Clinical trial NCT02542254: The Effects of RPL554 on Top of Standard COPD Reliever Medications
Official title: A Phase II, Randomised, Double Blind, Placebo Controlled, Six Way Crossover Study to Assess the Bronchodilator Effect of RPL554 Administered on Top of Salbutamol and Ipratropium in Patients With COPD.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease
Lead sponsor: Verona Pharma plc
Sponsor class: INDUSTRY
First posted: 2015-09-04
Enrollment: 36
Sex: ALL
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This study evaluates the addition of RPL554 to standard reliever medications for chronic obstructive pulmonary disorder (COPD). All patients will receive the same six treatments in a randomised sequence:

1. salbutamol,
2. ipratropium,
3. salbutamol + RPL554,
4. ipratropium + RPL554,
5. RPL554
6. Placebo

Detailed description: The purpose of this study is to investigate if RPL554 has an additive bronchodilator effect when administered in combination with standard of care bronchodilators in patients with COPD.This study investigates the pharmacodynamic effect of RPL554 using spirometry and whole body plethysmography compared to placebo, when administered in addition to a beta2 agonist (salbutamol), a muscarinic antagonist (ipratropium) or placebo.

Eligibility criteria: Inclusion Criteria:

* Provide informed consent
* Males not donating sperm and using adequate contraception or females who are surgically sterile or postmenopausal
* 12-lead ECG showing:Heart rate 45 to 90 bpm, QTcF≤450 msec, QRS ≤120 msec, PR interval ≤220 msec, no clinically significant abnormality
* Capable of complying with all study restrictions and procedures including ability to use the study nebuliser correctly.
* BMI 18 to 33 kg/m2 with a minimum weight of 45 kg.
* COPD diagnosis for at least 1 year and clinically stable COPD in previous 4 weeks
* Demonstrates reversibility to bronchodilator (two puffs of salbutamol followed by two puffs of ipratropium) via spirometry:

  * Post-bronchodilator FEV1/forced vital capacity (FVC) ratio of ≤0.70
  * Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal
  * ≥150 mL increase from pre-bronchodilator FEV1
* Chest X-ray showing no abnormalities
* Meet the concomitant medication restrictions and be expected to do so for the rest of the study.
* Smoking history of ≥10 pack years.
* Capable of withdrawing from long acting bronchodilators throughout the study and short acting bronchodilators for 8 hours prior to study treatment.

Exclusion Criteria:

* History of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation.
* COPD exacerbation requiring oral steroids in the previous 3 months
* History of one or more hospitalisations for COPD in the previous 12 months
* Respiratory tract infection (both upper and lower) treated with antibiotics in previous 12 weeks
* Evidence of cor pulmonale or clinically significant pulmonary hypertension.
* Other respiratory disorders
* Previous lung resection or lung reduction surgery.
* Oral therapies for COPD in the previous 3 months and throughout the study.
* Drug or alcohol abuse in the past 3 years
* Received an experimental drug within 3 months or five half lives, whichever is longer.
* Prior exposure to RPL554
* Patients with a history of chronic uncontrolled disease that the Investigator believes are clinically significant.
* Documented cardiovascular disease in last 3 months
* Major surgery, (requiring general anaesthesia) in the previous 6 weeks, or will not have fully recovered from surgery, or planned surgery through the end of the study.
* History of malignancy of any organ system within 5 years with the exception of localised skin cancers (basal or squamous cell)
* Clinically significant abnormal values for safety laboratory tests
* A disclosed history, or one known to the Investigator, of significant non compliance in previous investigational studies or with prescribed medications.
* Requires oxygen therapy, even on an occasional basis.
* Inability to adequately perform whole body plethysmography.
* Any other reason that the Investigator considers makes the subject unsuitable to participate.
* Patients with known hypersensitivity to atropine or its derivatives, or to ipratropium bromide, salbutamol or RPL554 or their excipients/components.

Primary outcomes:
measure: 8 hour spirometry
timeFrame: 8 hours
Secondary outcomes:
measure: 12 hour spirometry
timeFrame: 12 hours
measure: Whole body plethysmography
timeFrame: 4 hours
measure: Area under the curve (AUC)
timeFrame: 12 hours
measure: Maximum plasma concentration (Cmax)
timeFrame: 12 hours
measure: Time to maximum plasma concentration (Tmax)
timeFrame: 12 hours
measure: Adverse events
timeFrame: Up to 94 days
measure: Safety laboratory tests
timeFrame: Up to 94 days
measure: ECG
timeFrame: Up to 94 days
measure: Vital signs
timeFrame: Up to 94 days
Other outcomes:
Locations:
city: Manchester
country: United Kingdom
facility: Medicines Evaluation Unit
Study officials:
affiliation: Medicines Evaluation Unit
name: Dave Singh
role: PRINCIPAL_INVESTIGATOR
References:
citation: Singh D, Abbott-Banner K, Bengtsson T, Newman K. The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD. Eur Respir J. 2018 Nov 1;52(5):1801074. doi: 10.1183/13993003.01074-2018. Print 2018 Nov.