Study Investigating the Effect of 4 Doses of RPL554 Given in Addition to Tiotropium to Patients With COPD
Condition: COPD
Intervention: Ensifentrine (formerly RPL554) 0.375 mg twice daily plus placebo, in addition to tiotropium; Ensifentrine (formerly RPL554) 0.75 mg twice daily plus placebo, in addition to tiotropium; Ensifentrine (formerly RPL554) 1.5 mg twice daily plus placebo, in addition to tiotropium; Ensifentrine (formerly RPL554) 3.0 mg twice daily plus placebo, in addition to tiotropium; Ensifentrine (formerly RPL554) placebo twice daily, in addition to tiotropium
Intervention description: 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.; 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.; 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.; 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.; 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.
Intervention MeSH terms: Tiotropium Bromide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 416.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to investigate the dose response of RPL554 in patients with
      moderate to severe CHRONIC OBSTRUCTIVE PULMONARY DISEASE that are still symptomatic despite
      treatment with a stable background of tiotropium over 4 weeks of treatment. This study is
      intended to support optimal dose selection for a Phase III program evaluating RPL554 as an
      add-on treatment to standard of care therapy.
    

Eligibility criteria:

        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.