This is a randomized, double-blind, placebo-controlled, two-period cross-over study of nebulized ensifentrine (3 mg) or placebo administered BID for two 8-week Treatment Periods. All participants with receive both ensifentrine and placebo during participation. There are 7 in-clinic visits over a total duration of up to 24 weeks participation.

This is a randomized, double-blind, placebo-controlled, two-period cross-over study of nebulized ensifentrine (3 mg) or placebo administered BID for two 8-week Treatment Periods. All participants with receive both ensifentrine and placebo during participation.

Participants will be randomized 1:1 to receive ensifentrine or placebo first in Treatment Period 1 followed by the opposite treatment in Treatment Period 2:

1. Treatment Period 1: Ensifentrine; Treatment Period 2: Placebo.
2. Treatment Period 1: Placebo; Treatment Period 2: Ensifentrine.

All participants will take study supplied albuterol (to use as-needed) as well as a once daily COPD Maintenance Therapy during study participation.

The total duration of study participation is 22-24 weeks:

• Screening and Run-in Period: 2-4 weeks; participants will be screened for eligibility before entering a run-in period to ensure a stable background on a once daily COPD Maintenance Therapy.
• Treatment Period 1: 8 weeks; participants completing the Run-in Period and meeting all entry and Randomization Criteria will be randomized to 8 weeks of treatment with blinded, nebulized ensifentrine or placebo + once daily COPD Maintenance Therapy.
• Washout Period: 4 weeks; patients will only take once daily COPD Maintenance Therapy. There will be a follow-up phone call about 1 week after finishing Treatment Period 1.
• Treatment Period 2: 8 weeks of treatment with Study Medication (opposite of Treatment Period 1) + once daily COPD Maintenance Therapy.
• Safety follow-up: 1 week after Treatment Period 2

There are 7 scheduled in-clinic visits: Screening visit + three visits within each treatment period. There is an end of treatment safety telephone follow-up call about 1 week after each treatment period. Participants will have telephone reminders between in-clinic visits.

Inclusion Criteria:

Male and female patients 40-80 years of age with a history of cigarette smoking ≥10 pack years and an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines with symptoms compatible with COPD.

COPD Severity: Pre- and Post-albuterol/salbutamol FEV1/FVC ratio of <0.70; Post-albuterol/salbutamol FEV1 ≥30 % and ≤80% of predicted normal calculated using the National Health and Nutrition Examination Survey III.

Regular use of bronchodilator COPD therapy, in any form (e.g., LAMA, LABA, LAMA+LABA, LAMA+LABA+ICS), for at least 4 weeks prior to Screening and agrees to use study supplied COPD Maintenance Therapy once daily through the final study visit.

Capable of using the jet nebulizer correctly and complying with all study restrictions and procedures. Ability to perform acceptable spirometry in accordance with ATS/ERS guidelines. Ability to produce sputum samples during the induced sputum procedure.

Exclusion Criteria:

Any clinically diagnosed lung disease other than COPD such as current asthma, diffuse interstitial lung diseases, cystic fibrosis, or clinically significant bronchiectasis as determined by the Investigator. Hospitalizations for COPD, pneumonia, or Corona Virus Disease 2019 (COVID-19) in the 12 weeks prior to Screening; or a positive COVID-19 test result indicating an active infection at Screening.*Note: Patients with a positive COVID-19 antibody test from a past exposure who do not exhibit symptoms of an active COVID-19 infection are eligible to participate in the study. *A COVID-19 test may be performed at the visit or within 7 days prior to the visit (or as required locally). Asymptomatic patients with a positive COVID-19 test result indicating an active infection < 30 days prior to Screening or at Screening may be re-screened for eligibility after 30 days (or in accordance with local requirements).

Alanine aminotransferase (ALT) ≥ 2 x upper limit of normal (ULN), alkaline phosphatase and/or bilirubin > 1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). HIV infection or other immunodeficiency. History of cancer within the last 5 years, except for well-treated basal cell carcinoma and squamous cell carcinoma of the skin.

Any clinically significant 12-lead electrocardiogram abnormalities at screening or baseline, including corrected QT interval by Fridericia's correction method >450 ms for males or >480 ms for females or history of significant cardiac dysrhythmia, including long QT syndrome.

Known history of poor outcomes with sputum induction. Known hypersensitivity to ensifentrine or other medications used in the study (e.g., albuterol or salmeterol). Not suitable for study supplied once daily COPD Maintenance Therapy per label warnings and contraindications.

Taking prohibited medication. Prior receipt of Ohtuvayre or blinded nebulized study medication in an ensifentrine (RPL554) study. Note: Other ensifentrine formats (e.g., DPI, MPI) are not exclusionary.

Use of an experimental drug within 30 days or 5 half-lives of Screening, whichever is longer, and/or participation in a study treatment-free follow-up phase of a clinical trial within 30 days prior to Screening. Use of an experimental medical device or participation in a follow-up phase of an experimental medical device clinical trial within 30 days prior to Screening. Any other medical history, chronic uncontrolled diseases that the investigator considers clinically significant, examination or laboratory findings or reason that the Investigator considers makes the patient unsuitable to participate at Screening.