Study Investigating the Effect of 4 Doses of RPL554 Given in Addition to Tiotropium to Patients With COPD

COPD Clinical Trial

Official title:

A Phase II, Randomized, Double-Blind, Placebo Controlled Dose Ranging Study to Assess the Effect of RPL554 Added on to Tiotropium in Patients With Chronic Obstructive Pulmonary Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03937479
• Other study ID #: RPL554-CO-205
• Status: Completed
• Phase: Phase 2
• Start date: May 1, 2019
• Est. completion date: November 15, 2019

Study information

• Verified date: October 2020
• Source: Verona Pharma plc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

This is a Phase IIb, randomized, double-blind, placebo controlled, multiple dose, parallel group study to investigate the effects of 4 weeks of treatment with nebulized RPL554 (at different dose levels) compared to placebo in patients with moderate to severe CHRONIC OBSTRUCTIVE PULMONARY DISEASE on a stable background therapy of open-label tiotropium. The study comprises seven visits: Pre-screening (Visit 0), Screening (Visit 1) and then a Treatment Period consisting of Randomization (Visit 2), and weekly visits for 4 weeks (Visit 3 to Visit 6).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 416
• Est. completion date: November 15, 2019
• Est. primary completion date: November 15, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• COPD

Intervention

Drug:
• Ensifentrine (formerly RPL554) 0.375 mg twice daily plus placebo, in addition to tiotropium
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.
• Ensifentrine (formerly RPL554) 0.75 mg twice daily plus placebo, in addition to tiotropium
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.
• Ensifentrine (formerly RPL554) 1.5 mg twice daily plus placebo, in addition to tiotropium
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.
• Ensifentrine (formerly RPL554) 3.0 mg twice daily plus placebo, in addition to tiotropium
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.
• Ensifentrine (formerly RPL554) placebo twice daily, in addition to tiotropium
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.

Locations

Country	Name	City	State
United States	Vitalink Research - Anderson	Anderson	South Carolina
United States	Pinnacle Research Group, LLC	Anniston	Alabama
United States	Meris Clinical Research	Brandon	Florida
United States	Lowcountry Lung and Critical Care, PA	Charleston	South Carolina
United States	American Health Research	Charlotte	North Carolina
United States	New Horizons Clinical Research	Cincinnati	Ohio
United States	Clinical Research of West Florida	Clearwater	Florida
United States	VitaLink-Columbia	Columbia	South Carolina
United States	Aventiv Research, Inc	Columbus	Ohio
United States	Columbus Regional Research Institute	Columbus	Georgia
United States	VitaLink Research - Hamilton Mill	Dacula	Georgia
United States	Aventiv Research, Inc	Dublin	Ohio
United States	VitaLink Research - Duluth	Duluth	Georgia
United States	VitaLink Research - Easley	Easley	South Carolina
United States	Genesis Clinical Research and Consulting, LLC	Fall River	Massachusetts
United States	Pulmonary Research Institute of Southeast Michigan	Farmington Hills	Michigan
United States	Piedmont Research Partners, LLC	Fort Mill	South Carolina
United States	Cities Research Center	Fridley	Minnesota
United States	California Research Medical Group, Inc	Fullerton	California
United States	VitaLink Research-Gaffney	Gaffney	South Carolina
United States	Clinical Research of Gastonia	Gastonia	North Carolina
United States	VitaLink Research-Greenville	Greenville	South Carolina
United States	VitaLink Research-UPSTATE	Greenville	South Carolina
United States	Research Carolina of Huntersville	Huntersville	North Carolina
United States	Pulmonary Disease Specialists, PA d/b/a PDS Research	Kissimmee	Florida
United States	New Phase Research & Development	Knoxville	Tennessee
United States	Innovative Clinical Research	Lafayette	Colorado
United States	FMC Science, LLC	Lampasas	Texas
United States	Gwinnett Biomedical Research	Lawrenceville	Georgia
United States	Medical Research of Central Florida, LLC	Leesburg	Florida
United States	DCOL Center for Clinical Research	Longview	Texas
United States	Southern California Institute For Respiratory Diseases, Inc.	Los Angeles	California
United States	Metroplex Pulmonary and Sleep Center	McKinney	Texas
United States	Crisor, LLC	Medford	Oregon
United States	Clinical Trials of Florida, LLC	Miami	Florida
United States	Clinical Research of Lake Norman	Mooresville	North Carolina
United States	Clinical Research of Charleston	Mount Pleasant	South Carolina
United States	Peninsula Research, Ormond Beach, LLC	Ormond Beach	Florida
United States	Medsol Clinical Research Center, Inc	Port Charlotte	Florida
United States	Progressive Medical Research	Port Orange	Florida
United States	IACT Health	Rincon	Georgia
United States	Clinical Research of Rock Hill	Rock Hill	South Carolina
United States	Pasadena Center for Medical Research, LLC	Saint Petersburg	Florida
United States	Vitalink Research-Seneca	Seneca	South Carolina
United States	Fusion Clinical Research of Spartanburg, LLC	Spartanburg	South Carolina
United States	Spartanburg Medical Research	Spartanburg	South Carolina
United States	Vitalink Research-Spartanburg	Spartanburg	South Carolina
United States	VitaLink Research - Union	Union	South Carolina
United States	Vitalink	Winder	Georgia
United States	Florida Pulmonary Research Institute, LLC	Winter Park	Florida

Sponsors (3)

Lead Sponsor	Collaborator
Verona Pharma plc	Iqvia Pty Ltd, LGC Limited

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines.	Baseline and Week 4
Secondary	LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-3h FEV1 was defined as area under the curve over 3 hours of the FEV1, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4
Secondary	LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-12h FEV1 was defined as area under the curve over 12 hours of the FEV1, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4
Secondary	LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2 and 3
Secondary	LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4	Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and morning trough FEV1 was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4
Secondary	LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4	The E-RS scale consists of 11 questions, with 3 sub-domains of: breathlessness, cough and sputum, and chest symptoms. The E-RS sub-domain score was calculated as the sum from the relevant questions. The E-RS:COPD scale has a scoring range of 0 to 40. Higher scores indicates severe respiratory symptoms. Baseline was the mean over the 7 days prior to first intake of study treatment. Scores were derived weekly as the mean over 7 days prior to the visit, using only days where data was recorded. The E-RS:COPD was measured by daily electronic diary (e-diary).	Baseline and Weeks 1, 2, 3 and 4
Secondary	LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4	Patients completed the SGRQ-C consisting of 40 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 indicated a worse outcome. The SGRQ-C was measured at Week 2 and 4 visits.	Baseline, Weeks 2 and 4
Secondary	LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4	The TDI is a questionnaire that focussed on 3 sub-domains: functional impairment, magnitude of task and magnitude of effort. Sub-domain score was calculated as the sum from the related questions. Total score was calculated as the sum of the sub-domain scores. The TDI measures the change in dyspnea severity from the baseline as measured by the baseline dyspnea index. It was rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement). Higher scores indicate better outcome.	Weeks 2 and 4
Secondary	LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4	The PGAC is a single question assessment to determine whether patients noticed a change in their breathing since the start of the study. Patients were asked to respond to a PGAC question asking, "Compared with prior to the study start, how do you feel your breathing is?" on a scale of '1=much worse' to '5=much better', with '3=no change'. Higher scores indicate better outcome.	Weeks 2 and 4
Secondary	LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication	Use of rescue medication (albuterol) per visit was calculated as the LS mean use daily over total number of days between previous visit (inclusive) and the following visit. Baseline use was the mean over the last 7 days of the run-in phase (calculated as the sum of puffs taken, divided by number of days data has been recorded).	Baseline and Weeks 1, 2, 3 and 4
Secondary	LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4	Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and peak FVC was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2, 3 and 4
Secondary	LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4	Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-3h FVC was defined as area under the curve over 3 hours of the FVC, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4
Secondary	LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4	Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-12h FVC was defined as area under the curve over 12 hours of the FVC, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4
Secondary	LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4	Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and morning trough FVC was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines.	Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4
Secondary	Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2	Blood samples were taken to determine steady-state plasma concentrations of tiotropium prior to and following 14 days of treatment with RPL554.	Pre-dose on Day 1 and Week 2
Secondary	Steady-State Plasma Concentrations of RPL554 at Week 2	Blood samples were taken to determine steady-state plasma concentrations of RPL554 following 14 days of treatment with RPL554.	Pre-dose at Week 2
Secondary	Number of Patients With Treatment Emergent Adverse Events (TEAEs)	An adverse event (AE) was defined as any undesirable experience occurring to a patient, or worsening in a patient, whether considered related to the study medication or not. All AEs which started after the first dose of study treatment or started prior to first dose of study treatment and worsened, based on the Investigator's assessment of severity, on or after first dose of study treatment were considered to be treatment-emergent. A serious adverse event is any adverse experience that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other important medical events.	TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks.