Evaluating the Asthmatic Response to an Experimental Infection With Rhinovirus in the Atopic
Study Details
Study Description
Brief Summary
In patients with asthma, reactions to allergens in the environment (such as mold, pollen, weed, domestic pets, and dust allergens) play an important role in causing asthma symptoms. However, upper respiratory tract infections, typically those caused by the common cold virus, rhinovirus, can also cause asthma to get worse. In previous studies at the University of Virginia, it was found that mild asthmatics, who had high levels of the allergy antibody (called IgE) in their blood, developed more persistent cold and chest symptoms when they were given an infection with rhinovirus (the most frequent cause of the common cold). The cold symptoms produced by rhinovirus tend to peak during the first 4 -7 days of the cold. These symptoms, including nasal congestion, are similar to what you have experienced with previous colds.
This study is being done to learn how a common cold caused by a viral infection affects people with asthma. The goal is to learn how to improve the care of asthma symptoms caused by the common cold virus (called rhinovirus). Most adults experience one or two colds caused by rhinovirus every year. In addition, 75-80% of asthma exacerbations caused by viral infections are caused by this virus, primarily in children. Adults are less likely to experience significant changes in their asthma symptoms when they get colds, because they have developed protective immune responses from previous colds which help diminish symptoms.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
Using rhinovirus strain 16 (RV-16) for inoculation, this study is designed to examine mechanisms of the asthmatic response to RV in the atopic host. In keeping with this, the primary objective of this investigation will be to test the hypothesis that mild asthmatics enrolled in this study will experience significantly increased lower respiratory tract symptoms over the first 4 days after experimental inoculation with RV-16 than non-allergic, non-asthmatic controls (as shown in our previous studies). It is anticipated that the results will serve to guide the development of new treatments to prevent asthma attacks provoked by RV. This will be a 5 week longitudinal study of 18 young allergic adults with mild asthma and 18 non-asthmatic controls who will be evaluated for 1 week to establish baseline symptoms and lung function, followed by an inoculation with rhinovirus (strain-16) and subsequent clinical and laboratory (mechanistic) monitoring for an additional 4 weeks. To participate in this study, subjects must live within 90 minutes by car from the University of Virginia.
Note: This study has been reviewed and is being monitored for safety by the NIH/NIAID Safety Monitoring Committee and by teh University of Virginia IRB (#12673). The virus pool used for inoculation has been produced under GMP conditions and is approved for this research by the FDA.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Asthmatic subjects Subjects with Asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus. |
Biological: Rhinovirus
|
| Active Comparator: Without Asthma Subjects without asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus |
Biological: Rhinovirus
|
Outcome Measures
Primary Outcome Measures
- Airway Symptom Scores Experienced by Subjects During the 1st 4 Days of the Infection [4 days]
The primary endpoint will be based on the comparison of cumulative lower respiratory tract symptom scores (CLRTS) in the asthmatic subjects compared to the non-asthmatic subjects over the first 4 days of acute infection. The symptoms evaluated daily included wheeze, chest tightness, shortness of breath, and cough. Symptom scores, including wheeze, shortness of breath, and chest discomfort were recorded by subjects twice daily. Each symptom was scored on a scale of 1-3. Therefore, the total maximum (worst) score for a day would be 24. The scores recorded daily could range from 0 to 24.
Secondary Outcome Measures
- Airway Symptom Scores Experienced by Subjects During the 1st 4 Days of the Infection Evaluated Without Cough. [4 days]
Symptom scores, including wheeze, shortness of breath, and chest discomfort were recorded by subjects twice daily. Each symptom was scored on a scale of 1-3. Therefore, the total maximum (worst) score for a day would be 18. The scores recorded daily could range from 0 to 18.
Eligibility Criteria
Criteria
Inclusion Criteria • ALL SUBJECTS:
-
Subjects must be able to understand and provide written informed consent
-
Age 18 to < 40 years of age, any gender, any racial/ethnic origin.
-
Participant must be willing to comply with study procedures and requirements. Participant must be considered eligible for participation based on results of screening procedures conducted by protocol number 20100686 at VCU and IRB# 12656 at UVA.
Subjects with asthma
Criteria for inclusion will include those:
-
with physician-diagnosed, mild asthma who are only using bronchodilators (e.g. albuterol) for symptom control.
-
Asthma Control Test (ACT) Questionnaire Score a > 19 at enrollment (See Appendix: Asthma Control Test).
-
Short-acting beta-agonist use < daily in last 4 weeks
-
FEV1 > 70%, or FEV1/FVC ratio > 75% for subjects with FVC values between 80 and 87% predicted whose FEV1 values fall below 70%. a positive methacholine challenge test (i.e. at least a 20% fall in FEV1) at a methacholine concentration of 16 mg/ml or less (15). The methacholine test will not be done if subjects have used albuterol within 4 hours of the test procedure.Evidence for atopy demonstrated during screening (under IRB protocol# 12656) as judged by positive prick skin tests to one or more aero-allergens.
Control subjects. Criteria for inclusion will include those who do not have a history of asthma or allergic disorders (e.g. allergic rhinitis, atopic dermatitis, or food allergies).
Exclusion Criteria ALL SUBJECTS:
-
Inability or unwillingness of a participant or subject's legal representative to give written informed consent and HIPPA authorization
-
Positive test for serum neutralizing antibody to RV-16. Subjects with a neutralizing antibody titer > 1:4 will be excluded.
-
Chronic heart disease, lung diseases other than asthma, or other chronic illnesses, including primary and/or secondary immunodeficiency.
-
An upper or lower respiratory tract infection within six weeks prior to enrollment
-
Who have required nasal or sinus surgery, excluding surgery for a deviated septum within 12 months prior to enrollment.
-
Who have a 5 pack/year history of smoking, or any smoking within the last 6 months.
-
Female subjects who are or who plan to become pregnant during the study, or who are nursing a baby. Additionally, to be included in this study, a woman of child-bearing potential must have a negative urine pregnancy test at screening, during the run-in, and prior to viral inoculation and agree to use an effective method of birth control such as, but not limited to, birth control pills, contraceptive foam, diaphragm, IUD, abstinence, or condoms.
-
Absolute neutrophil count (ANC) < 1800 cells/mm3 (or 1.8 K/uL) detected during screening within 6 weeks of enrollment.
Subjects with asthma
Criteria for exclusion will include those:
-
Who have required inhaled steroids (used for asthma), nasal steroids (used for allergic rhinitis), cromolyn, nedocromil sodium, ipratropium bromide, or leukotriene modifiers during the month prior to enrollment, oral steroids within 6 weeks of enrollment, omalizumab (Xolair®) within 12 months prior to enrollment, or who are currently using beta adrenergic blocking agents.
-
Who have been hospitalized or treated in the emergency room (unless the treatment involved the use of a bronchodilator only) for asthma within the last three years.
-
To avoid RV-16 inoculations in subjects with more restrictive lung volumes, those whose FVC is < 80% predicted will be excluded. Subjects who are currently receiving allergen immunotherapy (IT), or who have received allergen IT within the last 3 years.
-
Subjects who have had one or more night time awakenings caused by asthma symptoms and/or who have needed their SABA (albuterol) inhaler for asthma symptoms > 4 days during the week before enrollment, or during the week before the inoculation with RV-16.
Control subjects
• Who have a positive methacholine test, or positive prick skin tests at screening under IRB protocol # 12656.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Virginia | Charlottesville | Virginia | United States | 22908 |
Sponsors and Collaborators
- University of Virginia
- National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
- Principal Investigator: Heymann W Peter, MD, University of Virginia
Study Documents (Full-Text)
More Information
Publications
None provided.- 12673
- R01AI020565
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Asthmatic Subjects | Without Asthma |
|---|---|---|
| Arm/Group Description | Subjects with Asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus. Rhinovirus | Subjects without asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus Rhinovirus |
| Period Title: Overall Study | ||
| STARTED | 12 | 14 |
| COMPLETED | 12 | 14 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Asthmatic Subjects | Without Asthma | Total |
|---|---|---|---|
| Arm/Group Description | Subjects with Asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus. Rhinovirus | Subjects without asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus Rhinovirus | Total of all reporting groups |
| Overall Participants | 12 | 14 | 26 |
| Age (years) [Mean (Full Range) ] | |||
| Mean (Full Range) [years] |
24.1
|
21.9
|
22.9
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
9
75%
|
10
71.4%
|
19
73.1%
|
| Male |
3
25%
|
4
28.6%
|
7
26.9%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
12
100%
|
14
100%
|
26
100%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
2
16.7%
|
0
0%
|
2
7.7%
|
| White |
10
83.3%
|
14
100%
|
24
92.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Total IgE level (International Units/ml) [Geometric Mean (Full Range) ] | |||
| Geometric Mean (Full Range) [International Units/ml] |
1239
|
14
|
110
|
| Negative serum antibody to Rhinovirus-16 (Count of Participants) | |||
| Count of Participants [Participants] |
12
100%
|
14
100%
|
26
100%
|
Outcome Measures
| Title | Airway Symptom Scores Experienced by Subjects During the 1st 4 Days of the Infection |
|---|---|
| Description | The primary endpoint will be based on the comparison of cumulative lower respiratory tract symptom scores (CLRTS) in the asthmatic subjects compared to the non-asthmatic subjects over the first 4 days of acute infection. The symptoms evaluated daily included wheeze, chest tightness, shortness of breath, and cough. Symptom scores, including wheeze, shortness of breath, and chest discomfort were recorded by subjects twice daily. Each symptom was scored on a scale of 1-3. Therefore, the total maximum (worst) score for a day would be 24. The scores recorded daily could range from 0 to 24. |
| Time Frame | 4 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| One asthmatic subject completed the study, but was dropped according to protocol because that subject acquired a cold after enrollment, but before rhinovirus inoculation. One subject without asthma was dropped according to protocol, because they did not develop a cold after inoculation with rhinovirus. |
| Arm/Group Title | Asthmatic Subjects | Without Asthma |
|---|---|---|
| Arm/Group Description | Subjects with Asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus. Rhinovirus | Subjects without asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus Rhinovirus |
| Measure Participants | 11 | 13 |
| Mean (95% Confidence Interval) [units on a scale] |
8.72
|
2.77
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Asthmatic Subjects, Without Asthma |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.049 |
| Comments | ||
| Method | Negative binomial regression | |
| Comments | ||
| Title | Airway Symptom Scores Experienced by Subjects During the 1st 4 Days of the Infection Evaluated Without Cough. |
|---|---|
| Description | Symptom scores, including wheeze, shortness of breath, and chest discomfort were recorded by subjects twice daily. Each symptom was scored on a scale of 1-3. Therefore, the total maximum (worst) score for a day would be 18. The scores recorded daily could range from 0 to 18. |
| Time Frame | 4 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| One asthmatic subject completed the study, but was dropped according to protocol because that subject acquired a cold after enrollment, but before rhinovirus inoculation. One subject without asthma was dropped according to protocol, because they did not develop a cold after inoculation with rhinovirus. |
| Arm/Group Title | Asthmatic Subjects | Without Asthma |
|---|---|---|
| Arm/Group Description | Subjects with Asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus. Rhinovirus | Subjects without asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus Rhinovirus |
| Measure Participants | 11 | 13 |
| Mean (95% Confidence Interval) [units on a scale] |
6.09
|
0.08
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Asthmatic Subjects, Without Asthma |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Negative binomial regression | |
| Comments | ||
Adverse Events
| Time Frame | 5 years | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Collection of adverse events is described in our protocol reviewed and approved by our IRB and the NIH. | |||
| Arm/Group Title | Asthmatic Subjects | Without Asthma | ||
| Arm/Group Description | Subjects with Asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus. Rhinovirus | Subjects without asthma whose cold and chest symptoms will be evaluated one week before and 4 weeks after an inoculation with rhinovirus Rhinovirus | ||
All Cause Mortality |
||||
| Asthmatic Subjects | Without Asthma | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | 0/14 (0%) | ||
Serious Adverse Events |
||||
| Asthmatic Subjects | Without Asthma | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | 0/14 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Asthmatic Subjects | Without Asthma | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/12 (16.7%) | 1/14 (7.1%) | ||
| Blood and lymphatic system disorders | ||||
| Neutropenia | 0/12 (0%) | 0 | 1/14 (7.1%) | 2 |
| Gastrointestinal disorders | ||||
| Upset stomach | 1/12 (8.3%) | 1 | 0/14 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Allergic Rhinitis | 1/12 (8.3%) | 1 | 0/14 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT 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.
Results Point of Contact
| Name/Title | Dr. Peter W. Heymann |
|---|---|
| Organization | University of Virginia |
| Phone | 434-242-8209 |
| pwh5a@virginia.edu |
- 12673
- R01AI020565