Conditions: Chronic Bronchitis Chronic Obstructive Pulmonary Disease
Keywords: Chronic Bronchitis IONIS-ENaCRx
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the effect of ION-827359 on forced expiratory volume in 1 second (FEV1) in participants with mild to moderate COPD with CB.

Detailed description:
This was a multi-center, double-blind, placebo-controlled, randomized, Phase 2a study of ION-827359 in up to 180 participants. The participants were randomized to receive oral inhalation of either ION-827359 or placebo for up to 13 weeks. At the end of 13 weeks, participants entered a 10-week post-treatment evaluation period.

Arms:
arm 1: Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks. arm 2: Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks. arm 3: Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.

Interventions: intervention 1: ION-827359 intervention 2: Placebo intervention 3: ION-827359
Intervention descriptions: intervention 1: ION-827359 administered by oral inhalation intervention 2: Placebo administered by oral inhalation intervention 3: ION-827359 administered by oral inhalation

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Safety, 
Tolerability, and Efficacy of ION-827359 in Patients With Mild to Moderate 
COPD With Chronic Bronchitis 
NCT04441788 
 
26-August-2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Official Title: 
A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Safety, 
Tolerability, and Efficacy of ION-827359 in Patients with Mild to Moderate 
COPD with Chronic Bronchitis 
 
 
NCT Number: 
NCT04441788 
 
Document Date: 
Protocol Amendment 3 : 02 February 2021 


 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
ION-827359-CS2 
 
A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the 
Safety, Tolerability, and Efficacy of ION-827359 in Patients with 
Mild to Moderate COPD with Chronic Bronchitis 
 
2 February 2021 
 
Protocol Amendment 3 
 
EudraCT No: 2020-000210-15 
 
 
Trial Sponsor: 
Ionis Pharmaceuticals 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 760-931-9200 
Fax: 
Key Sponsor Contact: 
Dr. 
Phone: 
Fax: 


ION-827359-CS2 
Protocol 
CONFIDENTIAL 
Protocol Amendment 3 
2 February 2021 
2 
 
 
, M.D. 
 
ION-827359-CS2 
Protocol Amendment 3 
EudraCT No: 2020-000210-15 
Clinical Phase: 2a 
 
A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the 
Safety, Tolerability, and Efficacy of ION-827359 in Patients with 
Mild to Moderate COPD with Chronic Bronchitis 
 
Protocol History 
Original Protocol: 
21 January 2020 
Protocol Amendment 1: 28 May 2020 
Protocol Amendment 2: 10 August 2020 
 
 
 
 
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. 


ION-827359-CS2 
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2 February 2021 
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PROTOCOL SIGNATURE PAGE 
 
 
Protocol Number: 
ION-827359-CS2 
Protocol Title: 
A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Safety, 
Tolerability, and Efficacy of ION-827359 in Patients with Mild to Moderate 
COPD with Chronic Bronchitis 
Amendment: 
Protocol Amendment 3 
Date: 
2 February 2021 
 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “A 
Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Safety, Tolerability, and Efficacy of 
ION‑827359 in Patients with Mild to Moderate COPD with CB” dated 2 February 2021, and agree to 
conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc. 
 
 
 
 
 
Investigator’s Signature 
 
 
Investigator’s Name (please print) 
Date (DD Month YYYY) 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT .......................................................................................................... 9 
PROTOCOL SYNOPSIS ............................................................................................................... 10 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................... 16 
STUDY GLOSSARY .................................................................................................................... 17 
1. 
OBJECTIVES AND ENDPOINTS ............................................................................ 19 
1.1. 
Objectives .................................................................................................................... 19 
1.1.1. 
Primary Objective ....................................................................................................... 19 
1.1.2. 
Secondary Objectives .................................................................................................. 19 
1.1.3. 
Additional/Exploratory Objectives ............................................................................. 19 
1.2. 
Study Endpoints .......................................................................................................... 19 
1.2.1. 
Primary Endpoint ........................................................................................................ 19 
1.2.2. 
Secondary Endpoints ................................................................................................... 19 
1.2.3. 
Exploratory Endpoints ................................................................................................ 20 
1.2.3.1. 
Pharmacokinetic (PK) Endpoints ................................................................................ 20 
2. 
BACKGROUND AND RATIONALE ....................................................................... 20 
2.1. 
Overview of Disease ................................................................................................... 20 
2.2. 
Therapeutic Rationale ................................................................................................. 21 
2.3. 
ION‑827359 ................................................................................................................ 21 
2.3.1. 
Mechanism of Action .................................................................................................. 21 
2.3.2. 
Chemistry .................................................................................................................... 22 
2.3.3. 
Preclinical Experience ................................................................................................. 22 
2.3.4. 
Clinical Experience ..................................................................................................... 22 
23 
2.5. 
Benefit-Risk Assessment ............................................................................................ 23 
2.5.1. 
Overall Assessment of Benefit:Risk ........................................................................... 24 
3. 
EXPERIMENTAL PLAN ........................................................................................... 24 
3.1. 
Study Design ............................................................................................................... 24 
3.2. 
Number of Study Centers ............................................................................................ 24 
3.3. 
Number of Patients ...................................................................................................... 24 
3.4. 
Overall Study Duration and Follow-up ....................................................................... 24 
3.4.1. 
Screening ..................................................................................................................... 24 


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3.4.2. 
Treatment .................................................................................................................... 24 
3.4.3. 
Post-Treatment ............................................................................................................ 25 
3.5. 
End-of-Study ............................................................................................................... 25 
4. 
PATIENT ENROLLMENT ........................................................................................ 25 
4.1. 
Screening ..................................................................................................................... 25 
4.2. 
Randomization/Registration ........................................................................................ 25 
4.3. 
Replacement of Patients .............................................................................................. 26 
4.4. 
Unblinding of Treatment Assignment .......................................................................... 26 
5. 
SUBJECT ELIGIBILITY ........................................................................................... 26 
5.1. 
Inclusion Criteria ......................................................................................................... 26 
5.2. 
Exclusion Criteria ....................................................................................................... 27 
6. 
STUDY PROCEDURES ............................................................................................ 29 
6.1. 
Study Schedule ............................................................................................................ 29 
6.1.1. 
Screening ..................................................................................................................... 29 
6.1.2. 
Baseline Period ........................................................................................................... 30 
6.1.3. 
Treatment Period ......................................................................................................... 30 
6.1.4. 
Post-Treatment Period ................................................................................................ 31 
6.2. 
Study/Laboratory Assessments ................................................................................... 31 
6.3. 
Restriction on the Lifestyle of Subjects ...................................................................... 31 
6.3.1. 
Contraception Requirements ....................................................................................... 31 
6.3.2. 
Other Requirements .................................................................................................... 32 
7. 
STUDY DRUG ........................................................................................................... 32 
7.1. 
Study Drug Description ............................................................................................... 32 
7.1.1. 
ION‑827359 ................................................................................................................ 32 
7.1.2. 
Placebo ........................................................................................................................ 32 
7.2. 
Packaging and Labeling .............................................................................................. 33 
7.3. 
Study Drug Accountability .......................................................................................... 33 
8. 
TREATMENT OF PATIENTS .................................................................................. 33 
8.1. 
Study Drug Administration ......................................................................................... 33 
8.2. 
Other Protocol-Required Drugs .................................................................................. 33 
8.3. 
Protocol-Required Treatment Procedures ................................................................... 33 
8.3.1. 
Spirometry ................................................................................................................... 33 


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8.3.2. 
Diffusing Capacity (DLCO) ........................................................................................ 34 
34 
8.3.4. 
Plethysmography ......................................................................................................... 34 
8.3.5. 
HRCT .......................................................................................................................... 35 
8.3.6. 
Sputum Collection ....................................................................................................... 35 
8.3.7. 
SGRQ .......................................................................................................................... 35 
8.3.8. 
COPD Assessment Test (CAT) ................................................................................... 35 
8.3.9. 
EXACT – Respiratory Symptoms (E-RS) .................................................................. 36 
8.4. 
Treatment Precautions ................................................................................................. 36 
8.5. 
Safety Monitoring Rules ............................................................................................. 36 
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests ................................................... 36 
8.5.2. 
Safety Monitoring Rules for Platelet Count Results ................................................... 37 
8.6. 
Stopping Rules for Liver Chemistry Elevations ......................................................... 39 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations ......................................................... 39 
8.6.2. 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules 
for Renal Function Test Results .................................................................................. 39 
8.6.3. 
Stopping Rule for Platelet Count Results ................................................................... 40 
8.6.4. 
Stopping Rule for Serum Potassium ............................................................................ 40 
8.7. 
Adjustment of Dose and/or Treatment Schedule ........................................................ 40 
8.8. 
Discontinuation of Study Drug/Treatment .................................................................. 40 
8.9. 
Withdrawal of Patients from the Study Procedures .................................................... 41 
8.10. 
Concomitant Therapy and Procedures ........................................................................ 41 
8.10.1. 
Concomitant Therapy .................................................................................................. 41 
8.10.2. 
Concomitant Procedures ............................................................................................. 42 
8.11. 
Treatment Compliance ................................................................................................ 42 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 42 
9.1. 
Sponsor Review of Safety Information ....................................................................... 42 
9.2. 
Regulatory Requirements ............................................................................................. 42 
9.3. 
Definitions ................................................................................................................... 43 
9.3.1. 
Adverse Event ............................................................................................................. 43 
9.3.2. 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction ............ 44 
9.3.3. 
Serious Adverse Event (SAE) ..................................................................................... 44 
9.4. 
Monitoring and Recording Adverse Events ................................................................ 45 


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9.4.1. 
Serious Adverse Events .............................................................................................. 45 
9.4.2. 
Non-Serious Adverse Events ...................................................................................... 45 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) ......................................... 45 
9.4.3.1. 
Relationship to the Study Drug ................................................................................... 46 
9.4.3.2. 
Severity ....................................................................................................................... 46 
9.4.3.3. 
Action Taken with Study Drug .................................................................................... 47 
9.4.3.4. 
Treatment Given for Adverse Event ........................................................................... 47 
9.4.3.5. 
Outcome of the Adverse Event ................................................................................... 47 
9.4.3.6. 
Follow-up of Adverse Event ....................................................................................... 48 
9.5. 
Procedures for Handling Special Situations ................................................................ 48 
9.5.1. 
Abnormalities of Laboratory Tests ............................................................................. 48 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................. 49 
9.5.3. 
Dosing Errors .............................................................................................................. 49 
9.5.4. 
Contraception and Pregnancy ..................................................................................... 49 
10. 
STATISTICAL CONSIDERATIONS ........................................................................ 50 
10.1. 
Stratification, Subsets, and Covariates ........................................................................ 50 
10.2. 
Sample Size Considerations ........................................................................................ 50 
10.3. 
Populations .................................................................................................................. 51 
10.4. 
Definition of Baseline ................................................................................................. 51 
10.5. 
Interim Analysis and Multiplicity ............................................................................... 51 
10.6. 
Planned Methods of Analysis ..................................................................................... 51 
10.6.1. 
Demographic and Baseline Characteristics ................................................................. 51 
10.6.2. 
Safety Analysis ........................................................................................................... 51 
10.6.3. 
Efficacy Analysis ........................................................................................................ 52 
10.6.3.1. 
Analysis of Primary Endpoint ..................................................................................... 52 
10.6.3.2. 
Analysis of Secondary Endpoints ............................................................................... 52 
10.6.4. 
Pharmacokinetic Analysis............................................................................................ 53 
10.6.5. 
Additional Analyses .................................................................................................... 53 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 53 
11.1. 
Informed Consent ........................................................................................................ 53 
11.2. 
Ethical Conduct of the Study ....................................................................................... 54 
11.3. 
Independent Ethics Committee/Institutional Review Board ....................................... 54 


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11.4. 
Subject Confidentiality ................................................................................................54 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ...............................................55 
12.1. 
Protocol Amendments .................................................................................................55 
12.2. 
Study Termination .......................................................................................................55 
12.3. 
Study Documentation and Storage ..............................................................................55 
12.4. 
Study Monitoring ........................................................................................................56 
12.5. 
Language .....................................................................................................................57 
12.6. 
Compensation for Injury .............................................................................................57 
13. 
REFERENCES............................................................................................................58 
14. 
APPENDICES ............................................................................................................60 
APPENDIX A. SCHEDULE OF PROCEDURES ......................................................................61 
APPENDIX B. LIST OF LABORATORY ANALYTES ........................................................... 66 
APPENDIX C. PK SAMPLING SCHEDULE ...........................................................................68 
APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING TO 
LABORATORY ABNORMALITIES ..............................................................70 
 
 
 
 
LIST OF TABLES 
Table 1: 
Withhold Time for Bronchodilators Prior to Study Visit: ..........................................30 
Table 2: 
Study Drug Characteristics ..........................................................................................32 
Table 3: 
Study Drug Dosing Information ..................................................................................33 
Table 4: 
Additional Labs to be Performed in the Event of a Platelet Count 
< 75,000/mm3 .................................................................................................................................................................. 38 


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PROTOCOL AMENDMENT 
 
Protocol Number: 
ION-827359-CS2 
Protocol Title: 
A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the 
Safety, Tolerability, and Efficacy of ION-827359 in Patients with Mild 
to Moderate COPD with Chronic Bronchitis 
Amendment Number: 
3 
Amendment Date: 
2 February 2021 
 
 
The major purpose of this amendment is to help prevent any potential bronchospasm after 
inhalation of Study Drug. 
A list of changes to the protocol are below: 
 
Protocol 
Section 
Description of Change 
Rationale 
Section 6.1.3 
Treatment 
Period 
The following is deleted from Table 1 (Withhold times for 
bronchodilators): 
LABA (e.g., formoterol or salmeterol) 24 hours 
Ultra-LABA (e.g., indacaterol, vilanterol, or olodaterol 
36 hours 
LAMA (e.g., tiotropium, umeclidinium, aclidinium, or 
glycopyrronium) 36 – 48 hours 
The following is added: 
The usual dose of bronchodilators should not be taken the 
morning of the visit, until after spirometry is performed and 
prior to dosing (if applicable) with the study medication. 
Albuterol (salbutamol) 2 puffs, should be dosed prior to study 
drug both for in-clinic and at-home dosing. 
To help prevent 
any potential 
bronchospasm 
Appendix A 
Schedule of 
Procedures 
Footnote 2 (vital signs) currently reads: 
2 BP, heart rate (HR), respiratory rate (RR), temperature 
Will be amended to: 
2 BP, heart rate (HR), respiratory rate (RR), temperature, and 
pulse oximetry 
Correct an 
omission. 
Appendix A 
Schedule of 
Procedures 
Footnote g added for spirometry on Day 1: 
Perform spirometry (pre-Study Drug) pre and 20-30 minutes 
post albuterol dose (2 puffs) and then perform spirometry 1 and 
2 hours post-Study Drug dosing. 
Collect baseline 
post-albuterol 
spirometry 


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PROTOCOL SYNOPSIS 
 
Protocol Title 
A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the 
Safety, Tolerability, and Efficacy of ION‑827359 in Patients with 
Mild to Moderate COPD with Chronic Bronchitis 
Study Phase 
2a 
Indication 
Chronic Bronchitis (CB) 
Primary Objective 
To evaluate the efficacy of ION‑827359 in patients with mild to 
moderate CB over 13 weeks of treatment 
Secondary Objectives 
• To evaluate the effect of ION‑827359 on symptoms of CB 
• To evaluate the effect of ION‑827359 on quality of life (QoL) in 
COPD patients with CB 
• To evaluate the pharmacokinetics of ION‑827359 in COPD 
patients with CB 
• To evaluate the safety and tolerability of ION‑827359 compared 
to placebo 
Exploratory Objectives 
• To assess changes in lung volumes (RV, FRC) 
• To assess changes in lung mucins (total, MUC5AC, and MUC5B) 
• To assess changes in regional lung ventilation in low dose high 
resolution CT scanning (HRCT) scans 
• To determine mRNA target engagement and inflammatory 
biomarkers 
• To evaluate the dose response of ION‑827359 
Study Design 
Double-blind, placebo-controlled, multi-center study 
Number of Patients 
Approximately 180 patients 
Study Population 
Inclusion Criteria 
1. Must have given written informed consent (signed and dated) and 
any authorizations required by local law and be able to comply 
with all study requirements 
2. Males or females. Aged 40–70 inclusive at the time of informed 
consent 
3. Females must be non-pregnant and non-lactating, and either 
surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy) or post-menopausal 
(defined as 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the post-menopausal 
range for the laboratory involved) 


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PROTOCOL SYNOPSIS (Continued) 
 
Study Population (Continued) 
Inclusion Criteria Continued 
Males must be surgically sterile or abstinent*, if engaged in 
sexual relations with a female of child-bearing potential, the 
subject must be using a condom in addition to a highly effective 
contraceptive method by the partner from the time of signing the 
informed consent form until at least 10 weeks after the last dose 
of Study Drug (ION‑827359 or placebo) 
* Abstinence is only acceptable as true abstinence, i.e., when this 
is in line with the preferred and usual lifestyle of the patient. 
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 
4. BMI < 35.0 kg/m2 
5. Patients with a diagnosis of COPD as defined by the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) 
• Ability to perform acceptable and reproducible spirometry 
• Post-bronchodilator (4 puffs of albuterol) spirometry at 
Screening demonstrating the following 
• FEV1/FVC ratio of < 0.70 
• FEV1 ≥ 50% and ≤ 90% of predicted normal 
6. Clinically stable COPD in the 4 weeks prior to Screening (Visit 1) 
7. Current and former smokers with smoking history of ≥ 20 pack 
years 
8. Meet SGRQ definition of CB (See Section 6.1.1) 
9. CAT score of ≥ 10 
Exclusion Criteria 
1. Clinically significant abnormalities in medical history (e.g., 
previous acute coronary syndrome within 6 months of Screening, 
major surgery within 3 months of Screening) or physical 
examination 
2. Screening laboratory results as follows, or any other clinically 
significant abnormalities in screening laboratory values that 
would render a subject unsuitable for inclusion 
• Urine protein/creatinine (P/C) ratio ≥ 0.3 mg/mg. In the 
event of P/C ratio above this threshold eligibility may be 
confirmed by a quantitative total urine protein measurement 
of < 300 mg/24 hr 


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PROTOCOL SYNOPSIS (Continued) 
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Study Population (Continued) 
Exclusion Criteria (Continued) 
• 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 
• ALT, AST, bilirubin, alkaline phosphatase, serum creatinine, 
BUN > 1.5 × upper limit of normal (ULN) 
• Platelet count < LLN 
• Serum potassium > 5.2 mmol/L 
• Estimated GFR< 60 mL/min (as determined by the 
Cockcroft-Gault Equation for creatinine clearance) 
3. Any active infection requiring systemic antiviral or antimicrobial 
therapy that will not be completed prior to Study Day 1 
4. Unwillingness to comply with study procedures, including 
follow-up, as specified by this protocol, or unwillingness to 
cooperate fully with the Investigator 
5. Active infection with human immunodeficiency virus (HIV), 
hepatitis C or hepatitis B 
6. Uncontrolled hypertension (BP > 160/100 mm Hg) 
7. Malignancy within 5 years, except for basal or squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix 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 PI and reviewed by the Sponsor Medical 
Monitor 
8. Treatment with another investigational drug, biological agent, or 
device within 1 month of Screening, or 5 half-lives of 
investigational agent, whichever is longer 
9. Previous treatment with an oligonucleotide (including siRNA) 
within 4 months of screening if single dose received, or within 
12 months of screening if multiple doses received 
10. Clinically important pulmonary disease other than COPD 
11. Asthma as a primary or main diagnosis according to the Global 
Initiative for Asthma (GINA) guidelines (GINA 2011) or other 
accepted guidelines. Patients with a past medical history of 
asthma (e.g. childhood or adolescence) may be included 
12. Treatment with systemic corticosteroids and/or antibiotics, 
and/or hospitalization for a COPD exacerbation within 4 weeks 
prior to enrolment (Visit 1) 


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PROTOCOL SYNOPSIS (Continued) 
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Study Population (Continued) 
Exclusion Criteria (Continued) 
13. Acute upper or lower respiratory infection requiring antibiotics 
or antiviral medication within 4 weeks prior to enrolment 
(Visit 1) 
14. Long term oxygen therapy (LTOT) 
15. Patients participating in, or scheduled for, an intensive (active) 
COPD rehabilitation program (patients who are in the 
maintenance phase of a rehabilitation program are eligible to 
take part) 
16. Recent history of, or current drug or alcohol abuse 
17. Concomitant medication restrictions: Oral anticoagulants, oral 
steroids (e.g. prednisone or Medrol), theophylline, chronic 
azithromycin, or roflumilast 
18. Have any other conditions, which, in the opinion of the 
Investigator would make the subject unsuitable for inclusion, or 
could interfere with the subject participating in or completing 
the Study 
19. A positive PCR test for SARS-CoV-2 at any time prior to 
randomization 
Treatment Groups 
Patients will be randomized 2:2:1:1 to treatment with: 
• ION‑827359 37.5 mg (1.5 mL) once per week 
• ION‑827359 75mg (3 mL) once per week 
• Placebo (1.5 mL) once per week 
• Placebo (3 mL) once per week 
Study Drug Dosage and 
Administration 
ION‑827359 (25mg/mL) and placebo will be supplied in stoppered 
glass vials. A total of 1.5 mL or 3 mL will be placed into a 
Pari eFlow® nebulizer and administered by oral inhalation once 
weekly. 
 
 
Study Visit Schedule and 
Procedures 
Blood and urine samples will be collected regularly throughout the 
study for safety, PK, and PD analyses. Appendix B shows a list of 
analytes required for the study. The safety of ION‑827359 will be 
monitored in an ongoing fashion throughout the trial. 
Screening and Baseline: Study Days -28 to -1 
Laboratory and other study procedures will be performed to assess 
eligibility during the Screening Period. Patients will also receive a 
SARS-CoV-2 PCR test based on nasal/oral swab. Patients will be 
given an electronic diary to record their baseline daily symptoms 
starting on Day -7. 


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PROTOCOL SYNOPSIS (Continued) 
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Study Visit Schedule and 
Procedures (Continued) 
Treatment: Study Days 1 to 85 
Eligible patients will be randomized 2:2:1:1 to ION‑827359 (37.5 or 
75 mg) or matching placebos. Patients will receive nebulized doses 
of Study Drug once weekly starting on Study Day 1. Both in-clinic 
and at-home dosing of ION‑827359 will be performed. Patients will 
record their symptoms in a daily electronic diary and return for study 
visits to include monitoring and spirometry. There are 3 subset 
studies: 
1. A subset of up to about 24 patients will have PK profile 
sampling performed after the first and last dose 
2. A subset of up to about 60 patients will have low dose 
inspiratory and expiratory HRCT scans to assess regional lung 
ventilation performed before and post-treatment 
3. A subset of up to about 18 patients will undergo bronchoscopy 
and BAL for target engagement and inflammatory biomarkers 
before and post-treatment 
A patient may be enrolled in a maximum of 1 subset study 
Post-Treatment: Study Days 86 to 162 
Patients are to return to the Study Center for post-treatment visits on 
Study Days 92, 120 and 162. 
Patients that discontinue treatment are encouraged to remain in the 
study for the Post-Treatment Evaluation Period and will conduct 
procedures outlined at Study Day 92 visit upon discontinuation of 
Study Drug. 
Patients will continue their stable COPD medication regimen 
throughout the study (screening treatment and post-treatment 
periods). 
Primary Endpoints 
Change from Baseline to the primary time point (defined as the 
average of Weeks 13 and 14) in FEV1 compared to placebo 
Secondary Endpoints 
• Change from Baseline in the E-RS (evaluating respiratory 
symptoms) daily symptom diary to the primary time point 
• Change from Baseline in the CAT to the Week 14 time point 
• Change from Baseline in SGRQ to the Week 14 time point 
• Change from Baseline in post-bronchodilator FEV1 
• Pharmacokinetics 
• Incidence and severity of treatment-emergent adverse events 
(TEAE) 
• Abnormal findings in laboratory assessments, ECG, and vital 
signs 


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PROTOCOL SYNOPSIS (Continued) 
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Exploratory Endpoints 
• 
Change from Baseline in sputum mucins (total, MUC5AC, and 
MUC5B) 
• 
Change from Baseline in ENaC mRNA levels from bronchial 
brushings 
• 
Change from Baseline in inflammatory biomarkers from 
bronchoalveolar lavage 
• 
Change from Baseline in FRC (functional respiratory capacity) 
and RV (residual volume) 
• 
Change from Baseline in regional lung volumes as measured by 
HRCT 
Statistical Considerations 
The sample size assumptions for the primary endpoint include: 
• 
The increase in FEV1 from Baseline to the primary time point in 
the ION‑827359 treatment group is 100 mL; no change in the 
placebo group 
• 
Standard deviation of change in FEV1 is 220 mL 
• 
Significance level (alpha) of 0.05 (2-sided test) 
With the above assumptions, a sample size of 174 patients 
(58 patients in each ION‑827359 treatment groups and 29 patients in 
each placebo group) will provide a power of at least 80% for the 
primary comparison (pooled ION‑827359 treatment groups vs. 
pooled placebo groups). Approximately 180 patients will be enrolled 
in this trial to account for a 3% dropout rate. 
Sponsor 
Ionis Pharmaceuticals 


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EARLY 
TREATMENT 
TERMINATION 
Early Term Visit 
(Study Day 92) 
POST-TREATMENT 
EVALUATIONS 
Days 86 to 162 
DOSE TREATMENT 
PERIOD 
Days 1 to 85 
Dosing on Days 1,8,15, 22, 29, 36, 43, 
50, 57, 64, 71, 78, and 85 
END-OF-STUDY 
PROCEDURES 
Day 162 
 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BASELINE 
Days -7 to -1 
SCREEN 
Days -28 to -7 


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STUDY GLOSSARY 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUCt 
area under the plasma concentration-time curve from time zero to time t 
BAL 
bronchoalveolar lavage 
βhCG 
beta-subunit of human chorionic gonadotropin (pregnancy test) 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
centigrade 
C5a 
complement factor C5a (activated complement split product) 
CAT 
COPD assessment test 
CB 
chronic bronchitis 
CL 
systemic clearance 
CMV 
cytomegalovirus 
COPD 
chronic obstructive pulmonary disease 
CS 
clinically significant 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
dL 
deciliter 
DLCO 
diffusing capacity 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated glomerular filtration rate 
ENaC 
epithelial sodium channel 
ERS 
European Respiratory Society 
E-RS 
EXACT respiratory symptoms 
FAS 
Full Analysis Set 
FEV1 
forced expiratory volume in 1 second 
FRC 
functional residual capacity 
FSH 
follicle stimulating hormone 
FVC 
forced vital capacity 
g 
gram 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HRCT 
high resolution CT scanning 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 


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IgM 
immunoglobulin M 
IL-5 
interleukin-5 
IL-8 
interleukin-8 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ION-827359 
antisense inhibitor of ENaC 
kg 
kilogram 
m2 
square meter 
MAD 
multiple-ascending dose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
mm 
millimeter 
mRNA 
messenger ribonucleic acid 
NCI 
National Cancer Institute 
NCS 
not clinically significant 
NOAEL 
no adverse effect level 
on study 
the patient is ‘on study’ from signing of the informed consent until their last 
study visit 
P/C 
urine protein/creatinine 
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 
RV 
residual volume 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SGRQ 
St. George’s Respiratory Questionnaire 
siRNA 
small interfering ribonucleic acid 
TLC 
total lung capacity 
Study Day 1 
defined as the first day Study Drug product is administered to the patient 
Study Drug 
ION‑827359 or placebo 
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 
woman of child-bearing potential 


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1. 
OBJECTIVES AND ENDPOINTS 
1.1. 
Objectives 
1.1.1. 
Primary Objective 
To evaluate the effect of ION‑827359 on forced expiratory volume in 1 second (FEV1) in 
patients with mild to moderate chronic obstructive pulmonary disease (COPD) with chronic 
bronchitis (CB) 
 
1.1.2. 
Secondary Objectives 
• To evaluate the effect of ION‑827359 on symptoms of CB 
• To evaluate the effect of ION‑827359 on quality of life (QoL)in patients of CB 
• To evaluate the pharmacokinetics (PK) of ION‑827359 in patients with CB 
• To evaluate the safety and tolerability of ION‑827359 compared to placebo 
1.1.3. 
Additional/Exploratory Objectives 
• Assess changes in PD markers 
• Assess changes in lung volumes 
• Assess changes in lung ventilation 
• Assess target engagement 
1.2. 
Study Endpoints 
1.2.1. 
Primary Endpoint 
Change from Baseline to the primary time point (defined as the average of Weeks 13 and 14) in 
FEV1 compared to placebo 
 
1.2.2. 
Secondary Endpoints 
• Change from Baseline in the EXACT respiratory symptoms (E-RS) (evaluating 
respiratory symptoms) daily symptom diary to the primary time point 
• Change from Baseline in the COPD assessment test (CAT) to the Week 14 time point 
• Change from Baseline in St. George’s Respiratory Questionnaire (SGRQ) to the 
Week 14 time point 
• Change from Baseline in post-bronchodilator FEV1 
• Pharmacokinetics (Section 1.2.3.1) 
• Safety Endpoints 
− Incidence and severity of treatment-emergent adverse events (TEAE) 
− Abnormal findings in laboratory assessments, electrocardiogram (ECGs), and 
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1.2.3. 
Exploratory Endpoints 
The tertiary and PD endpoints include: 
• Change from Baseline in sputum mucins (total, MUC5AC, and MUC5B) 
• Change from Baseline in epithelial sodium channel (ENaC) messenger ribonucleic 
acid (mRNA) levels from bronchial brushings 
• Change from Baseline in inflammatory biomarkers from bronchoalveolar lavage 
(BAL) 
• Change from Baseline in functional respiratory capacity (FRC) and residual volume 
(RV) 
• Change from Baseline in regional lung volumes as measured by high resolution CT 
scanning (HRCT) 
 
1.2.3.1. 
Pharmacokinetic (PK) Endpoints 
Plasma exposure over time will be summarized using data from PK profile samples collected 
following the first and last dose in a subset of patients, as well as trough samples collected in all 
patients throughout the study. In addition, potential PK/PD correlation on relevant biomarkers 
may be evaluated. 
 
2. 
BACKGROUND AND RATIONALE 
2.1. 
Overview of Disease 
Chronic Bronchitis (CB) is an inflammatory disease of the bronchi, especially the central 
bronchi, and is characterized by excessive mucus secretion. Classically this is defined as 
significant sputum production for at least 3 months for at least 2 successive years. Abnormalities 
in mucus production and properties are critical to the pathophysiology of the disease. Patients 
suffer from varying degrees of chronic cough, sputum expectoration, and dyspnea. CB is 1 of 
the 2 underlying diagnoses for COPD, the other being emphysema. COPD is characterized by 
progressive and incompletely reversible airflow obstruction. 
Chronic Bronchitis is quite common in the general population, with a wide range of 
3.4%-22.0% of the adult population. This variability is caused largely by the varying definitions 
of CB (Kim and Criner 2015). It appears that CB affects approximately 10 million individuals in 
the U.S., interestingly including significant number of individuals without a diagnosis of COPD 
(de Oca et al. 2012). Among COPD patients those with CB have greater smoking exposure, 
more symptoms, and worse general health than the general COPD population. In the COPD 
Gene study the prevalence of CB in the COPD population was 26.2% using the classical 
definition and 39% using a definition based on the SGRQ (de Oca et al. 2012). 
Airway mucus obstruction appears to play an important role in the pathogenesis of chronic 
inflammation and infection that drives the disease progression in COPD (Fahy and Dickey 
2010). Multiple studies have demonstrated that CB in COPD patients is associated with 
accelerated lung function decline, increased risk of exacerbations, and increased mortality. As a 


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result of the increased exacerbation rates in CB there are greater number of emergency room 
visits and hospitalizations. In a large cross-sectional study of COPD patients in Belgium the 
number of exacerbations was 2.08 per year for the CB group vs. 1.05 in the non-CB group 
(Corhay et al. 2013). Some 37.3% of patients with CB had 2 or more exacerbations per year as 
compared to 14.2% without CB. Similar trends were seen in the COPD Gene and SPIROMICS 
studies. As exacerbation rates are high in CB, an emphasis on reduction of these rates has been 
perused. Roflumilast is a phosphodiesterase-4 (PDE4) inhibitor which has been shown to reduce 
exacerbation rates only in patients with CB, but not in a general COPD population. 
Bronchodilators remain the mainstay of treatment for all patients with COPD. However, no 
therapy has been demonstrated to reduce the mortality rate in COPD or decrease the rate of 
progression of the disease. There remains a significant unmet medical need for additional 
therapeutic interventions. 
 
2.2. 
Therapeutic Rationale 
Chronic Bronchitis is a disease of chronic mucus hypersecretion which predisposes patients 
to lower respiratory infections and is linked to disease progression and mortality. The 
study by Kesimer also found that airway mucin concentrations are linked to COPD severity 
(Kesimer et al. 2018) and may be a biomarker of CB. The airway in CB has been demonstrated 
to be dehydrated as a result of dysregulated ion transport along with an increase in goblet cells 
and mucus production (Graeber et al. 2013). A recent study suggested that the mucus 
hyperconcentration along with airway adherence is more important than the loss of mucous 
transport in bronchitic airway pathology (Livraghi-Butrico et al. 2017). This adherent mucus 
blocks airflow, which is in part responsible for reduced lung function, but more importantly is 
the site of bacterial airway infections. Furthermore, the mucus plugs themselves are 
pro-inflammatory, probably through local epithelial hypoxia which induces interleukin-1 (IL-1) 
and interleukin-8 (IL-8) secretion. It has been demonstrated that cigarette smoke induces ENaC 
activity, which results in sodium absorption from the airway and thereby hyper-concentrated 
airway mucus (Downs et al. 2013). It has been demonstrated that a potent and selective ENaC 
inhibitor with a long duration of action can indeed increase airway surface liquid (ASL) height 
and airway hydration (Astrand et al. 2015). In a woodsmoke murine model, an ENaC ASO 
resulted in a decrease in airway mucus and inflammation (Ionis data on file). Additionally, 
delivery of the EnaC ASO in a NEDD4L mouse model of cystic fibrosis resulted in a 
decrease in mucus gene expression (Gob5, Muc5ac) and a decrease in neutrophilic inflammation 
(Crosby et al. 2017). There was significant improvement in airway hyperreactivity. When 
ION‑827359 was dosed in healthy volunteers there was a decrease in mucus mRNA including 
Gob5 and MUC5AC. Therefore, ION‑827359 may be effective in treating an underlying defect 
in CB, specifically the increased mucus production and the hyper-concentrated mucus which 
result in impaired airflow and recurrent infections. 
2.3. 
ION‑827359 
2.3.1. 
Mechanism of Action 
 


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or cEt modifications to the sugar moieties (Seth et al. 2008). 
 
 
 
 
Maximal antisense-mediated reduction of target mRNA levels 
is typically greater than 90% of control levels in sensitive tissues (Crooke and Bennett 1996; 
Zhang et al. 2010). Furthermore, reduction in target mRNA levels using this approach correlates 
directly with a subsequent reduction in target protein levels. 
2.3.2. 
Chemistry 
 
 
 
The phosphorothioate modifications impart 
in vivo stability to the molecule by providing resistance to nucleases but also confer a substantial 
PK benefit by increasing the binding to plasma proteins, preventing renal excretion of ASOs 
(Geary et al. 2008). 
. 
Two (2) of these segments, the 3 nucleotides at both the 5′ and 3′ ends, contain constrained ethyl 
 
 
 
 
 
Uniformly modified ASOs are not capable of eliciting RNase H1-induced 
catalytic cleavage of complementary mRNA (Monia et al. 1993). The gapmer design provides 
greatly improved metabolic stability and affinity to ASOs and maintains RNase H1-mediated 
antisense activity. 
 
2.3.3. 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with ION‑827359 can be 
found in the Investigator’s Brochure. 
 
2.3.4. 
Clinical Experience 
The safety and tolerability of ION‑827359 has been evaluated in a Phase 1 clinical trial in 
64 healthy volunteers. Please refer to the Investigator’s Brochure for a detailed description. 
This study was a single-ascending dose (SAD) / multiple-ascending dose (MAD) study with 
4 cohorts of 8 patients in each part. Doses in the SAD study ranged from 3 mg to 100 mg 
nebulized. In the MAD study the doses ranged from 10 mg to 75 mg with 5 doses over 4 weeks, 


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except for the final cohort where 10 doses were given. ION‑827359 was well-tolerated without 
any serious adverse event (SAEs) or adverse events (AE) of concern. There were also no 
changes in clinical or laboratory measures, including no evidence of hyperkalemia. There is 
currently on-going a MAD trial in adult patients with cystic fibrosis. 
 
 
 
2.5. 
Benefit-Risk Assessment 
Detailed information concerning the benefit-risk assessment of ION‑827359 can be found in the 
Investigator’s Brochure. However, there are no known risks associated with ENaC inhibition in 
the lung. Genetic mutations leading to loss of ENaC function result in pseudohypoaldosteronism 
in which these patients have difficulty managing sodium balance in the body. This may result in 
renal sodium wasting, hyponatremia, and hyperkalemia. These were not seen in the Phase 1 
study of ION‑827359 but subjects will be monitored for these in this trial. 
Due to the current COVID-19 pandemic, there may be risks to the patients by traveling to 
research sites. Sites should follow their specific regional guidance (i.e., institutional, local, state, 
federal, country-level, as applicable) with regard to receiving patients for clinical trials. Visits 
should continue as long as it is deemed safe to do so. Additional mitigation steps and a study 
pause may be necessary as conditions warrant. Post-treatment follow-up visits may be done 
remotely, if necessary. If a study patient becomes infected with COVID-19 or develop 
COVID-19-related symptoms, the patient should notify the study staff/Investigator and notify 
their treating Physician that they are participating in a clinical trial with ION-827359. To our 
knowledge, ION-827359 has no immunosuppressive effects. 
The known potential risks to study participants associated with ION‑827359 are elaborated on in 
the Guidance to Investigator section of the Investigator’s Brochure. 


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2.5.1. 
Overall Assessment of Benefit:Risk 
Taking into account the measures taken to minimize risk to patients participating in this study, 
the potential risks identified in association with ION‑827359 are justified by the anticipated 
benefits that may be afforded to patients with CB. 
 
3. 
EXPERIMENTAL PLAN 
3.1. 
Study Design 
This will be a Phase 2a, double blind, randomized, placebo-controlled, dose-ranging study. 
Patients with CB associated with COPD will be randomized to ION‑827359 or matching placebo 
administered by oral inhalation once weekly for 13 weeks. 
 
3.2. 
Number of Study Centers 
This study will be conducted at multiple centers in Europe. 
 
3.3. 
Number of Patients 
Approximately 180 patients are planned to be enrolled in this study. Patients will be randomized 
to ION‑827359 at a dose of 37.5 mg, ION‑827359 at a dose of 75 mg, or placebo. 
3.4. 
Overall Study Duration and Follow-up 
The study will consist of Screening, Treatment, and Post-Treatment Periods. Please refer to the 
Schedule of Procedures in Appendix A. 
The study for an individual patient will generally consist of the following Periods: 
• A ≤ 4-week Screening Period. The last week of which is the Run-in Period 
• A 13-week Treatment Period during which study medication (ION‑827359 or 
placebo) will be administered by nebulization once per week (both in-clinic and at 
home dosing) 
• A 10-week Post-Treatment Period 
Patients may be required to attend additional visits for monitoring of AEs or abnormal 
investigation results. The frequency of additional monitoring will be determined by the Study 
Medical Monitor in consultation with the Investigator. 
3.4.1. 
Screening 
Subject eligibility for the study will be determined within 4 weeks prior to study entry. 
 
3.4.2. 
Treatment 
Eligible patients will report to the Study Center for study treatment as per the Schedule of 
Procedures in Appendix A. Study medication (ION‑827359 or placebo) will be administered 
once per week, for 13 weeks with dosing both in-clinic and at home. 


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3.4.3. 
Post-Treatment 
Patients are to return to the Study Center for follow-up visits on Study Days 92 and 120. The 
final study visit will be Study Day 162. 
 
3.5. 
End-of-Study 
The End-of-Study is defined as last patient, last visit when all patients have completed the last 
visit of the Post-Treatment Period. 
 
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 subject information and/or 
recruitment material. 
Patients or their legally acceptable representatives must sign the consent form before any 
screening tests or assessments, including fasting prior to screening blood draws, are performed. 
At the time of consent, the subject 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 subject 
identification number. This number will be used to identify the subject throughout the trial and 
must be used on all study documentation related to that subject. The screening number and 
subject identification number must remain constant throughout the entire trial. In the event the 
subject is re-consented and re-screened the subject must be given a new screening number. 
Screening numbers and subject identification numbers, once assigned, will not be re-used. 
 
4.2. 
Randomization/Registration 
Patients will be randomized, after all Baseline and Screening assessments have been completed 
and after the Investigator has verified that they are eligible per criteria in Sections 5.1 and 5.2. 
No subject may begin treatment prior to randomization and assignment of a unique subject 
identification number. 
Using an Interactive Voice/Web-Response System (IXRS), eligible patients will be randomized 
in a 2:2:1:1 ratio to receive ION‑827359 37.5 mg (1.5 mL), ION‑827359 75 mg (3 mL), 
Placebo 1.5 mL, and Placebo 3 mL, respectively. Cohort A will be defined as those subjects 
receiving 1.5 mL of Study Drug or placebo, and Cohort B as those receiving 3 mL of Study Drug 
or placebo. These cohorts will run concurrently. 
There will be 4 separate and independent randomizations: 
• PK subgroup: approximately 24 patients 
• HRCT subgroup: approximately 60 patients 
• Bronchoscopy subgroup: approximately 18 patients 
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The randomization lists will be prepared by an independent external vendor. Sites will be 
designated as to which subgroups they will be participating in. All subjects at those sites will 
contribute to the specific subgroup, unless the subject refuses to consent to the procedure in 
which case they may enroll into the Other subgroup. 
 
4.3. 
Replacement of Patients 
Patients who withdraw from the study will not be replaced. 
 
4.4. 
Unblinding of Treatment Assignment 
The Sponsor and all patients, monitors, and Study Center personnel related to the study, will be 
blinded throughout the study. However, if a subject has suffered a SAE (as defined in 
Section 9.3.3), and/or when knowledge of the treatment assignment will impact the clinical 
management of the subject, the Investigator will have the ability to unblind the treatment 
assignment for that subject using the automated interactive response technology (IRT) system. 
The Sponsor or designee will be informed of the unblinding of a subject within 24 hours. An 
unblinded randomization schema will be maintained securely at the Sponsor’s designated 
vendor. In addition, all suspected unexpected serious adverse reaction (SUSAR) 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, as knowledge of the 
treatment arm could influence subject assessment. 
An unblinded interim analysis may be performed and the results summarized by treatment group 
at the end of the Treatment Period of the study. 
 
5. 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria at 
Screening and randomization. 
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. Aged 40–70 inclusive at the time of informed consent 
3. Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or 
post-menopausal (defined as 12 months of spontaneous amenorrhea without an 
alternative medical cause and follicle stimulating hormone (FSH) levels in the 
post-menopausal range for the laboratory involved) 
Males must be surgically sterile or abstinent*, if engaged in sexual relations with a 
female of child-bearing potential, the subject must be using a condom and a highly 
effective contraceptive method by the partner from the time of signing the informed 
consent form until at least 10 weeks after the last dose of Study Drug (ION‑827359 or 
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* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient. 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. 
4. BMI < 35.0 kg/m2 
5. Patients with a diagnosis of COPD as defined by the American Thoracic Society 
(ATS)/European Respiratory Society (ERS) 
• Ability to perform acceptable and reproducible spirometry 
• Post-bronchodilator (4 puffs of albuterol) spirometry at Screening demonstrating the 
following: 
• FEV1/ forced vital capacity (FVC) ratio of < 0.70 
• FEV1 ≥ 50% and ≤ 90% of predicted normal 
6. Clinically stable COPD in the 4 weeks prior to Screening (Visit 1) 
7. Current and former smokers with smoking history of ≥ 20 pack years 
8. Meet SGRQ definition of CB (See Section 6.1.1) 
9. CAT score ≥ 10 
 
5.2. 
Exclusion Criteria 
1. Clinically significant abnormalities in medical history (e.g., previous acute coronary 
syndrome within 6 months of screening, congestive heart failure, major surgery within 
3 months of Screening) or physical examination 
2. Screening laboratory results as follows, or any other clinically significant abnormalities 
in screening laboratory values that would render a subject unsuitable for inclusion 
• Urine protein/creatinine (P/C) ratio ≥ 0.3 mg/mg. In the event of P/C ratio above this 
threshold eligibility may be confirmed by a quantitative total urine protein 
measurement of < 300 mg/24 hr 
• 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 
• alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline 
phosphatase (ALP), serum creatinine, blood urea nitrogen (BUN) > 1.5 × upper limit 
of normal (ULN) 
• Platelet count < LLN 
• Serum potassium > 5.2 mmol/L 
• Estimated GFR < 60 mL/min (as determined by the Cockcroft-Gault Equation for 
creatinine clearance) 
3. Any active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to first day Study Drug product is administered to the patient 
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4. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
5. Active infection with human immunodeficiency virus (HIV), hepatitis C or hepatitis B 
6. Uncontrolled hypertension (blood pressure (BP) > 160/100 mm Hg) 
7. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix 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 PI and reviewed by the 
Sponsor Medical Monitor 
8. Treatment with another investigational drug, biological agent, or device within 1 month 
of Screening, or 5 half-lives of investigational agent, whichever is longer 
9. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid 
[siRNA]) within 4 months of screening if single dose received, or within 12 months of 
screening if multiple doses received 
10. Clinically important pulmonary disease other than COPD 
11. Asthma as a primary or main diagnosis according to the Global Initiative for Asthma 
(GINA) guidelines (GINA 2011) or other accepted guidelines. Patients with a past 
medical history of asthma (e.g. childhood or adolescence) may be included 
12. Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization for a 
COPD exacerbation within 4 weeks prior to enrolment (Visit 1) 
13. Acute upper or lower respiratory infection requiring antibiotics or antiviral medication 
within 4 weeks prior to enrolment (Visit 1) 
14. Long term oxygen therapy (LTOT) 
15. Patients participating in, or scheduled for, an intensive (active) COPD rehabilitation 
program (patients who are in the maintenance phase of a rehabilitation program are 
eligible to take part) 
16. Recent history of, or current drug or alcohol abuse 
17. Concomitant medication restrictions: Oral anticoagulants, oral steroids (e.g., prednisone 
or Medrol), theophylline, chronic azithromycin, or roflumilast 
18. Have any other conditions, which, in the opinion of the Investigator would make the 
subject unsuitable for inclusion, or could interfere with the subject participating in or 
completing the Study 
19. A positive PCR test for SARS-CoV-2 at any time prior to randomization 


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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. A 4-week period is provided for 
completing screening assessments and determining subject eligibility for the study. Safety labs 
may be re-tested up to 2 additional times for determination of subject eligibility. Patients will 
also receive a SARS-CoV-2 PCR test. The study site will record basic personal information 
including name, contact details, gender, height, weight, date of birth, age, ethnicity, and racial 
origin (to be used only for clinical purposes). 
During the Screening Period, subjects will undergo a medical history and physical examination 
including vital signs, 12-lead ECG, and have blood and urine samples taken for clinical 
laboratory testing. Chronic obstructive pulmonary disease specific questionnaires (SGRQ, CAT) 
will be administered and scoring performed on the SGRQ to assess the diagnosis of CB. 
Spirometry will be performed at Screening including efforts before and 20-30 minutes after 
inhalation of 4 puffs of albuterol. Plethysmography for determination of lung volumes will also 
be performed during the Screening Period, as per Section 8.3.4. 
The definition of CB by the SGRQ is based on the following 2 questions: 
1. Over the last 4 weeks, I have coughed: 
• Almost every day 
• Several days a week 
• A few days a month 
• Only with lung/respiratory infections 
• Not at all 
2. Over the last 4 weeks, I have brought up phlegm (sputum): 
• Almost every day 
• Several days a week 
• A few days a month 
• Only with lung/respiratory infections 
• Not at all 
In order to be diagnosed as CB the patients must answer that they have cough AND phlegm 
almost every day or several times a week. 


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A subset of up to about 60 patients will undergo low dose, HRCT scanning of the lung, with 
scanning to occur at 2 different lung volumes – FRC and at total lung capacity (TLC). See 
Section 8.3.5. 
A separate subset of up to 18 patients will undergo bronchoscopy, as per Section 8.3.3. 
Training for self-administration (by patient or caregiver) of Study Drug will be initiated at 
Week-1 and will include appropriate use and cleaning of the eFlow® nebulizer. Training will 
continue at randomization and throughout the Treatment Period. 
6.1.2. 
Baseline Period 
One (1) week (7 ± 1 days) prior to randomization the patient will return for the start of the 
Run-in Period. At this visit the patient will be dispenses an electronic diary and be instructed 
in its use. The diary is to be used once daily during the Run-in and Treatment Periods. 
A minimum of 4 days of diary entry in the 7 days prior to Day 1 is required for the patient to be 
randomized. The patient will also receive education on the use of a nebulizer and it’s cleaning. 
The patient will be instructed to return in 1 week for the randomization visit (Day 1). 
6.1.3. 
Treatment Period 
Eligible patients will be administered Study Drug (ION‑827359 or placebo) on a weekly basis 
for a total of 13 doses. These doses will be administered in the clinic on Days 1, 15, 29, 43, 57, 
and 85. Doses on Days 8, 22, 36, 50, 64, 71, and 78 will be self-administered by the patient at 
home. Safety and clinical laboratory evaluations will be performed periodically throughout the 
Treatment Period (Appendix A, Appendix B and Appendix C). A subset of about 24 patients 
will undergo additional blood sampling for PK analysis after dosing on Day 1 and Day 85. The 
subset of patients undergoing HRCT scans will have a follow-up scan performed on Day 92. 
Any AEs and concomitant medications will be recorded. All safety data including AEs, BP, and 
concomitant medications will be reviewed by the Sponsor’s Medical Monitor or designee on an 
ongoing basis throughout the trial. 
Prior to each visit (after Screening) the patient’s bronchodilators should be withheld as follows: 
Table 1: 
Withhold Time for Bronchodilators Prior to Study Visit: 
 
Bronchodilator 
Withhold Time 
SABA (e.g., albuterol or salbutamol) 
6 hours 
SAMA (e.g., ipratropium bromide) 
12 hours 
 
Patients should be contacted prior to their visits to remind them to withhold medications as 
above. Patients should be queried at each visit about their concomitant medications, and visits 
should be rescheduled if these withhold times are not met. The usual dose of bronchodilators 
should not be taken the morning of the visit, until after spirometry is performed and prior to 
dosing (if applicable) with the study medication. Albuterol (salbutamol) 2 puffs, should be 
dosed prior to study drug both for in-clinic and at-home dosing. 
Visits should occur at the same time of day as on Day 1 (± 2 hours). 


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6.1.4. 
Post-Treatment Period 
After the last dose (Study Day 85), or last dose for early termination subjects, subjects will return 
to the clinic on Study Day 92 for final efficacy assessments. The efficacy assessments on 
Day 92 include COPD questionnaires (SGRQ and CAT), spirometry, and plethysmography (to 
be performed in that order). Safety assessments will also be performed at this visit. There will 
be additional post-treatment study visits on Days 120 and 162, which can occur remotely if 
necessary. Patients who discontinue from the study during this period should return for a final 
visit with the procedures as per the schedule for the Day 162 visit. 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. 
 
6.2. 
Study/Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study. A list of these analytes is 
contained in Appendix B. 
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). 
 
6.3. 
Restriction on the Lifestyle of Subjects 
6.3.1. 
Contraception Requirements 
Male subjects must refrain from sperm donation and either be abstinent† or, if engaged in 
sexual relations with a woman of child-bearing potential (WOCBP), the subject must use a 
condom and the subject’s non-pregnant female partner must use a highly effective 
contraception method from the time of signing the informed consent form until at least 
10 weeks after their last dose of Study Drug. Highly effective contraception for the male subject 
comprises a vasectomy with negative semen analysis at Follow-up. Highly effective 
contraception for WOCBP partners of male subjects comprises surgical sterilization 
(e.g., bilateral tubal occlusion), hormonal contraception associated with inhibition of ovulation 
(combined estrogen and progestogen containing, or progestogen-only), intrauterine contraception 
device or intrauterine hormone-releasing system (IUS). Male subjects with partners that are 
pregnant must use condoms to ensure that the fetus is not exposed to the Study Drug. 
For subjects who are exclusively in same sex relationships contraceptive requirements do not 
apply. If a subject who is in a same sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described and as 
outlined in the protocol and ICF. 
†Note: Abstinence (i.e., refraining from heterosexual intercourse throughout the duration of 
study participation) is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient. 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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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: 
• Post-menopausal: 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 post-menopausal range for the 
laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Posthysterectomy 
Note: A female condom and a male condom should not be used together as friction 
between the 2 can result in either or both products failing. 
 
6.3.2. 
Other Requirements 
Patients must refrain from taking strenuous exercise/activity (for example heavy lifting, weight 
training, intense aerobics classes etc.) for at least 72 hours prior to study visits. 
All patients will be required to fast for at least 2 hours before and 1 hour after dosing. 
Additionally, patients must not smoke 2 hours before and 1 hour after dosing with Study Drug. 
Furthermore, patients should refrain from smoking within an hour of each spirometry. 
 
7. 
STUDY DRUG 
7.1. 
Study Drug Description 
Study Drug (ION‑827359 or Placebo) characteristics are listed in Table 2. 
 
7.1.1. 
ION‑827359 
A solution of ION‑827359 (25 mg/mL) contained in stoppered glass vials and its storage and 
preparation instructions will be provided by the Sponsor. ION‑827359 must be stored securely 
at 2-8 °Celsius (C)and be protected from light. 
 
7.1.2. 
Placebo 
Phosphate-buffered saline (PBS) Solution for Inhalation contained in stoppered glass vials will 
be used as the placebo for this study. Storage and preparation instructions will be provided by 
the Sponsor. PBS Solution for Inhalation must be stored at 2-8 °C and be protected from light. 
Table 2:    Study Drug Characteristics 
 
Study Drug 
ION‑827359 
Placebo 
Strength 
25 mg/mL 
not applicable 
Route of Administration 
Inhaled via PARI nebulizer 
Inhaled via PARI nebulizer 


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7.2. 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug (ION‑827359 or 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 (ION‑827359 or placebo) supplies provided by the Sponsor. After accountability is 
complete, the Study Center must either destroy used Study Drug or return all used and unused 
Study Drug (ION‑827359 or placebo) to the Sponsor or designee. 
 
8. 
TREATMENT OF PATIENTS 
8.1. 
Study Drug Administration 
Please refer to the Study Drug Manual provided by the Sponsor for more detailed instructions for 
Study Drug (ION‑827359 or placebo) preparation and administration. 
Table 3: 
Study Drug Dosing Information 
 
Cohort 
Volume to Administer 
Total Dose 
A 
1.5 mL 
37.5 mg or placebo 
B 
3.0 mL 
75 mg or placebo 
 
 
8.2. 
Other Protocol-Required Drugs 
Per eligibility criteria, patients must be on a stable regimen of medications to treat their COPD 
and will continue on these medications throughout the trial. The study nebulizer (Pari eFlow®) is 
only for use with the study medication and no other medications should be administered via this 
nebulizer. 
 
8.3. 
Protocol-Required Treatment Procedures 
8.3.1. 
Spirometry 
Spirometry assessments will be made in accordance with ATS/ERS guidelines (Graham et al. 
2019). At all time points, 3 technically acceptable measurements should be made and recorded. 
Spirometry assessments may be performed up to 8 times to obtain 3 acceptable readings 
according to ATS guidelines (Graham et al. 2019). The highest FEV1 and FVC readings from 
each assessment will be used for analysis even if the FEV1 and FVC values come from 
2 different forced exhalations. The baseline values are those performed immediately (within 
30 minutes) prior to inhalation of study medication. The reference values will be that of 
GLI 2012. Spirometry will be performed by a central vendor who will perform quality control 
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8.3.2. 
Diffusing Capacity (DLCO) 
Diffusing capacity will be performed during the Screening Period. Assessments will be made in 
accordance with ATS/ERS guidelines, including the use of appropriate quality control measures 
to minimize data variability (Macintyre et al. 2005). The average of at least 2 acceptable tests 
will be reported, with a maximum of 5 attempts. There should be a minimum of 4 minutes 
between tests. The report will also include the percent of predicted DLCO (Crapo and Morris 
1981), and the DLCO corrected for alveolar volume (VA). A DLCO corrected for haemoglobin 
will be calculated using the standard equation: DLCO, predicted for Hb = DLCO, predicted x. 
(1.7Hb/(10.22 + Hb)). 
 
 
 
8.3.4. 
Plethysmography 
Lung volumes will be determined by plethysmography during the Screening Period and again at 
Day 92. The technique for determination of lung volumes will be made in accordance with 
ATS/ERS guidance (Wanger et al. 2005). The lung volumes will include the FRC, or the 
amount of gas present in the lung at end-expiration during tidal breathing, and the RV, or the 
volume of gas remaining in the lung after maximal exhalation. For quality control, the mouth 
pressure transducer should be physically calibrated daily prior to use. 


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8.3.5. 
HRCT 
A subset of 60 patients will undergo HRCT of their lungs during Screening and on Day 92. Each 
site performing these scans will be individually trained in the scanning protocol, sending images 
to the central vendor, and monitoring patients breathing during the scan. The computed 
tomography (CT) scans will be performed at both TLC and FRC. The following parameters will 
be calculated for each patient: 
• Lung and Lobar Volume at TLC and FRC 
• Specific Airway Volume at TLC and FRC 
• Specific Airway Resistance at TLC and FRC 
• Blood vessel % and density on lobar level at TLC 
• Internal Airflow Distribution based on lobar expansion from FRC to TLC 
• Image based ventilation/perfusion (V/Q) 
• Airway Wall Volume at TLC 
• Emphysema score at TLC 
• Air Trapping at FRC 
• Aerosol deposition from FRC to TLC 
8.3.6. 
Sputum Collection 
Patients will be encouraged to produce spontaneous sputum which will be collected from 
patients during the Screening Period, and in the mornings prior to study visits on Days 1, 29, 43, 
85, 92, and 162. The sputum will be frozen at the study site and shipped on dry ice to a central 
laboratory. The laboratory manual will provide further instructions. 
8.3.7. 
SGRQ 
The SGRQ is a patient completed, disease-specific instrument designed to measure impact on 
overall health, daily life, and perceived well-being in patients with obstructive airways disease. 
This study will utilize the shorter 40-item version (SGRQ-C) which does not specify a Recall 
Period and has been validated specifically for COPD patients. Scores of the SGRQ-C range 
from 0 to 100, with higher scores indicating more limitations. 
8.3.8. 
COPD Assessment Test (CAT) 
The CAT is an eight-item patient completed questionnaire designed to quantify the impact of 
COPD symptoms on the health status of patients. The CAT is easy for patients to complete 
and provides a score of 0–40 to indicate the impact of disease. In clinically stable COPD 
patients, the CAT was found to be closely related to the St George's Respiratory Questionnaire. 
The CAT score can also provide a reliable measure of exacerbation severity in COPD patients 
(Jones et al. 2011). 


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8.3.9. 
EXACT – Respiratory Symptoms (E-RS) 
The EXACT –E-RS scale is a patient-reported outcome (PRO) measure designed to measure the 
symptoms of patients with COPD. The E-RS utilizes 11 respiratory symptom items from the 
existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS 
total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough 
and sputum, and chest symptoms (Leidy et al. 2014). The E-RS will be collected on the daily 
e-diary, which will include all 14 items from the EXACT questionnaire. 
 
8.4. 
Treatment Precautions 
Patients should be dosed in a different room from any other patient participating in the 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 – Baseline is defined as the average of 
Screening and Day 1 
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. 
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 
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 retest must be 
available prior to administering the next dose of Study Drug (ION‑827359 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 retest 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 subject is appropriate. If any of the stopping criteria described 
below (refer to Sections 8.6.1 to 8.6.4 are met, the subject will be permanently discontinued from 
further treatment with Study Drug (ION‑827359 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. 


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In the event of an ALT or AST measurement that is > 3 × ULN (or the greater of 2 × baseline 
value or 3 × ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above. 
Additional, confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 × ULN. 
Frequency of Repeat Measurements: Patients with confirmed ALT or AST levels > 3 × ULN (or 
the greater of 2 × baseline value or 3 × ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, ALP, international normalized ratio [INR] and total bilirubin) 
retested at least once-weekly until ALT and AST levels become ≤ 1.2 × 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: 
• Obtain a more detailed history of symptoms and prior and concurrent diseases 
• Obtain further history for concomitant drug use (including nonprescription 
medications, herbal and dietary supplement preparations), alcohol use, recreational 
drug use, and special diets 
• Obtain a history for exposure to environmental chemical agents and travel 
• Serology for viral hepatitis (hepatitis A virus (HAV) IgM, HBsAg, hepatitis C virus 
(HCV) antibody, Cytomegalovirus (CMV) immunoglobulin M (IgM), and EBV 
antibody panel) 
• Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
magnetic resonance imaging (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 subject’s ALT and/or AST levels reach 5 × ULN. 
For a definition of Baseline, please refer to guidance in Section 8.5. 
 
8.5.2. 
Safety Monitoring Rules for Platelet Count Results 
Platelet count will be monitored at least every 4 weeks during the Treatment Period. The 
Investigator should review all platelet count results within 48 hours of receipt. If a patient’s 
platelet count falls to 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. 
In the event of a platelet count < 75,000/mm3, additional laboratory investigations should be 
conducted (Table 4). 


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Table 4: 
Additional Labs to be Performed in the Event of a Platelet Count 
< 75,000/mm3 
 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
Citrated sample for platelets 
Coagulation panel (prothrombin time [PT]/INR, activated partial thromboplastin time [aPTT]) 
CBC with reticulocytes and mean platelet volume (MPV) 
Serum B12 and folate 
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 
CMV 
EBV 
Parvo B19 
Helicobacter pylori (IgG serum test) 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
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. 


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8.6. 
Stopping Rules for Liver Chemistry Elevations 
For the purposes of the stopping rules, Baseline is defined as: 
• Insert a description of what will constitute the Baseline for each of the tests that will 
be used in the stopping rules. This does not need to be the same definition as will be 
used in the statistical testing, but it is anticipated that in the same definition will be 
used wherever possible to avoid confusion 
• Monitoring rules for liver chemistry tests – Baseline is defined as average of 
Screening and Day 1 
• Temporary stopping rules for renal function tests – Baseline is defined as average of 
Screening and Day 1 
• Stopping rules for platelets – Baseline is defined as the last non-missing value prior to 
the first dose 
 
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 subject 
with Study Drug (ION‑827359 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), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or concomitant eosinophilia (> ULN) 
 
8.6.2. 
Stopping Rules for Renal Function Test Results / Temporary Stopping Rules for 
Renal Function Test Results 
In the event of laboratory results for either of the following criteria, dosing of a subject with 
Study Drug (ION‑827359 or placebo) will be stopped permanently: 
1. Confirmed serum creatinine increase that is both ≥ 0.5 mg/dL (26.5 µmol/L) and ≥ 40% 
above Baseline creatinine values (refer to definition of Baseline in Section 8.6) 
2. Proteinuria, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24 hour) 
The follow-up schedule for any events meeting either of these stopping criteria will be 
determined by the Investigator in consultation with the Sponsor Medical Monitor or designee. 


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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 (ION‑827359 or placebo) may be stopped 
temporarily: 
1. Serum creatinine increase that fulfills all of the following criteria: ≥ 0.5 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, dipstick 2 + (confirmed by dipstick retest and then further confirmed by a 
quantitative total urine protein measurement of > 1.0 g/24 hour) 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator in consultation with the Sponsor Medical 
Monitor or designee. 
 
8.6.3. 
Stopping Rule for Platelet Count Results 
In the event of a confirmed platelet count less than 75,000/mm3, dosing of a subject with 
Study Drug (ION‑827359 or placebo) will be stopped permanently. The platelet count should be 
tested weekly until it is above 100,000/mm3 then subsequent monitoring should be per the 
schedule of procedures. 
8.6.4. 
Stopping Rule for Serum Potassium 
In the event of a laboratory result demonstrating a severe elevation of serum potassium 
(> 5.6 mmol/L) at any time point, which was confirmed on reanalysis, dosing of the subject will 
be stopped permanently unless there is a clear etiology explaining the observed increase. 
 
8.7. 
Adjustment of Dose and/or Treatment Schedule 
There is no adjustment of dose and/or treatment schedule. 
 
8.8. 
Discontinuation of Study Drug/Treatment 
A subject must permanently discontinue study treatment for any of the following: 
• The subject becomes pregnant. Report the pregnancy according to instructions in 
Section 9.5.4 
• The subject withdraws consent 
• The subject experiences an AE that necessitates permanent discontinuation of 
Study Drug 
• The subject develops laboratory test abnormalities that meet any of the stopping rules 
listed in Sections 8.6.1 to 8.6.3 
• The subject experiences an AE that necessitates unblinding of the Investigator to the 
subject’s treatment assignment 
• Subject has PCR test positive for SARS-CoV-2 
The reason for discontinuation of Study Drug must be recorded in the electronic Case Report 
Form (eCRF) and source documentation. 


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Patients who discontinue Study Drug will remain in the study and continue protocol required 
tests and assessments will enter the Post-Treatment Period unless consent is withdrawn. For 
patients withdrawn for reasons other than withdrawal of consent every effort should be made to 
complete the early termination of study procedures and observations at the time of withdrawal 
(see Appendix A) and ideally within 2 weeks from the last dose of Study Drug. If the patient 
declines or is unable to participate in the above, the Investigator should clarify what type of 
follow-up the subject 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 study procedures for any of the following: 
• Withdrawal of consent 
• The subject is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from study procedures might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal. All information, including the reason for withdrawal from study, must be 
recorded in the eCRF as appropriate. 
Any subject who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request. These patients should be 
encouraged to complete the early termination study procedures and observations at the time of 
withdrawal (Appendix A). 
8.10. 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the subject’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 
Screening and the last visit (Visit 11). 


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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 are disallowed concomitant therapies: 
• Oral corticosteroids 
• Theophylline 
• Roflumilast 
• See Table 1, Section 6.1.3 for bronchodilator use prior to visits 
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 
Screening and last study visit (Visit 11). 
 
8.11. 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded in the eCRF by Study Center 
staff. 
Patients will record treatment in a dosing diary that will be reviewed periodically by Study 
Center staff and the Clinical Monitor. 
 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
9.1. 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee in 
accordance with the applicable Ionis and/or designee SOPs throughout the conduct of the clinical 
trial. 
9.2. 
Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of SAEs including SUSARs per the International Conference on Harmonization 
(ICH) guidelines E2A and ICH Good Clinical Practice (GCP). Country-specific regulatory 
requirements will be followed in accordance with local country regulations and guidelines. 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of all reported SAEs and 
determine if there is a reasonable possibility that the Study Drug (ION‑827359 or placebo) is 
causally related to a reported SAE. While the Sponsor may upgrade an Investigator’s decision it 


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is not permissible to downgrade the Investigator’s opinion for the purposes of determining 
whether the SAE meets the definition of a SUSAR. 
The Sponsor or designee will evaluate the available information for all reported SAEs and decide 
if there is a reasonable possibility that the Study Drug (ION‑827359 or placebo) caused the AE 
and, therefore, 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. 
For the purpose of regulatory reporting of SUSARs, there are no “expected” AEs in this study 
population. For Study Drug (ION‑827359 or placebo) “expected” AEs, refer to the 
Investigator’s Brochure. 
The Sponsor or designee will monitor these protocol-specified SAEs using the incidence rate of 
the event compared to the rate expected in a non-Study Drug exposed population. If the 
aggregate analysis indicates that an event is occurring more frequently or at a greater severity 
than expected, then the event will be reported. 
SAEs will be evaluated on a case by case basis to determine whether there is a reasonable 
possibility that the drug caused the event. If the event is considered by the Sponsor or designee 
to meet the definition of a SUSAR, the event will be reported. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of medicinal 
(investigational) product, whether or not the AE is considered related to the medicinal 
(investigational) product. 
An AE can therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
• Recurrence of an intermittent medical condition (e.g., headache) not present at 
Baseline 
• Any deterioration in a laboratory value or other clinical test (e.g., 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 
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9.3.2. 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction 
Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not have been established, ADR is defined as follows: 
All noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reactions. 
The phrase "responses to a medicinal product" means that a causal relationship between the 
medicinal product and the AE has been determined by the Sponsor as at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
Suspected Unexpected Adverse Drug Reaction 
A suspected unexpected ADR is any ADR, the nature or severity of which is not consistent with 
the applicable product information, e.g., Investigator's Brochure for an unapproved medicinal 
(investigational) product. 
A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction. 
 
9.3.3. 
Serious Adverse Event (SAE) 
A SAE is any AE that in the view of either the Investigator or Sponsor, meets any of the 
following criteria: 
• Results in death 
• Is life threatening: that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject 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 subject 
(whether the subject 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 subject and may require 
medical or surgical intervention to prevent 1 of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
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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. 
 
9.4. 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened. The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible. Before a 
diagnosis is confirmed, all symptoms should be reported as separate AEs. 
9.4.1. 
Serious Adverse Events 
In the interest of subject safety, and in order to fulfill regulatory requirements, all SAEs 
(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 subject signs the informed consent form and stop at the end of the subject’s 
Follow-up Period which is defined as the last study visit (Visit 11). 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 electronic SAE submission form whenever possible. In 
situations where the electronic SAE submission is unavailable, an Initial SAE Form should be 
completed and a copy should be faxed or emailed to the Sponsor or designee. The SAE 
reporting instruction, including the fax number and email address can be found in the 
Investigator site file for the study. 
Detailed information should be actively sought and included as Follow-Up as soon as additional 
information becomes available. All SAEs will be followed until resolution. Serious Adverse 
Events that remain ongoing past the subject’s last protocol-specified follow-up visit will be 
evaluated by the Investigator and Sponsor. If the Investigator and Sponsor agree the subject’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 subject signs the informed consent form 
and will stop at the end of the subject’s Follow-up Period, which is defined as Visit 11. The 
Investigator will monitor each subject 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. 


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9.4.3.1. 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ION‑827359 or placebo) is characterized by 1 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 subject’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and Study Drug (ION‑827359 or placebo) administration 
• Unlikely/Remote: An event for which an alternative explanation is more likely 
(e.g., concomitant medications or ongoing medical conditions) or the temporal 
relationship to Study Drug (ION‑827359 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 subject’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 AEs at the injection site will be 
graded based on criteria from the Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials, Sept 2007 (refer to Appendix D). 
Any AE not listed in Appendix D will be graded as follows: 
• Mild: The event is easily tolerated by the subject and does not affect the subject’s 
usual daily activities 
• Moderate: The event causes the subject more discomfort and interrupts the subject’s 
usual daily activities 
• Severe: The event is incapacitating and causes considerable interference with the 
subject’s usual daily activities 
The severity of AEs and SAEs relating to laboratory tests and AEs at the injection site will be 
graded based on criteria from the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0, November 2017 (refer to Appendix D). Any AE not listed in Appendix D will be 
graded as follows: 
• Mild: The event is easily tolerated by the subject and does not affect the subject’s 
usual daily activities 
• Moderate: The event causes the subject more discomfort and interrupts the subject’s 
usual daily activities 
• Severe: The event is incapacitating and causes considerable interference with the 
subject’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). 


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9.4.3.3. 
Action Taken with Study Drug 
Action taken with Study Drug (ION‑827359 or placebo) due to the event is characterized by 1 of 
the following: 
• None: No changes were made to Study Drug (ION‑827359 or placebo) 
administration and dose 
• Not Applicable: SAE/AE was reported during Screening Period prior to Study Drug 
administration 
• Permanently Discontinued: Study Drug was discontinued and not restarted 
• Temporarily Interrupted, Restarted – Same Dose: Dosing and/or dosing 
frequency was temporarily interrupted/changed or delayed due to the AE and 
restarted at the same dose 
• Reduced Dose: Dosing was reduced, temporarily interrupted or delayed due to the 
AE and restarted at the next lower dose or reduced dosing frequency 
9.4.3.4. 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form. Treatment should also be recorded on the concomitant 
treatment or ancillary procedures eCRF, as appropriate. 
9.4.3.5. 
Outcome of the Adverse Event 
If the event is a non-serious AE, then the event’s outcome is characterized by 1 of the following: 
• AE Persists: Patient terminates from the trial and the AE continues 
• Recovered: Patient recovered completely from the AE 
• Became Serious: The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable): AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by 1 of the following: 
• Ongoing: SAE continuing 
• Persists (as non-serious AE): Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF 
(the SAE resolution date should be entered as the date of onset of that AE) 
• Recovered: Patient recovered completely from the SAE (the date of recovery should 
be entered as the SAE resolution date) 
• Recovered with Sequelae: The signs/symptoms of the reported SAE have improved 
but not completely resolved, and a new baseline for the subject is established since 
full recovery is not expected 
• Fatal: Patient died (the date of death should be entered as the SAE resolution date) 
• Unknown: The outcome of the reported SAE is not available, e.g., patient is lost to 
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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 subject or the female partner of male study 
subject until pregnancy outcome is available. 
Sponsor Follow-Up 
For SAEs, adverse event of special interest (AESI) and pregnancy cases in patients who have 
completed or terminated study, the Sponsor or a designee should follow -up by telephone, fax, 
email, and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
9.5. 
Procedures for Handling Special Situations 
9.5.1. 
Abnormalities of Laboratory Tests 
Clinically significant (CS) 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. CS 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. 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) 
The Investigator is responsible for reviewing and signing all laboratory reports. The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 


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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 subject 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 subject’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 subject’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 (ION‑827359 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 subject 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 subject takes a dose 
of Study Drug (ION‑827359 or placebo) that exceeds protocol specifications and the subject 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 AE associated with an overdose or incorrect administration of 
Study Drug should be recorded on the AE eCRF. If the associated AE fulfills seriousness 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event). 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4. 
Contraception and Pregnancy 
Patients must continue to use appropriate contraception with their partners, or refrain from sexual 
activity, as described in Section 6.3.1. 
If a subject becomes pregnant or a pregnancy is suspected, or if a male subject makes or 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. 


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Payment for all aspects of obstetrical care, child or related care will be the subject’s 
responsibility. 
Female patients: If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed. The subject with a confirmed pregnancy will be immediately 
withdrawn from treatment with Study Drug. However, the subject 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 subject 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 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., pregnancy ICF 
may be required. 
Male patients: The progress of the pregnancy of a male subject’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion). If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
follow-up with the mother and may request access to the mother and infant’s medical 
records to obtain additional information relevant to the pregnancy progress and outcome. 
A longer follow-up may be required if a newborn child experiences a medical condition. 
Follow-up will be performed to the extent permitted by the applicable regulations and privacy 
considerations; e.g., partner ICF may be required. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Stratification, Subsets, and Covariates 
There are 3 subgroups: PK, HRCT and Bronchoscopy subgroups. Details of the prespecified 
subgroup analyses will be provided in the Statistical Analysis Plan (SAP). 
In general, the covariates will include baseline measurements (where applicable). The details 
will be provided in Section 10.6.3. 
 
10.2. 
Sample Size Considerations 
The sample size assumptions for the primary endpoint include: 
• The increase in FEV1 from Baseline to the primary time point in the ION‑827359 
treatment group is 100 mL; no change in the placebo group 
• Standard deviation of change in FEV1 is 220 mL 
• Significance level (alpha) of 0.05 (2-sided test) 
With the above assumptions, a sample size of 174 patients (58 patients in each ION‑827359 
treatment groups and 29 patients in each placebo group) will provide a power of at least 80% for 
the primary comparison (pooled ION‑827359 treatment groups vs. pooled placebo groups). 
Approximately 180 patients will be enrolled in this trial to account for a 3% dropout rate. 


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10.3. 
Populations 
Full Analysis Set (FAS): all randomized patients who received at least 1 dose of Study Drug 
(ION‑827359 or placebo) and who have at least 1 post-Baseline efficacy assessment 
(i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, SGRQ-C score, or 
post-bronchodilator FEV1 assessment). 
Per Protocol Set (PPS): a subset of FAS who have received at least 9 doses of Study Drug and 
have no significant protocol deviations that would be expected to affect efficacy assessments. 
Safety Set: All patients who are randomized and receive at least 1 dose of Study Drug. 
PK Population: All patients who are randomized and receive at least 1 dose of Study Drug. 
10.4. 
Definition of Baseline 
For all assessments, baseline will be defined as the last non-missing measurement prior to the 
first Study Drug administration, except for liver chemistry which is an average of the values at 
Screening and Day 1. 
10.5. 
Interim Analysis and Multiplicity 
No interim analyses are planned. 
 
10.6. 
Planned Methods of Analysis 
All eCRF data, lab data transfers, and any outcomes derived from the data will be provided in the 
patient data listings. Patient data listings will be presented for all patients enrolled into the study. 
Descriptive summary statistics including n, mean, median, standard deviation, standard error, 
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 by treatment group. Where appropriate, p-values will be reported. All 
primary and secondary efficacy endpoints will be assessed on the FAS and PPS, with the former 
being the basis for the primary efficacy analysis. All safety assessments will be performed on 
the Safety Set. The PK analyses will be conducted in the PK population. 
The 2 placebo groups will be pooled and analyzed as a single placebo group. 
 
10.6.1. 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
treatment group. Patient randomization will be summarized by treatment group. The patient 
disposition will be summarized. All patients enrolled will be included in a summary of patient 
disposition. 
10.6.2. 
Safety Analysis 
Treatment duration and amount of Study Drug (ION‑827359 or placebo) received will be 
summarized by treatment group. 
All treatment emergent AEs, all treatment emergent AEs potentially related to Study Drug, all 
treatment emergent serious AEs, and all treatment emergent serious AEs potentially related to 


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Study Drug (ION‑827359 or placebo) will be summarized for each treatment group using the 
Medical Dictionary for Regulatory Activities (MedDRA™) coding system, by system organ class, 
preferred term, relationship to Study Drug, and severity. Narratives of deaths, SAEs, including 
early withdrawals from treatment and from study due to AE, will also be provided. 
Laboratory tests to ensure subject safety including chemistry panel, complete blood count with 
differential, coagulation panel, 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 administration, as appropriate. 
Vital sign and ECG measures will be tabulated by treatment group. In addition, the number of 
patients who experience abnormalities in clinical laboratory evaluations will be summarized by 
treatment group. 
 
10.6.3. 
Efficacy Analysis 
 
10.6.3.1. Analysis of Primary Endpoint 
The primary analysis of the primary endpoint is to compare the change from Baseline to the 
primary time point (defined as the average of Weeks 13 and 14) in FEV1 between the pooled 
ION‑827359 treatment group (ION‑827359 37.5 mg and ION‑827359 75 mg) and the pooled 
placebo group using the Mixed Effects Model with Repeated Measures (MMRM) model. The 
response variable is the change from Baseline at post-Baseline visit up to the primary time point. 
The MMRM model will include effects of treatment (ION‑827359 or placebo), time 
(categorical), treatment-by-time interaction, and Baseline value. The primary analysis will be 
conducted in the FAS. The null hypothesis of the primary analysis is that the change from 
Baseline to the primary time point in FEV1 is the same between the pooled ION‑827359 and 
pooled placebo treatment groups. The alternative hypothesis is that the change from Baseline to 
the primary time point in FEV1 is different between the pooled ION‑827359 and pooled placebo 
treatment groups. 
The primary analysis described above will be repeated in the PPS as a sensitivity analysis. The 
secondary analyses of the primary endpoint will include the comparison of each individual 
ION‑827359 treatment group to the pooled placebo group in both FAS and PPS. The data will 
be analyzed using the same method as the primary analysis. 
The exploratory analyses of the primary measurement will include the change from Baseline to 
each individual time point other than the primary time point. 
 
10.6.3.2. Analysis of Secondary Endpoints 
The secondary endpoints include change from Baseline to the primary time point in the E-RS 
total and subscale scores, change from Baseline to Week 14 in CAT score, SGRQ-C total and 
component scores, change from Baseline to the primary time point in post-bronchodilator FEV1. 
The primary analysis of each secondary endpoint is the comparison between the pooled 
ION‑827359 treatment group (ION‑827359 37.5 mg and ION‑827359 75 mg) and the pooled 
placebo group in the FAS. The analyses will be repeated in PPS as sensitivity analyses. 


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The secondary analyses of each secondary endpoint will include the comparison of each 
individual ION‑827359 treatment group to the pooled placebo group in both FAS and PPS.The 
data will be analyzed using a similar method to the primary endpoint. 
The exploratory analyses of the secondary measurements will include the change from Baseline 
to each individual time point other than the primary time point or Week 14. 
 
10.6.4. 
Pharmacokinetic Analysis 
The plasma PK of ION‑827359 will be assessed in subjects from the PK subgroup following 
inhalational administration by nebulization. Non-compartmental PK analysis of ION‑827359 
will be carried out on each individual subject data set. The maximum observed drug 
concentration (Cmax) and the time taken to reach maximal concentration (Tmax) will be 
obtained directly from the concentration-time data. Partial areas under the plasma 
concentration-time curve from zero time (pre-dose) to selected times (t) after the inhalational 
administration (AUCt) will be calculated using linear-up log-down trapezoid method. Plasma 
clearance (CL/F) will be calculated by dose/AUCt, where appropriate. The plasma half-life 
(t½λz) associated with the apparent terminal elimination will be calculated if data permits, from 
the equation, t½λz = 0.693/λz, where λz is the rate constant associated with the apparent terminal 
elimination phase. 
Other PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist. 
Plasma PK parameters will be summarized using descriptive statistics. Additional details 
regarding the PK analysis will be described in the SAP. 
Potential relationships between selected PD and PK measures may also be explored, where 
deemed appropriate. 
10.6.5. 
Additional Analyses 
The exploratory and PD analyses include comparison of change from Baseline in total sputum 
mucin, MUC5AC, MUC5B levels, FRC and RV, regional lung volumes as measured by HRCT, 
and ENaC mRNA analysis from bronchial brushings between ION‑827359 and placebo groups. 
Cytokines will also be analyzed from the BAL as in Appendix B. Details of these analyses will 
be provided in the SAP. 
 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1. 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor or designee. 
Before a subject’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the subject 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 (ION‑827359 or placebo) are administered. The subject must be 
given sufficient time to consider whether to participate in the study. 


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The acquisition of informed consent and the subject’s agreement or refusal to notify his/her 
primary care physician should be documented in the subject’s medical records and the informed 
consent form should be signed and personally dated by the subject or a legally acceptable 
representative 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 subject or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally acceptable 
representative, the Investigator must provide an impartial witness to read the informed consent 
form to the subject and must allow for questions. Thereafter, both the subject or legally 
acceptable representative and the witness must sign the informed consent form to attest that 
informed consent was freely given and understood. 
11.2. 
Ethical Conduct of the Study 
All applicable regulations and guidelines of current GCP as well as the demands of national drug 
and data protection laws and other applicable regulatory requirements must be followed. 
 
11.3. 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written subject 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 or designee 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 the Sponsor or designee 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. 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 or designee. 
11.4. 
Subject Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained. On the case report 
forms or other documents submitted to the Sponsor or designee, patients should be identified by 
initials (if permitted by local law) and a subject identification number only. Documents that are 


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not for submission to the Sponsor or designee (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 subject’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 subject to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the subject. 
 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1. 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee. 
Agreement from the Investigator must be obtained for all protocol amendments and amendments 
to the informed consent document. The regulatory authority and IEC/IRB must be informed of 
all amendments and give approval for any amendments likely to affect the safety of the patients 
or the conduct of the trial. The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor or designee. 
12.2. 
Study Termination 
The Sponsor or designee 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 or designee should notify the IEC/IRB in writing of the trial’s completion 
or early termination and send a copy of the notification to the Sponsor or designee. 
12.3. 
Study Documentation and Storage 
An eCRF utilizing an Electronic Data Capture (EDC) 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 subject’s case report 
form data are obtained. These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, imaging, and correspondence. 
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 
ICH GCP, suitable for inspection at any time by representatives from the Sponsor or designee 
and/or applicable regulatory authorities. Elements should include: 
• Subject files containing completed case report forms, informed consents, and 
supporting copies of source documentation 


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• 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 or designee 
• 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 case report forms must be 
maintained and be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
designee 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 or designee. 
 
12.4. 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., case report forms and other pertinent data) provided that 
subject confidentiality is respected. 
The Sponsor monitor or designee is responsible for inspecting the case report forms 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 subject medical records and other study-related records 
needed to verify the entries on the case report forms. 
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 case report forms, 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 
subject data received by the Sponsor or designee. During this review, subject 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 case report form. These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case 
report form, the data queries, and the Study Center notifications, and agrees with the content. 


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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 
Astrand AB, Hemmerling M, Root J, et al. Linking increased airway hydration, ciliary beating, 
and mucociliary clearance through ENaC inhibition. Am J Physiol Lung Cell Mol Physiol 2015; 
308: L22-32. 
Corhay JL, Vincken W, Schlesser M, et al. Chronic bronchitis in COPD patients is associated 
with increased risk of exacerbations: a cross-sectional multicentre study. Int J Clin Pract 2013; 
67: 1294-1301. 
Crapo RO and Morris AH. Standardized single breath normal values for carbon monoxide 
diffusing capacity. Am Rev Respir Dis 1981; 123: 185-189. 
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu Rev 
Pharmacol Toxicol 1996; 36: 107-129. 
Crosby JR, Zhao C, Jiang C, et al. Inhaled ENaC antisense oligonucleotide ameliorates cystic 
fibrosis-like lung disease in mice. J Cyst Fibros 2017; 16: 671-680. 
de Oca MM, Halbert RJ, Lopez MV, et al. The chronic bronchitis phenotype in subjects with and 
without COPD: the PLATINO study. Eur Respir J 2012; 40: 28-36. 
Downs CA, Kreiner LH, Trac DQ, et al. Acute effects of cigarette smoke extract on alveolar 
epithelial sodium channel activity and lung fluid clearance. Am J Respir Cell Mol Biol 2013; 49: 
251-259. 
Fahy JV and Dickey BF. Airway mucus function and dysfunction. N Engl J Med 2010; 363: 
2233-2247. 
FDA. 2005. Guidance for industry: estimating the maximum safe starting dose in initial clinical 
trials for therapeutics in adult healthy volunteers. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ 
UCM078932.pdf. 
Geary RS, Yu RZ, Siwkowski A, et al. 2008 Chapter 11: Pharmacokinetic/Pharmacodynamic 
Properties of Phosphorothioate 2 -O-(2-Methoxyethyl)-Modified Antisense Oligonucleotides in 
Animals and Man. in S. T. Crooke (ed.), Antisense Drug Technology: Principles, Strategies, and 
Applications (CRC Press: Boca Raton). 
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. 
Graeber SY, Zhou-Suckow Z, Schatterny J, et al. Hypertonic saline is effective in the prevention 
and treatment of mucus obstruction, but not airway inflammation, in mice with chronic 
obstructive lung disease. Am J Respir Cell Mol Biol 2013; 49: 410-417. 
Graham BL, Steenbruggen I, Miller MR, et al. Standardization of Spirometry 2019 Update. An 
Official American Thoracic Society and European Respiratory Society Technical Statement. Am 
J Respir Crit Care Med 2019; 200: e70-e88. 
Jones PW, Brusselle G, Dal Negro RW, et al. Properties of the COPD assessment test in a cross- 
sectional European study. Eur Respir J 2011; 38: 29-35. 
Kesimer M, Smith BM, Ceppe A, et al. Mucin Concentrations and Peripheral Airway 
Obstruction in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2018; 198: 
1453-1456. 


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Kim V and Criner GJ. The chronic bronchitis phenotype in chronic obstructive pulmonary 
disease: features and implications. Curr Opin Pulm Med 2015; 21: 133-141. 
Leidy NK, Murray LT, Monz BU, et al. Measuring respiratory symptoms of COPD: performance 
of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials. Respir Res 2014; 15: 
124. 
Livraghi-Butrico A, Grubb BR, Wilkinson KJ, et al. Contribution of mucus concentration and 
secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. 
Mucosal Immunol 2017; 10: 829. 
Macintyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath determination of 
carbon monoxide uptake in the lung. Eur Respir J 2005; 26: 720-735. 
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. 
Seth PP, Siwkowski A, Allerson CR, et al. Design, synthesis and evaluation of constrained 
methoxyethyl (cMOE) and constrained ethyl (cEt) nucleoside analogs. Nucleic Acids Symp Ser 
(Oxf) 2008: 553-554. 
Wanger J, Clausen JL, Coates A, et al. Standardisation of the measurement of lung volumes. Eur 
Respir J 2005; 26: 511-522. 
Yu RZ, Kim TW, Hong A, et al. Cross-species pharmacokinetic comparison from mouse to man 
of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein 
B-100. Drug Metab Dispos 2007; 35: 460-468. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway factor 
XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. 
Blood 2010; 116: 4684-4692. 


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14. 
APPENDICES 


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APPENDIX A. SCHEDULE OF PROCEDURES 


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Appendix A. Schedule of Procedures 
 
Screen 
Run-in 
Period 
Treatment Period (13 Weeks) 
Post-Treatment Period (10 Weeks)+ 
Study Week/Day 
S-28 to 
S-7 
Day -7 
W1 D1 
W3 D15 
W5 D29 
W7 D43 
W9 D57 
W13 D85 
W14 D92 
(and Early 
Term) 
W15 D9915 
W18 D120 
W24 D162 
Visit Window (Days) 
NA 
± 1 
NA 
± 2 
± 3 
± 3 
± 3 
± 2 
± 5 
± 5 
± 5 
± 5 
Scheduled Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
9a 
10 
11 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Medical History 
X 
Body Weight and 
Height10 
X 
X 
X 
Physical Exam1 
X 
X 
X 
Vital Signs2 
X 
X 
Xa, c 
Xa 
Xa 
Xa 
Xa 
Xa, c 
X 
X 
X 
HIV, Hepatitis B & C 
X 
FSH/ βhCG3 
X 
SARS-CoV-2 PCR test 
X 
Chemistry Panel5, 6 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
Hematology6 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
Urinalysis7 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
Drug/Alcohol Screen9 
X 
X 
PT, INR, aPTT4 
X 
X 
X 
Spirometry 
Xb 
Xg 
Xa 
Xa 
Xa 
Xd 
Xb 
X 
X 
X 
Collect sputum for mucin 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Plethysmography 
X 
X 


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Screen 
Run-in 
Period 
Treatment Period (13 Weeks) 
Post-Treatment Period (10 Weeks)+ 
Study Week/Day 
S-28 to 
S-7 
Day -7 
W1 D1 
W3 D15 
W5 D29 
W7 D43 
W9 D57 
W13 
D85 
W14 D92 
(and Early 
Term) 
W15 D9915 
W18 D120 
W24 D162 
Visit Window (Days) 
NA 
± 1 
NA 
± 2 
± 3 
± 3 
± 3 
± 2 
± 5 
± 5 
± 5 
± 5 
Scheduled Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
9a 
10 
11 
Diffusing Capacity 
X 
Administer SGRQ and 
CAT questionnaires 
X 
Xa 
Xa 
Xa 
X 
Xa 
Inflammatory 
biomarkers8 
Xa 
X 
X 
Dispense electronic diary 
and instruct in its use 
X 
Collect electronic diary 
X 
ECG (12-Lead) in 
Triplicate 
X 
Xd 
Xa 
Xa 
Xd 
Xa 
X 
X 
Study Drug (ION‑827359 
or placebo) 
Administration12 
X 
X 
X 
X 
X 
X 
Dispense Study Drug for 
home administration 
X16 
X17 
Educate on use of 
nebulizer and dispense 
X 
Review use of nebulizer 
X 
X 
X 
X 
X 
Collect nebulizer 
X 


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Screen 
Run-in 
Period 
Treatment Period (13 Weeks) 
Post-Treatment Period (10 
Weeks)+ 
Study Week/Day 
S-28 to 
S-7 
Day -7 
W1 D1 
W3 D15 
W5 D29 
W7 D43 
W9 D57 
W13 D85 
W14 D92 
(and Early 
Term) 
W15 D9915 W18 D120 
W24 D162 
Visit Window 
(Days) 
NA 
± 1 
NA 
± 2 
± 3 
± 3 
± 3 
± 2 
± 5 
± 5 
± 5 
± 5 
Scheduled Visit 
Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
9a 
10 
11 
HRCT scans13 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Blood 
Sampling11 
Xa, e 
Xa 
Xa 
Xa 
Xa, e 
X 
X 
X 
X 
Note: If not specifically labeled, “X” means anytime. S, Screening Day, D, Day, W, Week 
* Subjects that terminate early during the Post-Treatment Period should complete all procedures for Study Day 162 
+ Post-Treatment Period visits can occur remotely, if necessary. 
1 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 
2 BP, heart rate (HR), respiratory rate (RR), temperature, and pulse oximetry 
3 Women who are not surgically sterile 
4 For subjects in the bronchoscopy subgroup 
5 Fasting only for the screening lab. During this time the patient can drink water and they should ensure that they consume sufficient water in order to not 
become dehydrated 
6 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) 
7 If hematuria or 2 + proteinuria is observed, see confirmation guidance in Section 8.5 
8 Stored at -80 °C. Can be used 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.) in this or subsequent clinical studies of ION‑827359 
9 Urine test at Screening. Day 1 can be done at the site using established methods, e.g., a breathalyzer or urine test 
10 Height at Visit 1 only 
11 If time is not specified PK draw can be done anytime 
12 At-home dosing to occur on Days 8, 22, 36, 50, 64, 71, and 78 (± 1 day) 


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Legend (Continued) 
13 For subjects in the HRCT subgroup 
15 Visit is only for subjects in the PK subgroup 
16 Dispense 1 box of Study Drug for use at-home. Additional drug may be dispensed as necessary (e.g., lost, broken, or spilled vials) 
17 Dispense 1 box of Study Drug for patients in Dose Cohort B. 
 
Time (time is in reference to Study Drug (ION‑827359 or placebo) administration): 
a Pre-dose 
b Pre- and 20-30 minutes post-albuterol dose 
c Pre-dose, and 2 hour 
d Pre-dose, 1, and 2 hour 
e For the subset of patients with full PK sampling; Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24 hours post-inhalation (window of ± 10% of the timepoint in minutes) 
f In the morning, prior to study visit 
g Perform spirometry (pre-Study Drug) pre and 20-30 minutes post albuterol dose (2 puffs) and then perform spirometry 1 and 2 hours post-Study Drug dosing. 


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APPENDIX B. LIST OF LABORATORY ANALYTES 


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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 ION‑827359 or other similar 
oligonucleotides. 
 
Clinical Chemistry Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Cholesterol 
• Uric Acid 
• Total bilirubin 
• Direct (conjugated) 
bilirubin 
• Indirect (unconjugated) 
bilirubin 
• ALT 
• AST 
• Alkaline phosphatase 
• Creatinine kinase 
• GGT 
• eGFR (calculation) 
Screening Tests 
• HBsAg 
• Hepatitis C antibody 
• HIV antibody 
• FSH (women only) 
• Serum βhCG 
• Drug/Alcohol screen 
Sputum 
• Total Mucin 
• MUC5AC 
• MUC5B 
Coagulation4 
• aPTT (sec) 
• PT (sec) 
• INR 
Hematology 
• Red blood cells 
• Hemoglobin 
• Hematocrit 
• MCV, MCH, MCHC 
• Platelets 
• White blood cells 
• WBC Differential (% 
and absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
Pharmacokinetics1 
 
• ION-827359 
concentrations in 
plasma 
Inflammatory 
• Hs-CRP 
BAL Biomarkers3 
• Cell count and diff 
• IL-8 
• IL-5 
• IP-10 
• TGF-β 
Urinalysis 
• Color 
• Appearance 
• Specific gravity 
• pH 
• P/C Ratio 
• Protein 
• Blood 
• Ketones 
• Urobilinogen 
• Glucose 
• Bilirubin 
• Leukocyte esterase 
• Nitrate 
• Microscopic 
examination2 
1 Plasma and urine PK samples may also be used for profiling of drug binding proteins, bioanalytical method 
validation purposes, stability assessments, metabolite assessments, immunogenicity testing (or possibly for 
purposes of immunogenicity assay development and/or validation), or to assess other actions of ION‑827359 with 
plasma constituents 
2 Will be performed on abnormal findings unless otherwise specified 
3 Additional cytokines and mediators may be measured as needed 
4 For subjects in the bronchoscopy subgroup 


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APPENDIX C. PK SAMPLING SCHEDULE 


 
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Appendix C. PK Sampling Schedule 
 
 
W1 D1 
W3 
D15 
W5 
D29 
W9 
D57 
W13 D85 
W14 D92 
(and Early Term) 
W15 
D99 
W18 
D120 
W24 
D162 
Non-PK 
Subgroup 
Pre-dose 
Pre- 
dose 
Pre- 
dose 
Pre- 
dose 
Pre-dose 
Anytime 
n/a 
Anytime Anytime 
PK 
Subgroup 
Pre-dose, 0.5, 1, 1.5, 2, 3, 
4, 6, 8,12, and 24 hours 
Post-inhalation 
Pre- 
dose 
Pre- 
dose 
Pre- 
dose 
Pre-dose, 0.5, 1, 1.5, 2, 3, 
4, 6, 8,12, and 24 hours 
Post-inhalation 
Anytime 
Anytime Anytime Anytime 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
69 


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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 AEs relating to lab test abnormalities and AEs at the 
injection site are based upon the Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0, November 2017 
 


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Appendix D. Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
(Continued) 
 


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Appendix D. Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
(Continued) 
 


 
1 
02 Feb 2021 
ION-827359-CS2 Protocol Amendment 3: A Double-Blind, Placebo-Controlled, 
Phase 2a Study to Assess the Safety, Tolerability, and Efficacy of ION827359 in 
Patients with Mild to Moderate COPD with Chronic Bronchitis 
Version: 
Version Date: 
Title: 
 
 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
APPROVALS: 
 
02-Feb-2021 22:48:57 GMT+0000 


 
 
Official Title: 
A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Safety, 
Tolerability, and Efficacy of ION-827359 in Patients with Mild to Moderate 
COPD with Chronic Bronchitis 
 
 
NCT Number: 
NCT04441788 
 
Document Date: 
SAP Version 1.0 : 26 August 2021 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
ION-827359 CS2 
 
A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the 
Safety, Tolerability, and Efficacy of ION-827359 in Patients with 
Mild to Moderate COPD with Chronic Bronchitis 
 
Date: August 24, 2021 
 
Version: 1.0 


Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
August 24, 2021 
ION-827359-CS2 
CONFIDENTIAL 
ii 
 
 
 
Statistical Analysis Plan Signature Page 
 
 
Approved by: See electronic signature and date attached at end of document 
Ionis Pharmaceuticals, Inc. 
 
 
See electronic signature and date attached at end of document 
Ionis Pharmaceuticals, Inc. 
 
 
See electronic signature and date attached at end of document 
 
Ionis Pharmaceuticals, Inc. 


Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
August 24, 2021 
ION-827359-CS2 
CONFIDENTIAL 
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Table of Contents 
1 
INTRODUCTION ..................................................................................................5 
1.1 
Study Overview ..................................................................................................5 
1.2 
Objectives ...........................................................................................................6 
1.2.1 
Primary Objective ..........................................................................................6 
1.2.2 
Secondary Objectives .....................................................................................6 
1.2.3 
Exploratory Objectives ...................................................................................6 
1.3 
Endpoints ............................................................................................................6 
1.3.1 
Primary Efficacy Endpoints ...........................................................................6 
1.3.2 
Secondary Efficacy Endpoints .......................................................................6 
1.3.3 
Safety Endpoints ............................................................................................7 
1.3.4 
Exploratory Endpoints ....................................................................................7 
1.3.5 
Exploratory Endpoints ....................................................................................7 
2 
PROCEDURES ......................................................................................................7 
2.1 
General Overview of Procedures ........................................................................7 
2.2 
Randomization & Treatment Allocation ............................................................8 
2.3 
Conduct ..............................................................................................................8 
2.4 
Data Monitoring .................................................................................................8 
2.4.1 
Safety Data Monitoring ..................................................................................8 
2.5 
Data Management................................................................................................9 
2.5.1 
Case Report Form Data ..................................................................................9 
2.5.2 
Laboratory Data ..............................................................................................9 
2.5.2.1 
Bal/Bronchial Brushing ............................................................................ 9 
2.5.2.2 
Sputum Mucins (Total, MUC5AC, and MUC5B) ................................... 9 
2.5.2.3 
Central Laboratory Data ........................................................................... 9 
2.5.3 
ECG Data .......................................................................................................9 
2.5.4 
Spirometry, DLCO, and Plethysmography Data ..........................................10 
2.5.5 
HRCT Data ...................................................................................................10 
2.5.6 
Diary and Questionnaire Data (E-RS, CAT, SGRQ) ....................................10 
2.5.7 
Pharmacokinetics Data .................................................................................10 
3 
ANALYTICAL PLAN .........................................................................................10 
3.1 
General Overview of Analyses.........................................................................10 
3.1.1 
Statistical Methods .......................................................................................10 
3.1.2 
Subject Population Analyzed .......................................................................13 
3.1.3 
Sample Size Consideration ...........................................................................13 
3.1.4 
Planned Interim Analysis ..............................................................................14 
3.1.5 
Incomplete or Missing Data .........................................................................14 
3.2 
Demographic and Baseline Characteristics and Patient Disposition ................14 
3.3 
Efficacy Analyses .............................................................................................15 
3.3.1 
Change from Baseline in FEV1 at the Primary Time Point ..........................15 


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Statistical Analysis Plan 
August 24, 2021 
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3.3.2 
Analysis of Secondary Endpoints ................................................................ 16 
3.3.2.1 
Change from Baseline in E-RS Total and Subscale Scores at the 
Primary Time Point ............................................................................... 16 
3.3.2.2 
Change from Baseline in CAT at Week 14 ............................................ 18 
3.3.2.3 
Change from Baseline in SGRQ at Week 14 ......................................... 19 
3.3.2.4 
Change from Baseline in Post-Bronchodilator FEV1 at Week 13 ......... 21 
3.3.3 
Analysis of Exploratory Endpoints ............................................................. 21 
3.3.3.1 
Change from Baseline in Sputum Mucins (Total, MUC5AC, 
and MUC5B) .........................................................................................21 
3.3.3.2 
Change from Baseline in ENaC (mRNA) Levels from 
Bronchial Brushings at Week 13 ...........................................................22 
3.3.3.3 
Change from Baseline in Inflammatory Biomarkers from BAL at 
Week 13 .................................................................................................22 
3.3.3.4 
Change from Baseline in Inflammatory Biomarkers from Sputum .......22 
3.3.3.5 
Change from Baseline in FRC and RV at Week 14 ...............................22 
3.3.3.6 
Change from Baseline in Regional Lung Volumes as measured by 
HRCT at Week 14 .................................................................................22 
3.4 
Safety Analyses ............................................................................................... 22 
3.4.1 
Exposure ...................................................................................................... 22 
3.4.2 
Adverse Events ............................................................................................ 22 
3.4.3 
Laboratory Measurements ........................................................................... 23 
3.4.4 
Vital Signs, Weight, and BMI ..................................................................... 24 
3.4.5 
Physical Examinations................................................................................. 24 
3.4.6 
12-Lead Electrocardiograms (ECG) ........................................................... 24 
3.4.7 
Prior and Concomitant Medications ............................................................ 25 
3.5 
Pharmacokinetic Analysis ............................................................................... 25 
3.5.1 
Plasma Concentration Data ......................................................................... 26 
3.5.2 
Plasma Pharmacokinetic Parameters ........................................................... 26 


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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. 
As with any statistical analysis plan (SAP), the proposed methods and approaches to the data 
analysis should be viewed as flexible. The statistical analysis to some degree is iterative since 
so much of the planning is based on statistical and other assumptions, which require 
verification. 
1.1 
Study Overview 
This is a Phase 2a, double blind, randomized, placebo-controlled, dose-ranging study, will be 
conducted at multiple centers in Europe. Patients with CB associated with COPD will be 
randomized to ION‑827359 or matching placebo administered by oral inhalation once 
weekly for 13 weeks. 
Approximately 180 patients are planned to be enrolled in this study. Patients will be 
randomized in a 2:2:1:1 ratio to the following 4 treatment groups respectively: 
• ION‑827359 37.5 mg (1.5 mL) once per week 
• ION‑827359 75mg (3 mL) once per week 
• Placebo (1.5 mL) once per week 
• Placebo (3 mL) once per week 
There are 3 subset studies: 
1. A subset of up to about 24 patients will have PK profile sampling performed after the 
first and last dose 
2. A subset of up to about 60 patients will have low dose inspiratory and expiratory 
HRCT scans to assess regional lung ventilation performed before and post-treatment 
3. A subset of up to about 18 patients will undergo bronchoscopy and BAL for target 
engagement and inflammatory biomarkers before and post-treatment 
A patient may be enrolled in a maximum of 1 subset study. 
The study will consist of Screening, Treatment, and Post-Treatment Periods. Please refer to 
the Schedule of Procedures in protocol Appendix A. The study for an individual patient will 
generally consist of the following Periods: 
• A ≤ 4-week Screening Period. The last week of which is the Run-in Period 
• A 13-week Treatment Period during which study medication (ION‑827359 or placebo) 
will be administered by nebulization once per week (both in-clinic and at home dosing) 
• A 10-week Post-Treatment Period 


6 
 
 
Ionis Phannaceuticals, Inc. 
Statistical Analysis Plan 
CONFIDENTIAL 
 August 24, 2021 
ION-827359-CS2 
 
Patients may be required to attend additional visits for monitoring of AEs or abno1mal 
investigation results. The frequency of additional monitoring will be determined by the 
Sponsor Medical Monitor in consultation with the Investigator. 
Due to a combination of findings in a recently completed chronic toxicology study in non- 
human primates and the totality of the data collected to date in this and other studies ofENaC 
inhibition, the study treatment has been te1minated on April 29th, 2021, after 60 patients 
have been randoinized and 59 patients have been dosed. All patients who were on treatment 
at the time of study treatment tennination will stop the treatment, continue in the study to 
complete the early tennination visit (Week 14 Day 92) and the 10-week Post-Treatment 
period. 
1.2 
Objectives 
 
1.2.1 
Primary Objective 
To evaluate the effect ofION-827359 on forced expirato1y volume in 1 second (FEVl) in 
patients with mild to moderate chronic obstructive pulmonaiy disease (COPD) with chronic 
bronchitis (CB). 
1.2.2 
Secondary Objectives 
• 
To evaluate the effect ofION-827359 on symptoms of CB 
• 
To evaluate the effect ofION-827359 on quality of life (QoL) in patients of CB 
• 
To evaluate the phaimacokinetics (PK) ofION-827359 in patients with CB 
• 
To evaluate the safety and tolerability of ION-827359 compai·ed to placebo 
 
1.2.3 
Exploratory Objectives 
• 
Assess changes in PD markers 
• 
Assess changes in lung volumes 
• 
Assess changes in lung ventilation 
• 
Assess tai·get engagement 
 
1.3 
Endpoints 
 
1.3.1 
Primary Efficacy Endpoints 
Change from Baseline to the primary time point (defined as the average of Weeks 13 and 14) 
in FEVl compared to placebo. 
 
1.3.2 
Secondary Efficacy Endpoints 
• 
Change from Baseline in the EXACT respiratory symptoms (E-RS) (evaluating 
respiratory symptoms) daily symptom diaiy to the primaiy time point 
• 
Change from Baseline in the COPD assessment test (CAT) to the Week 14 time point 


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• Change from Baseline in St. George’s Respiratory Questionnaire (SGRQ) to the 
Week 14 time point 
• Change from Baseline in post-bronchodilator FEV1 
• Pharmacokinetics 
 
1.3.3 Safety Endpoints 
• Incidence and severity of treatment-emergent adverse events (TEAE) 
• Abnormal findings in laboratory assessments, electrocardiogram (ECGs), and vital 
signs 
 
1.3.4 Exploratory Endpoints 
The tertiary and PD endpoints include: 
• Change from Baseline in sputum mucins (total, MUC5AC, and MUC5B) 
• Change from Baseline in epithelial sodium channel (ENaC) messenger ribonucleic 
acid (mRNA) levels from bronchial brushings 
• Change from Baseline in inflammatory biomarkers from bronchoalveolar lavage 
(BAL) 
• Change from Baseline in functional respiratory capacity (FRC) and residual volume 
(RV) 
• Change from Baseline in regional lung volumes as measured by high resolution CT 
scanning (HRCT) 
 
1.3.5 Exploratory Endpoints 
Plasma exposure over time will be summarized using data from PK profile samples collected 
following the first and last dose in a subset of patients, as well as trough samples collected in 
all patients throughout the study. In addition, potential PK/PD correlation on relevant 
biomarkers may be evaluated. 
 
2 PROCEDURES 
2.1 
General Overview of Procedures 
Ionis Pharmaceuticals, Inc. will review all study data including source documents, CRFs, 
laboratory reports, and other external data. The study site will enter subject source data into 
the case report form. Laboratory data will be transferred electronically to Ionis 
Pharmaceuticals, Inc. 


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2.2 
Randomization & Treatment Allocation 
Patients will be randomized, after all Baseline and Screening assessments have been 
completed and after the Investigator has verified that they are eligible per criteria in protocol 
Sections 5.1 and 5.2. 
No subject may begin treatment prior to randomization and assignment of a unique subject 
identification number. 
Eligible patients will be randomized using an Interactive Voice/Web-Response System 
(IXRS) in a 2:2:1:1 ratio to receive ION‑827359 37.5 mg (1.5 mL), ION‑827359 75 mg 
(3 mL), Placebo 1. 5 mL, and Placebo 3 mL, respectively. Cohort A will be defined as those 
subjects receiving 1.5 mL of Study Drug or placebo, and Cohort B as those receiving 3 mL 
of Study Drug or placebo. These cohorts will run concurrently. 
There will be 4 separate and independent randomizations: 
• PK subgroup: approximately 24 patients 
• HRCT subgroup: approximately 60 patients 
• Bronchoscopy subgroup: approximately 18 patients 
• Other: patients who are not in the above 3 subgroups, approximately 78 
Randomization information will be concealed from the Investigators and patients until the 
end of the study, with the exception of an emergency situation involving a patient that 
requires unblinding of the treatment assignment. 
 
2.3 
Conduct 
The study will be conducted in accordance with current Good Clinical Practice (GCP) and 
International Conference on Harmonization (ICH) guidelines, the World Medical Association 
Declaration of Helsinki guidelines, the Food and Drug Administration (FDA) Code of 
Federal Regulations, and all other local regulatory requirements. 
 
2.4 
Data Monitoring 
 
2.4.1 Safety Data Monitoring 
Ionis Pharmaceuticals, Inc. (Ionis) (or designee) is responsible for processing all reported 
adverse events (AEs). All serious adverse events (SAEs), reported to Ionis (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 (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 (or 
designee) will also prepare a safety notification letter and transmit it to study site. 


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2.5 Data Management 
 
2.5.1 Case Report Form 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. Ionis 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 reviews all data for accuracy and validity and generates additional queries in the EDC 
system when necessary. The data is corrected or an explanation concerning the query is 
provided in the EDC system. After all data are entered, reviewed (by Data Management and 
Clinical Development) and queried, and all queries resolved, the database is locked. 
 
2.5.2 Laboratory Data 
 
2.5.2.1 Bal/Bronchial Brushing 
Bal cell counts and differentials will be analyzed by local labs and entered in the EDC system 
by the investigator site staff. 
 
2.5.2.2 Sputum Mucins (Total, MUC5AC, and MUC5B) 
The sputum samples will be analyzed by PPD Development (PPD) for sputum mucins. 
Additionally, sputum from baseline and end of study will be sent to Spirovation for 
determination of cytokines and complement levels. Ionis, PPD, and Spirovation are 
responsible for the format of the safety laboratory electronic data transfers and the transfer 
schedule. The data results will not be stored in the EDC system. PPD, Spirovation, and Ionis 
are responsible for the review of the data. This process involves reviewing the patient and 
visit identifiers in the PPD data against the visit identifiers collected in the EDC system. 
 
2.5.2.3 Central Laboratory Data 
The sites will collect the blood and urine samples and send to the central vendor, Medpace. 
Ionis and Medpace are responsible for the format of the safety laboratory electronic data 
transfers and the transfer schedule. Central laboratory data results will not be stored in the 
EDC system. Medpace and Ionis are responsible for the review of the clinical laboratory 
data. This process involves reviewing the patient and visit identifiers in the central laboratory 
data results data against the central lab data identifiers collected in the EDC system. 
Investigator sites have access to the data via lab reports sent directly from the laboratory or 
through the laboratory’s web portal (in which case Investigators only have access to data 
from their site). 
 
2.5.3 ECG Data 
Ionis and ERT are responsible for the format of the cardiac safety and ECG data transfers and 
the transfer schedule. Cardiac safety and ECG data will not be stored in the EDC system. 


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Ionis and ERT are also responsible for the data reconciliation, which involves reviewing the 
patient and visit identifiers in the cardiac safety and ECG data against the visit identifiers 
collected in the EDC system. 
 
2.5.4 Spirometry, DLCO, and Plethysmography Data 
Ionis and ERT are responsible for the format of the spirometry, DLCO and plethysmography 
data transfers and the transfer schedule. The spirometry, DLCO and plethysmography data 
will not be stored in the EDC system. Ionis and ERT are also responsible for the data 
reconciliation, which involves reviewing the patient and visit identifiers in the spirometry, 
DLCO and plethysmography data against the visit identifiers collected in the EDC system. 
 
2.5.5 HRCT Data 
The sites will perform the computed tomography (CT) scans at both TLC and FRC and send 
the images to a central vendor, FLUIDDA. The outcome data will be generated by 
FLUIDDA. Ionis and FLUIDDA are responsible for the format of the data transfers and the 
transfer schedule. The data will not be stored in the EDC system. Ionis and ERT are also 
responsible for the data reconciliation, which involves reviewing the patient and visit 
identifiers in the cardiac safety and ECG data against the visit identifiers collected in the 
EDC system. 
Since no patients have been enrolled in the HRCT subgroup at the time of treatment 
termination, the HRCT data are not collected. 
 
2.5.6 Diary and Questionnaire Data (E-RS, CAT, SGRQ) 
The diary and questionnaire data will be captured by ERT eCOA System. Patients will enter 
their assessments into the system using a tablet or other handheld devices. Ionis and ERT are 
responsible for the format of the electronic data transfers and the transfer schedule. The data 
will not be stored in the EDC system. Ionis and ERT are also responsible for the review of 
the data. This process involves reviewing the patient and visit identifiers in the questionnaire 
data against the data identifiers collected in the EDC system. 
 
2.5.7 Pharmacokinetics Data 
Ionis Pharmaceuticals, Inc. is responsible for the management and review of the plasma drug 
concentration data. Final data, which has been approved by Quality Assurance, will be stored 
in version-controlled repository 
 
3 
ANALYTICAL PLAN 
3.1 
General Overview of Analyses 
 
3.1.1 
Statistical Methods 
Descriptive summary statistics including number of subjects, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 


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(minimum, 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. As a Phase 2a study, 
adjustments for multiplicity of testing will generally not be used. 
PK parameters will be summarized using number of Subjects, mean, standard deviation, 
coefficient of variation (CV), geometric mean, geometric %CV, median, minimum, and 
maximum. 
General Presentation Considerations 
The minimum and maximum will be reported to the same number of decimal places as the 
raw data recorded in the database. The mean, median, lower quartile and upper quartile will 
be reported to one more decimal place than the raw data recorded in the database. The 
standard deviation will be reported to two more decimal places than the raw data recorded in 
the database. In general, the maximum number of decimal places reported shall be four for 
any summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts and percentages. Any planned collapsing of 
categories will be detailed in the text and the data displays. 
Percentages will be presented to one decimal place and not be presented for zero counts. 
Percentages will be calculated using n as the denominator. 
P-values greater than or equal to 0.0001, in general, will be presented to four decimal places. 
P-values less than 0.0001 will be presented as “<0.0001”. 
Confidence intervals will be presented to one more decimal place than the raw data. 
Baseline definition 
Baseline E-RS total and subscale scores are defined as the average of daily scores collected 
on Day 1 and within 6 days prior to Day 1. 
Baseline liver chemistry parameters (ALT, AST, and total, direct and indirect bilirubin, 
alkaline phosphatase) are defined as the average of the non-missing values at Screening and 
Day 1 pre-dose, and any values in between. 
Baseline ECG assessments are defined as the last triplicate prior to the first Study Drug 
administration. For numeric results, the baseline is the average of the triplicate. For character 
results, baseline is the worst result of the triplicate. 
Baseline for other assessments is defined as the last non-missing measurement prior to the 
first Study Drug administration. 
Primary time point definition 
The primary time point is defined as the average of Weeks 13 and 14. If the assessment is 
missing in one of the two time points, then non-missing assessment will be used. 
End of treatment period assessment definition 


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The end of treatment period assessments are defined as the last available assessments within 
14 days after the last dose. 
Analytical visits: 
Efficacy/PD data including spirometry, CAT, SGRQ, sputum mucins, ENaC mRNA, 
inflammatory biomarkers, during the treatment period will be mapped to analysis visit as 
specified in the table ( 
Efficacy/PD Measure Visit Windows) below. The intent of these visit windows is not to align 
with those prescribed for visit scheduling in the clinical study protocol but, rather, based on 
the protocol-defined target study day, to delineate mutually exclusive windows so that all 
assessments proximal to a particular study week can be integrated to best represent the 
patient’s status during that period of the study. 
If a patient discontinued early from the treatment period but attended applicable landmark 
visits to collect assessments, then those assessments collected within 14 days after the last 
dose of Study Drug will be included as long as they are within the defined analysis windows. 
The unscheduled visits will also be included if they are collected within 14 days after the last 
dose of Study Drug and within the defined analysis windows. 
If there are multiple assessments within a visit window, the visit nearest the scheduled date 
will be used unless 2 visits are equally near, in which case the average will be used for 
continuous results, and the worst will be used for categorical results. 
Efficacy/PD Measure Visit Windows 
 
Measure 
Mapped Visit (Week) 
Target Day 
Study Day Window 
Spirometry assessments 
1 – 1 hour post dose 
1 
1 
1 – 2 hours post dose 
1 
1 
3 
15 
2-22 
5 
29 
23 to 36 
7 
43 
37 to 50 
9 
57 
51 to 71 
9 – 1 hour post dose 
57 
51 to 71 
9 – 2 hours post dose 
57 
51 to 71 
13 
85 
72 to 88 
14 
92 
89 to 99 
CAT and SGRQ 
5 
29 
2 to 43 
9 
57 
44 to 74 
14 
92 
75 to 99 
EXACT 
2 
8 
2-8 
3-14 
15-99 
(Week-1)*7-5 to 
(Week-1)*7+1 
Sputum mucins 
5 
29 
23 to 36 


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Measure 
Mapped Visit (Week) 
Target Day 
Study Day Window 
7 
43 
37 to 64 
13 
85 
65 to 88 
14 
92 
89 to 99 
Plethysmography assessments, 
14 
92 
75 to 99 
Data collected under visit labels containing Weeks 18, 24, Days 120 or 162 will not be 
mapped to analysis week. 
Visits after Week 14 are part of the post-treatment assessment period. The efficacy and PD 
data during the post-treatment period will be summarized using the visit labels provided in 
the data. 
Other data will be summarized using the visit labels provided in the data. Multiple results 
with the same visit label will be averaged. Results with visit labels as “Unscheduled” will not 
be included in the by-visit summary tables and figures, but will be included in determining 
baseline, and in the laboratory abnormality summaries and shift analyses. 
All data will be presented in data listings. 
Laboratory data: 
 
For potassium all central and local labs will be included in the data summary; for other lab 
assessments, only the central lab assessments will be included in the data summary. 
All central and local labs will be included in the data listings. 
 
3.1.2 
Subject Population Analyzed 
Full Analysis Set (FAS): all randomized patients who received at least 1 dose of Study Drug 
(ION‑827359 or placebo) and who have at least 1 post-Baseline efficacy assessment 
(i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). 
Safety Set: All patients who are randomized and receive at least 1 dose of Study Drug. 
PK Population: All subjects who are randomized and receive at least 1 dose of active Study 
Drug (ION-827359) and have at least 1 evaluable PK sample collected and analyzed with 
reportable result. This population will be used for PK analyses. 
In addition to the above analysis populations, it is recognized that some data displays will be 
provided for “All Screened”, “Screening Failures” and “All Randomized” subjects but no 
data analysis will be executed in these populations except for the disposition table that 
includes all screened subjects. 
The Per-Protocol Set (PPS), FAS - Bronchoscopy Subgroup, PPS - Bronchoscopy Subgroup, 
FAS-HRCT and PPS-HRCT subgroups are defined in the protocol but have been removed 
from this SAP. 


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3.1.3 
Sample Size Consideration 
The sample size assumptions for the primary endpoint include: 
• The increase in FEV1 from Baseline to the primary time point in the ION‑827359 
treatment group is 100 mL; no change in the placebo group 
• Standard deviation of change in FEV1 is 220 mL 
• Significance level (alpha) of 0.05 (2-sided test) 
With the above assumptions, a sample size of 174 patients (58 patients in each ION‑827359 
treatment groups and 29 patients in each placebo group) will provide a power of at least 80% 
for the primary comparison (pooled ION‑827359 treatment groups vs. pooled placebo 
groups). 
Approximately 180 patients will be enrolled in this trial to account for a 3% dropout rate. 
 
3.1.4 
Planned Interim Analysis 
No interim analysis is planned for this study. 
3.1.5 
Incomplete or Missing Data 
For EXACT daily diary, if no more than three items are missing, and no more than two of 
items 9–11 are missing, the missing items will be imputed using the mean of the remaining 
answered items, rounded to the nearest integer and capped at the maximum score available 
for that item. Otherwise, the E-RS score will be considered missing for the day. 
For CAT questionnaire, if the score is missing for only one item, the missing value will be 
imputed by the mean value of the remaining seven items. If two or more items are missing, 
then the CAT score will be considered missing for the visit. 
For SGRQ-C questionnaire Part 1, missed items are treated as if the answer was in the 
negative. A maximum of one missed item is permitted for this section. 
For SGRQ-C questionnaire Part 2, items in questions 9, 10, 11, 12, 13 all require a response 
of either ‘True’ or ‘False’. If neither box is ticked, the item should be coded as missing. The 
weight for that item should then be removed from the total possible for that component (and 
the total score). A maximum of 3 missed items for the Activity component (items in 
questions 9 and 12) and a maximum of 5 items for the Impacts component (items in 
questions 8, 10, 11, 13, 14) are permitted. 
 
3.2 
Demographic and Baseline Characteristics and Patient Disposition 
Baseline and demographic variables will be summarized descriptively by treatment group 
and for each analysis population. 
Demographic and baseline characteristics to be presented include age, age category (<18, 18 
to 64, ≥65 years), gender, race, ethnicity, height, weight, BMI, , percent predicted DLCO, , 
baseline spirometry assessments, E-RS scores, CAT scores, SGRQ scores, sputum mucins, 
FRC and RV. 


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For race summary, if multiple races are recorded in database, ‘Multiple Race’ will be used in 
the summary table but details records in the listing. 
A separate table will be created for the targeted medical history and smoking history, and 
will include duration since diagnosis of COPD, COPD exacerbations that required 
hospitalization in the last year (yes/no), number of hospitalizations for COPD exacerbations 
in the last year, COPD exacerbations that required oral corticosteroids and/or antibiotic in the 
last year (yes/no), number of COPD exacerbations in the last year that required oral 
corticosteroids and/or antibiotics, diagnosis with asthma (yes/no), diagnosis with coronary 
artery disease (yes/no), diagnosis of congestive heart failure (yes/no), ever used tobacco 
cigarettes (yes/no), number of packs tobacco per day and number of years smoking. 
The duration since diagnosis of COPD will be calculated as the difference between informed 
consent date and COPD diagnosis date plus 1 day then divided by 365.25. The partial COPD 
dates will be imputed using the following rules: 
• If both month and day are missing then assign July 1st 
• If only day is missing then assign 15th 
Other medical history data will be provided in the data listing and summarized using 
MedDRA SOC and preferred term. 
Subject enrollment and disposition will be summarized by treatment group. The summary 
will include: the number of subjects screened, the number of screen failures, the reason for 
screen failure, the number of subjects randomized, the number and percentage of subjects 
dosed, the number and percentage of subjects in each analysis population, the number and 
percentage of subjects in each subgroup, the number and percentage of subjects completing 
treatment, the primary reason for terminating treatment, the number of subjects completing 
post-treatment follow-up, and the primary reason for terminating post-treatment follow-up. 
The percentages will be calculated based on the number of patients randomized. 
 
3.3 
Efficacy Analyses 
All efficacy analyses will be performed on the FAS. Due to the fact that study treatment 
terminated after only 60 patients have been randomized, 59 patients have been dosed, and 10 
patients have completed the Week 14, all analyses will be descriptive. The model-based 
analyses described in the protocol will not be conducted. 
 
3.3.1 
Change from Baseline in FEV1 at the Primary Time Point 
The FEV1 and other spirometry assessments, as well as change and percent change from 
baseline to the primary time point, end of treatment period, and other study visits will be 
summarized by treatment group using descriptive statistics. 
At each time point, 3 technically acceptable measurements will be made and recorded. The 
best readings from each time point for each assessment will be used for analysis. 
In addition to the descriptive summary, the proportion of patients who have a greater than 
20% reduction in FEV1 post treatment and the proportion of doses that resulted in a greater 
than 20% reduction in FEV1 will be tabulated by treatment group. 


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3.3.2 
Analysis of Secondary Endpoints 
 
3.3.2.1 
Change from Baseline in E-RS Total and Subscale Scores at the Primary Time 
Point 
The E-RS assesses respiratory symptoms using the following 11 respiratory symptom items 
from the EXACT. 
The response for each item will be scored according to the E-RS User Manual Version 3.0 as 
below: 
 
E-RS™ Individual Items 
Response 
Score 
1. Chest congested 
Not at all 
0 
Slightly 
1 
Moderately 
2 
Severely 
3 
Extremely 
4 
2. Cough 
Not at all 
0 
Rarely 
1 
Occasionally 
2 
Frequently 
3 
Almost constantly 
4 
3. Mucus/phlegm 
Not at all 
0 
A little 
1 
Some 
1 
A great deal 
2 
A very great deal 
3 


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E-RS™ Individual Items 
Response 
Score 
4. Difficulty bring up mucus 
Not at all 
0 
Slightly 
1 
Moderately 
2 
Quite a bit 
3 
Extremely 
4 
5. Chest discomfort 
Not at all 
0 
Slight 
1 
Moderate 
2 
Severe 
3 
Extreme 
4 
6. Tight chest 
Not at all 
0 
Slightly 
1 
Moderately 
2 
Severely 
3 
Extremely 
4 
7. Breathlessness 
Not at all 
0 
Slightly 
1 
Moderately 
2 
Severely 
3 
Extremely 
4 
8. Describe breathlessness 
Unaware of breathlessness 
0 
Breathlessness during strenuous activity 
1 
Breathlessness during light activity 
2 
Breathlessness when washing or dressing 3 
Present when resting 
3 
9. Short of breath personal activities 
Not at all 
0 
Slightly 
1 
Moderately 
2 
Severely 
3 
Extremely 
3 
Too breathlessness to do these 
4 


Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
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E-RS™ Individual Items 
Response 
Score 
10. Short of breath indoor activities 
Not at all 
0 
Slightly 
1 
Moderately 
2 
Severely 
3 
Extremely 
3 
Too breathlessness to do these 
3 
11. Short of breath outdoor activities 
Not at all 
0 
Slightly 
1 
Moderately 
2 
Severely 
3 
Extremely 
3 
Too breathlessness to do these 
3 
 
Patients’ daily E-RS total scores will be computed by summing across responses to the 11 
items, the score ranges from 0 to 40. The same summation procedure will be used for 
obtaining the three subscale scores: E-RS Breathlessness is the sum of items 7, 8, 9, 10 and 
11, the score ranges from 0 to 17; E-RS Cough & Sputum is the sum of items 2, 3, 4, the 
score ranges from 0 to 11; and E-RS Chest is the sum of items 1, 5, 6, and score ranges from 
0 to 12. The higher scores indicate more severe respiratory symptoms. 
Missing EXACT items will be imputed using the rules described in Section 3.1.5 in this SAP. 
The data will be mapped to study week based on the visit window specified in section 3.1.1. 
The data in the visit window will be averaged. If patients complete less than 4 daily 
assessments in a week, then the E-RS scores will be considered as missing for the week. 
The change from baseline in the E-RS total and the 3 subscale scores to primary time point 
and over time as well as change from baseline to the end of treatment period will be 
summarized by treatment group using descriptive statistics. 
 
3.3.2.2 
Change from Baseline in CAT at Week 14 
The CAT contains eight items: cough, phlegm, chest tightness, breathlessness, limited 
activities, confidence leaving home, sleeplessness and energy. Each item is presented as a 
semantic 6-point differential scale from 0 to 5. The total CAT score ranges from 0–40. 
Higher scores indicate a more severe impact of COPD on a patient’s life. 
If the score is missing for only one item, the missing value will be imputed by the mean 
value of the remaining seven items. If two or more items are missing, then the CAT score 
will be considered missing for the visit. 
The change from baseline in the CAT score at Week 14 and other study visits as well as 
change from baseline to the end of treatment period will be summarized by treatment group 
using descriptive statistics. 


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3.3.2.3 
Change from Baseline in SGRQ at Week 14 
The SGRQ is a patient completed, disease-specific instrument designed to measure impact 
onoverall health, daily life, and perceived well-being in patients with obstructive airways 
disease and includes 50 items addressing three domains of HRQL (symptoms, activity 
limitations, and impact of the disease on daily life). Recall periods in the questionnaire 
include the past 4 weeks and the present. 
This study will utilize the shorter 40-item version (SGRQ-C) which does not specify a Recall 
Period. A five-point scale is used for rating the symptoms, and a true/false binary scale is 
used for activity limitations. Items are assigned a weight according to the degree of distress 
in the calculation of the overall score as below: 
 
Part 1: 
Question 1: I cough: 
Most days 80.6 
Several days 46.3 
With chest infections 28.1 
Not at all 0.0 
Question 2: I bring up phlegm (sputum): 
Most days 76.8 
Several days 47.0 
With chest infections 30.2 
Not at all 0.0 
Question 3: I have shortness of breath: 
Most days 87.2 
Several days 50.3 
Not at all 0.0 
Question 4: I have attacks of wheezing: 
Most days 86.2 
Several days 71.0 
A few days 45.6 
With chest infection 36.4 
Not at all 0.0 
Question 5: How many attacks of chest trouble have you had 
3 or more 80.1 
1 or 2 attacks 52.3 
None 0.0 
Question 6: How often do you have good days (with little chest trouble)? 
None 93.3 
A few 76.6 
Most are good 38.5 
Every day 0.0 
Question 7: If you have a wheeze, is it worse in the morning? 
No 0.0 
Yes 62.0 


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Statistical Analysis Plan 
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Part 2 
Question 8: How would you describe your chest condition? 
The most important problem I have 82.9 
Causes me a few problems 34.6 
Causes no problem 0.0 
Question 9: Questions about what activities usually make you feel breathless. 
Getting washed or dressed 82.8 
Walking around the home 80.2 
Walking outside on the level 81.4 
Walking up a flight of stairs 76.1 
Walking up hills 75.1 
Question 10: More questions about your cough and breathlessness. 
My cough hurts 81.1 
My cough makes me tired 79.1 
I get breathless when I talk 84.5 
I get breathless when I bend over 76.8 
My cough or breathing disturbs my sleep 87.9 
I get exhausted easily 84.0 
Question 11: Questions about other effects your chest trouble may have on you. 
My cough or breathing is embarrassing in public 74.1 
My chest trouble is a nuisance to my family, friends or neighbors 79.1 
I get afraid or panic when I cannot get my breath 87.7 
I feel that I am not in control of my chest problem 90.1 
I have become frail or an invalid because of my chest 89.9 
Exercise is not safe for me 75.7 
Everything seems too much of an effort 84.5 
Question 12: Questions about how activities may be affected by your breathing. 
I take a long time to get washed or dressed 74.2 
I cannot take a bath or shower, or I take a long time 81.0 
I walk more slowly than other people, or I stop for rests 71.7 
Jobs such as housework take a long time, or I have to stop for rests 70.6 
If I walk up one flight of stairs, I have to go slowly or stop 71.6 
If I hurry or walk fast, I have to stop or slow down 72.3 
My breathing makes it difficult to do things such as walk up hills, carry things up 
stairs, light gardening such as weeding, dance, play bowls or play golf 74.5 
My breathing makes it difficult to do things such as carry heavy loads, dig the 
garden or shovel snow, jog or walk at 5 miles per hour, play tennis or swim 71.4 
Question 13: We would like to know how your chest trouble usually affects your daily 
life. 
I cannot play sports or games 64.8 
I cannot go out for entertainment or recreation 79.8 
I cannot go out of the house to do the shopping 81.0 
I cannot do housework 79.1 
I cannot move far from my bed or chair 94.0 


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Statistical Analysis Plan 
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Question 14: Tick the statement which you think best describes how your chest affects 
you. 
It does not stop me doing anything I would like to do 0.0 
It stops me doing one or two things I would like to do 42.0 
It stops me doing most of the things I would like to do 84.2 
It stops me doing everything I would like to do 96.7 
 
The symptoms component consists of all the questions in Part 1. The activity component 
consists of questions 9 and 12 in Part 2 of the questionnaire. The impact component consists 
of questions 8, 10, 11, 13, 14 in Part 2 of the questionnaire 
The score for each component is calculated separately by dividing the summed weights by 
the maximum possible weight for that component and expressing the result as a percentage: 
 
 
 
 
The total score is calculated in similar way: 
 
 
 
 
The 0% and 100% represent the best and worst possible health status, respectively. 
Missing items will be imputed using the rules described in Section 3.1.5 in this SAP. 
The SGRQ-C total score and component scores, as well as the absolute and percent change 
from baseline at Week 14, end of treatment period and other study visits will be summarized 
by treatment group using descriptive statistics. 
 
3.3.2.4 
Change from Baseline in Post-Bronchodilator FEV1 at Week 13 
The post-bronchodilator FEV1, as well as the absolute and percent changes from baseline 
will be summarized by treatment group and study visit using descriptive statistics. The 
absolute and percent changes from baseline to the end of treatment period will also be 
summarized. 
 
3.3.3 
Analysis of Exploratory Endpoints 
 
3.3.3.1 
Change from Baseline in Sputum Mucins (Total, MUC5AC, and MUC5B) 
The sputum mucins results, absolute change and percent change from baseline will be 
summarized by treatment group and study visit using descriptive statistics. 


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3.3.3.2 
Change from Baseline in ENaC (mRNA) Levels from Bronchial Brushings at 
Week 13 
Due to the limited post-treatment bronchial brushing samples, the data will only be provided 
in the data listing. 
 
3.3.3.3 
Change from Baseline in Inflammatory Biomarkers from BAL at Week 13 
Due to the limited post-treatment BAL samples, the data will only be provided in the data 
listing. 
 
3.3.3.4 
Change from Baseline in Inflammatory Biomarkers from Sputum 
The results, absolute change and percent change from baseline in the inflammatory 
biomarkers will be summarized by treatment group and study visit using descriptive 
statistics. 
 
3.3.3.5 
Change from Baseline in FRC and RV at Week 14 
The FRC and RV, as well as the absolute change and percent change from baseline will be 
summarized by treatment group and study visit using descriptive statistics. 
 
3.3.3.6 
Change from Baseline in Regional Lung Volumes as measured by HRCT at 
Week 14 
Since no patients have been enrolled in the HRCT subgroup at the time of treatment 
termination and the HRCT data are not collected. The data analysis will not be conducted. 
 
3.4 
Safety Analyses 
Safety analyses will be performed on the safety population. 
 
3.4.1 Exposure 
 
Treatment duration, number of doses, amount of Study Drug and number of patients with 
dose interruption will be summarized by Part and treatment group. 
The treatment duration (days) for each patient is defined as last dose date - first dose date +1. 
 
3.4.2 Adverse Events 
An adverse event will be regarded as treatment emergent if it is present prior to receiving the 
first dose of study drug and subsequently worsens, or is not present prior to receiving the first 
dose of study drug but subsequently appears. 
In addition, if the severity of an AE changes during the study, a separate AE will be recorded 
for each severity on the AE CRF. The “first” and “second” AE records will be identified 
based on the AE start date. AE start date of the second record will be the AE stop date of first 
record. These linked events should be compared pairwise. Consider the following two cases, 


Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
August 24, 2021 
ION-827359-CS2 
CONFIDENTIAL 
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where the AE severity (mild/moderate/severe) and seriousness (Yes/No) between the two 
records in a pair are compared. 
 
Case 1: The first AE record in the pair occurs before the first dosing, and the second 
AE record occurs after the first dosing. 
If the AE severity or seriousness of the second record is worse than that of the first 
record, then only the second AE is deemed as a TEAE. Otherwise, neither record is 
considered as TEAE. 
 
Case 2: Both AE records in the pair occur after first dosing. 
The worst AE is considered as a TEAE. 
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. 
The incidence of AEs will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term and system organ class for: 
• Any treatment emergent adverse events 
• 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 patient 
summarization, a patient is classified according to the highest severity if the patient 
reported one or more events. Adverse events with missing severity will categorized 
as “Missing” for this summary 
• Related treatment emergent adverse events by severity 
• Serious treatment emergent adverse events 
• Serious and related treatment emergent adverse events 
AEs that lead to investigational drug discontinuation will be listed. Non-treatment emergent 
adverse event will be flagged in the data listing. 
 
3.4.3 
Laboratory Measurements 
The list of safety lab analytes collected throughout the study is provided in protocol 
Appendix B. 
All lab data collected will be presented in subject listings. 


Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
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Results from chemistry, hematology, complements, and coagulation panels as well as the 
change and percent change from baseline will be summarized by treatment group and study 
visit using descriptive statistics. 
For ALT and AST, the number and percent of subjects falling in each of the following 
categories based on the confirmed results will be tabulated by treatment group 
• ALT/AST > 3 x ULN, which is confirmed 
• ALT/AST > 5 x ULN, which is confirmed 
For platelet, the number and percentage of subjects falling in each of the following categories 
based on the confirmed results will be tabulated by treatment group for 100,000/mm3 to 
<140,000/mm3 and <100,000/mm3. 
A confirmed value is based on a consecutive lab value within 7 days. If that value is in the 
same or worse category 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, then the worst value will be utilized in the analysis. 
 
3.4.4 
Vital Signs, Weight, and BMI 
Vital signs will include heart rate, respiratory rate, body temperature, systolic and diastolic 
blood pressure and pulse pressure. Summary tables will be created to present the descriptive 
statistics for vital sign values, weight, and BMI as well as the change and percent change 
from baseline at each study visits. 
 
3.4.5 
Physical Examinations 
Adverse changes in physical examinations that are deemed clinically significant by the 
Investigator will be classified as adverse events. All physical examination data will be 
provided in a data listing. 
 
3.4.6 
12-Lead Electrocardiograms (ECG) 
The ECG data will include heart rate, RR interval, PR interval, QRS Duration, QT interval, 
QTcF, QTcB, and overall interpretation. 
For the continuous variables above, descriptive statistics of the results at each study visit, as 
well as the changes and percent changes from baseline to each study visit, will be 
summarized by treatment group. The average of triplicates will be used in the summary. For 
the categorical responses to overall interpretation, the counts and percentages will be 
tabulated by treatment group. The worst case result of triplicates will be used in the 
summary. 
In addition to the descriptive summary, a shift analysis from baseline to the worst (highest) 
post-baseline QTcF and QTcB by treatment group will be conducted. The categories for the 
shift analysis will be: ≤450 msec, >450 msec to ≤480 msec, >480 msec to ≤500 msec, and 
>500 msec. The average of triplicates will be used to categorize the data. 


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Statistical Analysis Plan 
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The number and percent of patients experiencing an increase from baseline in QTcF and 
QTcB of greater than 30 msec or 60 msec at any time post-baseline will be summarized by 
treatment group. The average of triplicates will be used to determine the increase. 
Only data collected from the central reader and provided by ERT will be included in the 
summary table. The local ECG data will only be listed if collected. 
The ECG data will be presented in a subject listing. 
 
3.4.7 
Prior and Concomitant Medications 
Prior medications include medications started prior to the first dose of study medication 
regardless whether continued while on treatment or not. Concomitant medications include 
medications that patients are exposed to on or after the first dose of study medication. Partial 
or missing medication start date or end date will be imputed by the following imputation 
rules: 
Start date: 
• If year, month and day are all missing then assign the date of first dose of Study Drug 
• If month and day are missing and year is: 
o earlier than the year of the first dose of Study Drug then assign December 31 
o otherwise, assign January 1 
• If only day is missing and month-year is: 
o earlier than the month-year of the first dose of Study Drug then assign the last day 
of the month 
o otherwise, assign the first day of the month 
End date: imputation will be performed for the end date only if the day or month is missing 
(i.e., year is present): 
• If month and day are missing, then assign December 31 
• If only day is missing, then assign the last day of the month 
If the imputed start date is later than the imputed end date, then set the imputed start date to 
the imputed end date. 
Prior and concomitant medications will be coded using WHO Drug dictionary and 
summarized by ATC class, preferred name and by treatment group and Part. 
 
3.5 
Pharmacokinetic Analysis 
For pharmacokinetic (PK) assessment, plasma trough PK samples during the 13-week 
treatment period and post-treatment samples during the 10-week post-treatment follow up 
period will be collected from all patients in the study. Additionally, extensive plasma PK 


Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
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samples will be collected in the PK subgroup following the first (Day 1) and last (Day 85) 
inhalation administration. 
PK analysis will be conducted for the PK Population only. 
 
3.5.1 
Plasma Concentration Data 
Plasma concentrations of ION-827359 over time, along with the scheduled (nominal) and 
actual samples times (i.e., time from the end of inhalation) will be listed (when applicable) 
for each subject, by treatment, group/subgroup, cohort, nominal dose, and day. In addition, 
percent differences between scheduled and actual sampling times will be listed for all 
subjects. 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 corresponding SD, %CV, geometric mean, geometric 
%CV will be reported as not applicable. Summary statistics of the ION-827359 plasma 
concentrations will be tabulated by treatment, group/subgroup, 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. 
ION-827359 plasma concentration versus time (actual) profiles (up to 24 hours post dose 
and/or full profiles) following the dose on Days 1 and 85 for each subject in the PK subgroup 
and received ION-827359 active treatment, as well as the median plasma concentrations 
versus time (scheduled) profiles, will be presented graphically on linear and semilogarithmic 
scales. At the discretion of the pharmacokineticist and/or biostatistician, samples may be 
excluded from the median plots if there are large deviations between scheduled and actual 
sampling times. 
 
3.5.2 
Plasma Pharmacokinetic Parameters 
Non-compartmental pharmacokinetic analysis of ION-827359 will be carried out on each 
individual subject data set where full PK sampling profiles are collected (PK subgroup) using 
Phoenix WinNonlin version 8.0 or higher (Pharsight Corporation, Mountain View, CA). 
Plasma pharmacokinetic parameters in each subject (when applicable) will be determined. 
For calculation of PK parameters, all BLQ values will be set to zero. The following plasma 
PK parameters for ION-827359 will be calculated (when applicable and not necessarily 
limited to) and based on actual sampling times: 
• Cmax: the maximum observed ION-827359 concentration in plasma 
• Tmax: the time at which Cmax occurs 


Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
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• AUC0-24h: areas under the plasma concentration-time curve from time zero (pre-dose) 
to 24 hours will be calculated using the linear up-log down trapezoidal rule following 
the dose on Day 1 and Day 85 
• AUC0-168h (AUC): partial area under the plasma concentration-time curve (AUC) 
from time zero to 168 hours will be calculated using the linear up-log down 
trapezoidal rule following the dose on Day 85 
• CLss/F: Apparent plasma clearance at steady-state after inhalation administration. 
This parameter will be calculated as CLss/F = Actual Dose/AUC following the dose 
on Day 85 
• 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. This parameter will be calculated following the dose on Day 85. 
• Vz/F (L): Apparent volume of distribution in the terminal phase will be calculated 
from Vz/F = Actual Dose/(AUC x λz) following the dose on Day 85. 
λz shall be determined over a span equal to at least 1.5 x t1/2λz. A minimum of three data 
points in the elimination phase will be used to calculate lz using log-linear regression 
analysis and the adjusted correlation of determination values (r2_adj) shall be at or greater 
than 0.8 for the estimate to be accepted. If at least one of these three conditions are not 
fulfilled, the PK parameters depending on lz (i.e., t1/2λz and Vz/F) shall be flagged as not 
reliable if calculated and listed. They will generally be excluded from descriptive statistics 
and statistical testing procedures, or at the discretion of the pharmacokineticist, who is in 
charge of the PK analysis. 
Plasma pharmacokinetic parameters will be summarized using descriptive statistics (n, mean, 
SD, %CV, geometric mean, geometric %CV, median, minimum, and maximum) by cohort, 
nominal dose, and day. 
Exposure-response relationships will not be conducted due to the early termination of the 
study. 


 
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