Effect of OC459 on the Response to Rhinovirus Challenge in Asthma

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT02660489
• Collaborator: Medical Research Council (Other), Atopix Therapeutics, Ltd. (Industry)
• Enrollment: 44
• Location: 1
• Arms: 2
• Actual Duration (Months): 37
• Patients Per Site Per Month: 1.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Asthma; Rhinovirus; Picornaviridae Infections; Common Cold	Drug: OC459; Drug: Placebo; Other: Rhinovirus	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of the CRTH2 Antagonist OC459 on the Response to Rhinovirus Challenge in Asthma
• Actual Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Feb 1, 2018
• Actual Study Completion Date: Feb 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: OC459 (CRTH2 antagonist) OC459 50mg once daily for 5 weeks	Drug: OC459; Other Names: OC000459 ; Other: Rhinovirus; Inoculation with rhinovirus serotype 16
Placebo Comparator: Placebo Placebo tablet once daily for 5 weeks	Drug: Placebo; Other: Rhinovirus; Inoculation with rhinovirus serotype 16

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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)

3. 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)

4. 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)

5. 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

6. Viral Load (in Nasal Lavage Samples) [Up to 14 days post rhinovirus inoculation]

   Peak during infection (up to day 14)

7. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St Mary's Hospital	London	Greater London	United Kingdom	W2 1PG

Sponsors and Collaborators

• Imperial College London
• Medical Research Council
• Atopix Therapeutics, Ltd.

Investigators

• Principal Investigator: Sebastian L Johnston, MBBS PhD, National Heart & Lung Institute, Imperial College London

Study Documents (Full-Text)

• Study Protocol - Jul 4, 2017
• Statistical Analysis Plan - Mar 13, 2018

More Information

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT02660489
• Other Study ID Numbers: ORCA2015
• First Posted: Jan 21, 2016
• Last Update Posted: Feb 26, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Imperial College London: CRTH2 antagonist; Prostaglandin D2 receptor; Anti-Asthmatic Agents; OC459; Allergic asthma; Eosinophilia
• Additional relevant MeSH terms: Common Cold; Picornaviridae Infections; Asthma

Study Results

Participant Flow

Arm/Group Title	OC459 (CRTH2 Antagonist)	Placebo
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16
Period Title: Overall Study
STARTED	22	22
COMPLETED	16	14
NOT COMPLETED	6	8

Baseline Characteristics

Arm/Group Title	OC459 (CRTH2 Antagonist)	Placebo	Total
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Total of all reporting groups
Overall Participants	16	14	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.3 (8.9)	25.4 (3.8)	25.3 (6.9)
Sex: Female, Male (Count of Participants)
Female	9 56.3%	9 64.3%	18 60%
Male	7 43.8%	5 35.7%	12 40%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Total Lower Respiratory Symptom Score
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	OC459 (CRTH2 Antagonist)	Placebo
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16
Measure Participants	16	14
Median (Inter-Quartile Range) [score on a scale]	21	18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OC459 (CRTH2 Antagonist), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Change in Asthma Control Questionnaire (ACQ)-6 Score
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	OC459 (CRTH2 Antagonist)	Placebo
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16
Measure Participants	16	14
Mean (Standard Deviation) [score on a scale]	-0.01 (0.68)	0.17 (0.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OC459 (CRTH2 Antagonist), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Percentage Change in Peak Expiratory Flow Rate
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	OC459 (CRTH2 Antagonist)	Placebo
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16
Measure Participants	16	14
Mean (Standard Deviation) [percentage change]	-16.9 (10.2)	-13.1 (12.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OC459 (CRTH2 Antagonist), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.50
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Change in Forced Expiratory Volume in 1 Second (FEV1)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	OC459 (CRTH2 Antagonist)	Placebo
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16
Measure Participants	16	14
Mean (Standard Deviation) [percentage change]	-18.5 (11.3)	-12.7 (14.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OC459 (CRTH2 Antagonist), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Change in Exhaled Nitric Oxide (FeNO)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	OC459 (CRTH2 Antagonist)	Placebo
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16
Measure Participants	16	14
Median (Inter-Quartile Range) [percentage change]	58	23

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OC459 (CRTH2 Antagonist), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Changes in Airway Hyper Responsiveness (Histamine)
Description	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

Outcome Measure Data

Analysis Population Description

Two subjects (one from each group) were unable to complete PC20 at one of the time points for logistical reasons

Arm/Group Title	OC459 (CRTH2 Antagonist)	Placebo
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16
Measure Participants	15	13
Median (Inter-Quartile Range) [mg/mL]	-0.1	-0.64

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OC459 (CRTH2 Antagonist), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Viral Load (in Nasal Lavage Samples)
Description	Peak during infection (up to day 14)
Time Frame	Up to 14 days post rhinovirus inoculation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	OC459 (CRTH2 Antagonist)	Placebo
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16
Measure Participants	16	14
Median (Full Range) [viral copies / mL]	445861	215782

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OC459 (CRTH2 Antagonist), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Total Upper Respiratory Symptom Score
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	OC459 (CRTH2 Antagonist)	Placebo
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16	Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16
Measure Participants	16	14
Median (Inter-Quartile Range) [score on a scale]	33	41

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OC459 (CRTH2 Antagonist), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.66
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	9 weeks
Adverse Event Reporting Description	Participants were asked to record adverse events in a study diary that was completed daily. Participants were also asked about adverse events at study visits.
Arm/Group Title	OC459 (CRTH2 Antagonist)		Placebo
Arm/Group Description	OC459 50mg once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16		Placebo tablet once daily for 5 weeks Rhinovirus: Inoculation with rhinovirus serotype 16
All Cause Mortality
	OC459 (CRTH2 Antagonist)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/22 (0%)
Serious Adverse Events
	OC459 (CRTH2 Antagonist)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	OC459 (CRTH2 Antagonist)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/22 (18.2%)		2/22 (9.1%)
Nervous system disorders
Headache	4/22 (18.2%)	17	2/22 (9.1%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.