Trial Outcomes & Findings for 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) (NCT NCT04441788)

Last Updated: 2022-12-20

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

60 participants

Primary outcome timeframe

From Baseline up to average of Weeks 13 and 14

Results posted on

2022-12-20

Participant Flow

60 participants were randomized at 11 study centers in Czech Republic, Germany, Hungary and the United Kingdom.

Of the 60 randomized participants, one was randomized but did not receive study treatment as the participant was ineligible. The study included a 2-week screening period (including a diet-stabilization period), a 12-week treatment period, and a 10-week post-treatment evaluation period.

Participant milestones

Participant milestones
Measure	Placebo Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 Milligrams (mg) Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Overall Study STARTED	20	21	19
Overall Study COMPLETED	3	4	3
Overall Study NOT COMPLETED	17	17	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 Milligrams (mg) Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Overall Study Voluntary Withdrawl	0	1	0
Overall Study Ineligibility	1	0	0
Overall Study Adverse Event	0	0	4
Overall Study Study Terminated by Sponsor	16	16	12

Baseline Characteristics

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)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=19 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=21 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=19 Participants Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	Total n=59 Participants Total of all reporting groups
Age, Continuous	61.3 years STANDARD_DEVIATION 4.54 • n=5 Participants	61.8 years STANDARD_DEVIATION 5.86 • n=7 Participants	61.8 years STANDARD_DEVIATION 5.39 • n=5 Participants	61.6 years STANDARD_DEVIATION 5.23 • n=4 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	7 Participants n=7 Participants	5 Participants n=5 Participants	21 Participants n=4 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	14 Participants n=7 Participants	14 Participants n=5 Participants	38 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	19 Participants n=5 Participants	21 Participants n=7 Participants	19 Participants n=5 Participants	59 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	19 Participants n=5 Participants	21 Participants n=7 Participants	18 Participants n=5 Participants	58 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Forced Expiratory Volume in 1 Second (FEV1)	1.8317 liters STANDARD_DEVIATION 0.4670 • n=5 Participants	1.9311 liters STANDARD_DEVIATION 0.6608 • n=7 Participants	1.6536 liters STANDARD_DEVIATION 0.3498 • n=5 Participants	1.8097 liters STANDARD_DEVIATION 0.5193 • n=4 Participants

PRIMARY outcome

Timeframe: From Baseline up to average of Weeks 13 and 14

Population: FAS=all randomized participants who had ≥1 dose of study drug(ION 827359/placebo),≥1 post-Baseline efficacy assessment(i.e.,post-Baseline FEV1,Exacerbations of Chronic pulmonary Disease Tool\[EXACT\]Respiratory Symptoms\[E-RS\]score,Chronic Obstructive Pulmonary Disease\[COPD\]Assessment Test\[CAT\]score,or St.George's Respiratory Questionnaire-COPD Specific\[SGRQ-C score\],post-bronchodilator FEV1).Overall number analyzed:number of participants with data available for analyses in this outcome measure.

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=5 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=4 Participants Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo	0.0642 liters Standard Deviation 0.2506	-0.0240 liters Standard Deviation 0.3581	0.1336 liters Standard Deviation 0.1087

SECONDARY outcome

Timeframe: From Baseline up to average of weeks 13 and 14

Population: FAS included all randomized participants who received at least 1 dose of study drug (ION-827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Overall number of participants analyzed is the number of participants with data available for analyses in this outcome measure.

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.

Outcome measures

Outcome measures
Measure	Placebo n=4 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=5 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=4 Participants Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
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	-1.08 score on a scale Standard Deviation 1.171	-1.41 score on a scale Standard Deviation 2.486	-1.99 score on a scale Standard Deviation 4.217

SECONDARY outcome

Timeframe: From Baseline to Week 14

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).

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=5 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=3 Participants Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Change From Baseline in the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) to the Week 14 Time Point	-2.6 score on a scale Standard Deviation 2.51	-0.6 score on a scale Standard Deviation 3.78	0.0 score on a scale Standard Deviation 1.73

SECONDARY outcome

Timeframe: From Baseline to Week 14

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)

Outcome measures

Outcome measures
Measure	Placebo n=5 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=5 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=3 Participants Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Change From Baseline in St. George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score to the Week 14 Time Point	-15.93 score on a scale Standard Deviation 19.515	-1.74 score on a scale Standard Deviation 3.839	-0.76 score on a scale Standard Deviation 2.350

SECONDARY outcome

Timeframe: From Baseline to end of treatment (EOT) [Up to Week 14]

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.

Outcome measures

Outcome measures
Measure	Placebo n=3 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=5 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=3 Participants Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Change From Baseline in Post-Bronchodilator FEV1	0.0663 liters Standard Deviation 0.0685	0.0320 liters Standard Deviation 0.2379	0.1180 liters Standard Deviation 0.1006

SECONDARY outcome

Timeframe: Days 1 and 85

Population: Pharmacokinetic (PK) population included all participants who were randomized and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analyzed with reportable result. Number analyzed is the number of participants with data available for analysis at the specified time point.

Outcome measures

Outcome measures
Measure	Placebo n=6 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=6 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Cmax: Maximum Observed Plasma Concentration for ION-827359 Day 1	85.6 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 198	203 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 52.6	—
Cmax: Maximum Observed Plasma Concentration for ION-827359 Day 85	53.5 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation NA The geometric coefficient of variation was not estimable due to lower number of participants.	195 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 124	—

SECONDARY outcome

Timeframe: Days 1 and 85

Population: PK population included all participants who were randomized and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analyzed with reportable result. Number analyzed is the number of participants with data available for analysis at the specified time point.

Outcome measures

Outcome measures
Measure	Placebo n=6 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=6 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359 Day 1	1.54 hours Interval 0.567 to 2.05	1.64 hours Interval 0.667 to 2.12	—
Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359 Day 85	1.98 hours Interval 1.98 to 1.98	3.11 hours Interval 1.73 to 4.48	—

SECONDARY outcome

Timeframe: Days 1 and 85

Population: PK population consisted of all the participants who were randomized and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analyzed with reportable result. Number analyzed is the number of participants with data available for analysis at the specified time point.

Outcome measures

Outcome measures
Measure	Placebo n=6 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=6 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359 Day 1	528 hoursnanogram per milliliter (hng/mL) Geometric Coefficient of Variation 190	1323 hoursnanogram per milliliter (hng/mL) Geometric Coefficient of Variation 66.0	—
AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359 Day 85	312 hoursnanogram per milliliter (hng/mL) Geometric Coefficient of Variation NA The geometric coefficient of variation was not estimable due to lower number of participants.	2416 hoursnanogram per milliliter (hng/mL) Geometric Coefficient of Variation 252	—

SECONDARY outcome

Timeframe: Up to Week 24

Population: Safety population included all participants who were randomized and received at least 1 dose of study drug.

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.

Outcome measures

Outcome measures
Measure	Placebo n=19 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=21 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=19 Participants Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity Mild	10.5 percentage of participants	14.3 percentage of participants	15.8 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity Moderate	52.6 percentage of participants	38.1 percentage of participants	63.2 percentage of participants
Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity Severe	10.5 percentage of participants	0 percentage of participants	5.3 percentage of participants

SECONDARY outcome

Timeframe: Up to Week 24

Population: Safety population included all participants who are were randomized and received at least 1 dose of study drug.

Laboratory parameters for serum chemistry, hematology, urinalysis, coagulation, complement, and lipids were assessed.

Outcome measures

Outcome measures
Measure	Placebo n=19 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=21 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=19 Participants Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Percentage of Participants With Clinically Significant Change in Laboratory Values	0 percentage of participants	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: Up to Week 24

Population: Safety population included all participants who are were randomized and received at least 1 dose of study drug.

Vital signs included assessment of heart rate, blood pressure, respiratory rate, and temperature.

Outcome measures

Outcome measures
Measure	Placebo n=19 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=21 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=19 Participants Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Percentage of Participants With Clinically Significant Change in Vital Sign Parameters	0 percentage of participants	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: Up to Week 24

Population: Safety population included all participants who were randomized and received at least 1 dose of study drug.

ECG parameters of ventricular rate, PR interval, QRS duration, QT, or QTc were assessed.

Outcome measures

Outcome measures
Measure	Placebo n=19 Participants Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=21 Participants Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=19 Participants Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Percentage of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings	0 percentage of participants	0 percentage of participants	0 percentage of participants

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 14 other events

Deaths: 0 deaths

ION-827359 37.5 mg

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

ION-827359 75 mg

Serious events: 1 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=19 participants at risk Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=21 participants at risk Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=19 participants at risk Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Cardiac disorders Atrial flutter	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	4.8% 1/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.

Other adverse events

Additional Information

Ionis Pharmaceuticals, Inc

Phone: 800-679-4747

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=19 participants at risk Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 37.5 mg n=21 participants at risk Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.	ION-827359 75 mg n=19 participants at risk Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
Respiratory, thoracic and mediastinal disorders Cough	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	23.8% 5/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	36.8% 7/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	26.3% 5/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	21.1% 4/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	9.5% 2/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	26.3% 5/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Chest pain	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Sputum increased	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	10.5% 2/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Throat irritation	10.5% 2/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Bronchial irritation	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Dysphonia	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Rhinitis	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Sputum discoloured	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	10.5% 2/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	19.0% 4/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Gastrointestinal disorders Dyspepsia	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Gastrointestinal disorders Gastritis	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Gastrointestinal disorders Tongue dry	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Infections and infestations Nasopharyngitis	15.8% 3/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	4.8% 1/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Infections and infestations Urinary tract infection	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Infections and infestations Bronchitis	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Infections and infestations Oral candidiasis	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
General disorders Burning sensation	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	9.5% 2/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
General disorders Chest discomfort	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
General disorders Cyst	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
General disorders Pyrexia	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Investigations Blood creatine phosphokinase increased	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Investigations Blood glucose decreased	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Investigations FEV1/FVC ratio decreased	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Investigations SARS-CoV-2 test positive	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Nervous system disorders Headache	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	4.8% 1/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	10.5% 2/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Vascular disorders Arteriosclerosis	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Vascular disorders Peripheral vascular disorder	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Cardiac disorders Cyanosis	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Eye disorders Eye irritation	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Hepatobiliary disorders Cholecystitis	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Immune system disorders Vaccination complication	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Injury, poisoning and procedural complications Skin laceration	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Product Issues Product taste abnormal	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.
Psychiatric disorders Sleep disorder	5.3% 1/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/21 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.	0.00% 0/19 • Up to Week 24 Safety population included all participants who were randomized and received at least 1 dose of study drug.