• Part A: RPL554 Plasma Pharmacokinetic Parameter (AUC0-12) [ Time Frame: Day 1 ]
  RPL554 Plasma pharmacokinetics AUC0-12 (Area under the Curve) after single dose
• Part A: RPL554 Plasma Pharmacokinetic Parameter (AUC 0-t) [ Time Frame: Day 1 ]
  RPL554 Area under the curve at maximum concentration after a single dose
• Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life) [ Time Frame: Day 1 ]
  RPL554 Plasma pharmacokinetics Half-life concentration after a single dose
• Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) [ Time Frame: Day 7 ]
  Change from Baseline FEV1 to Peak FEV1 (over 4 hours) on Day 7

• Part A: Pharmacokinetic parameters AUC0-12 [ Time Frame: Approximately 70 days ]
  AUC0-12 (Area under the Curve)
• Part A: Pharmacokinetic parameters AUC 0-t [ Time Frame: Approximately 70 days ]
  Area under the curve at maximum concentration
• Part A: Pharmacokinetic parameters half life [ Time Frame: Approximately 70 days ]
  Half-life
• Part B: Peak FEV1 (forced expiratory volume) [ Time Frame: baseline to treatment period 5 day 7, which is approximately 70 days ]
  Change from baseline in Peak FEV1 measured after morning dosing on Day 7

• Part A: Change From Baseline in Average FEV1 (Over 4 Hours) [ Time Frame: Day 1 ]
  Change from Baseline FEV1 to Average FEV1 (over 4 hours) After Single Dose
• Part A: Change From Baseline in Average FEV1 (Over 12 Hours) [ Time Frame: Day 1 ]
  Change from Baseline FEV1 to Average FEV1 (over 12 hours) After Single Dose
• Part A: Change From Baseline in Peak FEV1 (Over 4 Hours) [ Time Frame: Day 1 ]
  Change from Baseline FEV1 to Peak FEV1 (over 4 hours) After Single Dose
• Part A: Safety and Tolerability / Hematology Safety Assessments [ Time Frame: Day 1 ]
  number of patients with treatment-emergent hematology abnormal laboratory assessments
• Part A: Safety and Tolerability / Blood Chemistry Safety Assessments [ Time Frame: Day 1 ]
  number of patients with treatment-emergent blood chemistry abnormal laboratory assessments
• Part A: Safety and Tolerability / Urinalysis Safety Assessments [ Time Frame: Day 1 ]
  number of patients with treatment-emergent urinalysis abnormal laboratory assessments
• Part A: Safety and Tolerability / Supine Vital Signs - Pulse Rate [ Time Frame: Day 1 ]
  Change from Baseline Pulse Rate to Peak Pulse Rate (over 4 hours) After Single Dose
• Part A: Safety and Tolerability / Supine Vital Signs - Blood Pressure [ Time Frame: Day 1 ]
  number of patients with treatment-emergent abnormal vital signs (blood pressure in mm Hg) (An increase from baseline of >=20 in systolic bp)
• Part A: Safety and Tolerability / ECG - QTcF [ Time Frame: Day 1 ]
  number of patients with treatment-emergent abnormal ECG parameters, QTcF in msec
• Part A: Safety and Tolerability / ECG - Heart Rate [ Time Frame: Day 1 ]
  number of patients with treatment-emergent clinically significant abnormal ECG parameters, heart rate in bpm
• Part B: Change From Baseline in Average FEV1 (Over 4 Hrs) [ Time Frame: Day 7 ]
  Change from baseline in average FEV1 (over 4 hours) on Day 7
• Part B: Change From Baseline in Average FEV1 (Over 12 Hours) [ Time Frame: Day 7 ]
  Change from baseline FEV1 in average FEV1 (over 12 hours) on Day 7
• Part B: Change From Baseline in Trough FEV1 [ Time Frame: Day 7 ]
  Change from Baseline FEV1 to Morning Trough FEV1 on Day 7
• Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) [ Time Frame: Day 1 ]
  Change from baseline FEV1 in peak FEV1 (over 4 hours) after first dose
• Part B: Change From Baseline in Average FEV1 (Over 4 Hours) [ Time Frame: Day 1 ]
  Change from baseline FEV1 in average FEV1 (over 4 hours) on Day 1
• Part B: Change From Baseline in Average FEV1 (Over 12 Hours) [ Time Frame: Day 1 ]
  Change from baseline FEV1 in average FEV1 (over 12 hours) on Day 1
• Part B: RPL554 Plasma Pharmacokinetic Parameter (Onset of Action) [ Time Frame: Day 1 ]
  Determination of onset of action (>10% increase in FEV1 from pre- to post-first dose, censored at 120 minutes) on Day 1
• Part B: Safety and Tolerability / Hematology Safety Assessments [ Time Frame: Day 7 ]
  number of patients with treatment-emergent hematology abnormal laboratory assessments (changes from normal at baseline to low or high on Day 7 or at the end of study in >3 patients in each treatment group).
• Part B: Safety and Tolerability / Blood Chemistry Safety Assessments [ Time Frame: Day 7 ]
  number of patients with treatment-emergent blood chemistry abnormal laboratory assessments (changes from normal at baseline to low or high on Day 7 in each treatment group).
• Part B: Safety and Tolerability / Urinalysis Safety Assessments [ Time Frame: Day 7 ]
  number of patients with treatment-emergent urinalysis abnormal laboratory assessments
• Part B: Safety and Tolerability / ECG - QTcF [ Time Frame: Day 7 ]
  number of patients with treatment-emergent clinically significant abnormal ECG parameters, QTcF in msec
• Part B: Safety and Tolerability / ECG - Heart Rate [ Time Frame: Day 7 ]
  number of patients with treatment-emergent abnormal ECG parameters, heart rate in bpm
• Part B: Safety and Tolerability / Supine Vital Signs - Pulse Rate [ Time Frame: Day 7 ]
  number of patients with treatment-emergent abnormal vital signs (pulse rate in bpm) An increase from baseline of >=20
• Part B: Safety and Tolerability / Supine Vital Signs - Blood Pressure [ Time Frame: Day 7 ]
  number of patients with treatment-emergent abnormal vital signs (systolic blood pressure in mm Hg) (An increase from baseline of >=20)
• Part B: Change From Baseline in Peak Pulse Rate (Day 1) [ Time Frame: Day 1 ]
  Change from baseline in peak pulse after first dose on Day 1
• Part B: Change From Baseline in Peak Pulse Rate (Day 7) [ Time Frame: Day 7 ]
  Change from baseline in peak pulse after morning dosing on Day 7
• Part B: RPL554 Plasma Pharmacokinetic Parameter (Tmax) [ Time Frame: Day 7 ]
  RPL554 steady-state PK (tmax) after morning dose on Day 7
• Part B: RPL554 Plasma Pharmacokinetic Parameter (Cmax) [ Time Frame: Day 7 ]
  RPL554 steady-state PK (Cmax and accumulation ratio) after morning dose on Day 7
• Part B: RPL554 Plasma Pharmacokinetic Parameter (AUC0-12h) [ Time Frame: Day 7 ]
  RPL554 steady-state PK (AUC0-12h and accumulation ratio) after morning dose on Day 7

• Part A: Safety and Tolerability / Hematology Safety Assessments [ Time Frame: 1 day ]
  number of patients with treatment-emergent hematology abnormal laboratory assessments
• Part A: Safety and Tolerability / Blood Chemistry Safety Assessments [ Time Frame: 1 day ]
  number of patients with treatment-emergent blood chemistry abnormal laboratory assessments
• Part A: Safety and Tolerability / Urinalysis Safety Assessments [ Time Frame: 1 day ]
  number of patients with treatment-emergent urinalysis abnormal laboratory assessments
• Part A: Safety and Tolerability / ECG - QTcF [ Time Frame: Start of treatment to day 1 ]
  number of patients with treatment-emergent abnormal ECG parameters, QTcF in msec
• Part A: Safety and Tolerability / ECG - Heart Rate [ Time Frame: Start of treatment to day 1 ]
  number of patients with treatment-emergent abnormal ECG parameters, heart rate in bpm
• Part A: Safety and Tolerability / Supine Vital Signs - Blood Pressure [ Time Frame: Start of treatment to day 1 ]
  number of patients with treatment-emergent abnormal vital signs (blood pressure in mm Hg)
• Part A: Safety and Tolerability / Supine Vital Signs - Pulse Rate [ Time Frame: Start of treatment to day 1 ]
  number of patients with treatment-emergent abnormal vital signs (pulse rate in bpm)
• Part A: Average AUC FEV1 Change from baseline (forced expiratory volume) [ Time Frame: Start of treatment to day 1 ]
  Change from baseline in average area under the curve 0-4 hours first forced expiratory volume after single dose
• Part A: Average FEV1 Change from baseline AUC0-12h [ Time Frame: Start of treatment to day 1 ]
  Change from baseline in average area under the curve 0-12 hours first forced expiratory volume after single dose
• Part A: Peak FEV1 Change from baseline after single dose [ Time Frame: Start of treatment to day 1 ]
  Change from baseline in peak first forced expiratory volume after single dose
• Part B: Safety and Tolerability / Hematology Safety Assessments [ Time Frame: 1 day ]
  number of patients with treatment-emergent hematology abnormal laboratory assessments
• Part B: Safety and Tolerability / Blood Chemistry Safety Assessments [ Time Frame: 1 day ]
  number of patients with treatment-emergent blood chemistry abnormal laboratory assessments
• Part B: Safety and tolerability / c. Urinalysis safety assessments [ Time Frame: 1 day ]
  number of patients with treatment-emergent urinalysis abnormal laboratory assessments
• Part B: Safety and Tolerability / ECG - QTcF [ Time Frame: Start of treatment to day 70 ]
  number of patients with treatment-emergent abnormal ECG parameters, QTcF in msec
• Part B: Safety and Tolerability / ECG - Heart Rate [ Time Frame: Start of treatment to day 70 ]
  number of patients with treatment-emergent abnormal ECG parameters, heart rate in bpm
• Part B: Safety and Tolerability / Supine Vital Signs - Blood Pressure [ Time Frame: Start of treatment to day 1 ]
  number of patients with treatment-emergent abnormal vital signs (blood pressure in mm Hg)
• Part B: Safety and Tolerability / Supine Vital Signs - Pulse Rate [ Time Frame: Start of treatment to day 1 ]
  number of patients with treatment-emergent abnormal vital signs (pulse rate in bpm)
• Part B: Change From Baseline in Trough FEV1 [ Time Frame: Day 7 ]
  Change from baseline in morning trough first forced expiratory volume at day 7

• Drug: Part A: RPL554
  1 dose of either 50mcg/100mcg/1500mcg/3000mcg/6000mcg or placebo via dry powder inhaler
• Drug: Part B: RPL554
  Patients will receive 4 or 5 repeat dose treatments in crossover fashion - doses will be confirmed after Part A
• Drug: Placebos

  Part A: 1 dose of either 50ncg/100ncg/1500ncg/3000ncg/6000ncg or placebo via dry powder inhaler.

  Part B: Patients will receive 4 or 5 repeat dose treatments in crossover fashion - doses will be confirmed after Part A.

• Active Comparator: Part A: RPL554
  Placebo controlled, parallel group single dose. Five of the 6 treatment arms will be double-blind and one will be single-blind
  Interventions:

  • Drug: Part A: RPL554
  • Drug: Placebos
• Active Comparator: Part B: RPL554
  Double-blind, placebo-controlled, complete block cross-over
  Interventions:

  • Drug: Part B: RPL554
  • Drug: Placebos

Inclusion Criteria:

1. 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.
2. For males, not to donate sperm and either be sexually abstinent or use contraception as specified by the protocol. For females, be of non-childbearing potential or use a highly effective form of contraception
3. 12-lead ECG with heart rate between 45 and 90 beats per minute, QTcF ≤450 msec for males, and ≤ 470 msec for females, QRS interval ≤120 msec and no clinically significant abnormality including morphology
4. Capable of complying with all study restrictions and procedures including ability to use the DPI correctly.
5. Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) with a minimum weight of 45 kg.
6. COPD diagnosis for 1 year [prior to screening
7. Ability to perform acceptable and reproducible spirometry.

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

   • FEV1/Forced Vital Capacity (FVC) ratio of ≤0.70
   • FEV1 ≥40 % and ≤80% of predicted normal
   • ≥150 mL increase from pre-bronchodilator FEV1
9. Clinically stable COPD in the 4 weeks prior to Screening and during the period between Screening and Part A.
10. A chest X-ray showing no abnormalities, which are both clinically significant and unrelated to COPD.
11. Meet the concomitant medication restrictions and be expected to do so for the rest of the study.
12. Current and former smokers with smoking history of ≥10 pack years. 14. Capable of withdrawing from long acting bronchodilators for the duration of the study, and short acting bronchodilators for 8 hours prior to dosing.

Exclusion Criteria:

1. A history of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation.
2. COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract infection requiring antibiotics, within 3 months of Screening or prior to Part A.
3. A history of one or more hospitalizations for COPD or pneumonia within 6 months of Screening or prior to Part A.
4. Intolerance or hypersensitivity to tiotropium, olodaterol, atropine, ipratropium, or RPL554.
5. Evidence of cor pulmonale or clinically significant pulmonary hypertension.
6. Other respiratory disorders
7. Previous lung resection or lung reduction surgery.
8. Use of immunosuppressive therapy, including oral corticosteroids
9. Pulmonary rehabilitation, unless such treatment has been stable from 4 weeks prior to Screening and remains stable during the study.
10. History of, or reason to believe a patient has, drug or alcohol abuse within the past 5 years.
11. Received an experimental drug within 30 days or five half lives, whichever is longer.
12. 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.
13. Documented cardiovascular disease, including 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
14. Use of non-selective oral β-blockers.
15. 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.
16. A disclosed history or one known to the Investigator, of significant non compliance in previous investigational studies or with prescribed medications.
17. Required use of oxygen therapy, even on an occasional basis.
18. History of malignancy of any organ system within 5 years, with the exception of localized skin cancers (basal or squamous cell).
19. Clinically significant abnormal values for safety laboratory tests (hematology, biochemistry, 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.
20. Any other reason that the Investigator considers makes the patient unsuitable to participate.