Dose Ranging Study of RPL554 in Chronic Obstructive Pulmonary Disease (COPD) Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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RPL554 is a dual inhibitor of PDE3 and 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 effects. PDE4 inhibitors (administered orally) have, however been associated with unfavorable gastrointestinal side effects such as nausea, emesis, diarrhea, abdominal pain, loss of appetite and weight loss. Dual PDE3/PDE4 inhibitors (administered by inhalation) have exhibited both bronchodilator and anti-inflammatory actions, with a more favorable side effect profile. It is plausible that increased efficacy with reduced side effects may be achievable with administration of a dual PDE3/4 inhibitor by the inhaled route compared to orally administered PDE3 or PDE4 inhibitors. The purpose of this study is to investigate the dose response of RPL554 in patients with COPD over 4 weeks. This length of time should allow for study of the bronchodilator response, measured predominantly by the peak forced expiratory volume in one second (FEV1), and the anti-inflammatory response, as measured predominantly by trough FEV1.

Official Title
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Phase IIb, Randomized, Double Blind, Placebo Controlled, Dose Ranging Study to Assess the Effect of RPL554 in Patients With Moderate to Severe COPD.

Conditions
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COPD

Intervention / Treatment
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* Drug: RPL554 suspension
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.75 mg RPL554<br> | Drug: RPL554 suspension<br>* A dual PDE3/PDE 4 inhibitor<br>|
| Experimental: 1.5 mg RPL554<br> | Drug: RPL554 suspension<br>* A dual PDE3/PDE 4 inhibitor<br>|
| Experimental: 3 mg RPL554<br> | Drug: RPL554 suspension<br>* A dual PDE3/PDE 4 inhibitor<br>|
| Experimental: 6 mg RPL554<br> | Drug: RPL554 suspension<br>* A dual PDE3/PDE 4 inhibitor<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Peak FEV1 (Over 3 Hours) at Week 4 | Spirometry assessments were used to assess pulmonary function including the forced expiratory volume in 1 second (FEV1). Peak FEV1 at Week 4 was defined as the maximum post-dose value among the 30 minutes, 1, 2 and 3 hour assessments collected at Visit 6. Baseline was defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2. A mixed model for repeated measures (MMRM) was used to model the change from baseline FEV1 using baseline FEV1 as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, and patient as random effect. The least squares (LS) mean change from baseline FEV1 to peak FEV1 (as measured over 3 hours) at Week 4 is presented. | Baseline (pre-dose, Visit 2) and Week 4 (Visit 6). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline FEV1 to Morning Trough FEV1 at Week 4 | Morning trough FEV1 was defined as the last pre-dose value at Visit 6. Baseline was defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2. MMRM was used to model the change from baseline FEV1 using baseline FEV1 as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, and patient as random effect. The LS mean change from baseline FEV1 to morning trough FEV1 at Week 4 is presented. | Baseline (pre-dose, Visit 2) and Week 4 (Visit 6). | 
| Mean Change From Baseline FEV1 to Average FEV1 (Over 12 Hours) at Day 1 and Week 4 | Average FEV1 over 12 hours was defined as the area under the curve from 0 to 12 hours post-dose (AUC[0-12]) of the FEV1 values collected during the visit under analysis (Day 1 or Week 4), divided by the length of the time interval of interest (in hours). The AUC was calculated using the trapezoidal rule. Baseline was defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2. MMRM was used to model the change from baseline FEV1 using baseline FEV1 as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, and patient as random effect. The LS mean change from baseline FEV1 to average FEV1 over 12 hours at Day 1 and at Week 4 is presented. | Baseline (pre-dose, Visit 2), up to 12 hours post-dose at Visit 2 (Day 1) and Visit 6 (Week 4). | 
| Mean Change From Baseline in COPD Symptoms Using the Exacerbations of Chronic Pulmonary Disease Tool Patient-Reported Outcome (EXACT-PRO) Scoring at Week 4 | Patients completed an electronic diary (e-diary) once daily which used the 14-item EXACT-PRO instrument to assess COPD symptoms. The EXACT-PRO instrument contains 11 respiratory symptom questions that comprise the derivative Evaluating Respiratory Symptoms (E-RS) instrument that was used to measure the effect of treatment with RPL554 on the severity of COPD symptoms overall. The E-RS tool contains 3 subscales to assess breathlessness, cough/sputum and chest symptoms. In addition to the subscale scores, a total score for the E-RS part was obtained. The raw totals for the E-RS score and for each of the subscales were converted to a scale range of 0 to 100 (least symptomatic to most symptomatic). MMRM was used to model the change from baseline using baseline as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, and patient as random effect. Baseline was the last non-missing assessment taken prior to investigational product start date. | Baseline (pre-dose, Visit 2) and Week 4 (Visit 6). | 
| Mean Change From Baseline in Breathlessness as Assessed Using the St George's Respiratory Questionnaire (SGRQ) at Week 4 | Patients completed the COPD specific SGRQ (SGRQ-C) consisting of 14 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 indicate a worse outcome. Baseline assessment was pre-dose at Visit 2. MMRM was used to model the change from baseline using baseline as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, patient as random effect. The LS mean change from baseline in the total, symptoms, activity and impact SGRQ-C scores are presented. | Baseline (pre-dose, Visit 2) and Week 4 (Visit 6). | 
| Number of Patients With Treatment Emergent Adverse Events (TEAEs) | The number of patients with TEAEs for each the following categories are presented: any TEAE, any drug-related TEAE, any severe TEAE, any serious TEAE, serious drug-related TEAE, any TEAE leading to drug interruption, any TEAE leading to drug discontinuation, and any TEAE leading to death. All AEs which started after the first dose of investigational product.or started prior to first dose and worsened, based on the Investigator assessment of severity, on or after first dose were considered to be treatment-emergent. | Up to end of study (approximately 6 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, bronchodilation, FEV1