Asthma, Common Cold, Picornaviridae Infections, Rhinovirus
Conditions
Keywords
CRTH2 antagonist, Prostaglandin D2 receptor, Anti-Asthmatic Agents, OC459, Allergic asthma, Eosinophilia
Brief summary
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
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.
Interventions
Sponsors
Medical Research Council
Atopix Therapeutics, Ltd.
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Lower Respiratory Symptom Score | During 14 days following rhinovirus inoculation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Peak Expiratory Flow Rate | Baseline and up to 14 days post rhinovirus inoculation | Percentage change from baseline (rhinovirus inoculation, day 0) to trough during infection (up to day 14) |
| Change in Forced Expiratory Volume in 1 Second (FEV1) | Baseline and up to 14 days post rhinovirus inoculation | Percentage change from baseline (rhinovirus inoculation, day 0) to trough during infection (up to day 14) |
| Change in Exhaled Nitric Oxide (FeNO) | Baseline and up to 10 days post rhinovirus inoculation | Percentage change from baseline (rhinovirus inoculation, day 0) to peak during infection (highest of measurements on days 3, 5, 7, 10 post inoculation) |
| Change in Asthma Control Questionnaire (ACQ)-6 Score | Baseline, 10 days post rhinovirus inoculation | 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. |
| Viral Load (in Nasal Lavage Samples) | Up to 14 days post rhinovirus inoculation | Peak during infection (up to day 14) |
| Total Upper Respiratory Symptom Score | During 14 days following rhinovirus inoculation | 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. |
| Changes in Airway Hyper Responsiveness (Histamine) | Baseline and 7 days post rhinovirus inoculation | 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 |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| OC459 (CRTH2 Antagonist) OC459 50mg once daily for 5 weeks
Rhinovirus: Inoculation with rhinovirus serotype 16 | 16 |
| Placebo Placebo tablet once daily for 5 weeks
Rhinovirus: Inoculation with rhinovirus serotype 16 | 14 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | no rhinovirus infection | 4 | 4 |
Baseline characteristics
| Characteristic | OC459 (CRTH2 Antagonist) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 25.3 years STANDARD_DEVIATION 8.9 | 25.4 years STANDARD_DEVIATION 3.8 | 25.3 years STANDARD_DEVIATION 6.9 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 18 Participants |
| Sex: Female, Male Male | 7 Participants | 5 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 |
| other Total, other adverse events | 4 / 22 | 2 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 |
Outcome results
Primary
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.
Time frame: During 14 days following rhinovirus inoculation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OC459 (CRTH2 Antagonist) | Total Lower Respiratory Symptom Score | 21 score on a scale |
| Placebo | Total Lower Respiratory Symptom Score | 18 score on a scale |
p-value: 0.78Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: Baseline, 10 days post rhinovirus inoculation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OC459 (CRTH2 Antagonist) | Change in Asthma Control Questionnaire (ACQ)-6 Score | -0.01 score on a scale | Standard Deviation 0.68 |
| Placebo | Change in Asthma Control Questionnaire (ACQ)-6 Score | 0.17 score on a scale | Standard Deviation 0.71 |
p-value: 0.49t-test, 2 sided
Secondary
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)
Time frame: Baseline and up to 10 days post rhinovirus inoculation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OC459 (CRTH2 Antagonist) | Change in Exhaled Nitric Oxide (FeNO) | 58 percentage change |
| Placebo | Change in Exhaled Nitric Oxide (FeNO) | 23 percentage change |
p-value: 0.12Wilcoxon (Mann-Whitney)
Secondary
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)
Time frame: Baseline and up to 14 days post rhinovirus inoculation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OC459 (CRTH2 Antagonist) | Change in Forced Expiratory Volume in 1 Second (FEV1) | -18.5 percentage change | Standard Deviation 11.3 |
| Placebo | Change in Forced Expiratory Volume in 1 Second (FEV1) | -12.7 percentage change | Standard Deviation 14 |
p-value: 0.36t-test, 2 sided
Secondary
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
Time frame: Baseline and 7 days post rhinovirus inoculation
Population: Two subjects (one from each group) were unable to complete PC20 at one of the time points for logistical reasons
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OC459 (CRTH2 Antagonist) | Changes in Airway Hyper Responsiveness (Histamine) | -0.1 mg/mL |
| Placebo | Changes in Airway Hyper Responsiveness (Histamine) | -0.64 mg/mL |
p-value: 0.12Wilcoxon (Mann-Whitney)
Secondary
Percentage Change in Peak Expiratory Flow Rate
Percentage change from baseline (rhinovirus inoculation, day 0) to trough during infection (up to day 14)
Time frame: Baseline and up to 14 days post rhinovirus inoculation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OC459 (CRTH2 Antagonist) | Percentage Change in Peak Expiratory Flow Rate | -16.9 percentage change | Standard Deviation 10.2 |
| Placebo | Percentage Change in Peak Expiratory Flow Rate | -13.1 percentage change | Standard Deviation 12.8 |
p-value: 0.5t-test, 2 sided
Secondary
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.
Time frame: During 14 days following rhinovirus inoculation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OC459 (CRTH2 Antagonist) | Total Upper Respiratory Symptom Score | 33 score on a scale |
| Placebo | Total Upper Respiratory Symptom Score | 41 score on a scale |
p-value: 0.66Wilcoxon (Mann-Whitney)
Secondary
Viral Load (in Nasal Lavage Samples)
Peak during infection (up to day 14)
Time frame: Up to 14 days post rhinovirus inoculation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OC459 (CRTH2 Antagonist) | Viral Load (in Nasal Lavage Samples) | 445861 viral copies / mL |
| Placebo | Viral Load (in Nasal Lavage Samples) | 215782 viral copies / mL |
p-value: 0.75Wilcoxon (Mann-Whitney)