A Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD

• ClinicalTrials.gov Identifier: NCT04535986
• Recruitment Status: Completed
• First Posted: September 2, 2020
• Results First Posted: November 13, 2023
• Last Update Posted: November 13, 2023
• Sponsor: Verona Pharma plc
• Collaborator: Iqvia Pty Ltd
• Information provided by (Responsible Party): Verona Pharma plc

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Chronic Obstructive Pulmonary Disease
• Interventions: Drug: Ensifentrine; Drug: Placebo
• Enrollment: 763

Participant Flow

Recruitment Details

This Phase 3, randomized, double-blind, placebo-controlled study was conducted in patients with moderate to severe chronic obstructive pulmonary disease (COPD) at 120 study centers in 12 countries between 29 Sep 2020 and 02 Dec 2022. Patients were randomized in a 5:3 ratio overall (1:1 over 24 weeks and 3:1 over 48 weeks), stratified by duration, smoking status and background medication use, to receive either ensifentrine or placebo.

Pre-assignment Details

Patients were screened for eligibility before entering a 28-day run in period to ensure a stable COPD treatment regimen and to collect baseline information on symptoms and rescue medication use.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description	3 milligram (mg) twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Period Title: Overall Study
Started	479	284
Received Treatment	477	283
Completed	400	245
Not Completed	79	39
Reason Not Completed
Death	4	5
COPD exacerbation withdrawal criteria	7	5
Coronavirus disease 2019 (COVID-19)	8	6
Adverse Event	10	1
Lack of Efficacy	3	2
Investigator discretion	3	0
Withdrawal by Subject	32	14
Lost to Follow-up	5	3
Other	7	3

Baseline Characteristics

Arm/Group Title		Ensifentrine	Placebo	Total
Arm/Group Description		3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.	Total of all reporting groups
Overall Number of Baseline Participants		479	284	763
Baseline Analysis Population Description		All patients randomized set included all patients in the enrolled set who were randomized to study medication.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	479 participants	284 participants	763 participants
		65.1 (7.12)	64.9 (7.73)	65.0 (7.35)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	479 participants	284 participants	763 participants
	Female	204	117	321
	Male	275	167	442
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	479 participants	284 participants	763 participants
Asian		13	11	24
Black or African American		16	9	25
White		437	251	688
Other		0	1	1
Not Reported		13	12	25
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	479 participants	284 participants	763 participants
Hispanic or Latino		15	6	21
Not Hispanic or Latino		464	278	742
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	479 participants	284 participants	763 participants
Bulgaria		28	17	45
Czechia		70	36	106
Germany		117	73	190
Greece		3	3	6
Hungary		25	14	39
South Korea		12	11	23
Poland		10	3	13
Romania		21	18	39
Russia		71	33	104
Slovakia		27	14	41
United Kingdom		8	4	12
United States		87	58	145

Outcome Measures

1. Primary Outcome

Title	Least Square (LS) Mean Change From Baseline in Average Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) at Week 12
Description	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Average FEV1 AUC0-12h was defined as AUC over 12 hours of the FEV1, divided by 12 hours. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on Day 1. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines.
Time Frame	Baseline (pre-dose on Day 1) and Week 12

Outcome Measure Data

Analysis Population Description

The modified Intent-to-Treat (mITT) population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment. 1 patient was missing a baseline FEV1 assessment.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description:	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Overall Number of Participants Analyzed	477	282
Least Squares Mean (Standard Error); Unit of Measure: liters
	0.0611 (0.01825)	-0.0256 (0.0195)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ensifentrine, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The analysis of covariance (ANCOVA) model was used to model the change from baseline FEV1 to average FEV1 AUC0-12h with treatment, region, background medication strata and smoking strata as fixed effects and baseline FEV1 as covariate.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.0868
	Confidence Interval	(2-Sided) 95%; 0.0551 to 0.1185
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0162
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	LS Mean Change From Baseline FEV1 to Peak FEV1 at Day 1 and Weeks 6, 12 and 24
Description	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Peak FEV1 is the maximum value in the 4 hours after dosing. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on Day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time Frame	Baseline (pre-dose on Day 1), post-dose on Day 1, Weeks 6, 12, and 24

Outcome Measure Data

Analysis Population Description

The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description:	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Overall Number of Participants Analyzed	477	282
Least Squares Mean (Standard Error); Unit of Measure: liters
Day 1 (Post-dose)	0.2274 (0.0130)	0.0755 (0.0138)
Week 6	0.2038 (0.0193)	0.0677 (0.0207)
Week 12	0.2042 (0.0201)	0.0570 (0.0217)
Week 24	0.1623 (0.0217)	0.0462 (0.0234)

3. Secondary Outcome

Title	LS Mean Change From Baseline to the Mean Weekly Evaluating-Respiratory Symptoms (E-RS) Total Score at Weeks 6, 12 and 24
Description	The E-RS scale consists of 11 questions, with 3 sub-domains of: breathlessness, cough and sputum, and chest symptoms. The E-RS sub-domain score was calculated as the sum from the relevant questions. The E-RS total score was derived as the sum of the raw scores of the 11 items ranging from 0 to 40. Higher scores indicates severe respiratory symptoms. Scores were derived weekly as the mean over 7 days prior to the visit, using only days where data was recorded. The E-RS was collected daily by electronic diary (e-diary). Baseline is the mean over the 7 days prior to the first intake of study medication, using only days where data was recorded.
Time Frame	Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24

Outcome Measure Data

Analysis Population Description

The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description:	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Overall Number of Participants Analyzed	475	281
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
Week 6	-1.944 (0.3581)	-1.157 (0.3831)
Week 12	-2.498 (0.3897)	-1.127 (0.4176)
Week 24	-2.249 (0.4247)	-1.298 (0.4573)

4. Secondary Outcome

Title	LS Mean Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at Weeks 6, 12 and 24
Description	The SGRQ questionnaire consists of 17 questions, split into 2 parts. Part 1 consisted of the first 8 questions and was related to the symptoms subdomain. The remaining 9 questions were in Part 2, which were related to the activity and impacts subdomains. The total score was calculated by dividing the summed weights by the maximum possible weight for all items in the questionnaire and expressing the result as a percentage. Score ranging from 0 to 100 and higher scores indicated a worse outcome. Baseline is the score calculated on Day 1 prior to 4 hour post-dose spirometry.
Time Frame	Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24

Outcome Measure Data

Analysis Population Description

The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description:	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Overall Number of Participants Analyzed	474	281
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
Week 6	-6.184 (0.9838)	-3.965 (1.0511)
Week 12	-5.665 (1.0163)	-2.652 (1.0859)
Week 24	-6.167 (1.1405)	-3.868 (1.2178)

5. Secondary Outcome

Title	LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 6, 12 and 24
Description	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Morning trough FEV1 was the last value collected prior to the morning dose. Baseline FEV1 is the mean of the two measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time Frame	Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24

Outcome Measure Data

Analysis Population Description

The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description:	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Overall Number of Participants Analyzed	477	282
Least Squares Mean (Standard Error); Unit of Measure: liters
Week 6	0.0112 (0.0181)	-0.0259 (0.0193)
Week 12	0.0076 (0.0190)	-0.0272 (0.0204)
Week 24	-0.0236 (0.0205)	-0.0369 (0.0219)

6. Secondary Outcome

Title	LS Mean Change From Baseline in Average FEV1 Area Under the Curve Over 4 Hours (AUC0-4h) at Day 1 and Weeks 6, 12 and 24
Description	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Average FEV1 AUC0-4h was defined as area under the curve over 4 hours of the FEV1, divided by 4 hours. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on Day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time Frame	Baseline (pre-dose on Day 1), post-dose on Day 1, Weeks 6, 12, and 24

Outcome Measure Data

Analysis Population Description

The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description:	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Overall Number of Participants Analyzed	477	282
Least Squares Mean (Standard Error); Unit of Measure: liters
Day 1 (Post-dose)	0.1495 (0.0108)	0.0099 (0.0115)
Week 6	0.1259 (0.0184)	-0.0044 (0.0196)
Week 12	0.1243 (0.0191)	-0.0149 (0.0203)
Week 24	0.0875 (0.0206)	-0.0139 (0.0220)

7. Secondary Outcome

Title	Percentage of SGRQ Responders at Weeks 6, 12 and 24
Description	The SGRQ questionnaire consists of 17 questions, split into 2 parts. Part 1 consisted of the first 8 questions and was related to the symptoms subdomain. The remaining 9 questions were in Part 2, which were related to the activity and impacts subdomains. The total score was calculated by dividing the summed weights by the maximum possible weight for all items in the questionnaire and expressing the result as a percentage. Responder was a patient with an improvement from baseline in SGRQ total score of 4 or more. Percentage of SGRQ responders are reported.
Time Frame	Weeks 6, 12 and 24

Outcome Measure Data

Analysis Population Description

The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description:	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Overall Number of Participants Analyzed	474	281
Measure Type: Number; Unit of Measure: percentage of patients
Week 6	50.8	40.6
Week 12	52.5	37.0
Week 24	58.2	45.9

8. Secondary Outcome

Title	LS Mean Change From Baseline to the Mean Weekly Rescue Medication Use at Weeks 6, 12 and 24
Description	Use of rescue medication (albuterol/salbutamol) per week was calculated as the LS mean use daily over 7 days. Daily rescue medication use was collected in an e-diary throughout the study. Baseline is the mean over the 7 days prior to the first intake of study medication, calculated as the sum of puffs taken, divided by number of days data has been recorded.
Time Frame	Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24

Outcome Measure Data

Analysis Population Description

The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description:	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Overall Number of Participants Analyzed	475	281
Least Squares Mean (Standard Error); Unit of Measure: rescue medication puffs per week
Week 6	-0.442 (0.1065)	-0.306 (0.1139)
Week 12	-0.469 (0.1155)	-0.182 (0.1234)
Week 24	-0.506 (0.1448)	-0.052 (0.1554)

9. Secondary Outcome

Title	LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 6, 12 and 24
Description	The TDI is a questionnaire that focused on 3 sub-domains: functional impairment, magnitude of task and magnitude of effort. Sub-domain score was calculated as the sum from the related questions. Total score was calculated as the sum of the sub-domain scores. The TDI measures the change in dyspnea severity from the baseline as measured by the baseline dyspnea index. It was rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement). Higher scores indicate better outcome. Change from baseline was assessed with the Baseline Dyspnea Index.
Time Frame	Weeks 6, 12 and 24

Outcome Measure Data

Analysis Population Description

The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description:	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Overall Number of Participants Analyzed	471	277
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
Week 6	1.3 (0.19)	0.6 (0.21)
Week 12	1.6 (0.21)	0.4 (0.23)
Week 24	1.9 (0.24)	0.8 (0.27)

10. Secondary Outcome

Title	LS Mean Change From Baseline FEV1 to Evening Trough FEV1 at Week 12
Description	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Evening trough FEV1 was the value collected at 12 hours post-morning dose and prior to the evening dose. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time Frame	Baseline (pre-dose on Day 1) and Week 12

Outcome Measure Data

Analysis Population Description

The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.

Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description:	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.
Overall Number of Participants Analyzed	477	282
Least Squares Mean (Standard Error); Unit of Measure: liters
	-0.0117 (0.0203)	-0.0697 (0.0214)

Adverse Events

Time Frame	Treatment-emergent adverse events (TEAEs; serious or non-serious), were collected from first dose of study medication up to 10 days after final study visit (24-week subset: at Week 24, approximately 25 weeks; 48-week subset: at Week 48, approximately 49 weeks). Serious Adverse Events (SAEs) assessed as related to study participation (eg, change in existing therapy) and which occurred prior to first dose of study medication were collected from time of consent through follow-up contact.
Adverse Event Reporting Description	The safety analysis included all randomized patients who received at least 1 dose (or partial dose) of study medication. TEAEs (serious or non-serious) that started or worsened in severity on or after first dose of study medication are reported. SAEs assessed as related to study participation and which occurred prior to first dose of study medication are not reported as it was pre-specified to report only TEAEs that started or worsened in severity on or after first dose of study medication.
Arm/Group Title	Up to Week 24: Ensifentrine	Up to Week 24: Placebo	From Week 24 to Week 48: Ensifentrine	From Week 24 to Week 48: Placebo
Arm/Group Description	3 mg twice daily via standard jet nebulizer.	Twice daily via standard jet nebulizer.	3 mg twice daily via standard jet nebulizer (patients that had at least 1 dose after Week 24 visit).	Twice daily via standard jet nebulizer (patients that had at least 1 dose after Week 24 visit).
All-Cause Mortality
	Up to Week 24: Ensifentrine	Up to Week 24: Placebo	From Week 24 to Week 48: Ensifentrine	From Week 24 to Week 48: Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/477 (0.42%)	4/283 (1.41%)	2/228 (0.88%)	1/70 (1.43%)
Serious Adverse Events
	Up to Week 24: Ensifentrine	Up to Week 24: Placebo	From Week 24 to Week 48: Ensifentrine	From Week 24 to Week 48: Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	32/477 (6.71%)	19/283 (6.71%)	11/228 (4.82%)	5/70 (7.14%)
Blood and lymphatic system disorders
Anaemia † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	1/70 (1.43%)
Cardiac disorders
Acute myocardial infarction † 1	0/477 (0.00%)	0/283 (0.00%)	1/228 (0.44%)	0/70 (0.00%)
Atrial fibrillation † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Bradycardia † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Myocardial ischaemia † 1	0/477 (0.00%)	0/283 (0.00%)	1/228 (0.44%)	0/70 (0.00%)
Stress cardiomyopathy † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Ear and labyrinth disorders
Vertigo † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Vestibular disorder † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Gastrointestinal disorders
Pancreatitis acute † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Hepatobiliary disorders
Bile duct stone † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Biliary dyskinesia † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Infections and infestations
COVID-19 † 1	2/477 (0.42%)	2/283 (0.71%)	1/228 (0.44%)	0/70 (0.00%)
COVID-19 pneumonia † 1	3/477 (0.63%)	1/283 (0.35%)	1/228 (0.44%)	0/70 (0.00%)
Lung abscess † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Myocarditis bacterial † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Pneumonia † 1	3/477 (0.63%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Pneumonia bacterial † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Pneumonia chlamydial † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Sepsis † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Urosepsis † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Injury, poisoning and procedural complications
Femur fracture † 1	0/477 (0.00%)	0/283 (0.00%)	1/228 (0.44%)	0/70 (0.00%)
Ligament sprain † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Lower limb fracture † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Pharyngeal injury † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Vascular pseudoaneurysm † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Osteoarthritis † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma metastatic † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Cholangiocarcinoma † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Laryngeal cancer † 1	0/477 (0.00%)	0/283 (0.00%)	1/228 (0.44%)	0/70 (0.00%)
Lung adenocarcinoma † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Lung neoplasm malignant † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Malignant melanoma † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Non-small cell lung cancer stage I † 1	0/477 (0.00%)	0/283 (0.00%)	1/228 (0.44%)	0/70 (0.00%)
Pancreatic carcinoma † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Pancreatic carcinoma metastatic † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Small cell lung cancer metastatic † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Transitional cell carcinoma † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Nervous system disorders
Cerebral microangiopathy † 1	0/477 (0.00%)	0/283 (0.00%)	1/228 (0.44%)	0/70 (0.00%)
Cerebrovascular accident † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Syncope † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Transient ischaemic attack † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Nephropathy toxic † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Uterine prolapse † 1	0/477 (0.00%)	0/283 (0.00%)	1/228 (0.44%)	0/70 (0.00%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	7/477 (1.47%)	6/283 (2.12%)	2/228 (0.88%)	0/70 (0.00%)
Pulmonary embolism † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Vascular disorders
Deep vein thrombosis † 1	0/477 (0.00%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Hypertension † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Hypotension † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Peripheral arterial occlusive disease † 1	1/477 (0.21%)	0/283 (0.00%)	0/228 (0.00%)	0/70 (0.00%)
Shock haemorrhagic † 1	1/477 (0.21%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
1 Term from vocabulary, MedDRA 25.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	1%
	Up to Week 24: Ensifentrine	Up to Week 24: Placebo	From Week 24 to Week 48: Ensifentrine	From Week 24 to Week 48: Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	90/477 (18.87%)	58/283 (20.49%)	16/228 (7.02%)	17/70 (24.29%)
Blood and lymphatic system disorders
Thrombocytopenia † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Cardiac disorders
Atrial fibrillation † 1	5/477 (1.05%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Supraventricular extrasystoles † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Gastrointestinal disorders
Food poisoning † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Toothache † 1	6/477 (1.26%)	2/283 (0.71%)	0/228 (0.00%)	0/70 (0.00%)
General disorders
Asthenia † 1	0/477 (0.00%)	0/283 (0.00%)	1/228 (0.44%)	1/70 (1.43%)
Chest pain † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Infections and infestations
Bronchitis † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
COVID-19 † 1	16/477 (3.35%)	9/283 (3.18%)	2/228 (0.88%)	2/70 (2.86%)
Cellulitis † 1	0/477 (0.00%)	3/283 (1.06%)	0/228 (0.00%)	0/70 (0.00%)
Conjunctivitis † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Gastroenteritis viral † 1	0/477 (0.00%)	0/283 (0.00%)	1/228 (0.44%)	1/70 (1.43%)
Helicobacter infection † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Nasopharyngitis † 1	13/477 (2.73%)	16/283 (5.65%)	6/228 (2.63%)	0/70 (0.00%)
Oral fungal infection † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Pulpitis dental † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Upper respiratory tract infection † 1	6/477 (1.26%)	5/283 (1.77%)	4/228 (1.75%)	0/70 (0.00%)
Urinary tract infection † 1	5/477 (1.05%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Investigations
Prostatic specific antigen increased † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	5/477 (1.05%)	3/283 (1.06%)	0/228 (0.00%)	0/70 (0.00%)
Back pain † 1	10/477 (2.10%)	1/283 (0.35%)	0/228 (0.00%)	0/70 (0.00%)
Haemarthrosis † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Spinal pain † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Nervous system disorders
Carotid artery stenosis † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Dizziness † 1	3/477 (0.63%)	4/283 (1.41%)	0/228 (0.00%)	0/70 (0.00%)
Headache † 1	16/477 (3.35%)	12/283 (4.24%)	4/228 (1.75%)	2/70 (2.86%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	3/477 (0.63%)	4/283 (1.41%)	0/228 (0.00%)	0/70 (0.00%)
Epistaxis † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Pulmonary mass † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Throat irritation † 1	1/477 (0.21%)	3/283 (1.06%)	0/228 (0.00%)	0/70 (0.00%)
Vascular disorders
Essential hypertension † 1	0/477 (0.00%)	0/283 (0.00%)	0/228 (0.00%)	1/70 (1.43%)
Hypertension † 1	11/477 (2.31%)	4/283 (1.41%)	0/228 (0.00%)	0/70 (0.00%)
1 Term from vocabulary, MedDRA 25.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Chief Medical Officer
• Organization: Verona Pharma plc
• Phone: See email
• EMail: info@veronapharma.com

• Responsible Party: Verona Pharma plc
• ClinicalTrials.gov Identifier: NCT04535986
• Other Study ID Numbers: RPL554-CO-301
• First Submitted: August 19, 2020
• First Posted: September 2, 2020
• Results First Submitted: August 30, 2023
• Results First Posted: November 13, 2023
• Last Update Posted: November 13, 2023