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

• ClinicalTrials.gov Identifier: NCT04542057
• Recruitment Status: Completed
• First Posted: September 9, 2020
• Results First Posted: July 24, 2023
• Last Update Posted: October 16, 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: 790

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 130 study centers in Belgium, Bulgaria, Canada, Denmark, Estonia, Hungary, Poland, Slovakia, Spain, United States of America between 22 September 2020 and 06 July 2022. Patients were randomized in a 5:3 ratio, stratified by smoking status and background medication use, manner 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 mg twice daily via standard jet nebulizer	twice daily via standard jet nebulizer
Period Title: Overall Study
Started	499	291
Received Treatment	498	291
Completed	393	218
Not Completed	106	73
Reason Not Completed
Death	3	1
COPD exacerbation withdrawal criteria	5	6
Coronavirus disease 2019 (COVID-19)	10	7
Adverse Event	15	6
COVID-19 adverse event	6	4
Lack of Efficacy	2	5
Study terminated by sponsor	1	0
Investigator discretion	2	1
Withdrawal by Subject	52	30
Lost to Follow-up	8	11
Other	2	2

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		499	291	790
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	499 participants	291 participants	790 participants
		65.0 (7.38)	65.3 (7.30)	65.1 (7.35)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	499 participants	291 participants	790 participants
	Female	254	153	407
	Male	245	138	383
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	499 participants	291 participants	790 participants
	American Indian or Alaska native	1	0	1
	Asian	1	1	2
	Black or African American	24	11	35
	White	472	276	748
	Other	1	3	4
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	499 participants	291 participants	790 participants
	Hispanic or Latino	26	14	40
	Not Hispanic or Latino	473	277	750
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	499 participants	291 participants	790 participants
Belgium		4	1	5
Bulgaria		78	53	131
Canada		7	6	13
Denmark		3	1	4
Estonia		18	2	20
Hungary		32	20	52
Poland		38	20	58
Slovakia		13	5	18
Spain		25	9	34
United States		281	174	455

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 (40 minutes before first administration 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.

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	498	291
Least Squares Mean (Standard Error); Unit of Measure: liters
	0.0480 (0.00941)	-0.0462 (0.01236)

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	0.0941
	Confidence Interval	(2-Sided) 95%; 0.0647 to 0.1236
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.01501
	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 (40 minutes before first administration 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	498	291
Least Squares Mean (Standard Error); Unit of Measure: liters
Day 1 (Post-dose)	0.2369 (0.00601)	0.0801 (0.00784)
Week 6	0.2158 (0.00969)	0.0636 (0.01276)
Week 12	0.1945 (0.01012)	0.0482 (0.01349)
Week 24	0.1957 (0.01099)	0.0434 (0.01475)

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 (average of 7 days before first administration 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	492	291
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
Week 6	-1.938 (0.2086)	-0.614 (0.2763)
Week 12	-2.051 (0.2245)	-1.161 (0.2963)
Week 24	-2.146 (0.2557)	-1.529 (0.3365)

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 (40 minutes before first administration 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	489	286
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
Week 6	-3.602 (0.5902)	-1.890 (0.7692)
Week 12	-4.019 (0.6171)	-2.942 (0.8168)
Week 24	-4.532 (0.6840)	-4.054 (0.9084)

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 (40 minutes before first administration 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	498	291
Least Squares Mean (Standard Error); Unit of Measure: liters
Week 6	0.0177 (0.00899)	-0.0261 (0.01181)
Week 12	0.0057 (0.00957)	-0.0435 (0.01266)
Week 24	-0.0066 (0.01006)	-0.0318 (0.01323)

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 (40 minutes before first administration 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	498	291
Least Squares Mean (Standard Error); Unit of Measure: liters
Day 1 (Post-dose)	0.1556 (0.00527)	0.0063 (0.00686)
Week 6	0.1357 (0.00932)	-0.0082 (0.01209)
Week 12	0.1148 (0.00943)	-0.0209 (0.01260)
Week 24	0.1148 (0.01036)	-0.0248 (0.01381)

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	489	286
Measure Type: Number; Unit of Measure: percentage of patients
Week 6	44.0	39.5
Week 12	45.2	43.0
Week 24	45.4	50.3

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 (average of 7 days before first administration 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	492	291
Least Squares Mean (Standard Error); Unit of Measure: avg number of rescue medication puffs
Week 6	-0.530 (0.0883)	-0.191 (0.1165)
Week 12	-0.573 (0.0745)	-0.288 (0.0976)
Week 24	-0.485 (0.0871)	-0.346 (0.1143)

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	484	286
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
Week 6	1.6 (0.12)	0.9 (0.16)
Week 12	1.8 (0.13)	1.2 (0.18)
Week 24	2.2 (0.15)	1.3 (0.20)

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 (40 minutes before first administration 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	498	291
Least Squares Mean (Standard Error); Unit of Measure: liters
	-0.0246 (0.01079)	-0.0783 (0.01358)

Adverse Events

Time Frame	Treatment-emergent adverse events (TEAEs) were collected from the first dose of study treatment up to 10 days after the final study visit at Week 24, approximately 25 weeks.
Adverse Event Reporting Description	The safety analysis 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 treatment received. The TEAEs defined as adverse events that started or worsened in severity on or after the first dose of study treatment are reported.
Arm/Group Title	Ensifentrine	Placebo
Arm/Group Description	3 mg twice daily via standard jet nebulizer	twice daily via standard jet nebulizer
All-Cause Mortality
	Ensifentrine	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	4/498 (0.80%)	1/291 (0.34%)
Serious Adverse Events
	Ensifentrine	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	28/498 (5.62%)	17/291 (5.84%)
Cardiac disorders
Acute left ventricular failure † 1	1/498 (0.20%)	0/291 (0.00%)
Atrial fibrillation † 1	1/498 (0.20%)	0/291 (0.00%)
Coronary artery disease † 1	0/498 (0.00%)	1/291 (0.34%)
Myocardial ischaemia † 1	0/498 (0.00%)	1/291 (0.34%)
Ear and labyrinth disorders
Vertigo positional † 1	1/498 (0.20%)	0/291 (0.00%)
General disorders
Adverse drug reaction † 1	1/498 (0.20%)	0/291 (0.00%)
Chest pain † 1	1/498 (0.20%)	0/291 (0.00%)
Infections and infestations
Pneumonia † 1	2/498 (0.40%)	4/291 (1.37%)
COVID-19 pneumonia † 1	2/498 (0.40%)	2/291 (0.69%)
Clostridium difficile infection † 1	0/498 (0.00%)	1/291 (0.34%)
Colonic abscess † 1	1/498 (0.20%)	0/291 (0.00%)
Erysipelas † 1	1/498 (0.20%)	0/291 (0.00%)
Septic shock † 1	0/498 (0.00%)	1/291 (0.34%)
Sinusitis † 1	1/498 (0.20%)	0/291 (0.00%)
Urinary tract infection † 1	1/498 (0.20%)	0/291 (0.00%)
Injury, poisoning and procedural complications
Ankle fracture † 1	1/498 (0.20%)	0/291 (0.00%)
Femur fracture † 1	0/498 (0.00%)	1/291 (0.34%)
Overdose † 1	1/498 (0.20%)	0/291 (0.00%)
Toxicity to various agents † 1	1/498 (0.20%)	0/291 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma † 1	1/498 (0.20%)	0/291 (0.00%)
Bladder cancer † 1	1/498 (0.20%)	0/291 (0.00%)
Laryngeal cancer stage II † 1	1/498 (0.20%)	0/291 (0.00%)
Lung adenocarcinoma † 1	1/498 (0.20%)	0/291 (0.00%)
Lung neoplasm malignant † 1	1/498 (0.20%)	0/291 (0.00%)
Oesophageal neoplasm † 1	0/498 (0.00%)	1/291 (0.34%)
Prostate cancer † 1	0/498 (0.00%)	1/291 (0.34%)
Nervous system disorders
Hemiparesis † 1	1/498 (0.20%)	0/291 (0.00%)
Psychiatric disorders
Suicide attempt † 1	1/498 (0.20%)	0/291 (0.00%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	10/498 (2.01%)	5/291 (1.72%)
Acute respiratory failure † 1 [1]	3/498 (0.60%)	0/291 (0.00%)
Bronchiectasis † 1	0/498 (0.00%)	1/291 (0.34%)
Interstitial lung disease † 1	0/498 (0.00%)	1/291 (0.34%)
Pneumothorax † 1	0/498 (0.00%)	1/291 (0.34%)
Respiratory failure † 1	0/498 (0.00%)	1/291 (0.34%)
1 Term from vocabulary, MedDRA 25.0; † Indicates events were collected by systematic assessment; [1] Acute respiratory failure secondary to these adverse events: COVID-19 pneumonia, acute diastolic congestive heart failure, and toxicity to various agents.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	1%
	Ensifentrine	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	68/498 (13.65%)	46/291 (15.81%)
Cardiac disorders
Angina pectoris † 1	1/498 (0.20%)	4/291 (1.37%)
Ear and labyrinth disorders
Vertigo † 1	1/498 (0.20%)	3/291 (1.03%)
Gastrointestinal disorders
Diarrhea † 1	8/498 (1.61%)	2/291 (0.69%)
Gastrooesophageal reflux disease † 1	2/498 (0.40%)	3/291 (1.03%)
Infections and infestations
COVID-19 † 1	16/498 (3.21%)	10/291 (3.44%)
Urinary tract infection † 1	7/498 (1.41%)	5/291 (1.72%)
Nasopharyngitis † 1	9/498 (1.81%)	3/291 (1.03%)
Sinusitis † 1	5/498 (1.00%)	0/291 (0.00%)
Tooth Abcess † 1	0/498 (0.00%)	4/291 (1.37%)
Musculoskeletal and connective tissue disorders
Back pain † 1	8/498 (1.61%)	5/291 (1.72%)
Nervous system disorders
Headache † 1	10/498 (2.01%)	7/291 (2.41%)
Respiratory, thoracic and mediastinal disorders
Dyspnea † 1	3/498 (0.60%)	4/291 (1.37%)
Vascular disorders
Hypertension † 1	5/498 (1.00%)	1/291 (0.34%)
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: NCT04542057
• Other Study ID Numbers: RPL554-CO-302
• First Submitted: September 1, 2020
• First Posted: September 9, 2020
• Results First Submitted: June 19, 2023
• Results First Posted: July 24, 2023
• Last Update Posted: October 16, 2023