Bronchodilator Effect of RPL554 Administered in Addition to Tiotropium/Olodaterol in Patients With COPD

RPL554 is a dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) which are known to have a role in modulating the inflammatory airway response in respiratory diseases, including COPD. PDE3 inhibitors act as bronchodilators whilst PDE4 inhibitors have anti-inflammatory properties and there is also evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive or synergistic anti-inflammatory and bronchodilator. The two doses of RPL554 (1.5 mg and 6 mg)have been selected based on the results from prior studies investigating single and multiple ascending doses in healthy subjects, single doses in asthmatics, single/multiple ascending doses in COPD patients, and 3 days of dosing in COPD patients. These doses were demonstrated to be both effective as a bronchodilator and well tolerated.

The purpose of the study is to investigate if RPL554 has an additive bronchodilator effect when administered in combination with a commonly used anticholinergic/β-agonist combination medication, tiotropium/olodaterol (Respimat), in this patient population measured by the peak forced expiratory volume in one second (FEV1), and forced vital capacity (FVC).

• RPL554 Suspension (Drug): A PDE3/4 inhibitor
• Placebo (Drug): A placebo solution
• Tiotropium/olodaterol (Respimat) (Drug): An anticholinergic/β-agonist combination medication

Primary outcomes

• Change From Baseline in Peak FEV1 on Day 3 [Change from pre-dose at 5, 15 and 30 minutes and 1, 1.5, 2 & 4 hours on Day 3]: Change from baseline FEV1 to peak FEV1 (measured as the greatest value in the 4 hours post-dose after the morning dose) on Day 3

Secondary outcomes

• Change From Baseline to Trough FEV1 on Day 4 [Change from pre-dose on Day 1 to pre-dose on Day 4]: Change from baseline to morning trough FEV1 on Day 4
• Change From Baseline in AUC0-4h FEV1 on Day 3 [Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the morning dose)]: Change from baseline FEV1 to AUC FEV1 over 4 hours post-dose after the morning dose on Day 3. The endpoint is measured as AUC/interval length (average) and measured in liters. (Note: Endpoint is AUC/interval length (average) so the units are in liters.)
• Change From Baseline in AUC0-12h FEV1 on Day 3 [Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 3 (after the morning dose)]: Change from baseline in AUC over 12 hours post-dose after the morning dose on Day 3. The endpoint is measured as AUC/interval length (average) and measured in liters (Note: Endpoint is AUC/interval length (average) so the units are in liters.)
• Change From Baseline in Peak FEV1 on Day 1 [Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 1 (after the morning dose), with the maximum change reported]: Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the morning dose on Day 1
• Change From Baseline in Peak FEV1 After Evening Dose on Day 3 [Change from pre-dose to each of the ollowing timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the evening dose), with the maximum change reported]: Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the evening dose on Day 3
• Change From Baseline in AUC0-12h FEV1 on Day 1 [Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 1 (after the morning dose)]: Change from baseline FEV1 to AUC FEV1 over 12 hours post-dose after the morning dose on Day 1. The endpoint is measured as AUC/interval length (average) and measured in liters (Note: Endpoint is AUC/interval length (average) so the units are in liters.)
• Determination of Onset of Action on Day 1 [Change from pre-dose to the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2 hours on Day 1 (after the morning dose)]: Time to >10% increase in FEV1 from pre-first dose, censored at 2 hours
• Residual Volume on Day 1 [Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)]: Change in residual volume during treatment
• Residual Volume on Day 3 [Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)]: Change in residual volume during treatment
• Functional Residual Capacity on Day 1 [Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)]: Change in functional residual capacity during treatment
• Functional Residual Capacity on Day 3 [Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)]: Change in functional residual capacity during treatment
• Specific Airway Conductance on Day 1 [Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)]: Change in specific airway conductance during treatment
• Specific Airway Conductance on Day 3 [Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)]: Change in specific airway conductance during treatment

Sex: All, ages: 40 Years to 80 Years

Inclusion Criteria:

1. Written informed consent
2. Male or female aged 40 and 80 years
3. 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
4. 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
5. Screening Holter report with a minimum of 18 hours recording that is able to be evaluated for rhythm analysis showing no abnormality which indicates a significant impairment of patient safety or which may significantly impair interpretation
6. Capable of complying with all study restrictions and procedures including ability to use the study nebulizer and Respimat® correctly.
7. Body mass index (BMI) between 18 and 36 kg/m2 and minimum weight of 45 kg.
8. COPD diagnosis for at least 1 year and clinically stable COPD for 4 week
9. Post-bronchodilator (two puffs of salbutamol/albuterol followed by two puffs of ipratropium) spirometry at Screening:

   * Post-bronchodilator FEV1/forced vital capacity (FVC) ratio of ≤0.70
   * Post-bronchodilator FEV1 ≥30 % and ≤70% of predicted normal
   * Demonstrates ≥150 mL increase from pre-bronchodilator FEV1
10. A chest X-ray showing no abnormalities, which are both clinically significant and unrelated to COPD.

12\. Meet the concomitant medication restrictions and be expected to do so for the rest of the study.

13\. 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, in the last 3 months
3. A history of one or more hospitalizations for COPD in the last 12 months
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 oral COPD medications, except mucolytics, in the last 3 months
9. Pulmonary rehabilitation, unless such treatment has been stable in the last 4 weeks
10. History of, or reason to believe a patient has, drug or alcohol abuse within the past 5 years.
11. Inability to perform acceptable spirometry or whole body plethysmography
12. Received an experimental drug within 30 days or five half lives, whichever is longer.
13. Patients with uncontrolled disease that the Investigator believes are clinically significant. This includes any hepatic disease, or an alanine aminotransferase or aspartate aminotransferase>2 x upper limit of normal (ULN).
14. Documented cardiovascular disease: arrhythmias, angina, recent (<1 year) or suspected myocardial infarction, congestive heart failure, unstable or uncontrolled hypertension, or diagnosis of hypertension in the last 3 months
15. Use of non-selective oral β-blockers.
16. Major surgery (requiring general anesthesia) in the last 6 weeks or will not have fully recovered from surgery, or planned surgery through the end of the study.
17. A disclosed history or one known to the Investigator, of significant non compliance in previous investigational studies or with prescribed medications.
18. Required use of oxygen therapy, even on an occasional basis.
19. Symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma.
20. History of malignancy of any organ system within 5 years, with the exception of localized skin cancers (basal or squamous cell).
21. Clinically significant abnormal values for safety laboratory tests (hematology, biochemistry, virology or urinalysis) as determined by the Investigator
22. Any other reason that the Investigator considers makes the patient unsuitable to participate.

Participant flow

Outcome results

• Change From Baseline in Peak FEV1 on Day 3 (Primary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Olodaterol 0.565 +/- 0.2783; 6 mg RPL554 and Tiotropium/Olodaterol 0.506 +/- 0.2506; Placebo and Tiotropium/Olodaterol 0.519 +/- 0.2809 (p 0.168)
• Change From Baseline to Trough FEV1 on Day 4 (Secondary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Olodaterol 0.186 +/- 0.2496; 6 mg RPL554 and Tiotropium/Olodaterol 0.178 +/- 0.2123; Placebo and Tiotropium/Olodaterol 0.150 +/- 0.2218 (p 0.115)
• Change From Baseline in AUC0-4h FEV1 on Day 3 (Secondary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Olodaterol 0.429 +/- 0.2518; 6 mg RPL554 and Tiotropium/Olodaterol 0.390 +/- 0.2246; Placebo and Tiotropium/Olodaterol 0.377 +/- 0.2485 (p 0.303)
• Change From Baseline in AUC0-12h FEV1 on Day 3 (Secondary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Olodaterol 0.390 +/- 0.2426; 6 mg RPL554 and Tiotropium/Olodaterol 0.347 +/- 0.2219; Placebo and Tiotropium/Olodaterol 0.337 +/- 0.2447 (p 0.067)
• Change From Baseline in Peak FEV1 on Day 1 (Secondary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Olodaterol 0.490 +/- 0.2219; 6 mg RPL554 and Tiotropium/Olodaterol 0.467 +/- 0.2393; Placebo and Tiotropium/Olodaterol 0.445 +/- 0.2306 (p 0.404)
• Change From Baseline in Peak FEV1 After Evening Dose on Day 3 (Secondary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Olodaterol 0.453 +/- 0.2625; 6 mg RPL554 and Tiotropium/Olodaterol 0.405 +/- 0.2581; Placebo and Tiotropium/Olodaterol 0.324 +/- 0.2211 (p 0.001)
• Change From Baseline in AUC0-12h FEV1 on Day 1 (Secondary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Olodaterol 0.333 +/- 0.1815; 6 mg RPL554 and Tiotropium/Olodaterol 0.308 +/- 0.1854; Placebo and Tiotropium/Olodaterol 0.303 +/- 0.1920 (p 0.096)
• Determination of Onset of Action on Day 1 (Secondary), Median, minutes: 1.5 mg RPL554 and Tiotropium/Olodaterol 10.0 (1 to 86); 6 mg RPL554 and Tiotropium/Olodaterol 6.0 (4 to 117); Placebo and Tiotropium/Olodaterol 11.0 (7 to 120) (p 0.945)
• Residual Volume on Day 1 (Secondary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1 -0.469 +/- 0.5521; 6 mg RPL554 and Tiotropium/Olodaterol on Day 1 -0.408 +/- 0.4803; Placebo and Tiotropium/Olodaterol on Day 1 -0.377 +/- 0.4810
• Residual Volume on Day 3 (Secondary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Olodaterol on Day 3 -0.323 +/- 0.4548; 6 mg RPL554 and Tiotropium/Olodaterol on Day 3 -0.313 +/- 0.8946; Placebo and Tiotropium/Olodaterol on Day 3 -0.184 +/- 0.6274
• Functional Residual Capacity on Day 1 (Secondary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1 -0.344 +/- 0.5097; 6 mg RPL554 and Tiotropium/Olodaterol on Day 1 -0.294 +/- 0.4524; Placebo and Tiotropium/Olodaterol on Day 1 -0.277 +/- 0.4279
• Functional Residual Capacity on Day 3 (Secondary), Mean, Liters: 1.5 mg RPL554 and Tiotropium/Oldaterol on Day 3 -0.490 +/- 0.4654; 6 mg RPL554 and Tiotropium/Oldaterol on Day 3 -0.408 +/- 0.6102; Placebo and Tiotropium/Oldaterol on Day 3 -0.382 +/- 0.5610
• Specific Airway Conductance on Day 1 (Secondary), Mean, 1/kPa*sec: 1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1 0.064 +/- 0.1148; 6 mg RPL554 and Tiotropium/Olodaterol on Day 1 0.042 +/- 0.0483; Placebo and Tiotropium/Olodaterol on Day 1 0.043 +/- 0.1072
• Specific Airway Conductance on Day 3 (Secondary), Mean, 1/kPa*sec: 1.5 mg RPL554 and Tiotropium/Olodaterol on Day 3 0.021 +/- 0.608; 6 mg RPL554 and Tiotropium/Olodaterol on Day 3 0.046 +/- 0.1060; Placebo and Tiotropium/Olodaterol on Day 3 0.016 +/- 0.0890

Adverse events

Time frame: From informed consent until the end of the study, approximately 2 months for each patient

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2018-05-28)
• Statistical Analysis Plan (PDF, 2018-10-18)

• Dave Singh, Principal investigator, Medicines Evaluation Unit