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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)

Primary Purpose

Chronic Bronchitis, Chronic Obstructive Pulmonary Disease

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ION-827359
Placebo
ION-827359
Sponsored by
Ionis Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Bronchitis focused on measuring Chronic Bronchitis, IONIS-ENaCRx

Eligibility Criteria

40 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 postmenopausal
  4. BMI < 35.0 kg/m^2
  5. Participants with a diagnosis of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS)

    1. Ability to perform acceptable and reproducible spirometry
    2. 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

  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
  9. CAT score ≥ 10

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

    1. 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
    2. 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
    3. alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline phosphatase (ALP), serum creatinine, blood urea nitrogen (BUN) > 1.5 × upper limit of normal (ULN)
    4. Platelet count < LLN
    5. Serum potassium > 5.2 mmol/L
    6. Estimated GFR < 60 mL/min (as determined by the Cockcroft-Gault Equation for creatinine clearance)
    7. A positive PCR test for SARS-CoV-2 at any time prior to randomization
  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 participant (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. Clinically important pulmonary disease other than COPD
  6. 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
  7. Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization for a COPD exacerbation within 4 weeks prior to enrolment (Visit 1)
  8. Acute upper or lower respiratory infection requiring antibiotics or antiviral medication within 4 weeks prior to enrolment (Visit 1)
  9. Long term oxygen therapy (LTOT)
  10. 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)
  11. Concomitant medication restrictions: Oral anticoagulants, oral steroids (e.g. prednisone or Medrol), theophylline, chronic azithromycin, or roflumilast
  12. 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

Sites / Locations

  • MediTrial s.r.o.
  • Plicni ambulance Kralupy
  • CEFISPIRO s.r.o.
  • Plicni Ambulance Rokycany, s.r.o.
  • PNEUMOLOGIE VARNSDORF s.r.o.
  • Pneumologisches Studienzentrum Markgrafenstrasse
  • MECS Research GmbH
  • Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH
  • Hamburger Institut far Therapieforschung GmbH
  • KLB Gesundheitsforschung Lubeck GmbH
  • IKF Pneumologie Mainz Helix Medical Excellence Center Mainz
  • ZMS-Zentrum fur medizinische Studien GmbH
  • Csongrad Megyei Mellkasi Betegsegek Szakkorhaza
  • Selye Janos Korhaz, Rendelointezet
  • Queen Anne Street Medical Centre, Heart Lung Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Experimental

Arm Label

Placebo

ION-827359 37.5 milligrams (mg)

ION-827359 75 mg

Arm Description

Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.

Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.

Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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).
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)
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.
Cmax: Maximum Observed Plasma Concentration for ION-827359
Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359
AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359
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.
Percentage of Participants With Clinically Significant Change in Laboratory Values
Laboratory parameters for serum chemistry, hematology, urinalysis, coagulation, complement, and lipids were assessed.
Percentage of Participants With Clinically Significant Change in Vital Sign Parameters
Vital signs included assessment of heart rate, blood pressure, respiratory rate, and temperature.
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.

Full Information

First Posted
June 18, 2020
Last Updated
November 24, 2022
Sponsor
Ionis Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04441788
Brief Title
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)
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Terminated
Why Stopped
Business Decision to Terminate Study
Study Start Date
December 22, 2020 (Actual)
Primary Completion Date
April 27, 2021 (Actual)
Study Completion Date
August 9, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ionis Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Bronchitis, Chronic Obstructive Pulmonary Disease
Keywords
Chronic Bronchitis, IONIS-ENaCRx

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Arm Title
ION-827359 37.5 milligrams (mg)
Arm Type
Experimental
Arm Description
Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Arm Title
ION-827359 75 mg
Arm Type
Experimental
Arm Description
Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Intervention Type
Drug
Intervention Name(s)
ION-827359
Intervention Description
ION-827359 administered by oral inhalation
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo administered by oral inhalation
Intervention Type
Drug
Intervention Name(s)
ION-827359
Intervention Description
ION-827359 administered by oral inhalation
Primary Outcome Measure Information:
Title
Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo
Description
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.
Time Frame
From Baseline up to average of Weeks 13 and 14
Secondary Outcome Measure Information:
Title
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
Description
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.
Time Frame
From Baseline up to average of weeks 13 and 14
Title
Change From Baseline in the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) to the Week 14 Time Point
Description
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).
Time Frame
From Baseline to Week 14
Title
Change From Baseline in St. George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score to the Week 14 Time Point
Description
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)
Time Frame
From Baseline to Week 14
Title
Change From Baseline in Post-Bronchodilator FEV1
Description
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.
Time Frame
From Baseline to end of treatment (EOT) [Up to Week 14]
Title
Cmax: Maximum Observed Plasma Concentration for ION-827359
Time Frame
Days 1 and 85
Title
Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359
Time Frame
Days 1 and 85
Title
AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359
Time Frame
Days 1 and 85
Title
Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity
Description
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.
Time Frame
Up to Week 24
Title
Percentage of Participants With Clinically Significant Change in Laboratory Values
Description
Laboratory parameters for serum chemistry, hematology, urinalysis, coagulation, complement, and lipids were assessed.
Time Frame
Up to Week 24
Title
Percentage of Participants With Clinically Significant Change in Vital Sign Parameters
Description
Vital signs included assessment of heart rate, blood pressure, respiratory rate, and temperature.
Time Frame
Up to Week 24
Title
Percentage of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings
Description
ECG parameters of ventricular rate, PR interval, QRS duration, QT, or QTc were assessed.
Time Frame
Up to Week 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
MediTrial s.r.o.
City
Jindrichuv Hradec
ZIP/Postal Code
37701
Country
Czechia
Facility Name
Plicni ambulance Kralupy
City
Kralupy Nad Vltavou
ZIP/Postal Code
27801
Country
Czechia
Facility Name
CEFISPIRO s.r.o.
City
Lovosice
ZIP/Postal Code
410 02
Country
Czechia
Facility Name
Plicni Ambulance Rokycany, s.r.o.
City
Rokycany
ZIP/Postal Code
33701
Country
Czechia
Facility Name
PNEUMOLOGIE VARNSDORF s.r.o.
City
Varnsdorf
ZIP/Postal Code
40747
Country
Czechia
Facility Name
Pneumologisches Studienzentrum Markgrafenstrasse
City
Berlin
ZIP/Postal Code
10969
Country
Germany
Facility Name
MECS Research GmbH
City
Berlin
ZIP/Postal Code
12203
Country
Germany
Facility Name
Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH
City
Grosshansdorf
ZIP/Postal Code
22927
Country
Germany
Facility Name
Hamburger Institut far Therapieforschung GmbH
City
Hamburg
ZIP/Postal Code
20354
Country
Germany
Facility Name
KLB Gesundheitsforschung Lubeck GmbH
City
Lübeck
ZIP/Postal Code
23552
Country
Germany
Facility Name
IKF Pneumologie Mainz Helix Medical Excellence Center Mainz
City
Mainz
ZIP/Postal Code
55128
Country
Germany
Facility Name
ZMS-Zentrum fur medizinische Studien GmbH
City
Warendorf
ZIP/Postal Code
48231
Country
Germany
Facility Name
Csongrad Megyei Mellkasi Betegsegek Szakkorhaza
City
Deszk
ZIP/Postal Code
6772
Country
Hungary
Facility Name
Selye Janos Korhaz, Rendelointezet
City
Komarom
ZIP/Postal Code
2900
Country
Hungary
Facility Name
Queen Anne Street Medical Centre, Heart Lung Center
City
London
ZIP/Postal Code
Nw1 8HU
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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)

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