Healthy Volunteers
Conditions
Keywords
normal
Brief summary
This research study will test different doses of RG-HRV16 to find the minimum dose needed to give research subjects cold symptoms of at least moderate intensity. The study will also test the safety of RG-HRV16. This information will be used in future studies (for example, to test antiviral preparations, sprays that could protect from getting a cold or decrease cold symptoms or to understand more about how rhinovirus can lead to asthma worsening). RG-HRV16 is a common cold virus that has been made in a new way and has not been used in humans before.
Detailed description
Rhinoviruses are the most frequently cause of the common cold. HRV16 (Family Picornaviridae Genus Rhinovirus type 16) has been used extensively to induce colds in studies of experimentally inoculated volunteers that are designed to study the pathogenesis of colds and effects of antiviral medications. Experimental inoculation with human rhinovirus type 16 (HRV16) administered intranasally via aerosolization has been used at the University of Wisconsin for over 30 years, and has proven to be a safe tool to reproducibly induce symptomatic colds. HRV has been linked with exacerbations of asthma and COPD, and this model has been used to evaluate inflammatory mechanisms and to test the efficacy of treatments for the common cold. Recent refinements in the technology available to produce and safety test reagents that are intended to be administered to human volunteers as part of research protocols has prompted us to produce a new lot of HRV16 in accordance with standards of current Good Manufacturing Procedures (cGMP). For this inoculum, we have used a cDNA clone (reverse genetics) to generate source virus, thus this new virus inoculum will be referred to as RG-HRV16. This approach has two main advantages over using viruses isolated from nasal secretions. First, several new respiratory viruses (e.g. metapneumovirus, bocavirus, SARS, rhinovirus group C) have been discovered in the past 10 years, and there is little doubt that additional viruses will be discovered. Therefore, it is impossible to ensure that nasal secretions that are chosen for isolation of seed virus contain only the pathogen of interest. This problem is minimized through the use of virus derived from a cDNA clone that was produced in E. coli. Second, RNA viruses, such as HRV, mutate as the virus grows because their RNA polymerases have no error-correcting function. The cDNA clone, reproduced by the much more accurate E. coli DNA polymerase, provides a stable source of virus sequence for production of future inocula. This study represents a first-in-human, phase 1 study to assess the safety of RG-HRV16 in humans and identify the dose needed to produce moderate-to-severe colds in 75% of HRV16-seronegative human volunteers.
Interventions
BIOLOGICALRG-HRV16
A suspension of the RG-HRV16 virus in Minimal Essential Media (MEM, HyClone) containing 0.1% Human Serum Albumin
DRUGPlacebo
The placebo to be used will be Minimal Essential Media (MEM, HyClone) containing 0.1% Human Serum Albumin. Placebo will be supplied in 2 ml borosilicate glass vials sealed with butyl stoppers containing 0.5 ml.
Sponsors
University of Wisconsin, Madison
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Capable and willing to grant written informed consent (in English) and cooperate with study procedures and requirements including willingness to avoid cold symptom medications during the study. 2. Age between 18 and 50 years (children and older adults will be excluded from the study due to the possibility of greater morbidity associated with upper respiratory infections in these age groups). 3. Absence of HRV16 neutralizing antibody. 4. Safety laboratory assessments within normal University of WI Hospital and Clinics (UWHC) ranges or grade 1 (mild) laboratory abnormalities which are deemed not clinically significant in the judgment of the PI. Labs to include CBC with differential and platelets, BUN, creatinine, AST, ALT and IgA and IgG serum immunoglobulins. Any lymphopenia outside of the normal range will be an absolute exclusion. 5. Subjects must be willing to refrain from taking nasal decongestants, antihistamines or cough/cold preparations (this includes dietary supplements and homeopathic preparations used specifically for cold/flu e.g., vitamin C, zinc, echinacea) within the 7 days prior to Visit 1 and throughout the study until after the completion of Visit 5.
Exclusion criteria
1. A chronic medical condition, which may increase risk or interfere with the conduct of the study, including, but not limited to heart disease, Type I of II diabetes mellitus, asthma, COPD, other chronic lung disease, perennial rhinitis and chronic rhinosinusitis. 2. Subjects with household contacts who are pregnant or planning a pregnancy during the main subject's participation, who have chronic respiratory disease, who are children under the age of 2 years, or who are adults over 50 years of age. 3. Subjects who provide healthcare services or work with elderly or children (e.g. daycare provider, senior citizen care giver). 4. Subjects with seasonal allergies will be excluded only if allergy symptoms are present at baseline, or are anticipated to occur during the study period. 5. Smoking within the past 6 months. 6. Subjects who have received immunosuppressive treatment within the last 12 months. 7. Upper respiratory infection (URI or sinusitis) in the past 4 weeks. 8. Subjects with a history of a significant adverse reaction or intolerance to a previous live, attenuated vaccine. 9. Pregnant or breastfeeding women or a woman who has a planned pregnancy during the course of the study. 10. Unwillingness of study participants to use adequate birth control methods during the course of the study. Adequate birth control methods include oral contraceptives, injections such as Depo-Provera, an intrauterine device or double-barrier contraception (combination of condom and contraceptive sponge or cervical cap and spermicide or another combination approved in writing by the Principal Investigator).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Adverse Events | 4 weeks | Safety as determined by the frequency of adverse event reporting examined by RG-HRV16 dose. |
| Number of Participants With Colds With at Least Moderate Intensity | 1 week | The percentage of colds of at least moderate intensity examined by RG-HRV16 dose; this will be measured by the number of subjects per RG-HRV16 dose group who have maximum weekly cold symptom score of ≥7 out of 39 on the modified Jackson criteria during the first week after inoculation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Cold Symptom Score | 4 weeks | The Mean Cold Symptom Score induced by each RG-HRV16 dose and by the placebo inoculation. The scale is called the Jackson Criteria for Cold Symptom Assessment. There are 13 variables of cold symptoms that each participant scores 0 (not present), 1 (mild), 2 (moderate) to 3 (severe), twice per day, once at 8am and once at 8pm. The 13 variables are: cough, nasal discharge, sneezing, stuffy nose, sore throat, headache, malaise, chilliness, shaking chills, fever, laryngitis, aching joints or muscles, and watery/burning eyes. The scores are added up for each time point, with a minimum score of 0 and a max score of 39 per time point. The highest score per day is taken and the highest score over the 7 day period starting from the day of the inoculation and for 7 days is deemed the mean cold symptom score. The higher the score, the more cold symptoms the participant reports and the worse the participant feels. |
| Infection Rate | 4 weeks | Infection rate per RG-HRV16 dose as measured by the percentage of individuals in the dosing group with detectable viral shedding. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 100 TCID50 RG-HRV16 dose of 100 TCID50 administered intranasally (0.25ml per nostril) one time.
RG-HRV16: A suspension of the RG-HRV16 virus in Minimal Essential Media (MEM, HyClone) containing 0.1% Human Serum Albumin | 10 |
| 500 TCID50 RG-HRV16 dose of 500 TCID50 administered intranasally (0.25ml per nostril) one time.
RG-HRV16: A suspension of the RG-HRV16 virus in Minimal Essential Media (MEM, HyClone) containing 0.1% Human Serum Albumin | 6 |
| 1,000 TCID50 RG-HRV16 dose of 1,000 TCID50 administered intranasally (0.25ml per nostril) one time.
RG-HRV16: A suspension of the RG-HRV16 virus in Minimal Essential Media (MEM, HyClone) containing 0.1% Human Serum Albumin | 10 |
| 10,000 TCID50 RG-HRV16 dose of 10,000 TCID50 administered intranasally (0.25ml per nostril) one time.
RG-HRV16: A suspension of the RG-HRV16 virus in Minimal Essential Media (MEM, HyClone) containing 0.1% Human Serum Albumin | 0 |
| Placebo Diluent administered intranasally (0.25ml per nostril) one time.
Placebo: The placebo to be used will be Minimal Essential Media (MEM, HyClone) containing 0.1% Human Serum Albumin. Placebo will be supplied in 2 ml borosilicate glass vials sealed with butyl stoppers containing 0.5 ml. | 10 |
| Total | 36 |
Baseline characteristics
| Characteristic | 100 TCID50 | 500 TCID50 | 1,000 TCID50 | 10,000 TCID50 | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 6 Participants | 10 Participants | 0 Participants | 10 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 5 Participants | 10 Participants | 0 Participants | 10 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 4 Participants | 8 Participants | 0 Participants | 10 Participants | 32 Participants |
| Region of Enrollment United States | 10 participants | 6 participants | 10 participants | — | 10 participants | 36 participants |
| Sex: Female, Male Female | 8 Participants | 3 Participants | 6 Participants | 0 Participants | 9 Participants | 26 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 4 Participants | 0 Participants | 1 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 6 | 0 / 10 | 0 / 0 | 0 / 10 |
| other Total, other adverse events | 4 / 10 | 1 / 6 | 5 / 10 | 0 / 0 | 3 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 6 | 0 / 10 | 0 / 0 | 0 / 10 |
Outcome results
Primary
Frequency of Adverse Events
Safety as determined by the frequency of adverse event reporting examined by RG-HRV16 dose.
Time frame: 4 weeks
Population: The trial completed and met its goal before needing to enroll into the 10,000 TCID50 group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 100 TCID50 | Frequency of Adverse Events | 4 Participants |
| 500 TCID50 | Frequency of Adverse Events | 1 Participants |
| 1,000 TCID50 | Frequency of Adverse Events | 5 Participants |
| 10,000 TCID50 | Frequency of Adverse Events | 0 Participants |
| Placebo | Frequency of Adverse Events | 3 Participants |
Primary
Number of Participants With Colds With at Least Moderate Intensity
The percentage of colds of at least moderate intensity examined by RG-HRV16 dose; this will be measured by the number of subjects per RG-HRV16 dose group who have maximum weekly cold symptom score of ≥7 out of 39 on the modified Jackson criteria during the first week after inoculation
Time frame: 1 week
Population: The trial completed and met its goal before needing to enroll into the 10,000 TCID50 group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 100 TCID50 | Number of Participants With Colds With at Least Moderate Intensity | 4 Participants |
| 500 TCID50 | Number of Participants With Colds With at Least Moderate Intensity | 2 Participants |
| 1,000 TCID50 | Number of Participants With Colds With at Least Moderate Intensity | 7 Participants |
| 10,000 TCID50 | Number of Participants With Colds With at Least Moderate Intensity | 0 Participants |
| Placebo | Number of Participants With Colds With at Least Moderate Intensity | 0 Participants |
Secondary
Infection Rate
Infection rate per RG-HRV16 dose as measured by the percentage of individuals in the dosing group with detectable viral shedding.
Time frame: 4 weeks
Population: The trial completed and met its goal before needing to enroll into the 10,000 TCID50 group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 100 TCID50 | Infection Rate | 10 Participants |
| 500 TCID50 | Infection Rate | 6 Participants |
| 1,000 TCID50 | Infection Rate | 10 Participants |
| 10,000 TCID50 | Infection Rate | 0 Participants |
| Placebo | Infection Rate | 0 Participants |
Secondary
Mean Cold Symptom Score
The Mean Cold Symptom Score induced by each RG-HRV16 dose and by the placebo inoculation. The scale is called the Jackson Criteria for Cold Symptom Assessment. There are 13 variables of cold symptoms that each participant scores 0 (not present), 1 (mild), 2 (moderate) to 3 (severe), twice per day, once at 8am and once at 8pm. The 13 variables are: cough, nasal discharge, sneezing, stuffy nose, sore throat, headache, malaise, chilliness, shaking chills, fever, laryngitis, aching joints or muscles, and watery/burning eyes. The scores are added up for each time point, with a minimum score of 0 and a max score of 39 per time point. The highest score per day is taken and the highest score over the 7 day period starting from the day of the inoculation and for 7 days is deemed the mean cold symptom score. The higher the score, the more cold symptoms the participant reports and the worse the participant feels.
Time frame: 4 weeks
Population: For the manuscript, the 500 TCID50 group was excluded from this analysis due to incomplete data that could not be analyzed appropriately.~The trial completed and met its goal before needing to enroll into the 10,000 TCID50 group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 100 TCID50 | Mean Cold Symptom Score | 7.5 peak symptom score | Standard Deviation 5 |
| 500 TCID50 | Mean Cold Symptom Score | 7.3 peak symptom score | Standard Deviation 1.9 |
| 1,000 TCID50 | Mean Cold Symptom Score | 11.4 peak symptom score | Standard Deviation 7.8 |
| Placebo | Mean Cold Symptom Score | 1.9 peak symptom score | Standard Deviation 1.7 |