To investigate wether or not the study drug is still working and safe after 6 days of daily dosing.The study drug will be adminstered to asthmatics.

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2011-001698-22-NL
• Date of registration: 03/05/2011
• Prospective Registration: No
• Primary sponsor: Verona Pharma plc
• Public title: To investigate wether or not the study drug is still working and safe after 6 days of daily dosing.The study drug will be adminstered to asthmatics.
• Scientific title: EVALUATION OF THE EFFICACY AND SAFETY OF 6 REPEATED DAILY DOSES OF NEBULISED RPL554 0.018 mg/kg (6X) IN ALLERGIC ASTHMATICS - Daily Dose RPL554
• Date of first enrolment: 29/04/2011
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-001698-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: no Open: no Single blind: yes Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 1

Countries of recruitment

Netherlands

Contacts

• Name: Chief Executive Officer
• Affiliation: Verona Pharma plc

• Name: Chief Executive Officer
• Affiliation: Verona Pharma plc

Key inclusion & exclusion criteria

Inclusion criteria:
•Healthy males between 18 and 55 years of age at screening (both inclusive)
•Clinically stable mild to moderate asthma, defined as
o Documented history of mild to moderate persistent asthma, first diagnosed by an MD at least 6 months prior to the screening visit and currently controlled by beta-agonists on an “as needed” basis only
o Clinically stable asthma, i.e. stable asthma symptoms and baseline prebronchodilator FEV1 values within 10% (i.e. study day 1 compared to screening) (preferably measured at the same time of day ±3 h); stable use of “as needed” Short-Acting Beta2 Agonist (SABA) but not on controller medication (see exclusion criteria)
o Pre-bronchodilator FEV1 =70% of predicted
o Documented bronchial hyper-responsiveness to inhaled Methacholine (MCh) with a PC20Meth of =8 mg/mL at screening
o No recent respiratory tract infections (within 3 weeks of screening and during study)
o Documented reversibility in lung function defined as = 12% or = 200 mL increase in FEV1 compared to pre-salbutamol 200 microgram value.
• No clinically relevant history of cardiovascular (including arrhythmias) disease; no active hyperthyroidism
• No clinically relevant history of chronic or malignant diseases (except for in situ basalioma)
• Body mass index (BMI) between 18 and 33 kg/m2 (both inclusive)
• Systolic blood pressure (SBP) 100-155 mmHg, diastolic blood pressure (DBP) 50-90 mmHg, and heart rate (HR) 45-90 beats per min (inclusive), measured on the arm with the highest blood pressure after resting for 5 min in the supine position
• No clinically significant findings on physical examination other than allergy and mild to moderate persistent asthma
• 12-lead ECG without clinically relevant abnormalities
• Non-smokers or ex-smokers (stopped for at least 6 months before screening, and <10 pack-years)
• No history of anaphylaxis, or of severe food or medication allergy
• Haematology, clinical chemistry and urinalysis test results not deviating from the normal range to a clinically relevant extent as deemed by the investigator
• Negative results from urine drug and cotinine screens (for nicotine use)
• Negative screening for Hepatitis B, Hepatitis C and HIV
• Documented allergy by a standardized Skin Prick Test (SPT): i.e. a positive wheal response to one or more of the common airborne allergens: Grass or tree Pollen, House Dust Mite, D. Farinae, cat, dog, or horse-dander, Aspergillus Fumigatus, A. Alternata, Artemisia Vulgaris (in the past 1 year)
• Steroid-naïve, or not on inhaled/nasal corticosteroids for at least one month and 8 weeks of systemic therapy before the study
• No use of anti-IgE (omalizumab) in the past 6 months
• No systemic or aerosol use of the following: leukotriene receptor antagonists (LTRA), theophylline, long acting beta agonists (LABA), or antihistamine such as H1 receptor antagonist for 2 weeks before the study
• No nasal medications (steroids, antihistamines, cromones) for one month (for nasal steroids), or 2 weeks for other medications; xylomethazoline (1 week); nasal NaCl 0.9% allowed
• Ability to communicate well with the investigator and to understand and comply with the requirements of the study
• Signed informed consent
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 16
F.1.3 Elderly (>=65 years) no
F.1.3.1 Numbe
Exclusion criteria:
• Desensitization therapy in the past 5 years
• Severe exacerbation requiring hospital evaluation and/or admission in the past 2 years
• Unstable/uncontrolled disease within 3 weeks of participation in the study
• History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug
• Treatment with another investigational drug within 3 months prior to screening
• Known hypersensitivity to any excipients of the drug formulations
• History or clinical evidence of alcoholism within the 3-year period prior to screening (i.e. regular use of more than 21 units of alcohol/week for males and more than 14 units/week for females)
• Excessive caffeine consumption, defined as > 8 cups/per day at screening – unable to discontinue caffeine consumption for at least 8 h before and during the testing
• History or any other clinical condition, judged to be a contraindication for participation in the study as judged by the PI
• Loss of 250 mL or more of blood within 3 months prior to screening
• Any abnormalities on lab or urine results outside the normal range, deemed clinically significant by the investigator (and with written consent of the sponsor)


Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Allergic asthma
MedDRA version: 13.1 Level: LLT Classification code 10001705 Term: Allergic asthma System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Intervention(s)

Product Name: RPL554
Product Code: RPL554
Pharmaceutical Form: Inhalation vapour, solution
Pharmaceutical form of the placebo: Inhalation vapour, solution
Route of administration of the placebo: Inhalation use

Primary Outcome(s)

Secondary Objective: I. Safety:
a. respiratory safety measured by FEV1, pulse oximetry and respiratory rate
b. cardiovascular safety measured by sitting blood pressure, heart rate, 12-lead ECG and telemetry
c. full haematological assessment; chemistry haematology at day -1, 3 and 6,
d. symptoms and adverse events, and,
e. plasma concentrations of RPL554 at pre-dose, 10 min, 15 min, ½ h, 1 h and 2 h post dose on each of 6 days of daily dosing with nebulised RPL554 and in addition at 4 h and 6 h on day 1, 3, and 6, and on day 7 (24 h after the last dose).
II. Exhaled breath condensate will be collected from exhaled air and assayed for RPL554 concentration at 30 min and 2 hour after dosing on day 2,
III. Pharmacokinetic profile of RPL554 by measuring the plasma concentrations at selected time points.

Main Objective: To investigate the efficacy of repeated daily doses of nebulised RPL554 (0.018 mg/kg) by assessing the effect on FEV1 at day 1, 3 and 6 after daily inhaled doses of nebulised RPL554 0.018 mg/kg (6X).

Primary end point(s): • Lung function: FEV1 (Forced Expiratory Volume in the first second)

Timepoint(s) of evaluation of this end point: FEV1 at during six hours post dose at Days -1, 1, 3 and 6.
15 en 5 min pre-dosing and post dosing at 15, 30, 45 and 60 45 min and every 30 min thereafter untill six hours after dosing.

Secondary Outcome(s)

Secondary end point(s): • Safety of nebulised RPL554 in patients with allergic asthma using standard safety measures:
o Respiratory safety (i.e., effects on the upper and lower airways):
? upper airways (nose): local irritation, sneezing, prolonged rhinorrhea, nasal congestion;
? throat: local irritation, redness, dryness, effect on the voice;
? lower airways (lung): coughing, dyspnoea/wheeze, clinically relevant decreases in breathing frequency and/or peripheral oxygen saturation (measured by pulse-oximetry during nebulisation) and/or decreases in spirometry (FEV1).
o Central safety (i.e. nausea, vomiting, emesis)
o Gastrointestinal safety/tolerability (i.e., abdominal discomfort or pain and/or diarrhoea).
o Cardiovascular safety (i.e., clinically relevant effects on heart rate & rhythm, and conduction times; and sitting blood pressure )
? 12-lead ECG (rhythm and conduction times- with particular care given to the QTc interval);
? ECG telemetry ;
? Blood pressure and heart rate
o Blood chemistry safety by standard clinical assessment
o Full haematological assessment
o Other of any symptoms and adverse events throughout the study
o Subjective tolerability (i.e., taste, aftertaste, and smell as well as nasal irritation) throughout the study
• Plasma concentrations of RPL554.
• RPL554 concentration in exhaled breath condensate (EBC)
• To determine the pharmacokinetics of RPL554 from blood analysis including relationship between PK and bronchodilation; and the relationship between PK and any AEs observed over time.
• Quality of life question: the patients will be asked if “How do you feel compared to the previous day” with regards to the asthma condition. Patients will also be contacted 3 days after the last study day and a similar question “How do you feel compared to how you felt during the study days” will be asked. This will be a multiple choice question and the only possible answers are 1) better; 2) same; 3) worse.

Timepoint(s) of evaluation of this end point: ECG telemetry up to approximately 2 h post-dosing. Blood pressure and heart rate at pre-dosing, during dosing and post-dosing at regular intervals up to approximately 2 h post-dosing on Day -1, 1, 3 and 6 and to approximately 6 h post-dosing on Day 2, 4, 5. Blood hem and chem on Day -1, 1, 3, 6 and on Day 7. Plasma concentrations of RPL554 at pre-dosing, 10 min, 15 min, 30 min, 1 h and 2 h on each of 6 days and in addition at 4 h and 6 h on Day 1, 3, and 6, and on day 7 (24 hours after the last dose). Other of any symptoms and adverse events throughout the study. Subjective tolerability throughout the study. RPL554 concentration in EBC collected at 30 min and 2 h after dosing on day 2. Quality of life question: At the end of Day -1 through to Day 7 and 3 days after the last study day.

Secondary ID(s)

VRP110330

CHDR1108

Source(s) of Monetary Support

Verona Pharma plc