E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001705 |
E.1.2 | Term | Allergic asthma |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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). |
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E.2.2 | Secondary objectives of the trial |
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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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) |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Lung function: FEV1 (Forced Expiratory Volume in the first second) |
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E.5.1.1 | 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. |
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E.5.2 | 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. |
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E.5.2.1 | 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |