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) in 16 allergic asthmatics.
ID
Source
Brief title
Condition
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The lungfunction will be measured by means of spirometry in which the FEV1 will
be assessed during 6 hours on day 1, 3 and 6
Secondary outcome
Respiratory safety (i.e., effects on the upper and lower airways):
Gastrointestinal safety/tolerability (i.e., nausea, vomiting, and abdominal
pain or diarrhea).
Cardiovascular safety (i.e., clinically relevant effects on heart rate &
rhythm, and conduction times; and sitting blood pressure Blood chemistry safety
by standard clinical assessment Full hematological assessment (i.e., cell
counts and coagulation status)
Symptoms and all adverse events Subjective tolerability (i.e., taste,
aftertaste, and smell as well as nasal irritation)
Pharmacokinetic measures, e.g. Cmax
Adverse Events
Drug and metabolite concentrations in urine samples
To explore the possibility of measuring RPL554 concentrations in exhaled breath
condensate.
Subjective measure: To explore the effect on quality of life of RPL554
Background summary
RPL554 is a dual inhibitor of two subtypes (3 and 4) of phosphodiesterase (PDE)
enzymes. These two subtypes are known to have a role in modulating the
inflammatory airway response in respiratory diseases, including allergic asthma
and rhinitis. PDE3 inhibitors act mostly as bronchodilators, while PDE4
inhibitors have anti-inflammatory properties. Pharmacological evidence from
animal experiments suggests that RPL554 may have potential therapeutic activity
in both allergic asthma and rhinitis. A recent combined phase I/IIa study,
designed to explore the safety and clinical efficacy of RPL554 in the dose
ranges between 0.003 to 0.072 mg/kg, in an adaptive design, has been recently
finalized at the Centre for Human Drug Research, Leiden, the Netherlands. In
this study, RPL554 was found to be both safe and already effective at single
inhaled doses (0.003 - 0.018 mg/kg) in 18 healthy volunteers, 16 allergic
asthmatics and 10 allergic rhinitics. In 16 males with clinically stable, mild
to moderate allergic asthma, a single inhaled dose of RPL554 (3X dose = 0.009
mg/kg and 6X dose = 0.018 mg/kg) showed potent bronchodilator effects,
producing a maximal 15% mean increase in FEV1 from baseline along with broncho
protective properties, increasing the PC20Methacholine by a mean increase of
almost 1.5 doubling doses versus placebo.
In a more recent study, also conducted at CHDR in Leiden, two cohorts with each
10 allergic asthmatics received a single dose of 0.036 mg/kg (12X) or 0.072
mg/kg (24X) respectively. The aim of the study was to assess the safety and
efficacy of higher doses of RPL554 compared to the previous study. The maximum
increase in long function of these two doses was comparable to the increase in
long function observed on another study with 0.018 mg/kg (6X). There were no
significant side effects apart from a observed increase in heart frequency in
the 0.072mg/kg dosing group.
Future studies with PRL554 are planned to assess its anti inflammatory
properties in which RPL554 will be dosed on a daily basis. These studies will
only be implemented is the occurrence of tachyphylaxis is ruled out in the
present study.
Study 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) in 16 allergic asthmatics.
Study design
This single-blind single-arm trial. The study will consist of a single-arm
active treatment assessing the safety and efficacy of (maximally 6) repeated
inhaled daily RPL554 doses (0.018 mg/kg) in patients with clinically stable,
allergic asthma, not on topical or systemic antiinflammatory therapy. The lung
fuction on day 1 will be compared with the long function on day 3 and 6.
Intervention
RPL554 or placebo
Study burden and risks
During the screening clinical significant abnormalities might be discovered,
while during the study after the methacholine the patients may develop
dyspnoea.
100 Borough High Street
London, UK SE1 1LB
GB
100 Borough High Street
London, UK SE1 1LB
GB
Listed location countries
Age
Inclusion criteria
Males.
Non-smokers .
Documented history of mild to moderate persistent asthma, currently controlled by beta-agonists on an *as needed* basis only.
Clinically stable asthma / baseline prebronchodilator FEV1 values within 10% (i.e. study day 1 compared to screening).
Pre-bronchodilator FEV1 >=70% of predicted.
Bronchial hyperresponsiveness to inhaled Methacholine (MBr or MCh) with a PC20Meth of <=8 mg/mL at screening.
Documented allergy by a standardized Skin Prick Test (SPT).
Reversibility in lung function for salbutamol.
Healthy.
Exclusion criteria
Desensitization therapy in the past 5 years.
Severe exacerbation requiring hospital evaluation.
Unstable/uncontrolled disease within 3 weeks of participation in the study.
History or clinical evidence of any disease.
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.
Excessive caffeine consumption.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-001698-22-NL |
| CCMO | NL36479.056.11 |