Clinical trial NCT03443414: Dose Ranging Study of RPL554 in Chronic Obstructive Pulmonary Disease (COPD) Patients
Official title: Phase IIb, Randomized, Double Blind, Placebo Controlled, Dose Ranging Study to Assess the Effect of RPL554 in Patients With Moderate to Severe COPD.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COPD
Keywords: COPD, bronchodilation, FEV1
Lead sponsor: Verona Pharma plc
Sponsor class: INDUSTRY
First posted: 2018-02-23
Enrollment: 405
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

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.

Primary outcomes:
measure: Mean Change From Baseline in Peak FEV1 (Over 3 Hours) at Week 4
timeFrame: Baseline (pre-dose, Visit 2) and Week 4 (Visit 6).
Secondary outcomes:
measure: Mean Change From Baseline FEV1 to Morning Trough FEV1 at Week 4
timeFrame: Baseline (pre-dose, Visit 2) and Week 4 (Visit 6).
measure: Mean Change From Baseline FEV1 to Average FEV1 (Over 12 Hours) at Day 1 and Week 4
timeFrame: Baseline (pre-dose, Visit 2), up to 12 hours post-dose at Visit 2 (Day 1) and Visit 6 (Week 4).
measure: Mean Change From Baseline in COPD Symptoms Using the Exacerbations of Chronic Pulmonary Disease Tool Patient-Reported Outcome (EXACT-PRO) Scoring at Week 4
timeFrame: Baseline (pre-dose, Visit 2) and Week 4 (Visit 6).
measure: Mean Change From Baseline in Breathlessness as Assessed Using the St George's Respiratory Questionnaire (SGRQ) at Week 4
timeFrame: Baseline (pre-dose, Visit 2) and Week 4 (Visit 6).
measure: Number of Patients With Treatment Emergent Adverse Events (TEAEs)
timeFrame: Up to end of study (approximately 6 weeks)
Other outcomes:
Locations:
city: Pleven
country: Bulgaria
facility: Clinic for pneumonology
city: Ruse
country: Bulgaria
facility: SHATPPD-Ruse EOOD
city: Sofia
country: Bulgaria
facility: Fifth MHAT - Sofia EAD
city: Sofia
country: Bulgaria
facility: MHAT 'Lyulin', EAD
city: Sofia
country: Bulgaria
facility: NMTH Tsar Boris III
city: Sofia
country: Bulgaria
facility: UMHAT 'Alexandrovska' EAD
city: Sofia
country: Bulgaria
facility: UMHAT 'Sveta Anna' AD
city: Stara Zagora
country: Bulgaria
facility: Medical Center Nov
city: Jindřichův Hradec
country: Czechia
facility: MediTrial s.r.o.
city: Teplice
country: Czechia
facility: Plicni stredisko Teplice
city: Berlin
country: Germany
facility: Aerzte fuer Lungen- und
city: Berlin
country: Germany
facility: Charite Campus Mitte
city: Berlin
country: Germany
facility: emovis GmbH
city: Berlin
country: Germany
facility: Studienpraxis Berlin
city: Frankfurt
country: Germany
facility: IKF Pneumologie GmbH & Co. KG
city: Frankfurt
country: Germany
facility: Praxis Dr. Keller
city: Gauting
country: Germany
facility: Inamed GmbH
city: Großhansdorf
country: Germany
facility: PRI Pulmonary Research
city: Hamburg
country: Germany
facility: Hamburger Institut fuer
city: Koblenz
country: Germany
facility: Gemeinschaftspraxis Dres
city: Leipzig
country: Germany
facility: POIS Leipzig GbR
city: Leipzig
country: Germany
facility: SALVUS UG Centre for Clinial Trials
city: Lübeck
country: Germany
facility: KLB Gesundheitsforschung
city: Munich
country: Germany
facility: Pneumologie Odeonsplatz
city: München
country: Germany
facility: Pneumologische Praxis Pasing
city: Neu Isenburg
country: Germany
facility: Ballenberger Freytag Wenisch
city: Peine
country: Germany
facility: Dr. Christian Schlenska
city: Bialystok
country: Poland
facility: Indywidualna Specjalistyczna
city: Białystok
country: Poland
facility: CERMED
city: Bychawa
country: Poland
facility: KLIMED Marek Klimkiewicz
city: Katowice
country: Poland
facility: Silmedic sp. z o.o.
city: Krakow
country: Poland
facility: Grazyna Pulka Specjalistyczny
city: Kraków
country: Poland
facility: Malopolskie Centrum Alergologii
city: Poznań
country: Poland
facility: NZOZ Alergo-MEDSpecjalistyczna
city: Skierniewice
country: Poland
facility: ETG Network Sp z o o
city: Warsaw
country: Poland
facility: Centrum Medyczne Pratia
city: Warsaw
country: Poland
facility: Mazowieckie Centrum Medyczne
city: Wroclaw
country: Poland
facility: Specjalistyczna Opieka
city: Wrocław
country: Poland
facility: Centrum Badan Klinicznych
city: Łódź
country: Poland
facility: Centrum Terapii Wspólczesnej
city: Łódź
country: Poland
facility: Uniwersytecki Szpital Klin
city: Bragadiru
country: Romania
facility: S.C Angisan S.R.L
city: Braşov
country: Romania
facility: S.C Clinica Pneumomedica S.R.L
city: Bucuresti
country: Romania
facility: Fundatia Dr. Victor Babes
city: Bucuresti
country: Romania
facility: Spitalul Clinic de Urgenta
city: Cluj-Napoca
country: Romania
facility: Spitalul Cl. Pneumoftiziologie
city: Constanţa
country: Romania
facility: Spitalul CldePneumoftiziologie
city: Iaşi
country: Romania
facility: Spitalul CldePneumoftiziologie
city: Manchester
country: United Kingdom
facility: Medicines Evaluation Unit
Study officials:
affiliation: Medicines Evaluation Unit (MEU)
name: Dr Singh
role: PRINCIPAL_INVESTIGATOR
References: