Ensifentrine (MK-5884) Study for the Prevention of Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in Adults With a History of Moderate or Severe Exacerbations While Receiving Standard of Care (SOC) (MK-5884-031/RPL554/ENHANCE-3) (ENHANCE-3)

November 5, 2026 updated by: Merck Sharp & Dohme LLC

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Ensifentrine (MK-5884) Versus Placebo for the Prevention of COPD Exacerbations in Adults With a History of Moderate or Severe Exacerbations While Receiving Standard of Care (ENHANCE-3)

The purpose of this study is to evaluate the efficacy and safety of ensifentrine (MK-5884) compared with placebo for the prevention of moderate and severe COPD exacerbation in adults with COPD and a history of exacerbations while receiving SOC treatment. The study will also evaluate the efficacy of ensifentrine compared with placebo in improving lung function, improving health related quality of life, and preventing severe exacerbations.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

2136

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Florida
      • Hialeah Gardens, Florida, United States, 33016
        • Recruiting
        • Family First Medical Research Center ( Site 4458)
        • Contact:
          • Study Coordinator
          • Phone Number: 786-665-9374
      • Loxahatchee Groves, Florida, United States, 33470
        • Recruiting
        • Advanced Pulmonary Research Institute ( Site 4427)
        • Contact:
          • Study Coordinator
          • Phone Number: 561-603-6688
    • Indiana
      • Valparaiso, Indiana, United States, 46383
        • Recruiting
        • Velocity Clinical Research ( Site 4464)
        • Contact:
          • Study Coordinator
          • Phone Number: 219-464-8302
    • New York
      • The Bronx, New York, United States, 10455
        • Recruiting
        • CHEAR Center LLC ( Site 4407)
        • Contact:
          • Study Coordinator
          • Phone Number: 347-270-1111
    • South Carolina
      • Charleston, South Carolina, United States, 29406
        • Recruiting
        • Lowcountry Lung & Critical Care, PA ( Site 4413)
        • Contact:
          • Study Coordinator
          • Phone Number: 843-572-8545
    • Tennessee
      • Chattanooga, Tennessee, United States, 37421
        • Recruiting
        • M3 Wake Research, Inc. ( Site 4440)
        • Contact:
          • Study Coordinator
          • Phone Number: 423-698-4584
    • Texas
      • Victoria, Texas, United States, 77901
        • Recruiting
        • Victoria Clinical Research Group ( Site 4430)
        • Contact:
          • Study Coordinator
          • Phone Number: 361-210-7869

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Inclusion Criteria include but are not limited to:

  • Has a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) that was made ≥12 months prior to randomization
  • Has been on the stable treatment with the same standard of care (SOC) with long-acting muscarinic antagonist (LAMA)/long-acting beta-2 agonist (LABA)/inhaled corticosteroid (ICS) or LAMA/LABA (if ICS is not appropriate), for at least 2 months prior to Screening
  • Has a documented history of ≥1 moderate or severe COPD exacerbation while on standard of care (SOC) within 1 year of Screening
  • Is a current or former cigarette smoker with a history of cigarette smoking ≥10 packyears at Screening (number of pack-years = [number of cigarettes per day/20] × number of years smoked [e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years]). Pipe, cigar, and/or e-cigarette/vape use cannot be used to calculate pack-year history.
  • Has post-bronchodilator forced expiratory volume 1 (FEV1) ≥25% and <70% of Predicted Normal Value

Exclusion Criteria:

Exclusion criteria include but are not limited to:

  • Has a history of intubation for respiratory failure within 1 year of Screening
  • Is receiving long-term oxygen therapy defined as >15 hours per day
  • Uses chronic bilevel positive airway pressure for treatment of respiratory condition unless for treatment of sleep apnea at a stable pressure for at least 3 months
  • Is currently using or has used a biologic therapy (e.g., dupilumab, mepolizumab, or tozorakimab) within 6 months prior to Screening Visit
  • Has history of or current malignancy of any organ system, treated or untreated within the past 5 years, except for localized basal or squamous cell carcinoma of the skin.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ensifentrine

Participants, who meet the criteria of being on standard of care (SOC) background treatment receive ensifentrine twice a day (bid) by oral inhalation via a standard jet nebulizer for up to 52 weeks.
Drug: Ensifentrine

Delivered twice daily by oral inhalation via a standard jet nebulizer

Other Names:
  • RPL554
  • MK-5884
Drug: Standard of Care (SOC)

Background treatment of LAMA/LABA/ICS or LAMA/LABA (if ICS is not appropriate) administered per product approved label delivered by oral inhalation as part of standard of care
Placebo Comparator: Placebo

Participants, who meet the criteria of being on SOC background treatment receive placebo bid by oral inhalation via a standard jet nebulizer for up to 52 weeks.
Drug: Standard of Care (SOC)

Background treatment of LAMA/LABA/ICS or LAMA/LABA (if ICS is not appropriate) administered per product approved label delivered by oral inhalation as part of standard of care

Other: Placebo

Placebo matched to ensifentrine delivered twice daily by oral inhalation via a standard jet nebulizer

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Annualized Rate of Adjudicated Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
Time Frame: Up to 52 Weeks

The annualized rate of moderate or severe exacerbations over 52 weeks will be reported.
Up to 52 Weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline in Forced Expiratory Volume in One Second Area Under the Curve From 0-4 Hours (FEV1 AUC0-4h)
Time Frame: Baseline and Week 12

FEV1 measures the volume of air exhaled during the first second of a forced exhalation maneuver from the point of maximal inspiration. FEV1 AUC0-4h represents the bronchodilator response over the 4-hour period following administration of study intervention. Spirometry will be performed to determine the FEV1. Change from baseline in average FEV1 AUC0-4h on Week 12 will be reported.
Baseline and Week 12
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score Responder Status
Time Frame: Baseline and Week 24

The SGRQ is a 50-item patient-reported outcome (PRO) questionnaire used to evaluate health-related quality of life (HRQOL) in patients with COPD. The questionnaire contains 3 domains: Symptoms (frequency and severity of respiratory symptoms), Activity (effect of disease on common daily physical activities), and Impacts (psychological effects of the disease). The recall period of the questionnaire is over the past 4 weeks. The total score ranges from 0 to 100, with lower scores indicating better health status. A clinically meaningful improvement in HRQOL, as measured by the SGRQ, is defined as a ≥4.0-point decrease in SGRQ total score. HRQOL, as measured by the percentage of SGRQ responders (≥4-point decrease) at Week 24 will be reported.
Baseline and Week 24
Annualized Rate of Adjudicated Severe COPD Exacerbations
Time Frame: Up to 52 Weeks

The annualized rate of adjudicated severe COPD exacerbations over 52 weeks will be reported.
Up to 52 Weeks
Number of Participants with at Least One Adverse Event (AE)
Time Frame: Up to 53 weeks

An AE is any untoward medical occurrence in a subject, temporally associated with the use of the study medication, whether or not considered related to the study medication. Number of participants who experience at least one AE will be reported.
Up to 53 weeks
Number of Participants who Discontinued Study Intervention Due to an Adverse Event
Time Frame: Up to 52 Weeks

An AE is any untoward medical occurrence in a subject, temporally associated with the use of the study medication, whether or not considered related to the study medication. Number of participants who discontinue study intervention due to an AE will be reported.
Up to 52 Weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Merck Sharp & Dohme LLC

Investigators

  • Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 2, 2026

Primary Completion (Estimated)

April 29, 2029

Study Completion (Estimated)

April 29, 2029

Study Registration Dates

First Submitted

September 30, 2026

First Submitted That Met QC Criteria

October 8, 2026

First Posted (Actual)

October 15, 2026

Study Record Updates

Last Update Posted (Actual)

November 6, 2026

Last Update Submitted That Met QC Criteria

November 5, 2026

Last Verified

November 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 5884-031
  • 2026-526255-61-00 (Registry Identifier: EU CT)
  • U1111-1337-6442 (Registry Identifier: UTN)
  • MK-5884-031 (Other Identifier: MSD)
  • RPL554 (Other Identifier: Verona)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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