg). 


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The administration of Study Drug for Cohort C and D may be delivered as a single injection or 
2 non-contiguous injections (If 2 non-contiguous injections, volumes such as, 0.6 mL × 2 for 120 
mg and 0.8 mL × 2 for 160 mg may be used). 
Please refer to the Study Drug Manual provided by the Sponsor or designee for more detailed 
instructions for Study Drug (ISIS 766720 or placebo) preparation and administration. 
Table 3 
Study Drug Dosing Information 
 
Cohort 
Volume to Administer 
Total Dose 
Cohort A 
0.6 mL 
60 mg or placebo 
Cohort B 
0.8 mL 
80 mg or placebo 
Cohort C 
1.2 mL 
120 mg or placebo 
Cohort D 
1.6 mL 
160 mg or placebo 
 
 
8.2. 
Other Protocol-Required Drugs 
Patients must be on stable maximum or maximally tolerated dose of SRL (lanreotide Autogel or 
octreotide LAR every *28 days), for a minimum of 3 months prior to screening and will be 
required to continue their SRL throughout the study. During study participation, SRL can be 
administered during clinic visits by the staff with the location of the injection recorded in eCRF. 
*  Patients who are on a stable monthly dosing regimen, but not exactly every 28 days will 
be allowed. Patients who are on a stable regimen that is not monthly e.g., every 3 weeks 
or every 6 weeks are excluded. 
 
8.3. 
Other Protocol-Required Treatment Procedures 
There is no other protocol required treatment procedures. 
 
8.4. 
Treatment Precautions 
There are no specific treatment precautions required for this study. 
 
8.5. 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring baseline is defined as: 
• Monitoring Rules for Liver Chemistry Tests, Renal parameters, and Platelets – Unless 
otherwise specified, baseline is defined as the average of pre-dosed values 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations for ISIS 766720 as well as other ASOs. 
Confirmation Guidance: At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring criteria presented below must 
be confirmed by performing measurements (ideally in the same laboratory that performed the 


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initial measurement) on new specimens. All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection). For stopping rules, if the initial 
laboratory result is observed during the Treatment Period, the results from the re-test must be 
available prior to administering the next dose of Study Drug (ISIS 766720 or placebo). 
Re-dosing Guidance: Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available. In general, patients who do not meet the 
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 
Study Drug (ISIS 766720 or placebo), 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 x 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 ≤ 1.2 × ULN or 1.2 × 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], hepatitis C virus [HCV] antibody, CMV IgM, and 
Epstein-Barr Virus [EBV] antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody) 


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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. Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels reach 5 × ULN. 
8.5.1.1. 
Dose Adjustments 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 Study Drug 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 
If a patient’s platelet count falls by 30% or greater from Baseline or the absolute platelet count is 
100,000/mm3 or less, then the patient’s platelet counts should be monitored weekly. In case of 
platelet reduction to below 75,000/mm3, the platelet monitoring rule defined in Stopping rules 
(Section 8.6.3) should be followed. 
Treatment should be held if there is no evaluable platelet count within the 2 weeks (+7 days) 
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. 
In the event of a platelet count < 75,000/mm3, additional laboratory investigations may be 
conducted in consultation with Medical Monitor (Table 4). 


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Table 4 
Additional Labs to be Performed in the Event of a Platelet Count 
< 75,000/mm3 
 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, activated partial thromboplastin time [aPTT]) 
CBC (complete blood count) with reticulocytes and mean platelet volume (MPV) 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement: total C3, total C4, Bb, C5a 
CRP measured by high sensitivity assay (hsCRP) 
Serology for: 
hepatitis B virus (HBV), HCV, HIV (if not done for screening) 
Rubella 
cytomegalovirus (CMV) 
EBV 
Parvo B19 
Helicobacter pylori (IgG serum test) 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
Vitamin B12 
Folic Acid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
Note: The above labs may change as additional data is assessed, and sites will be updated regarding any changes 
 
8.5.3. 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically- 
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth. If a minor bleeding event occurs, 
additional testing of coagulation parameters (aPTT, PT, INR) and platelet count should be 
performed. 


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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, Urine protein/creatinine ratio > 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 
 
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, dosing of a patient 
with Study Drug (ISIS 766720 or placebo) 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. 
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 Study Drug (ISIS 766720 or placebo) 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 of protocol) 
2. Proteinuria, Urine protein/creatinine ratio > 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 


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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 Study Drug 
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 5). 
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. 
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 major 
bleeding or clinically-relevant non-major bleeding (defined below; (Schulman and Kearon 2005; 
Buller et al. 2007), dosing with Study Drug 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 Study Medical Monitor 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 Study Drug, the platelet count falls below 75,000/mm3, further dosing 
of the patient with Study Drug 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 non-major bleeding (CRNMB) is defined as overt bleeding not meeting the 
criteria for major bleeding 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 major bleeding or 
clinically-relevant, non-major bleeding events (defined above), for example excess bruising, 
petechiae, gingival bleeding on brushing teeth. 


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Table 5 
Actions in Patients with Low Platelet Count 
 
Platelet Count on Rx 
Drug Dose 
Monitoring 
> 100,000/mm3 
No action 
Monitor every 2 weeks 
≥ 75,000 - 
≤ 100,000/mm3 
No action 
Monitor every week until 3 successive values 
> 100,000/mm3 
≥ 50,000 - < 75,000/mm3 
Pause dosing 
When platelet count returns to 
> 100,000/mm3 restart dosing only if 
approved by Sponsor Medical Monitor 
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 - < 50,000/mm3 
Permanently discontinue Study Drug 
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 Study Drug 
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). 
 
 
8.7. 
Adjustment of Dose and/or Treatment Schedule 
Dose adjustments, including dose interruptions, and/or decreasing the dose will be allowed for 
safety or tolerability after consultation with the Sponsor Medical Monitor. 
Patients may have their dose interrupted in response to AEs after consultation with Study 
Medical Monitor. 


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8.8. 
Discontinuation of Study Drug 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant. Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an AE that necessitates permanent discontinuation of Study 
Drug 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6.1 to Section 8.6.3 
• The patient experiences an AE that necessitates unblinding of the Investigator or 
Sponsor to the patient’s treatment assignment 
• The patient meets any of the following Exclusion Criteria (see Section 5.2) after 
discussion with the Sponsor Medical Monitor 
− 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/CT protocol 
The reason for discontinuation of Study Drug must be recorded in the electronic Case Report 
Form (eCRF) and source documentation. 
Patients who discontinue Study Drug should complete ETTX visit and then enter the 
Post-Treatment Period) unless consent is withdrawn. Minimally, every effort should be made to 
complete the early termination study procedures (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 notified to the Sponsor. 
 
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 


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• 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. 
Disallowed Concomitant Therapy 
The following medications or interventions cannot be started during the trial: other approved or 
investigational medications for acromegaly (e.g., pasireotide, dopamine agonist or pegvisomant), 
anti-obesity agents or weight loss programs, and chronic systemic use of glucocorticoids. 
Changes to a stable regimen of estrogen containing medication or antidiabetic medications 
allowed at screening may be considered after consultation with the Sponsor Medical Monitor or 
designee. 


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Any investigational therapeutic drug or device including other marketed agents at experimental 
dosages/utilities that are being tested for treatment of glucose lowering effects – 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 
Compliance with treatment dosing and SRL dosing is to be monitored and recorded in the eCRF 
by Study Center staff. 
There is not a patient diary for this trial for all patients, but there is a SRL dosing diary for 
patients who receive SRL administration outside of the clinic. 
 
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 Safety Management Plan throughout the conduct of the clinical trial. 
9.2. 
Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of SAEs including suspected unexpected serious adverse reactions (SUSARs) per 
the International Conference on Harmonization (ICH) guidelines E2A and ICH E6. 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 the Study Drug (ISIS 766720 or placebo) 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. 
Appropriate personnel at the Sponsor or designee will unblind SUSARs for the purpose of 
regulatory reporting. The Sponsor or designee will submit SUSARs to Regulatory Agencies in 
blinded or unblinded fashion according to local law. The Sponsor or designee will submit 
SUSARs to Investigators in a blinded fashion. 


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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/Study Drug. 
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 Study Drug 
• 
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) 
9.3.2. 
Adverse Drug Reaction and Unexpected Suspected 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 
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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 one 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 
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). 
Severity and seriousness need to be independently assessed for each AE recorded on the eCRF. 
 
9.3.3.1. 
Adverse Events of Special Interest (AESI) 
For the purpose of this study, severe reductions in platelet count < 50,000/mm3 accompanied by 
a major bleeding (MB) event or clinically-relevant non-major bleeding (CRNMB) event, or 
platelet count of < 25,000/mm3 independent of a MB or CRNMB event are considered as AEs of 
special interest and should be subject to 15-day expediting reporting by the Sponsor to the 
regulatory agencies. 


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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 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 Study Drug) should be 
reported to the Sponsor or designee within 24 hours of the Study Center’s first knowledge of the 
event. The collection of SAEs will begin after the patient signs the informed consent form and 
stop at the end of the patient’s Follow-up Period which is defined as ET15/PT15 visit. When the 
Investigator is reporting by telephone, it is important to speak to someone in person versus 
leaving a message. SAEs should be reported using an Initial Serious Adverse Event Form. The 
Form should be completed, and a copy faxed or emailed 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. 
 
9.4.2. 
Non-Serious Adverse Events 
The recording of non-serious AEs will begin after the patient signs the informed consent form 
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 Case 
Report Form: 
9.4.3.1. 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 766720 or placebo) is characterized by one of 
the following: 
• Related: There is clear evidence that the event is related to the use of Study Drug, 
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 
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• Unlikely: An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship 
to Study Drug (ISIS 766720 or placebo) 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 Study Drug 
9.4.3.2. 
Severity 
The severity of AEs and SAEs relating to laboratory tests and adverse events 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). 
9.4.3.3. 
Action Taken with Study Drug 
Action taken with Study Drug (ISIS 766720 or placebo) due to the event is characterized by one 
of the following. 
• None: No changes were made to Study Drug (ISIS 766720 or placebo) 
administration and dose 
• Permanently Discontinued: Study Drug 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 and/or dosing frequency: 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. 


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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 one 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 one 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 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) 
• Fatal: Patient died (the date of death should be entered as the SAE resolution date) 
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 Study Drug 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, the Sponsor or a designee should follow-up by telephone, 
fax, electronic mail, 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. 


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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. 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 must 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 
• 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 
Study Drug (ISIS 766720 or placebo) 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 Case Report Form. If the patient takes a dose 
of Study Drug (ISIS 766720 or placebo) 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 


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Study Drug should be recorded on the Adverse Event eCRF. If the associated adverse event 
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 
Patients 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 Study Drug. 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 
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 pregnancy progress and outcome. A longer follow-up may be 
required if the newborn child experiences a medical condition. 
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. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Study Endpoints, Subsets, and Covariates 
10.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in IGF-1 from Baseline to 28 Days after last 
dose (PTWk5 Visit). 
10.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
• Proportion of patients achieve normalized IGF-1 levels to within 1.2 times of gender 
and aged limits at 28 days after last dose (PTWk5 Visit) 
• Proportion of patients achieve normalized IGF-1 levels to within 1.0 times of gender 
and aged limits at 28 days after last dose (PTWk5 Visit) 
• Change from Baseline in serum IGF-1 over time 
• Percent change from Baseline in serum IGF-1 over time 
10.1.3. 
Tertiary and Pharmacodynamic Endpoints 
The tertiary and pharmacodynamic endpoints include: 
• Change from Baseline in growth hormone (GH) over time 
• Percent change from Baseline in GH over time 
• Change from Baseline over time in pharmacodynamic endpoints, including fasting 
plasma GHBP, acid-labile subunit (ALS), and insulin-like growth factor binding 
protein 3 (IGFBP3) 
• Percent change from Baseline over time in pharmacodynamic endpoints, including 
fasting plasma GHBP, ALS, and IGFBP3 
10.1.4. 
Exploratory Endpoints 
The exploratory endpoints include: 
• Glycemic parameters over time, including HbA1c, fasting plasma glucose and 
glycated albumin 
• Glycemic parameters during 2-hour oral glucose tolerance test, including plasma 
glucose, insulin and C-peptide 
• Acromegaly Quality of Life Questionnaire (AcroQoL) 
• Acromegaly Symptom and Treatment Score Questionnaire (ASTS) 
• Ring Size Assessment 


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10.1.5. 
Safety Endpoints 
The safety endpoints include: 
• Adverse events 
• Vital signs and weight and calculated BMI 
• Physical examination 
• Clinical laboratory tests 
• ECG 
• Use of concomitant medication 
10.2. 
Sample Size Considerations 
Based on prior clinical trial experience, it is estimated that the standard deviation of the mean 
percent change from Baseline IGF-1 is approximately 20%. In the Per Protocol Set, with at least 
planned 10 patients in the pooled placebo group and 10 patients in an ISIS 766720 dose group, 
there will be at least 90% power to detect a 45% difference in mean percent change from 
Baseline IGF-1 between each of the ISIS 766720 dose groups and the pooled placebo group at an 
alpha level of 0.05. 
10.3. 
Populations 
Safety Set: All patients who are randomized and receive at least 1 dose of Study Drug. 
Full Analysis Set (FAS): All randomized patients who receive at least 1 dose of Study Drug and 
have at least 1 post-baseline efficacy or pharmacodynamic assessment. 
Per Protocol Set (PPS): All FAS patients who complete at least 5 of the 6 doses of Study Drug 
with the first 3 doses administered on schedule 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 Study Drug and have at 
least one evaluable PK sample. 
 
10.4. 
Definition of Baseline 
Unless otherwise specified, baseline is defined as the last non-missing value prior to the first 
administration of Study Drug (ISIS 766720 or placebo). 
10.5. 
Interim Analysis 
To ensure patient safety, blinded data including the AEs and safety laboratory data will be 
reviewed by the Sponsor on an ongoing basis. 
An interim analysis may be conducted when at least 6 patients in the higher strata (> 2.5 x ULN 
IGF-1) or at least 6 patients in the lower strata (≤ 2.5 × ULN IGF-1) complete the Week 11 
(Study Day 71) assessments (2 weeks after Day 57 (e.g., 3 month) dose). Additional interim 
analysis for each cohort may also be conducted once each cohort completes the Post-Treatment 
Week 5 assessments. Unblinded data may be evaluated at this analysis for comparative safety 


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and efficacy. The Investigator, study staff, patients, monitors, Sponsor’s Medical Monitor and 
members of the Sponsor’s clinical operations team and data management team will remain 
blinded throughout the study. The analysis will be executed with controlled dissemination to 
ensure the integrity of ongoing data collection. Details of these controls will be described in the 
Statistical Analysis Plan (SAP). 
10.6. 
Planned Methods of Analysis 
The primary endpoint analysis will take place after all randomized patients complete Post- 
Treatment Week 5 and the database has been locked. The final analysis will take place after all 
randomized patients complete last visit of the Post-Treatment Period and the database has been 
locked. 
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. 
For data summaries and statistical analyses, the placebo patients from both cohorts will be 
pooled. The efficacy endpoints will be assessed on the FAS and Per Protocol Set 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 Study Drug (ISIS 766720 or placebo) received will be 
summarized by treatment group. The treatment-emergent adverse events (TEAEs) and SAEs 
will be summarized for each treatment group using the Medical Dictionary for Regulatory 
Activities (MedDRATM) coding system, by system organ class, preferred term, relationship to 
Study Drug, 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, CBC with differential, coagulation panel, 
complement etc., will be summarized by study visits for each treatment group. These safety 
variables will also be presented as change and percent change from Baseline over time after 
Study Drug (ISIS 766720 or placebo) administration, as appropriate. Vital sign, calculated BMI, 
and ECG measures will be summarized by treatment group. 
10.6.3. 
Efficacy Analysis 
The primary analysis will be the comparison of percent change from Baseline to PTWk5 
(28 days after last dose) in serum IGF-1 between an ISIS 766720 dose group and pooled placebo 
group in the Per Protocol Set. The data will be analyzed using analysis of variance (ANOVA) 


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with treatment and randomization stratification factor (screening IGF-1 level) as independent 
variables. In the case data departs substantially from normality, the nonparametric test, 
van Elteren Test, will be employed instead. 
The primary efficacy endpoint will also be assessed, as a secondary analysis, in the FAS. 
Additional secondary efficacy analyses are: 
• Comparison of change and percent change from Baseline to each schedule post- 
baseline visit in serum IGF-1 between each of the ISIS 766720 dose groups and the 
pooled placebo group in the PPS and FAS. The data will be analyzed in a similar 
way to the primary analysis 
• Difference between each of the ISIS 766720 dose groups and the pooled placebo 
group in the proportion of patients achieve normalized IGF-1 levels to within 
1.2 times of gender and aged limits at PTWk5 (28 days after last dose) will be 
assessed by a Fisher’s exact test in the PPS and FAS 
• Difference between each of the ISIS 766720 dose groups and the pooled placebo 
group in the proportion of patients achieve normalized IGF-1 levels to within 
1.0 times of gender and aged limits at PTWk5 (2 days after last dose) will be assessed 
by a Fisher’s exact test in the PPS and FAS 
Tertiary and pharmacodynamic analyses include: 
• Comparison of change and percent change from Baseline to each scheduled post- 
baseline visit in GH between each of the ISIS 766720 dose groups and the pooled 
placebo group. The data will be analyzed in a similar way to the primary analysis in 
both the PPS and FAS 
• Comparison of change and percent change from Baseline to each scheduled post- 
baseline visit in pharmacodynamic endpoints, including fasting plasma GHBP, acid- 
labile subunit (ALS), and IGFBP3, between each of the ISIS 766720 dose groups and 
the pooled placebo group. The data will be analyzed in a similar way to the primary 
analysis in both the PPS and FAS 
 
10.6.4. 
Pharmacokinetic Analysis 
Non-compartmental PK analysis of ISIS 766720 (as total full-length ASO) will be carried out on 
each individual patient data set. Calculated PK parameters may include: Maximum observed 
drug concentration (Cmax), time to reach Cmax (Tmax), area under the concentration-time curve 
from time zero (pre-dose) to select times after dose administration (AUCt), and the plasma 
half-life (t1/2λz) associated with the terminal disposition phase. Additional PK parameters may be 
calculated at the discretion of the PK analyst. Population PK analysis and PK/PD analysis with 
relevant PD biomarker levels using data from this study or in combination with data from other 
ISIS 766720 studies may be performed if deemed appropriate. 


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10.6.5. 
Additional Analyses 
The exploratory analyses include: 
• Comparison of change and percent change from Baseline to each scheduled post- 
baseline visit in Glycemic parameters, including HbA1c, and fasting plasma glucose 
and glycate albumin between each of the ISIS 766720 dose groups and the pooled 
placebo group. The data will be analyzed in a similar way to the primary analysis in 
both the Per Protocol Set and FAS. 
• Comparison of change and percent change from Baseline to each scheduled post- 
baseline visit in Glycemic parameters during 2 hours oral glucose tolerance test, 
including plasma glucose, insulin and C-peptide, between each of the ISIS 766720 
dose groups and the pooled placebo group. The data will be analyzed in a similar 
way to the primary analysis in both the Per Protocol Set and FAS. 
• Comparison of change and percent change from Baseline to each scheduled post- 
baseline visit in AcroQoL, ASTS and Ring Size between each of the ISIS 766720 
dose groups and the pooled placebo group. The data will be analyzed in a similar 
way to the primary analysis in both the Per Protocol Set and FAS. 
 
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 any Study Drug (ISIS 766720 or placebo) 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 informed 
consent form 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 
informed consent form 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. 


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11.3. 
Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB) 
A copy of the protocol proposed informed consent form, 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 informed consent form must be received by the 
Sponsor before recruitment of patients into the study and shipment of Study Drug. 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 th 
e Sponsor before recruitment of patients into the study and shipment of Study Drug. 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 informed consent forms) 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 


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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. 
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, Study Drug 
Product Accountability Record, Return of Study Drug Product for Destruction, final 
Study Drug 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 


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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. 
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. 


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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. 
Chi, KN, Eisenhauer E, Fazli L, et al. A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 
2'‑methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer.J Natl Cancer Inst 
2005. 97: 1287‑1296. 
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. 
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. 
Graham, MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense 
oligonucleotides.N Engl J Med 2017. 
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. 
Kastelein, JJ, Wedel MK, Baker BF, et al. Potent reduction of apolipoprotein B and low-density lipoprotein 
cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B.Circulation 2006. 114: 
1729‑1735. 
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. 
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. 
Sewell, KL, Geary RS, Baker BF, et al. Phase I trial of ISIS 104838, a 2'-methoxyethyl modified antisense 
oligonucleotide targeting tumor necrosis factor-alpha.J Pharmacol Exp Ther 2002. 303: 1334-1343. 


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Stockert, RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression.Physiol Rev 
1995. 75: 591-609. 
Trainer, P, Newell-Price J, Ayuk J, et al. A phase 2 study of antisense oligonucleotide therapy directed at the GH 
receptor demonstrates lowering of serum IGF1 in patients with acromegaly.Endocrine Abstracts 2015. 37 GP19.10. 
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. 
Viney, NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people 
with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.Lancet 2016. 388: 
2239-2253. 
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. 


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14. 
APPENDICES 


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APPENDIX A. SCHEDULE OF PROCEDURES 


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Appendix A Schedule of Procedures 
Study Period 
Screen 
Treatment Period 
Study Week 
-9 to -1 
1 
3 
5 
7 
9 
11 
13 
15 
16 
Study Day 
-63 to -1 
1 
15 
29 
43 
57 
71 
85 
99 
112A 
Visit Window ± Day 
0 
0 
3 
5 
5 
5 
5 
5 
5 
3 
Home Health Care Visit OptionB 
X 
X 
X 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Medical History 
X 
Disease History 
X 
MRI of sellar (if no prior MRI results within the 
last 6 months) or CT when MRI contraindicated 
X 
AcroQoL 
Xa 
Xa 
Xa 
ASTS17 
Xa 
Xa 
Xa 
Xa 
Xa 
Ring Size Measurement18 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Body Weight and Height1 
X 
X 
X 
X 
X 
Vital Signs2 
X 
Xa 
Xa 
Xa 
X 
Xa 
X 
Xa 
X 
Xa 
Physical Exam3 
X 
X 
X 
X 
X 
X 
ECG (12-Lead) in Triplicate4 
X 
Xa 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis B & C 
X 
FSH6 
X 
Pregnancy Test7 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Chemistry Panel (Fasting)8, 9 
X 
Xa 
Xa 
Xa 
X 
Xa 
X 
Xa 
X 
Xa 
Hematology9 
X 
Xa 
Xa 
Xa 
X 
Xa 
X 
Xa 
X 
Xa 
Partial PD Panel: GH, IGF-1, GHBP8 
Xa 
X 
X 
X 


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Study Period 
Screen 
Treatment Period 
Study Week 
-9 to -1 
1 
3 
5 
7 
9 
11 
13 
15 
16 
Study Day 
-63 to -1 
1 
15 
29 
43 
57 
71 
85 
99 
112A 
Visit Window ± Day 
0 
0 
3 
5 
5 
5 
5 
5 
5 
3 
Home Health Care Visit OptionB 
X 
X 
X 
Full PD Panel8, 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
hs CRP 
Xa 
Xa* 
Xa* 
PT, INR, aPTT 
X 
Xa 
Xa 
Xa 
Xa 
Pituitary Axis19, Thyroid panel 
X 
Xa 
Bone Biomarker 
Xa 
Xa 
Lipid panel8 
X 
Xa 
Xa 
Screening HbA1c 
X 
Glycemic Panel (Including HbA1c) and 2-hr. 
OGTT8, a 
X16, a,b 
Xa,b 
Archived Serum Sample11 
X 
Xa 
Xa 
Immunogenicity Testing 
Xa 
Xa 
Xa 
Xa 
Xa 
PK Blood Sampling12 
Xd 
Xa 
Xa 
Xa 
Xa 
Xd 
Urinalysis13 
X 
Xa 
Xa 
Xa 
X 
Xa 
X 
Xa 
X 
Xa 
Study Drug (ISIS 766720 or placebo) 
Administration 
X 
X 
X 
X 
X 
X 
Somatostatin Receptor Ligand (SRL)10 
Xc 
Xc 
Xc 
Xc 
Xc 
Patient Contact Option 
If a visit cannot be performed, patient contact is required by site personnel to assess 
Adverse Events and Concomitant Medications 


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Study Period 
Post-Treatment Period (14 Weeks) 
Study Week (Wk) from Last Dose 
PTWk3 
PTWk5 
PTWk7 
PTWk11 
PTWk15 
ETTX14,15 
ETPT14,15 
Study Day from Last Dose 
PTD1515 
PTD2915 
PTD4315 
PTD7115 
PTD9915 
NA 
NA 
Study Day from Day 1 
127 
141 
155 
183 
211 
NA 
NA 
Visit Window ± 
5 
3 
5 
5 
5 
NA 
NA 
Home Health Care Visit OptionB 
X 
X 
MRI of Sellar or CT when MRI 
contraindicated 
MRI/CT after treatment if clinically indicated as assessed by Sponsor and Investigator 
AcroQoL 
X 
X 
X 
X 
X 
ASTS17 
X 
X 
X 
X 
X 
X 
X 
Ring Size Measurement18 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
X 
X 
X 
Vital Signs2 
X 
X 
X 
X 
X 
X 
X 
Physical Exam3 
X 
X 
X 
X 
X 
ECG (12-Lead) in Triplicate4 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test7 
X 
X 
X 
X 
X 
Chemistry Panel (Fasting)8, 9 
X 
X 
X 
X 
X 
X 
X 
Hematology9 
X 
X 
X 
X 
X 
X 
X 
Partial PD Panel: GH, IGF-1, GHBP8 
X 
Full PD Panel8 
X 
X 
X 
X 
X 
X 
hs CRP 
X* 
X* 
PT, INR, aPTT 
X 
X 
X 
X 
Pituitary Axis19, Thyroid panel 
X 
X 
X 
X 
Bone Biomarker 
X 
X 
X 
X 


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Appendix A Schedule of Procedures Continued 
74 7o1f 84 
 
 
 
 
 
Study Period 
Post-Treatment Period (14 Weeks) 
Study Week (Wk) from Last Dose 
PTWk3 
PTWk5 
PTWk7 
PTWk11 
PTWk15 
ETTX14,15 
ETPT14,15 
Study Day from Last Dose 
PTD1515 
PTD2915 
PTD4315 
PTD7115 
PTD9915 
NA 
NA 
Study Day from Day 1 
127 
141 
155 
183 
211 
NA 
NA 
Visit Window ± 
5 
3 
5 
5 
5 
NA 
NA 
Home Health Care Visit OptionB 
X 
X 
Lipid panel8 
X 
X 
X 
X 
Glycemic Panel and 2 hr OGTT8,a 
Xb 
Xb 
Archived Serum Sample11 
X 
X 
X 
X 
Immunogenicity Testing 
X 
X 
X 
X 
X 
X 
X 
PK Blood Sampling12 
X 
X 
X 
X 
X 
X 
X 
Urinalysis13 
X 
X 
X 
X 
X 
X 
X 
Somatostatin Receptor Ligand (SRL)10 
Patient will remain on stable SRL monthly dosing regimen 
Patient Contact Option 
If a visit cannot be performed, patient contact is required by site personnel to assess 
Adverse Events and Concomitant Medications 
A 
Please note this visit is at the end of the 16th week at Day 112 
B 
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. These 
assessments should be attempted at the next clinic visit if not performed at the Home Health Care visit. A confirmation of ISIS 766720 dosing by the Home 
Health Provider should be obtained and documented in source within 48 hours. 
 
1 
Height at screening only 
2 
BP, HR, RR, temperature 
3 
Full physical exam to be given at screening and abbreviated physical exam to be given during treatment and Follow-up Period as indicated to assess changes 
from screening 
4 
Triplicate ECG study procedure will consist of 3 ECGs with 2 minutes between each ECG (± 2 mins window between each assessment) 
5 
(Left intentionally blank) 
6 
FSH: 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 


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7 
A pregnancy test is required for women who are of childbearing potential regardless of age. Serum at Screening, Dipstick acceptable after Screening. For 
patients requiring confirmation of menopause at Screening per protocol, a pregnancy test is required at Screening, however, once menopausal status is 
confirmed, a pregnancy test is not required in subsequent visits 
8 
Fasting is not required at Screening Visit. Fasted samples should be taken after fasting for 8 hours (or 10 hours prior to OGTT). During this time the patient 
can drink water and they should ensure that they consume sufficient water in order 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 over a 
period greater than 21 days (per Section 8.5.2), the test must be repeated or drawn and a result not meeting stopping rule must be obtained prior to next dose. 
In consultation with the Medical Monitor a local lab and central lab may be drawn and evaluated prior to dosing (per Section 6.2.1). 
10 
Plan to align all SRL injections to be either i) the same day as the Study Drug administration, or ii) up to 3 days after the Study Drug administration. If 
dosing is not done in the clinic, the date and time of each SRL dose will be documented by the patient in a SRL dosing diary and provided to the study center 
staff at subsequent visits. The window for SRL dosing is 1-3 days after Study Drug administration. The visit window in the Schedule of Procedures table is 
not applicable to SRL dosing 
11 
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.) 
12 
If time is not specified PK draw can be done at anytime 
13 
If hematuria or 2+ proteinuria is observed, see confirmation guidance in Section 8.5 
14 
If patient terminates early from the Treatment Period, an early termination visit from treatment (ETTX) is required as soon as possible. After ETTX visit, 
patient should continue in Post-Treatment Period, following the schedule in intervals relative to patient’s last dose. Patient terminating from the Post- 
Treatment Period should complete the early termination visit from post-treatment (ETPT) 
15 
PT = Post-Treatment visit; ETTX = Early Termination visit from treatment; ETPT = Early Termination visit from Post-Treatment Period 
16 
The Day 1 OGTT can be conducted between Day -7 and Day-1. The procedure can be conducted in the clinic or as arranged by a Home Health Care 
professional. After the 120-min blood draw, the fasting period is completed 
17 
Patients should leave ASTS Question #5 blank for Day 1 and Post-Treatment Days 127, 141, 155, 183, 211, and ETPT 
18 
If possible, the same study personnel should conduct the ring size assessment at each clinic visit 
19 
A morning cortisol sample is required, and the sample should be drawn prior to 09:00 
 
Time (time is in hours relative to Study Drug administration): 
a 
Pre-dose 
b 
-5, 0, 30, 60, 90, 120 mins (Note: The 2-hr. OGTT is conducted prior to Study Drug administration during the Treatment Period, these times are relative to 
oral glucose ingestion) 
c 
Any time after ISIS 766720 or placebo injection 
d 
Pre-dose, 1, 2, 4, 6 hours 
* 
May be analyzed 


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APPENDIX B. LIST OF LABORATORY ANALYTES 


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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 
Screening Tests 
• Hepatitis B surface 
antigen 
• Hepatitis C antibody 
• HIV antibody 
• FSH (women only) 
• Serum βhCG 
Coagulation 
• aPTT (sec) 
• PT (sec) 
• INR 
PD Panel (*Partial Panel) 
• IGF-1* 
• GH* 
• GHBP* 
• ALS 
• IGFBP3 
Hematology 
Inflammatory 
• Red blood cells 
• hs-CRP 
• Hemoglobin 
• Hematocrit 
• MCV, MCH, MCHC 
• Platelets 
• White blood cells 
• WBC Differential (% and 
absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
Thyroid Panel 
• TSH 
• Free T4 
• Total T3 
Urinalysis 
• Color 
• Appearance 
• Specific gravity 
• pH 
• P/C Ratio 
• A/C Ratio 
• Protein 
• Blood 
• Ketones 
• Urobilinogen 
• Glucose 
• Bilirubin 
• Leukocyte esterase 
• Nitrate 
• Microscopic examination2 
• 
• 
• 
• 
• 
• 
Glycemic Panel 
• HbA1c 
• Glucose 
• glycated albumin 
• During OGTT: Glucose, 
insulin and C-peptide 
Bone Biomarkers 
• Urinary N-telopeptide 
crosslink (NTX) 
• Bone specific alk phos 
• Amino terminal 
propeptide of Type 1 
procollagen (PINP) 
Pituitary Axis 
• Morning Cortisol (before 
09:00) 
• ACTH 
• Prolactin 
Lipid Panel 
• Total Cholesterol 
• LDL cholesterol 
• HDL cholesterol 
• Triglycerides 
• VLDL 
• Lp(a) 
Pharmacokinetics1 
• ISIS 766720 levels in 
plasma 
Immunogenicity1 
• Anti-ISIS 766720 
antibodies 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 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 
2 Will be performed on abnormal findings unless otherwise specified 


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APPENDIX C. PK SAMPLING SCHEDULE 


 
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Appendix C PK Sampling Schedule 
 
Treatment Period 
Post-Treatment Period 
Early 
Early 
Terminate 
from 
Terminate 
from Post- 
Week 1 
Week 3 
Week 5 
Week 9 
Week 13 
Week 16 
PTWk3 
PTWk5 
PTWk7 
PTWk11 
PTWk15 
Treatment 
Treatment 
D1 
D15 
D29 
D57 
D85 
D112 
D127 
D141 
D155 
D183 
D211 
ETTX 
ETPT 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Pre-dose, 
1, 2, 4, 
6 hours 
Post-SC 
Injection 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose, 
1, 2, 4, 
6 hours 
Post-SC 
Injection 
Anytime 
Anytime 
Anytime 
Anytime 
Anytime 
Anytime 
Anytime 
Note: If 6-hour PK sampling is not possible a protocol deviation can be entered 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING 
TO LABORATORY ABNORMALITIES 


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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, 
November 2017. 
 


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2 
20 May 2020 
ISIS 766720-CS2 Amend 4 - A DB, Placebo-Controlled, Phase 2 Study to Assess 
Safety, Tolerability, & Efficacy of 766720 Administered Once Every 28D for 16 
Wks in Pts w/Acromegaly Being Treated w/Long-acting SRL 
Version: 
Version Date: 
Title: 
 
 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
APPROVALS: 
 
20-May-2020 16:47:05 GMT+0000 


 
 
A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of ISIS 766720 (IONIS-GHR-LRx, an Antisense 
Inhibitor of the Growth Hormone Receptor) Administered Once Every 28 
Days for 16 Weeks in Patients With Acromegaly Being Treated With Long- 
acting Somatostatin Receptor Ligands (SRL) 
 
 
NCT03548415 
 
 
Statistical Analysis Plan Version 2.0: 05-March-2021 
Official Title: 
NCT Number: 
Document Dates: 


1 of 30 
 
 
Clinical Study Report 
CONFIDENTIAL 
Ionis Pharmaceuticals, Inc. 
Study Number: ISIS 766720-CS2 
 
 
1 March 2022 
16. Appendices 
 
 
1.9 
Documentation of Statistical Methods 
Statistical Analysis Plan, Version 2.0 (5 March 2021), is provided. 


2 of 30 
 
 
766720-CS02 Statistical Analysis Plan 
05 Mar 2021 | 2.0 
 
 
 
 
 
 
 
 
Name: 
Version: 
766720-CS02 Statistical Analysis Plan 
05 Mar 2021 
2 
 
 
 
 
 
 
 
 
APPROVALS: 
 
Approved 
05-Mar-2021 20:22:56 GMT+0000 
Approved 
05-Mar-2021 20:32:06 GMT+0000 
Approved 
05-Mar-2021 22:17:34 GMT+0000 
Approved 
08-Mar-2021 16:28:54 GMT+0000 


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Statistical Analysis Plan 
MAR 05, 2021 
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CONFIDENTIAL 
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Statistical Analysis Plan 
 
 
 
ISIS 766720 –CS2 
A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the 
Safety, Tolerability, and Efficacy of ISIS 766720 (IONIS GHR- 
LRX, an Antisense Inhibitor of the Growth Hormone Receptor) 
Administered Once Every 28 Days for 16 Weeks in Patients with 
Acromegaly Being Treated with Long-acting Somatostatin 
Receptor Ligands (SRL) 
 
 
 
 
 
Date: March 5, 2021 
Version: 2.0 
CONFIDENTIAL 
Confidential/Trade Secret information subject to 18-USC-1905 and to which all claims of privilege and 
confidentiality are asserted in both statutory and common law. Further dissemination may be made 
only with the express written permission of Ionis Pharmaceuticals, Inc. 


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,
Date 
 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court Carlsbad, CA 92010 
 
 
Compound Name: 
766720 
 
 
Protocol: 
CS2 
 
 
Study Title: 
A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, 
Tolerability, and Efficacy of ISIS 766720 (IONIS GHR-LRX, an Antisense Inhibitor 
of the Growth Hormone Receptor) Administered Once Every 28 Days for 16 Weeks 
in Patients with 
Acromegaly Being Treated with Long-acting Somatostatin Receptor Ligands (SRL) 
 
 
Issue Date: 
18 MAY 2020 (Protocol Amendment 4) 
 
 
 
 
See electronic signature and date attached to this document 
 
Date 
, 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
 
See electronic signature and date attached to this document 
 
 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
 
 
 
 
See electronic signature and date attached to this document 
 


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Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
 
See electronic signature and date attached to this document 
 
Date 
 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Date 


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Table of Contents 
1 
Introduction ................................................................................................................................... 6 
1.1 
Study Overview .................................................................................................................... 6 
1.2 
Objective .............................................................................................................................. 8 
1.2.1 
Primary Objectives .......................................................................................................................... 8 
1.2.2 
Secondary Objective ....................................................................................................................... 8 
1.2.3 
Tertiary Objectives .......................................................................................................................... 8 
1.2.4 
Exploratory Objectives .................................................................................................................... 8 
1.3 
Endpoints ............................................................................................................................. 8 
1.3.1 
Primary Efficacy Endpoint .............................................................................................................. 8 
1.3.2 
Secondary Efficacy Endpoints ........................................................................................................ 8 
1.3.3 
Tertiary and Pharmacodynamic Endpoints ...................................................................................... 9 
1.3.4 
Exploratory Endpoints ..................................................................................................................... 9 
1.3.5 
Safety Endpoints ............................................................................................................................. 9 
2 
Procedures ................................................................................................................................... 10 
2.1 
General Overview of Procedures ..................................................................................... 10 
2.2 
Randomization ................................................................................................................... 10 
2.3 
Conduct .............................................................................................................................. 10 
2.4 
Data Monitoring ................................................................................................................. 10 
2.4.1 
Safety Data Monitoring ................................................................................................................. 10 
2.5 
Data Management ............................................................................................................. 11 
2.5.1 
Case Report Form (CRF) Data ...................................................................................................... 11 
2.5.2 
Laboratory Data ............................................................................................................................ 11 
2.5.3 
Pharmacokinetics (PK) Data ......................................................................................................... 11 
3 
Analysis Plan ............................................................................................................................... 12 
3.1 
General Overview of Analyses .......................................................................................... 12 
3.2 
Sample Size Considerations .............................................................................................. 12 
3.3 
Scoring of Questionnaires and Ring Size Assessment .................................................... 13 
3.3.1 
Acromegaly Quality of Life Questionnaire (AcroQoL)................................................................. 13 
3.3.2 
Acromegaly Symptom and Treatment Score Questionnaire (ASTS) ............................................ 16 


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3.3.3 
Ring Size Assessment .................................................................................................................... 17 
3.4 
Statistical Methods ............................................................................................................ 17 
3.4.1 
Patient Population Analyzed ......................................................................................................... 17 
3.4.2 
Handling of Missing Data ............................................................................................................. 18 
3.4.3 
Planned Interim Analysis .............................................................................................................. 18 
3.5 
Demographic and Baseline Characteristics ..................................................................... 18 
3.6 
Efficacy (Pharmacodynamic) Analysis ............................................................................ 18 
3.6.1 
Primary Efficacy Analysis............................................................................................................. 18 
3.6.2 
Secondary Efficacy Analysis ......................................................................................................... 19 
3.6.3 
Tertiary and Pharmacodynamic Analyses ..................................................................................... 19 
3.6.4 
Exploratory Analyses .................................................................................................................... 19 
3.6.5 
Subgroup analysis on the glycemic parameters ............................................................................. 20 
3.7 
Pharmacokinetic Analysis ................................................................................................. 21 
3.7.1 
Plasma Concentration Data of Total Full-Length Oligonucleotides .............................................. 21 
3.7.2 
Plasma Pharmacokinetic Parameters ............................................................................................. 21 
3.7.3 
Pharmacokinetic/Pharmacodynamic Exposure-Response Analysis ............................................... 22 
3.7.4 
Immunogenicity (IM) Analysis ...................................................................................................... 22 
3.8 
Safety Analyses .................................................................................................................. 24 
3.8.1 
Exposure ....................................................................................................................................... 24 
3.8.2 
Adverse Events ............................................................................................................................. 24 
3.8.3 
Laboratory Measurements .............................................................................................................. 26 
3.8.4 
Vital Signs ..................................................................................................................................... 26 
3.8.5 
12-Lead Electrocardiograms (ECG) .............................................................................................. 26 
3.8.6 
Acromegaly Past Medications and Concomitant Medications ....................................................... 27 
4 
References ................................................................................................................................... 28 


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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 randomized, double blind, placebo-controlled, Phase 2 study to assess the safety, tolerability, 
and efficacy of ISIS 766720 administered once every 4 weeks for 16 weeks to patients with 
acromegaly uncontrolled (IGF-1 level between 1.3 x to 5 x ULN) on select long-acting SRL. Patients 
will be stratified by the screening IGF-1 level (IGF-1 > 2.5 x ULN or ≤ 2.5 x ULN age and sex 
adjusted by central lab). 
 
This study will be conducted at multiple centers worldwide at approximately 40 sites. Approximately 
60 patients are planned to be randomized in their corresponding randomization ratio (ISIS 766720 vs. 
Placebo) are as following: 
 
Cohort A:   ISIS 766720 60 mg + SRL or placebo + SRL (2 active :1 placebo) every 28 days. 
In addition, a booster dose of Study Drug is administered on Day 15. Total of 15 
patients are enrolled. 
 
Cohort B:   ISIS 766720 80 mg + SRL or placebo + SRL (2 active :1 placebo) every 28 days. 
In addition, a booster dose of Study Drug is administered on Day 15. Total of 15 
patients are enrolled. 
Cohort C: 
ISIS 766720 120 mg + SRL or placebo + SRL (5 active :1 placebo) every 28 days. 
In addition, a booster dose of Study Drug is administered on Day 15. Total of 12 
patients are enrolled. 
Cohort D: 
ISIS 766720 160 mg + SRL or placebo + SRL (5 active :1 placebo) every 28 days. 
In addition, a booster dose of Study Drug is administered on Day 15. Total of 12 
patients are enrolled. 
The study for an individual patient will generally consist of the following periods: 
 
• 
A ≤ 6-week Screening Assessment Period 
• 
A 16-week Treatment Period during which Study Drug will be administered as a once every 
28 days SC injection (except during Month 1 where a booster dose is administered on Day 
15) 
• 
A 14-week Post-Treatment Evaluation Period 
The study design and treatment schema are depicted as follows: 


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1.2 Objective 
1.2.1 
Primary Objectives 
To evaluate the efficacy of ISIS 766720 subcutaneous (SC) injection on serum insulin-like growth 
factor 1 (serum IGF-1) vs. placebo as an add-on therapy to long acting somatostatin receptor ligands 
(SRL) octreotide and lanreotide. 
 
To evaluate the safety and tolerability of ISIS 766720 SC injection vs. placebo as add-on therapy to 
SRL. 
 
1.2.2 
Secondary Objective 
To evaluate the effect of ISIS 766720 to normalize serum IGF-1 levels. 
 
1.2.3 
Tertiary Objectives 
To evaluate the effects of ISIS 766720 SC injection on GH over time. 
 
To evaluate the effects of ISIS 766720 SC injection on the following pharmacodynamic endpoints: 
fasting plasma GHBP, ALS, IGFBP3. 
 
1.2.4 
Exploratory Objectives 
To evaluate the effects of ISIS 766720 SC injection on the following glycemic parameters: HbA1c, 
fasting plasma glucose, glycated albumin as well as glucose, insulin and C-peptide 
during 2-hour oral glucose tolerance test. 
 
To evaluate the effects of ISIS 766720 SC injection on the clinical endpoints using AcroQoL, 
acromegaly sign and symptom treatment score questionnaire (ASTS) and ring size measurement. 
 
To evaluate pharmacokinetic (PK) exposure over time and potential PK/PD correlation on relevant 
biomarkers. 
 
1.3 Endpoints 
1.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in IGF-1 from Baseline to 28 Days after last dose 
(PTWk5 Visit). 
 
1.3.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
 
• 
Proportion of patients achieve normalized IGF-1 levels to within 1.2 times of gender and 
aged limits at 28 days after last dose (PTWk5 Visit) 
• 
Proportion of patients achieve normalized IGF-1 levels to within 1.0 times of gender and 
aged limits at 28 days after last dose (PTWk5 Visit) 
• 
Change from Baseline in serum IGF-1 over time 
• 
Percent change from Baseline in serum IGF-1 over time 


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1.3.3 
Tertiary and Pharmacodynamic Endpoints 
The tertiary and pharmacodynamic endpoints include: 
• 
Change from Baseline in growth hormone (GH) over time 
• 
Percent change from Baseline in GH over time 
• 
Change from Baseline over time in pharmacodynamic endpoints, including fasting plasma 
GHBP, acid-labile subunit (ALS), and insulin-like growth factor binding protein 3 (IGFBP3) 
• 
Percent change from Baseline over time in pharmacodynamic endpoints, including fasting 
plasma GHBP, ALS, and IGFBP3 
 
1.3.4 
Exploratory Endpoints 
The exploratory endpoints include: 
• 
Glycemic parameters over time, including HbA1c, fasting plasma glucose and glycated 
albumin 
• 
Glycemic parameters during 2-hour oral glucose tolerance test (OGTT), including plasma 
glucose, insulin and C-peptide 
• 
Acromegaly Quality of Life Questionnaire (AcroQoL) 
• 
Acromegaly Symptom and Treatment Score Questionnaire (ASTS) 
• 
Ring Size Assessment 
 
1.3.5 
Safety Endpoints 
The safety endpoints include: 
• 
Adverse events 
• 
Vital signs and weight and calculated Body mass index (BMI) 
• 
Physical examination 
• 
Clinical laboratory tests 
• 
Electrocardiogram (ECG) 
• 
Use of concomitant medication 


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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 LMU Munich via 
Medpace Reference Laboratories, and from PPD Development (plasma concentration data) to Ionis 
Pharmaceuticals, Inc. 
 
2.2 Randomization 
Patients will be randomized after all Screening assessments have been completed, after the 
Investigator has verified that they are eligible per criteria in protocol Sections 5.1 and 5.2. No patient 
may begin treatment prior to randomization and assignment of a unique patient identification number. 
Eligible patients will be stratified based on screening IGF-1 levels (≤ 2.5 x ULN or > 2.5 x ULN age 
and sex adjusted by central lab) and then patients will be randomized to 1 of 2 dose cohorts in a 1:1 
ratio (Cohort A or Cohort B). Within each dose cohort, patients will be further randomized to receive 
ISIS 766720 or placebo in a 2:1 ratio. 
Eligible patients for Cohorts C and D will be stratified based on screening IGF-1 levels (≤ 2.5 x ULN 
or > 2.5 x ULN, age and sex adjusted by central lab). Patients will be randomized to receive ISIS 
766720 or placebo in a 5:1 ratio. 
After enrollment in Cohort A and B is completed, Cohort C will begin enrollment. Cohort D may be 
conducted based on the safety and efficacy results of the lower-dose cohorts. 
 
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), are 
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 
study site. 


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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 (CRF) Data 
BioClinica (or designee) is responsible for creating the Electronic Data Capture (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 are corrected or an explanation concerning the query is provided in the EDC 
system. After all data are entered, reviewed (by Data Management and Clinical Development) and 
queried, and all queries resolved, the database is locked. 
 
2.5.2 
Laboratory Data 
Ionis Pharmaceuticals, Inc. is responsible for the format of the laboratory electronic data transfers, 
transfer schedule and review of the clinical laboratory data. This lab data will be stored as SAS data 
sets or Excel files. 
 
2.5.3 
Pharmacokinetics (PK) Data 
Ionis Pharmaceuticals, Inc. is responsible for the management and review of the plasma drug 
concentration data. This process involves reviewing the patient and visit identifiers (i.e., patient 
demographics) with the clinical data collected in the EDC system. The PK data are not stored in the 
EDC system. 


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3 ANALYSIS PLAN 
3.1 General Overview of Analyses 
Descriptive summary statistics including number of patients, mean, median, standard deviation, 
standard error of mean, 25th percentile, 75th percentile, minimum, and maximum for continuous 
variables, and counts and percentages for categorical variables will be used to summarize most data. 
All statistical tests will be conducted using 2-sided tests with 5% Type I error rate unless otherwise 
stated. 
PK parameters will be summarized to include number of patients, mean, standard deviation, 
coefficient of variation (CV), geometric mean, median, minimum, and maximum. 
Pooled groups: 
Patients who are placebo-treated will be pooled and analyzed as a single placebo group. Patients who 
are ISIS 766720-treated may be pooled and summarized as the ISIS 766720 low dose, and ISIS 
766720 high dose, or total ISIS 766720 treated group. 
Baseline definition: 
Unless otherwise specified, baseline is defined as the last non-missing value prior to the first 
administration of Study Drug (ISIS 766720 or placebo). 
The baseline for Platelets is defined as the average of all values prior to the first administration of 
Study Drug (ISIS 766720 or placebo). 
Analytical visits: 
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, but will be presented in data 
listings. 
 
 
3.2 Sample Size Considerations 
Based on prior clinical trial experience, it is estimated that the standard deviation of the mean percent 
change from Baseline IGF-1 is approximately 20%. In the per protocol set, with 10 patients in the 
pooled placebo group and 10 patients in each ISIS 766720 dose group, there will be at least 90% 
power to detect a 45% difference in mean percent change from Baseline IGF-1 between each of the 
ISIS 766720 dose groups and the pooled placebo group at an alpha level of 0.05. 


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3.3 Scoring of Questionnaires and Ring Size Assessment 
3.3.1 
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. 
Table 1: The AcroQoL Questionnaire 


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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 


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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 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: 
(X) − min 
𝑌 = [ 
] × 100 
(max − min) 
Here Y is the re-calculated score, and X is the sum of all the item responses within the dimension or 
study 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 ] × 100 
(110−22 
 
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 


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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. 
 
3.3.2 
Acromegaly Symptom and Treatment Score Questionnaire (ASTS) 
ASTS is an Ionis internally developed questionnaire to assess acromegaly symptom and treatment, 
which contains 6 items (Table 2). 
Table 2: The ASTS Questionnaire 
 
Item 
Question 
Response 
1 
I HAVE HEADACHES 
Always 
Most of the 
Sometimes 
Rarely 
Never 
THAT LAST ALL 
time 
DAY OR OVER 
MULTIPLE DAYS 
DESPITE 
MEDICATION 
2 
I EXPERIENCE 
Always 
Most of the 
Sometimes 
Rarely 
Never 
EXCESSIVE 
time 
SWEATING 
3 
I FEEL PUFFY, OR 
Always 
Most of the 
Sometimes 
Rarely 
Never 
HAVE SWOLLEN 
time 
FEET OR LEGS 
4 
I EXPERIENCE LOSS 
Always 
Most of the 
Sometimes 
Rarely 
Never 
OF SENSATION OR 
time 
NUMBNESS OR 
TINGLING IN MY 
HANDS 
5 
THE STUDY DRUG 
Completely 
Moderately 
Neither 
Moderately 
Completely 
INJECTION IS 
Agree 
Agree 
Agree nor 
Disagree 
Disagree 
BOTHERSOME TO 
Disagree 
ME 
6 
I EXPERIENCED 
Completely 
Moderately 
Neither 
Moderately 
Completely 
INCREASED 
Agree 
Agree 
Agree nor 
Disagree 
Disagree 
HEADACHE, 
Disagree 
SWELLING, OR 
EXCESS SWEATING 
IN THE LAST FEW 
DAYS BEFORE THIS 
UPCOMING 
LANREOTIDE / 
OCTREOTIDE 
INJECTION 
 
Each of the 6 items of the ASTS 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 


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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 the acromegaly symptom and treatment. 
The item 5 question does not apply to study Day 1 and post-treatment assessments, since the ASTS 
questionnaire is completed prior to receiving study drug injection on Day 1, and no study drug is 
administered during the post-treatment period. No change and percent change from baseline analyses 
will be performed for item 5, since no baseline (Day 1) is available for item 5. 
Each of the 6 items will be analyzed individually. If the response to an item is missing at a visit, it 
will not be included in the analysis for that item at that visit. The range of the individual score for 
each item is 1 to 5. 
In addition, a composite score (Acromegaly Symptom Composite Score) will be calculated by 
summing the ASTS item 1, item 2, item 3, and item 4 scores. If 1 or more of the 4 items has missing 
response, the Acromegaly Symptom Composite Score will not be calculated. The range of this 
composite score is 4 to 20. 
 
3.3.3 
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. 
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. 
 
3.4 Statistical Methods 
3.4.1 
Patient Population Analyzed 
The following analysis populations are defined for this study: 
• 
Safety Set: All patients who are randomized and receive at least 1 dose of Study Drug. 
 
• 
Full Analysis Set (FAS): All randomized patients who receive at least 1 dose of ISIS 766720 
or placebo and have at least 1 post-baseline efficacy or pharmacodynamic assessment. 
 
• 
Per Protocol Set (PPS): All FAS patients who complete at least 5 of the 6 doses of Study 
Drug with the first 3 doses administered on schedule 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 one evaluable PK sample. 


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3.4.2 
Handling of Missing Data 
Unless otherwise specified, missing values will not be imputed. 
 
3.4.3 
Planned Interim Analysis 
To ensure patient safety, blinded data including the AEs and safety laboratory data will be reviewed 
by the Sponsor on an ongoing basis. 
An interim analysis may be conducted when at least 6 patients in the higher strata (> 2.5 x ULN IGF- 
1) or at least 6 patients in the lower strata (≤ 2.5 x ULN IGF-1) complete the Week 11 (Study Day 71) 
assessments (2 weeks after Day 57 (e.g., 3 month) dose). Unblinded data may be evaluated at this 
analysis for comparative safety and efficacy. The Investigator, study staff, patients, monitors, 
Sponsor’s Medical Monitor and members of the Sponsor’s clinical operations team and data 
management team will remain blinded throughout the study. The analysis will be executed with 
controlled dissemination to ensure the integrity of ongoing data collection. The individuals involved 
in the unblinded interim analysis will be identified and documented at the time of unblinded interim 
analysis according to Ionis standard operation procedure (SOP). 
 
3.5 Demographic and Baseline Characteristics 
Demographic and Baseline characteristics (e.g., age, gender, ethnicity, race, weight, height, BMI) will 
be summarized using descriptive statistics by treatment group. 
BMI will be computed using the formula: BMI = (weight in kilograms) / [height in cm / 100]2 
Patient randomization and disposition will be summarized by cohort and treatment group. All patients 
enrolled will be included in the summary of disposition. 
Protocol deviations will be listed. 
 
3.6 Efficacy (Pharmacodynamic) Analysis 
3.6.1 
Primary Efficacy Analysis 
The primary analysis will be the comparison of percent change from Baseline to PTWk5 (28 days 
after last dose) in serum IGF-1 between an ISIS 766720 dose group and pooled placebo group in the 
Per Protocol Set. The data will be analyzed using analysis of variance (ANOVA) with treatment and 
randomization stratification factor (screening IGF-1 level) as independent variables. The normality 
assumption for the ANOVA model will be assessed by the Shapiro-Wilks test on the residuals. In the 
case data departs substantially from normality, the nonparametric test, van Elteren Test, will be 
employed instead. Additional analysis with baseline IGF-1 actual level as a covariate may be 
conducted. 
The primary analysis will take place after all patients complete Treatment Period and the database has 
been locked. 


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3.6.2 
Secondary Efficacy Analysis 
3.6.2.1 
Secondary analysis on the primary efficacy endpoint 
Comparison of percent change from Baseline to PTWk5 (28 days after last dose) in serum IGF-1 
between an ISIS 766720 dose group and pooled placebo group in the FAS will be carried out. The 
data will be analyzed in a similar way to the primary analysis. 
3.6.2.2 
Additional secondary efficacy analyses 
• 
Comparison of change and percent change from Baseline to each schedule post-baseline visit 
in serum IGF-1 between each of the ISIS 766720 dose groups and the pooled placebo group 
in the PPS and FAS. The data will be analyzed in a similar way to the primary analysis 
• 
Difference between each of the ISIS 766720 dose groups and the pooled placebo group in the 
proportion of patients achieve normalized IGF-1 levels to within 1.2 times of gender and aged 
limits at PTWk5 (28 days after last dose) will be assessed by Fisher’s exact test in the PPS 
and FAS 
• 
Difference between each of the ISIS 766720 dose groups and the pooled placebo group in the 
proportion of patients achieve normalized IGF-1 levels to within 1.0 times of gender and aged 
limits at PTWk5 (28 days after last dose) will be assessed by Fisher’s exact test in the PPS 
and FAS 
For the proportion difference, additional analyses may be conducted by logistic regression to consider 
additional covariates. 
 
3.6.3 
Tertiary and Pharmacodynamic Analyses 
The following analyses will be performed: 
• 
Comparison of change and percent change from Baseline to each scheduled post-baseline 
visit in GH between each of the ISIS 766720 dose groups and the pooled placebo group. The 
data will be analyzed in a similar way to the primary analysis in both the PPS and FAS 
• 
Comparison of change and percent change from Baseline to each scheduled post-baseline 
visit in pharmacodynamic endpoints, including fasting plasma GHBP, acid-labile subunit 
(ALS), and IGFBP3, between each of the ISIS 766720 dose groups and the pooled placebo 
group. The data will be analyzed in a similar way to the primary analysis in both the PPS and 
FAS 
Additional analyses may be conducted to explore the relationship among PDs. 
 
3.6.4 
Exploratory Analyses 
The exploratory analyses include: 
• 
Comparison of change and percent change from Baseline to each scheduled post-baseline 
visit in Glycemic parameters, including HbA1c, and fasting plasma glucose and glycate 
albumin between each of the ISIS 766720 dose groups and the pooled placebo group. The 
data will be analyzed in a similar way to the primary analysis in both the Per Protocol Set and 
FAS. 


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• 
Comparison of change and percent change from Baseline to each scheduled post-baseline 
visit in Glycemic parameters during 2 hours OGTT, including the area under curve (AUC) 
and the incremental AUC of plasma glucose, insulin and C-peptide, between each of the ISIS 
766720 dose groups and the pooled placebo group. The data will be analyzed in a similar way 
to the primary analysis in both the Per Protocol Set and FAS. 
• 
Comparison of change and percent change from Baseline to each scheduled post-baseline 
visit in AcroQoL (Global AcroQoL, Physical Dimension, Psychological Dimension, 
Appearance Sub-dimension, Personal Relationships Sub-dimension), ASTS and Ring Size 
between each of the ISIS 766720 dose groups and the pooled placebo group. The data will be 
analyzed in a similar way to the primary analysis in both the Per Protocol Set and FAS. 
Change and percent change from Baseline to each scheduled post-baseline visit in glycemic 
parameters during 2 hours OGTT, including the area under curve (AUC) and the incremental AUC 
(iAUC) of plasma glucose, insulin and C-peptide, will be summarized. The AUC will be calculated 
for plasma glucose, insulin and C-peptide taken between 0 to 120 minutes responses to the OGTT. 
The plasma measurement taken prior to start time of glucose ingestion (defined as T0 time) will be 
used as the T0 plasma glucose and all subsequent time point will be relative to this T0 in the AUC 
calculation. The actual sample time (defined by the sample time relative to the defined T0 time) will 
be used in the AUC calculation. If a scheduled 120 minutes result is missing, then the AUC will not 
be calculated. If the actual sample time of the scheduled 120 mins result is more than 135 mins or 
less than 105 mins, then the AUC will also not be calculated. If a scheduled result at other timepoints 
is missing, the data will be linearly interpolated using the results prior to and immediate after the 
missing result. 
The iAUC is defined as total AUC minus the rectangle area under basal (i.e., T0 plasma glucose 
measurement multiplied by actual sample time). 
Additional analyses for the AcroQoL and ASTS may be described in the other analysis plan for 
exploratory purpose. 
 
3.6.5 
Subgroup analysis on the glycemic parameters 
The comparison of change and percent change from Baseline to PTWk5 (28 days after last dose) in 
HbA1c and Glycemic parameters during 2 hours OGTT, including AUC and incremental AUC of 
plasma glucose and C-peptide, between each of the ISIS 766720 dose groups and pooled placebo 
group will be performed on the following baseline HbA1c subgroups in the PPS: 
• 
<5.7% vs. >=5.7% 
• 
<6.5% vs. >=6.5% 
• 
<7.5% vs. >=7.5% 
• 
<8.0% vs. >=8.0% 
• 
<8.5% vs. >=8.5% 
• 
<9.0% vs. >=9.0% 
• 
<6.5% vs. 6.5-8% vs. >8% 
The data will be analyzed in a similar way to the primary analysis. 


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3.7 Pharmacokinetic Analysis 
Pharmacokinetic (PK) analysis will be conducted in the PK Population. The plasma PK of ISIS 
766720 (as total full-length oligonucleotide or ISIS 766720-equivalent [ISIS 766720-eq.]) will be 
assessed following first and last SC dose administration(s). 
Metabolite identification and profiling may be determined in some of the collected plasma samples 
and will be reported separately. 
 
3.7.1 
Plasma Concentration Data of Total Full-Length Oligonucleotides 
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) will be listed 
(when applicable) for each patient, by treatment group, dose cohort, nominal dose, 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. 
Plasma concentrations below the lower limit of quantification (LLOQ) will be indicated by “BLQ”. 
For the purpose of calculating typical descriptive statistics (n, mean, SD, %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 
and %CV, as well as geometric mean and geometric% CV, will be reported as not applicable. 
Summary statistics of the ISIS 766720-eq plasma concentrations will be tabulated by treatment group, 
dose cohort, nominal dose, day, and scheduled time point. At the discretion of the pharmacokineticist 
and/or biostatistician, samples may be excluded from descriptive statistics if there are large deviations 
between scheduled and actual sampling times, or large deviations between actual dose and nominal 
dose. 
ISIS 766720-eq. plasma trough (pre-dose) and post-treatment concentration versus time (actual) 
profiles for each individual patient that received ISIS 766720 active treatment, as well as the mean (± 
SD or SE) plasma concentrations versus time (scheduled) profiles following first and last dose, will 
be presented graphically on linear and semilogarithmic scales without and with stratification by 
patient immunogenicity status (see Section 3.7.4). At the discretion of the pharmacokineticist and/or 
biostatistician, samples may be excluded from the mean plots if there are large deviations between 
scheduled and actual sampling times. 
 
3.7.2 
Plasma Pharmacokinetic Parameters 
The plasma PK of ISIS 766720 (as total full-length ASO) will be assessed following first- and last- 
dose SC administration(s). Non-compartmental pharmacokinetic analysis of ISIS 766720 (as total 
full-length ASO) will be carried out on each individual patient data set where full PK sampling 
profiles and/or 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 Day 1 
and Day 112. 


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2. Tmax: the time at which Cmax occurs will be determined on Day 1 and Day 112. 
3. AUC0-6hr: partial area under the plasma concentration-time curve (AUC) from time zero to 6 
hours will be calculated using the linear-up log-down trapezoidal rule on Day 1 and Day 112. 
4. CL0-6hr /F (L/hr): partial clearance (e.g. 6 hr) divided by F (fraction of the dose absorbed) 
determined by Dose/AUC0-6hrwill be determined on Day 1 and Day 112. 
5. 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 
coefficient of determination values (r2 adjusted) has to be at or greater than 0.8 for the estimate 
to be accepted. This parameter will only be calculated following the dose on Day 112 for all 
evaluable patients receiving active study drug. 
Plasma pharmacokinetic parameters will be summarized using descriptive statistics (n, mean, 
SD, %CV, geometric mean, geometric %CV, median, minimum, and maximum) by treatment group, 
dose cohort, nominal dose, and day. 
 
3.7.3 
Pharmacokinetic/Pharmacodynamic Exposure-Response Analysis 
Exposure-response correlations may be explored graphically between plasma exposure (AUC, Cmax, 
Cmin, as appropriate) and selected PD measures (e.g. serum IGF-1, GH, and GHBP levels). 
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. 
 
3.7.4 
Immunogenicity (IM) Analysis 
Samples collected at pre-dose on Days 1, 29, 57, 85, and 112, and anytime on Day 127, 141, 155, 
183, and 211, including early termination samples for IM assessment may be analyzed for 
anti-ISIS 766720 antibodies (ADA). However, plasma samples collected at other time points (for 
PK purposes) may also potentially be evaluated if deemed of further interest and warranted by the 
pharmacokinetic scientist. An evaluable sample will be designated ‘IM positive’ based on both 
positive screening and confirmation assay results (i.e., confirmed positive result), and otherwise will 
be deemed ‘IM negative’. Sample IM results (screen positive/negative, confirmed positive/negative 
or unevaluable, and when applicable, titer of anti-ISIS 766720 antibodies) before, during, and after 
treatment with study drug (ISIS 766720 or placebo) (sample IM status) will be listed by treatment and 
dose. 
Study patients will be given ‘IM positive’ status if they have at least one confirmed positive sample 
result at any time during the treatment or post-treatment evaluation periods. Study patients will be 
given ‘IM negative’ status if all evaluated IM sample results during the treatment and post-treatment 
evaluation periods are IM negative and they have at least one evaluable IM result collected post study 
drug treatment. Otherwise, a study patient will be given ‘unknown’ IM status. Patient IM results 
will be listed by treatment and dose for all evaluable patients, which will include but may not be 
limited to: patient IM status (positive, negative or unknown), 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), the time of last evaluable IM sample collected (Tlast sampling), peak titer, and time to 
reach peak titer. The onset of ADA and time to reach peak titer will be calculated by: 


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• 
Onset in days = The date of first sample has “positive” sample IM status - first dose date +1; 
• 
Time to reach peak titer in days = The date of first peak titer observed- first dose date +1; 
Other immunogenicity data analysis (e.g. classification as transient or persistent status for IM positive 
patients) may be conducted if there are sufficient number of patients with transient IM status. 
Transient and Persistent ADA definitions are defined below and based on Shankar et al. (2014). 
Transient ADA response will be defined as: 
• 
Treatment-induced ADA detected only at one sampling time point during the treatment or 
follow-up observation period (excluding the last sampling time point, which will be 
considered persistent unless shown to be undetectable at a later time) or 
• 
Treatment-induced ADA detected at two or more sampling time points during the treatment 
(including follow-up period if any), where the ﬁrst and last ADA-positive samples 
(irrespective of any negative samples in between) are separated by a period less than 16 
weeks, and the patient’s last sampling time point is ADA-negative. 
Persistent ADA response will be defined as: 
• 
Treatment-induced ADA detected at two or more sampling time points during the treatment 
(including follow-up period if any), where the ﬁrst and last ADA-positive samples 
(irrespective of any negative samples in between) are separated by a period of 16 weeks or 
longer or 
• 
Treatment-induced ADA detected only at the last sampling time point of the study treatment 
period or at a sampling time point with less than 16 weeks before an ADA-negative last 
sample. 
The sample IM incidence (number) and incidence rate (percent) at each evaluated study time point, 
and for the overall treatment and post-treatment evaluation period, as well as patient IM incidence 
and incidence rate, will be determined and appropriately summarized by treatment, as the total 
number of and percentage of evaluated patients with IM negative, positive, and unknown status. 
Patients with positive IM status may further be classified as transient or persistent status if applicable, 
and incidence and incidence rate for being transient or persistent will be appropriately summarized. 
Furthermore, onset, titer over time, and peak titer of the ADA response, if applicable, will be also 
appropriately summarized (using descriptive statistics) as median, quartiles (25% and 75%), and 
range and presented graphically, if deemed appropriate, by treatment at the discretion of the 
designated study pharmacokineticist and/or statistician (e.g., summarized at each evaluated study time 
point and overall; summarized by observed peak titer values from the individual IM positive patients; 
etc.). 
In addition to PK assessments (Section 3.7.2), selected safety (Section 3.8) and efficacy (Sections 3.6) 
assessments may be further stratified by patient IM status (i.e., patient IM status being positive, 
negative or unknown) and presented in tables and/or graphically, as deemed appropriate or warranted 
by the designated study pharmacokineticist, medical monitor, and/or biostatistician. Other 
stratifications (e.g., based on antibody titer, onset of ADA, etc.) of selected PK, efficacy and safety 
assessments may also be performed if deemed warranted at the discretion of the pharmacokineticist, 
medical monitor, and/or biostatistician. 


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3.8 Safety Analyses 
The safety analysis will be conducted on the Safety Set. 
 
3.8.1 
Exposure 
Treatment duration and amount of Study Drug (ISIS 766720 or placebo) received will be summarized 
by treatment group. The treatment duration for each subject is defined as last dose date - first dose 
date +1. 
 
3.8.2 
Adverse Events 
The incidence of AEs will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.1 (or higher) preferred term and system organ class (SOC) for: 
• 
Any treatment emergent adverse events (TEAEs) 
• 
Related treatment emergent adverse events. Related is defined as “Related”, “Possible”, 
or missing relationship to study drug 
• 
Any treatment emergent adverse events by severity. At each level of subject 
summarization, a subject is classified according to the highest severity if the subject 
reported one or more events. Adverse events with missing severity will categorized as 
“Missing” for this summary 
• 
Serious treatment emergent adverse events 
• 
Treatment emergent adverse events leading to study drug permanently discontinued 
SAEs and non-serious AEs that lead to study discontinuation or investigational drug discontinuation 
will be listed separately. Non-treatment emergent adverse event will be flagged in the data 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 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. 


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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. 
The most conservative approach will be used to determine if the event occurs after the treatment. For 
example, if the onset date or resolution date of an AE is prior to the first study treatment date, it will 
be considered to have occurred prior to the study period. If the onset or resolution date of an AE is a 
partial date with only month or year available or complete missing, then the event is assumed to be 
within the study period unless the year is prior to the year of the first study treatment date, or if in the 
same year, the month is prior to the month of the first study treatment date. 
3.8.2.1 
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 pruitus, 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 injection site is the principal reason for discontinuation. 
Percentage of injections leading to local cutaneous reaction at the injection site will be calculated as 
follows for each subject: (A/B)*100, where A=number of injections with a LCRIS, and B=total 
number of injections. Doses that are split across multiple injections are counted as a single injection 
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. 
3.8.2.2 
Flu-like Reactions 
Flu-like reactions will also be summarized by preferred term. 
Flu-like reactions are defined as either (A) flu-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, and 
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 the 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. 
3.8.2.3 
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 


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with a check box to indicate. AESI will be summarized by preferred term. A listing of AESI will also 
be generated. 
 
3.8.3 
Laboratory Measurements 
Bone biomarkers, pituitary axis, thyroid panel, inflammatory, lipid panel, chemistry, hematology, 
coagulation, complement and urinalysis (result, change and percent change from baseline) will be 
summarized by treatment group and each post-baseline visit. 
 
 
For ALT and AST, the number and percent of subjects falling in each of the following categories will 
be tabulated by treatment group: 
• 
ALT/AST > 3 x ULN, confirmed 
• 
ALT/AST > 5 x 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 that value is in the same or worse category then the initial value is 
confirmed. If the consecutive value is in a better category then the initial value is confirmed using the 
consecutive value category. If there is no retest within 7 days 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 100,000mm3 to lower limit of normal 
• 
Confirmed Platelet count 75,000 to < 100,000mm3 
• 
Confirmed Platelet count 50,000 to < 75,000mm3 
• 
Confirmed Platelet count 25,000 to < 50,000mm3 
• 
Confirmed Platelet count < 25,000mm3 
• 
Confirmed ≥ 30% Platelet count decrease from baseline 
 
Subjects with more than one confirmed value will be counted exactly once under the worst confirmed 
category. 
 
3.8.4 
Vital Signs 
Vital signs will include heart rate, respiratory rate, body temperature, calculated BMI, and systolic 
and diastolic blood pressure. Vital signs will be summarized by treatment group for vital sign values 
as well as the change and percent change from baseline at each post-baseline visit. 
 
3.8.5 
12-Lead Electrocardiograms (ECG) 
Safety 12 lead ECG will be performed in triplicate at the visits indicated in the protocol Schedule of 
Procedures. The baseline is defined as the average of the triplicate prior the first dose of study drug. 


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The ECG data will include ventricular rate (VR), PR interval, QRS duration, QT, QTcF (QT 
corrected using the Fridericia’s formula), and QTcB (QT corrected using the Bazett’s formula). QTcF 
and QTcB will be calculated based on the subject’s reportable ECG data at each time point using the 
formula described below: 
QTcF = QT / (RR) 1/3, where RR= 60/VR 
QTcB = QT / (RR) 1/2, where RR= 60/VR 
Only calculated QTcB and QTcF will be summarized and included in the data listing. The QTcB and 
QTcF values recorded on the CRF will not be summarized and will be excluded from the data listing. 
For the continuous variables above, descriptive statistics (n, mean, standard error, standard deviation, 
median, 25th percentile, 75th percentile, minimum and maximum) of the average of triplicate 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 worst of 
triplicate results at each visit will be summarized by counts and percentages. All the ECG data 
collected in triplicate, except the CRF QTcB and QTcF values, will be listed. 
 
3.8.6 
Acromegaly Past Medications and Concomitant Medications 
Acromegaly Past Medications and concomitant medications will be coded using WHO Drug 
dictionary (version March 2018) and summarized by ATC class, generic name and treatment group. 


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4 REFERENCES 
1) “Acromegaly Quality of Life Questionnaire (AcroQoL) User’s Manual.” Version: August 
2017. 
2) “Acromegaly Quality of Life Questionnaire (AcroQoL).” Xavier Badia, Susan M Webb, Luis 
Prieto and Nuria Lara. Health and Quality of Life Outcomes 2004, 2:13 
3) G Shankar et al. Assessment and reporting of the clinical immunogenicity of therapeutic proteins 
and peptides-harmonized terminology and tactical recommendations AAPS J. 2014 
Jul;16(4):658-73.