Effect of OC459 on the Response to Rhinovirus Challenge in Asthma

Study Overview
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Brief Summary
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The aim of this study is to assess the effectiveness of a CRTH2 receptor antagonist, OC459, in preventing or attenuating the worsening of asthma symptoms during rhinovirus infection. The study is a double blind, randomised trial in which half the subjects will receive OC459 and the other half placebo, before being inoculated with rhinovirus, that would normally induce a worsening of asthma symptoms i.e. an exacerbation.

Detailed Description
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Asthma is the most common chronic respiratory disease, and in many countries prevalence is rising. The major morbidity, mortality and health care costs related to asthma are a result of periods of acutely increased symptomatology called 'exacerbations'. Most exacerbations are caused by rhinovirus, the virus associated with the common cold. There are few treatments to prevent and treat exacerbations, and despite these >50% of adult asthmatics reported having an exacerbation in the last year. There is therefore a major unmet need. Experimentally inoculating patients with asthma with rhinovirus, a methodology that has been safely used for >15 years, induces an infection and worsening symptoms in  85%. This model offers the possibility to investigate treatment effects on asthma exacerbations with a small number of subjects, minimising the numbers exposed to a novel drug with limited safety data. In contrast, trials of therapies powered to evaluate an effect on naturally occurring exacerbations require several hundred subjects, a long study period to capture enough events, and are significantly more expensive to carry out. Using this model the investigators have shown that several inflammatory molecules, including prostaglandin D2 (PGD2), are significantly increased during rhinovirus-induced asthma exacerbations, with the levels of PGD2 strongly correlating with the severity of the symptoms. Moreover other studies have shown that when PGD2 binds the CRTH2 receptor, it stimulates the release of a number of inflammatory molecules also associated with asthma exacerbations. Blocking the CRTH2 receptor therefore appears an extremely promising target with potential to limit the virus-induced inflammation underpinning many asthma exacerbations.

Official Title
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Effect of the CRTH2 Antagonist OC459 on the Response to Rhinovirus Challenge in Asthma

Conditions
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Asthma, Rhinovirus, Picornaviridae Infections, Common Cold

Intervention / Treatment
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* Drug: OC459
* Drug: Placebo
* Other: Rhinovirus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18--55 years Male or female Clinical diagnosis of asthma for at least 6 months prior to screening An Asthma Control Questionnaire (ACQ) Score >0.75 Positive histamine challenge test (PC20 <8 µg/ml, or <12 µg/ml and bronchodilator response ≥ 12%) Worsening asthma symptoms with infection since last change in asthma therapy Positive skin prick test to common aeroallergens (e.g. animal epithelia, dust mite) Treatment comprising inhaled corticosteroids (ICS) or combination inhaler (Long -Acting Beta Agonist with ICS), with a daily ICS dose of at least 100mcg fluticasone or equivalent. Participant is willing for their GP to be informed of their participation. English speaker Exclusion Criteria: Presence of clinically significant diseases other than asthma, which, in the opinion of the investigator, may either put the patient at risk because of participation in the trial, or diseases which may influence the results of the study or the patient's ability to take part in it Smoking history over past 12 months Seasonal allergic rhinitis symptoms at screening Asthma exacerbation or viral illness within the previous 6 weeks Current or concomitant use of oral steroids, anti--leukotrienes or monoclonal antibodies Pregnant or breast-feeding women (patients should not be enrolled if they plan to become pregnant during the time of study participation) Contact with infants <6 months or immunocompromised persons, elderly and infirm at home or at work Subjects who have known evidence of lack of adherence to medications and/or ability to follow physician's recommendations

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OC459 (CRTH2 antagonist)<br>OC459 50mg once daily for 5 weeks | Drug: OC459<br> <br> * Other names: OC000459;Other: Rhinovirus<br>* Inoculation with rhinovirus serotype 16<br>|
| Placebo Comparator: Placebo<br>Placebo tablet once daily for 5 weeks | Drug: Placebo<br> <br> Other: Rhinovirus<br>* Inoculation with rhinovirus serotype 16<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Lower Respiratory Symptom Score | Sum of daily scores for 14 days. Seven symptoms (cough on waking, wheeze on waking, daytime cough, daytime wheeze, daytime chest tightness, daytime breathlessness, nocturnal cough/wheeze/breathlessness) ranked from 0 (none) to 3 (severe). Range 0 to 294; higher is more symptomatic. | During 14 days following rhinovirus inoculation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Asthma Control Questionnaire (ACQ)-6 Score | Change from baseline (rhinovirus inoculation, day 0) to day 10. The ACQ was developed to measure the adequacy of asthma control in clinical research and in clinical practice. The ACQ-6 asks subjects to grade their asthma control, assessed through six questions, over the previous seven days. Each question is rated on a seven-point scale ranging from 0 (well controlled) to six (extremely poorly controlled). The ACQ-6 score is the mean of the scores on the 6 items. Mean scores of =<0.75 indicate well-controlled asthma, scores between 0.76 and < 1.5 indicate partly controlled asthma, and a score >= 1.5 indicates uncontrolled asthma. | Baseline, 10 days post rhinovirus inoculation | 
| Percentage Change in Peak Expiratory Flow Rate | Percentage change from baseline (rhinovirus inoculation, day 0) to trough during infection (up to day 14) | Baseline and up to 14 days post rhinovirus inoculation | 
| Change in Forced Expiratory Volume in 1 Second (FEV1) | Percentage change from baseline (rhinovirus inoculation, day 0) to trough during infection (up to day 14) | Baseline and up to 14 days post rhinovirus inoculation | 
| Change in Exhaled Nitric Oxide (FeNO) | Percentage change from baseline (rhinovirus inoculation, day 0) to peak during infection (highest of measurements on days 3, 5, 7, 10 post inoculation) | Baseline and up to 10 days post rhinovirus inoculation | 
| Changes in Airway Hyper Responsiveness (Histamine) | Assessed as the provocation concentration of histamine producing a 20% fall in FEV1, or PC20 Change from baseline (rhinovirus inoculation, day 0) to day 7 | Baseline and 7 days post rhinovirus inoculation | 
| Viral Load (in Nasal Lavage Samples) | Peak during infection (up to day 14) | Up to 14 days post rhinovirus inoculation | 
| Total Upper Respiratory Symptom Score | Sum of daily scores for 14 days. Eight upper respiratory symptoms (sneezing; runny nose; blocked or stuffy nose; sore throat or hoarse voice; headache or face pain; generally unwell; chill, fever or shivery; cough) ranked from 0 (none) to 3 (severe). Range 0 to 336; higher is more symptomatic. | During 14 days following rhinovirus inoculation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRTH2 antagonist, Prostaglandin D2 receptor, Anti-Asthmatic Agents, OC459, Allergic asthma, Eosinophilia