A Study to Assess the Safety, Tolerability, and Efficacy of ION-827359 in Participants With Mild to Moderate Chronic Obstructive Pulmonary Disease (COPD) With Chronic Bronchitis (CB)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Chronic Bronchitis, Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: ION-827359
* Drug: Placebo
* Drug: ION-827359


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 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 Males or females. Aged 40-70 inclusive at the time of informed consent Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or postmenopausal BMI < 35.0 kg/m^2 Participants 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: i. FEV1/ forced vital capacity (FVC) ratio of < 0.70 ii. FEV1 ≥ 50% and ≤ 90% of predicted normal Clinically stable COPD in the 4 weeks prior to Screening (Visit 1) Current and former smokers with smoking history of ≥ 20 pack years Meet SGRQ definition of CB CAT score ≥ 10 Exclusion Criteria 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 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) A positive PCR test for SARS-CoV-2 at any time prior to randomization 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 participant (Study Day 1) Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator Clinically important pulmonary disease other than COPD Asthma as a primary or main diagnosis according to the Global Initiative for Asthma (GINA) guidelines (GINA 2011) or other accepted guidelines. Participants with a past medical history of asthma (e.g. childhood or adolescence) may be included Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization for a COPD exacerbation within 4 weeks prior to enrolment (Visit 1) Acute upper or lower respiratory infection requiring antibiotics or antiviral medication within 4 weeks prior to enrolment (Visit 1) Long term oxygen therapy (LTOT) Participants participating in, or scheduled for, an intensive (active) COPD rehabilitation program (participants who are in the maintenance phase of a rehabilitation program are eligible to take part) Concomitant medication restrictions: Oral anticoagulants, oral steroids (e.g. prednisone or Medrol), theophylline, chronic azithromycin, or roflumilast 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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks. | Drug: Placebo<br>* Placebo administered by oral inhalation<br>|
| Experimental: ION-827359 37.5 milligrams (mg)<br>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks. | Drug: ION-827359<br>* ION-827359 administered by oral inhalation<br>|
| Experimental: ION-827359 75 mg<br>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks. | Drug: ION-827359<br>* ION-827359 administered by oral inhalation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Baseline was defined as the last non-missing measurement prior to the first study drug administration. The primary time point was defined as the average of weeks 13 and 14. FAS=Full analysis set. | From Baseline up to average of Weeks 13 and 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) Respiratory Symptoms (E-RS) Daily Symptom Diary Total Score to the Primary Time Point | The E-RS scale is a participant-reported outcome (PRO) designed to measure the symptoms of participants with chronic obstructive pulmonary disease (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 (comprised of 5 items, score range [0-17]), cough and sputum (comprised of 3 items, score range [0-11]), and chest symptoms (comprised of 3 items, score range [0-12]). The E-RS was collected on the daily e-diary. The total score was derived by summing the 11-item scores and ranged between 0 to 40 with higher values indicating severe respiratory symptoms. The primary time point was defined as the average of weeks 13 and 14. | From Baseline up to average of weeks 13 and 14 | 
| Change From Baseline in the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) to the Week 14 Time Point | The CAT is an eight-item questionnaire that was completed by the participant and is designed to quantify the impact of COPD symptoms on the health status of participants. Each item is rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment). The total CAT score is calculated by summing the scores of all items and ranges from 0 to 40. Higher scores indicate a severe condition (more severe impact of COPD on a participant's life). | From Baseline to Week 14 | 
| Change From Baseline in St. George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score to the Week 14 Time Point | The SGRQ is a participant completed, a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in participants with obstructive airway disease. The shorter 40-item version (SGRQ-C) which does not specify a Recall Period and has been validated specifically for COPD participants was used in this study. It consists of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome (more limitations) | From Baseline to Week 14 | 
| Change From Baseline in Post-Bronchodilator FEV1 | Post-bronchodilator FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation after administration of bronchodilator. Baseline was defined as the last non-missing measurement prior to the first study drug administration. | From Baseline to end of treatment (EOT) [Up to Week 14] | 
| Cmax: Maximum Observed Plasma Concentration for ION-827359 |  | Days 1 and 85 | 
| Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359 |  | Days 1 and 85 | 
| AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359 |  | Days 1 and 85 | 
| Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity | 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. A TEAE is defined as any AE starting or getting worse on or after the first dose of the study drug. The severity of a TEAE was assessed by the investigator and classified into one of the following: mild, moderate, and severe. | Up to Week 24 | 
| Percentage of Participants With Clinically Significant Change in Laboratory Values | Laboratory parameters for serum chemistry, hematology, urinalysis, coagulation, complement, and lipids were assessed. | Up to Week 24 | 
| Percentage of Participants With Clinically Significant Change in Vital Sign Parameters | Vital signs included assessment of heart rate, blood pressure, respiratory rate, and temperature. | Up to Week 24 | 
| Percentage of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings | ECG parameters of ventricular rate, PR interval, QRS duration, QT, or QTc were assessed. | Up to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Bronchitis, IONIS-ENaCRx