• LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 [ Time Frame: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4 ]
  Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-3h FEV1 was defined as area under the curve over 3 hours of the FEV1, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
• LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 [ Time Frame: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4 ]
  Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-12h FEV1 was defined as area under the curve over 12 hours of the FEV1, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
• LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 [ Time Frame: Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2 and 3 ]
  Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
• LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 [ Time Frame: Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4 ]
  Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and morning trough FEV1 was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
• LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 [ Time Frame: Baseline and Weeks 1, 2, 3 and 4 ]
  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:COPD scale has a scoring range of 0 to 40. Higher scores indicates severe respiratory symptoms. Baseline was the mean over the 7 days prior to first intake of study treatment. Scores were derived weekly as the mean over 7 days prior to the visit, using only days where data was recorded. The E-RS:COPD was measured by daily electronic diary (e-diary).
• LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 [ Time Frame: Baseline, Weeks 2 and 4 ]
  Patients completed the SGRQ-C consisting 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. The SGRQ-C was measured at Week 2 and 4 visits.
• LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 [ Time Frame: Weeks 2 and 4 ]
  The TDI is a questionnaire that focussed 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.
• LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 [ Time Frame: Weeks 2 and 4 ]
  The PGAC is a single question assessment to determine whether patients noticed a change in their breathing since the start of the study. Patients were asked to respond to a PGAC question asking, "Compared with prior to the study start, how do you feel your breathing is?" on a scale of '1=much worse' to '5=much better', with '3=no change'. Higher scores indicate better outcome.
• LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication [ Time Frame: Baseline and Weeks 1, 2, 3 and 4 ]
  Use of rescue medication (albuterol) per visit was calculated as the LS mean use daily over total number of days between previous visit (inclusive) and the following visit. Baseline use was the mean over the last 7 days of the run-in phase (calculated as the sum of puffs taken, divided by number of days data has been recorded).
• LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 [ Time Frame: Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2, 3 and 4 ]
  Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and peak FVC was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
• LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 [ Time Frame: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4 ]
  Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-3h FVC was defined as area under the curve over 3 hours of the FVC, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
• LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 [ Time Frame: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4 ]
  Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-12h FVC was defined as area under the curve over 12 hours of the FVC, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
• LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 [ Time Frame: Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4 ]
  Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and morning trough FVC was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
• Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 [ Time Frame: Pre-dose on Day 1 and Week 2 ]
  Blood samples were taken to determine steady-state plasma concentrations of tiotropium prior to and following 14 days of treatment with RPL554.
• Steady-State Plasma Concentrations of RPL554 at Week 2 [ Time Frame: Pre-dose at Week 2 ]
  Blood samples were taken to determine steady-state plasma concentrations of RPL554 following 14 days of treatment with RPL554.
• Number of Patients With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. ]
  An adverse event (AE) was defined as any undesirable experience occurring to a patient, or worsening in a patient, whether considered related to the study medication or not. All AEs which started after the first dose of study treatment or started prior to first dose of study treatment and worsened, based on the Investigator's assessment of severity, on or after first dose of study treatment were considered to be treatment-emergent. A serious adverse event is any adverse experience that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other important medical events.

• Change from baseline in average area under the curve 0-3h first forced expiratory volume [ Time Frame: Start of treatment to Week 4 ]
  Change from baseline in average area under the curve 0-3h first forced expiratory volume at visits 2 to 6
• Change from baseline in average area under the curve 0-12h first forced expiratory volume [ Time Frame: Start of treatment to Week 4 ]
  Change from baseline in average area under the curve 0-12h first forced expiratory volume at Visits 2 to 6
• Change from baseline in peak first forced expiratory volume [ Time Frame: Start of treatment to Week 3 ]
  Change from baseline in peak first forced expiratory volume at Visits 2 to 5
• Change from baseline in morning trough first forced expiratory volume [ Time Frame: Week 1 to Week 4 ]
  Change from baseline in morning trough first forced expiratory volume at Visits 3 to 6
• Changes from baseline to the mean weekly values over weeks 1 to 4 in chronic obstructive pulmonary disease symptoms [ Time Frame: Week 1 to Week 4 ]
  Changes from baseline to the mean weekly values over weeks 1 to 4 in chronic obstructive pulmonary disease symptoms, as measured by daily e-Diary
• Change from baseline in the SGRQ-C, TDI, PGAC questionnaires [ Time Frame: Week 2 and Week 4 ]
  Change from baseline in the SGRQ-C, TDI, PGAC questionnaires
• Change from baseline to the mean weekly values over weeks 1 to 4 in rescue medication use [ Time Frame: Week 1 to Week 4 ]
  Change from baseline (i.e., mean over the last 7 days of run-in) to the mean weekly values over weeks 1 to 4 in rescue medication use
• Change from baseline in peak and average area under the curve and forced vital [ Time Frame: Week 1 to Week 4 ]
  Change from baseline in peak and average area under the curve 0-3h forced vital capacity. Forced vital capacity at Visits 2 to 6, in average area under the curve 0-12 forced vital capacity. Forced vital capacity at Visits 2 and 6 and in morning trough forced vital capacity at Visits 3 to 6.
• Trough plasma concentration of tiotropium [ Time Frame: Start of treatment and Week 2 ]
  Trough plasma concentration of tiotropium at Visits 2 and 4, and trough plasma concentration of RPL554 at Visit 4
• Adverse events [ Time Frame: Throughout study (from start of treatment through Week 4) ]
  Treatment-emergent adverse events
• Laboratory assessments [ Time Frame: Week 4 ]
  Number of patients with treatment-emergent abnormal laboratory assessments
• ECG [ Time Frame: Start of treatment, Week 1 and Week 4 ]
  Number of patients with treatment-emergent abnormal ECG parameters
• Vital signs [ Time Frame: Start of treatment to Week 4 ]
  Number of patients with treatment-emergent abnormal vital signs

• Drug: Ensifentrine (formerly RPL554) 0.375 mg twice daily plus placebo, in addition to tiotropium

  Patients will be randomized to receive one of the following treatment arms plus tiotropiuim:

  ● RPL554 0.375 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.

• Drug: Ensifentrine (formerly RPL554) 0.75 mg twice daily plus placebo, in addition to tiotropium

  Patients will be randomized to receive one of the following treatment arms plus tiotropiuim:

  ● RPL554 0.75 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.

• Drug: Ensifentrine (formerly RPL554) 1.5 mg twice daily plus placebo, in addition to tiotropium

  Patients will be randomized to receive one of the following treatment arms plus tiotropiuim:

  ● RPL554 1.5 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.

• Drug: Ensifentrine (formerly RPL554) 3.0 mg twice daily plus placebo, in addition to tiotropium

  Patients will be randomized to receive one of the following treatment arms plus tiotropiuim:

  ● RPL554 3.0 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.

• Drug: Ensifentrine (formerly RPL554) placebo twice daily, in addition to tiotropium

  Patients will be randomized to receive one of the following treatment arms plus tiotropiuim:

  ● Placebo twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.

• Experimental: RPL554 0.375 mg twice daily
  RPL554 0.375 mg twice daily
  Intervention: Drug: Ensifentrine (formerly RPL554) 0.375 mg twice daily plus placebo, in addition to tiotropium
• Experimental: RPL554 0.75 mg twice daily
  RPL554 0.75 mg twice daily
  Intervention: Drug: Ensifentrine (formerly RPL554) 0.75 mg twice daily plus placebo, in addition to tiotropium
• Experimental: RPL554 1.5 mg twice daily
  RPL554 1.5 mg twice daily
  Intervention: Drug: Ensifentrine (formerly RPL554) 1.5 mg twice daily plus placebo, in addition to tiotropium
• Experimental: RPL554 3.0 mg twice daily
  RPL554 3.0 mg twice daily
  Intervention: Drug: Ensifentrine (formerly RPL554) 3.0 mg twice daily plus placebo, in addition to tiotropium
• Placebo Comparator: Placebo twice daily
  Placebo twice daily
  Intervention: Drug: Ensifentrine (formerly RPL554) placebo twice daily, in addition to tiotropium

Inclusion Criteria:

• Sign an informed consent document indicating they understand the purpose of and procedures required for the study and are willing to participate in the study.
• Male or female aged between 40 and 80 years inclusive, at the time of informed consent.

• Must agree to meet the following from the first dose up to 1 month after the last dose of study medication:

  • If male:

    • Not donate sperm
    • Either: be sexually abstinent in accordance with a patient's usual and preferred lifestyle (but agree to abide by the contraception requirements below should their circumstances change)
    • Or: use a condom with all sexual partners. If the partner is of childbearing potential the condom must be used with spermicide and a second reliable form of contraception must also be used (e.g., diaphragm/cap with spermicide, established hormonal contraception, intra-uterine device)

  • If female:

    • be of non-childbearing potential or use a highly effective form of contraception

• Have a 12-lead ECG recording at Screening showing the following (and no changes in the pre-dose value at the first treatment deemed clinically significant by the Investigator):

  • Heart rate between 45 and 90 beats per minute
  • QT interval corrected for heart rate using Fridericia's formula (QTcF) ≤450 msec for males, and ≤ 470 msec for females
  • QRS interval ≤ 120 msec
  • No clinically significant abnormality including morphology (e.g., left bundle branch block, atrio-ventricular nodal dysfunction, ST segment abnormalities consistent with ischemia)
• Capable of complying with study restrictions and procedures, including ability to use the nebulizer correctly.
• Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) with a minimum weight of 45 kg.
• COPD diagnosis: Patients with a diagnosis of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines (Celli and MacNee, 2004) with symptoms compatible with COPD for at least 1 year prior to Screening.
• Ability to perform acceptable and reproducible spirometry.

• Post-bronchodilator (four puffs of albuterol) spirometry at Screening demonstrating the following:

  • FEV1/ FVC ratio of ≤0.70
  • FEV1 ≥30% and ≤70% of predicted normal* *National Health and Nutrition Examination Survey (NHANES) III (Hankinson et al, 1999) will be used as the reference for normal predicted values.
• Clinically stable COPD in the 4 weeks prior to Screening (Visit 1) and during the period between Visits 1 and 2.
• A score of ≥2 on the modified Medical Research Council (mMRC) dyspnea scale at Screening.
• A chest X-ray (posterior-anterior) at Screening, or in the 12 months prior to Screening showing no clinically significant abnormalities unrelated to COPD.
• Meet the concomitant medication restrictions and be expected to do so for the rest of the study.
• Current and former smokers with smoking history of ≥10 pack years.
• Capable of withdrawing from long acting bronchodilators (other than tiotropium) for the duration of the study, and short acting bronchodilators for 6 hours prior to dosing.

Exclusion Criteria:

• A history of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation.
• COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract infection requiring antibiotics, within 3 months of Screening or prior to the first treatment.
• A history of one or more hospitalizations for COPD or pneumonia within 6 months of Screening or prior to the first treatment.
• Intolerance or hypersensitivity to albuterol, tiotropium or other muscarinic receptor antagonists.
• Other respiratory disorders: Patients with a current diagnosis of asthma, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung diseases, uncontrolled or unstable sleep apnea, known alpha-1 antitrypsin deficiency, core pulmonale, clinically significant pulmonary hypertension or other active pulmonary diseases.
• Previous lung resection or lung reduction surgery.
• Pulmonary rehabilitation, unless such treatment has been stable from 4 weeks prior to Screening and remains stable during the study.
• Oral therapies for COPD (e.g. oral steroids, theophylline, and roflumilast) or antibiotics within 3 months prior to Screening, or ICS therapy within 4 weeks prior to Screening
• Prior exposure to RPL554.
• History of, or reason to believe a patient has, drug or alcohol abuse within the past 5 years.
• Received an experimental drug within 30 days or five half-lives, whichever is longer.
• Women who are pregnant or breast-feeding.
• Patients with uncontrolled disease including, but not limited to, endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal, hematological, urological, immunological, psychiatric, or ophthalmic diseases that the Investigator believes are clinically significant. This includes any hepatic disease or moderate to severe renal impairment.
• Documented clinically significant cardiovascular disease such as: any history of arrhythmias, angina, recent (<1 year) or suspected myocardial infarction, congestive heart failure, unstable or uncontrolled hypertension, or diagnosis of hypertension within 3 months prior to Screening.
• Use of non-selective oral β-blockers.
• Major surgery (requiring general anesthesia) within 6 weeks prior to Screening, lack of full recovery from surgery at Screening, or planned surgery through the end of the study.
• Required use of oxygen therapy, even on an occasional basis.
• History of malignancy of any organ system within 5 years, with the exception of localized skin cancers (basal or squamous cell).
• Clinically significant abnormal values for laboratory safety tests (hematology, blood chemistry, viral serology or urinalysis) at Screening, as determined by the Investigator. In particular, alanine aminotransferase or aspartate aminotransferase cannot be more than twice the upper limit of normal.
• Patients with conditions which are sensitive to antimuscarinic effects such as narrow angle glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction.
• Current marijuana use (all forms).
• A disclosed history or one known to the Investigator, of significant non-compliance in previous investigational studies or with prescribed medications.
• Any other reason that the Investigator considers makes the patient unsuitable to participate.

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