Dose Ranging Study of RPL554 in Chronic Obstructive Pulmonary Disease (COPD) Patients
Condition: COPD
Intervention: RPL554 suspension; Placebo
Intervention description: A dual PDE3/PDE 4 inhibitor; Placebo solution
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Masking description: The nebuliser cup will be obscured to prevent the Investigator or outcomes assessor so the contents are not visible to the Investigator our outcomes assessor. The visual appearance of the study medication will not be discussed with the subject
Enrollment: 405.0
Sex: All
Minimum age: 40 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: COPD, bronchodilation, FEV1

Summary:

      The study investigates the effect of 4 weeks of twice daily treatment of four different doses
      of RPL554 (a phosphodiesterase [PDE]3/4 inhibitor) or placebo in patients with moderate to
      severe chronic obstructive pulmonary disease (COPD). Patients will be equally allocated to
      one of the five treatment options.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Provide informed consent

          -  Male or female aged 40 to 75 years

          -  Meeting specified contraception requirements

          -  12-lead electrocardiogram with heart rate 50-90 beats per minute, QT interval
             corrected using Fridericia's formula (QTcF) ≤450 msec (males) or ≤470 msec (females),
             QRS interval ≤120 msec, PR interval ≤200 msec and no clinically significant
             abnormalities

          -  Capable of complying with all study restrictions and procedures, including ability to
             use the study nebulizer correctly.

          -  Body mass index (BMI) 18 to 35 kg/m2 and minimum weight 45 kg.

          -  COPD diagnosis with symptoms compatible with COPD for at least 1 year

          -  Clinically stable COPD in the previous 4 weeks

          -  Ability to perform acceptable and reproducible spirometry.

          -  Post-bronchodilator spirometry at screening must demonstrate FEV1/forced vital
             capacity (FVC) ratio of ≤0.70 and FEV1 must be ≥40 % to ≤80% of predicted normal

          -  Chest X-ray (posterior-anterior) at screening, or chest X-ray, magnetic resonance
             imaging (MRI) or computed tomography (CT) scan in the last 12 months, showing no
             abnormalities which are both clinically significant and 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 a smoking history of ≥10 pack years.

          -  Capable of withdrawing long acting bronchodilators until the end of the treatment
             period, and short acting bronchodilators for 8 hours prior to administration of study
             medication.

        Exclusion Criteria:

          -  A history of life-threatening COPD including Intensive Care Unit admission and
             requiring intubation.

          -  COPD exacerbation requiring oral steroids in the previous 3 months

          -  A history of one or more hospitalizations for COPD in the previous 6 months

          -  Lower respiratory tract infection treated with antibiotics in the previous 3 months

          -  Evidence of cor pulmonale or clinically significant pulmonary hypertension.

          -  Patients with a current diagnosis of asthma, active tuberculosis, lung cancer,
             bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung diseases, sleep apnea,
             known alpha-1 antitrypsin deficiency or other active pulmonary diseases.

          -  Previous lung resection or lung reduction surgery.

          -  Oral therapies for COPD (e.g. oral steroids, theophylline, and roflumilast) in the
             previous 3 months and throughout the study.

          -  Pulmonary rehabilitation, unless such treatment has been stable from 4 weeks prior to
             Visit 1) and remains stable during the trial.

          -  A history of, or reason to believe a subject has, drug or alcohol abuse in the
             previous 3 years.

          -  Received an experimental drug within 30 days or five half-lives of the first dose

          -  Prior exposure to RPL554.

          -  Women who are pregnant or breast-feeding.

          -  Patients with a history of current uncontrolled disease that the Investigator believes
             are clinically significant.

          -  myocardial infarction in the previous 6 month; congestive heart failure, a history of
             unstable or uncontrolled hypertension, or has been diagnosed with hypertension in last
             3 months.

          -  Use of oral beta blockers.

          -  Major surgery (requiring general anesthesia) in the previous 6 weeks, lack of full
             recovery from surgery at screening, or planned surgery through the end of the study.

          -  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 safety laboratory tests

          -  Significant non-compliance in previous investigational studies or with prescribed
             medications.

          -  Requirement for oxygen therapy, even on an occasional basis.

          -  Known hypersensitivity to RPL554 or its excipients/components.

          -  Abnormal clinically significant 12 lead Holter findings,

          -  Any other reason that the Investigator considers makes the subject unsuitable to
             participate.