Common Cold
Conditions
Brief summary
This study evaluates the performance of ColdZyme® mouth spray on prevention and alleviation of induced rhinovirus upper respiratory tract infection in healthy volunteers. Half of participants will receive ColdZyme® mouth spray while the other half will receive placebo.
Detailed description
Common colds can be caused by a number of viruses, e.g. rhinoviruses, coronaviruses, influenza viruses and others. The majority of colds are however caused by rhinovirus infection, which is responsible for up to 80% of all common colds. This study evaluates the effect of creating a physical barrier on the pharyngeal mucosal membrane to prevent or reduce virus cell entry during common cold infection to reduce total virus load and common cold symptoms in vivo in relation to placebo.
Interventions
DEVICEColdZyme® mouth spray
DEVICEPlacebo
Sponsors
Enzymatica AB
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 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male or female subjects between 18-65 years. The investigator judges the definition of healthy by detailed medical history and physical examination. 2. Females of childbearing potential: should use reliable method of birth control. Reliable methods are hormonal contraceptives (combination pills, injections or implants), intrauterine device, condom or declared absence of sexual contact. Post-menopausal woman is defined as absence of menstrual discharge for at least two years. 3. Signed informed consent form prior to any study-related procedures. 4. Willingness and ability to complete the study. 5. Perceived to have had at least one cold per year.
Exclusion criteria
1. Smoker, during the last 12 months. 2. Any cold symptom within the last month such as sore throat, sneezing, rhinorrhoea, malaise, nasal obstruction or cough. 3. Presence of serum neutralising antibodies against human rhinovirus16 at screening. 4. Active allergic rhinitis, asthma or chronic obstructive pulmonary disease in last year. 5. Positive for fur allergy (if subject is likely to come in contact with the specific pet) and/or dust-mite allergy in skin prick test at screening. 6. Nasal disease, e.g. nasal polyposis, significant septal deviation, chronic rhinosinusitis, etc. 7. Females: Pregnant, breast-feeding or intentions to become pregnant during the study. 8. Active autoimmune disease in last year. 9. Evidence or history of drug or alcohol abuse. 10. Use of any prescribed or non-prescribed medication (except for contraceptives, paracetamol and ibuprofen) within 2 weeks prior to the first administration of investigational product until the end of study. 11. Use of any over the counter cold prophylaxis products such as C-vitamins, zinc or Echinacea within 1 month prior to the first administration of investigational product until the end of study. 12. Participation in other clinical study within 60 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduction in Viral Load in the URT | 7 days | Reduction in viral load in the URT(Upper Respiratory Tract), after challenge with rhinovirus, in relation to placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Prevention of Asymptomatic URTI | 11 days | Asymptomatic URTI will be assessed by quantification of viral load at peak day (day with highest viral load measured by oropharyngeal swab). Will be assessed by quantification of viral load at peak day (day with highest viral load). A subject is considered to be a success if the viral load is not different from the base-line value (from day 0). Otherwise will the subject be classified as a failure to prevent asymptomatic URTI. |
| Fewer Days With Symptomatic URTI | 11 days | The number of days with cold is defined as the sum of all days with a total score of ≥ 6 according to the modified method of Jackson. |
| Fewer Days With Asymptomatic URTI | 11 days | The number of days with asymptomatic URTI is defined as the sum of all days with a viral load significantly different from the baseline. |
| Prevention of Symptomatic URTI (Upper Respiratory Tract Infection) | 11 days | Reduction of number of days having a total symptom severity score of 6 or higher using a 5-graded Jackson scale, in relation to placebo. Will be assessed by the severity of cold symptoms quantified by the modified method of Jackson at peak day (day with highest score). A subject is considered to be a success if the total symptom score is below 6. Otherwise will the subject be classified as a failure to prevent symptomatic URTI. |
| Lower Daily Total Symptom Score | Day 0-10 | Jackson score was used and the \*mean\* sum of the score is reported. Jackson score is based on the sum of 5 severity points in the following scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 =very severe), where 0 is minimum and 4 is maximum score, for eight cold symptoms: sneezing, nasal obstruction, nasal discharge, sore throat, cough, headache, chilliness, and malaise. |
| Lower Daily Score of Individual Symptoms | Day 10 | Mean (average) value of the participants' score per symptom on day 10 is reported, i.e. per symptom, the total sum of participants self-reported Jackson score from 0 to 4, divided with number of participants on day 10. The Jackson scale for eight cold symptoms is used in the rating, using the following scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 =very severe , where 0 is no symptom and 4 is maximum symptoms (worsed), for eight cold symptoms: sneezing, nasal obstruction, nasal discharge, sore throat, cough, headache, chilliness, and malaise. |
| Lower Level of Proinflammatory Proteins | 11 days | Nasal samples will be analysed for the quantity of IL-6 (Interleukin 6), IL-8 and IFNα (Interferon alpha). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ColdZyme ColdZyme® mouth spray. Treatment (6 doses per day) will be applied for 11 days from the day of inoculation.
ColdZyme® mouth spray | 23 |
| Placebo Sugar based mouth spray manufactured to mimic ColdZyme® mouth spray. Treatment (6 doses per day) will be applied for 11 days from the day of inoculation.
Placebo | 23 |
| Total | 46 |
Baseline characteristics
| Characteristic | Placebo | ColdZyme | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 23 Participants | 46 Participants |
| Age, Continuous | 23.3 years STANDARD_DEVIATION 3.3 | 24.0 years STANDARD_DEVIATION 5.7 | 23.7 years STANDARD_DEVIATION 4.6 |
| Region of Enrollment Sweden | 23 participants | 23 participants | 46 participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 21 Participants |
| Sex: Female, Male Male | 12 Participants | 13 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 23 | 4 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 23 |
Outcome results
Primary
Reduction in Viral Load in the URT
Reduction in viral load in the URT(Upper Respiratory Tract), after challenge with rhinovirus, in relation to placebo
Time frame: 7 days
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| ColdZyme | Reduction in Viral Load in the URT | Oropharyngeal | 3.6 log 10 copies/mL | Standard Error 0.6 |
| ColdZyme | Reduction in Viral Load in the URT | Nasal | 4.9 log 10 copies/mL | Standard Error 0.6 |
| Placebo | Reduction in Viral Load in the URT | Oropharyngeal | 3.3 log 10 copies/mL | Standard Error 0.6 |
| Placebo | Reduction in Viral Load in the URT | Nasal | 4.1 log 10 copies/mL | Standard Error 0.6 |
Comparison: Oropharyngealp-value: 0.7146ANCOVA
Comparison: Nasalp-value: 0.3543ANCOVA
Secondary
Fewer Days With Asymptomatic URTI
The number of days with asymptomatic URTI is defined as the sum of all days with a viral load significantly different from the baseline.
Time frame: 11 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ColdZyme | Fewer Days With Asymptomatic URTI | 1.0 Days with asymptomatic cold | Standard Deviation 1.1 |
| Placebo | Fewer Days With Asymptomatic URTI | 1.4 Days with asymptomatic cold | Standard Deviation 1 |
Secondary
Fewer Days With Symptomatic URTI
The number of days with cold is defined as the sum of all days with a total score of ≥ 6 according to the modified method of Jackson.
Time frame: 11 days
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| ColdZyme | Fewer Days With Symptomatic URTI | 2.0 Days with symptomatic cold | Standard Deviation 2.3 |
| Placebo | Fewer Days With Symptomatic URTI | 3.0 Days with symptomatic cold | Standard Deviation 3.1 |
Secondary
Lower Daily Score of Individual Symptoms
Mean (average) value of the participants' score per symptom on day 10 is reported, i.e. per symptom, the total sum of participants self-reported Jackson score from 0 to 4, divided with number of participants on day 10. The Jackson scale for eight cold symptoms is used in the rating, using the following scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 =very severe , where 0 is no symptom and 4 is maximum symptoms (worsed), for eight cold symptoms: sneezing, nasal obstruction, nasal discharge, sore throat, cough, headache, chilliness, and malaise.
Time frame: Day 10
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ColdZyme | Lower Daily Score of Individual Symptoms | Cough Day 10 | 0.26 score on a scale | Standard Deviation 0.69 |
| ColdZyme | Lower Daily Score of Individual Symptoms | Headache Day 10 | 0.22 score on a scale | Standard Deviation 0.67 |
| ColdZyme | Lower Daily Score of Individual Symptoms | Rhinorrhea Day 10 | 0.52 score on a scale | Standard Deviation 0.85 |
| ColdZyme | Lower Daily Score of Individual Symptoms | Malaise Day 10 | 0.48 score on a scale | Standard Deviation 0.85 |
| ColdZyme | Lower Daily Score of Individual Symptoms | Nasal obstruction Day 10 | 0.39 score on a scale | Standard Deviation 0.72 |
| ColdZyme | Lower Daily Score of Individual Symptoms | Hoarseness Day 10 | 0.26 score on a scale | Standard Deviation 0.54 |
| ColdZyme | Lower Daily Score of Individual Symptoms | Sore/scratchy throat Day 10 | 0.26 score on a scale | Standard Deviation 0.62 |
| ColdZyme | Lower Daily Score of Individual Symptoms | Chilliness Day 10 | 0.0 score on a scale | Standard Deviation 0 |
| ColdZyme | Lower Daily Score of Individual Symptoms | Sneezing Day 10 | 0.22 score on a scale | Standard Deviation 0.52 |
| Placebo | Lower Daily Score of Individual Symptoms | Chilliness Day 10 | 0.4 score on a scale | Standard Deviation 0.21 |
| Placebo | Lower Daily Score of Individual Symptoms | Rhinorrhea Day 10 | 0.57 score on a scale | Standard Deviation 0.73 |
| Placebo | Lower Daily Score of Individual Symptoms | Cough Day 10 | 0.65 score on a scale | Standard Deviation 1.15 |
| Placebo | Lower Daily Score of Individual Symptoms | Nasal obstruction Day 10 | 0.52 score on a scale | Standard Deviation 0.85 |
| Placebo | Lower Daily Score of Individual Symptoms | Sore/scratchy throat Day 10 | 0.30 score on a scale | Standard Deviation 0.7 |
| Placebo | Lower Daily Score of Individual Symptoms | Headache Day 10 | 0.13 score on a scale | Standard Deviation 0.46 |
| Placebo | Lower Daily Score of Individual Symptoms | Malaise Day 10 | 0.43 score on a scale | Standard Deviation 0.73 |
| Placebo | Lower Daily Score of Individual Symptoms | Hoarseness Day 10 | 0.30 score on a scale | Standard Deviation 0.63 |
| Placebo | Lower Daily Score of Individual Symptoms | Sneezing Day 10 | 0.17 score on a scale | Standard Deviation 0.65 |
Secondary
Lower Daily Total Symptom Score
Jackson score was used and the \*mean\* sum of the score is reported. Jackson score is based on the sum of 5 severity points in the following scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe, 4 =very severe), where 0 is minimum and 4 is maximum score, for eight cold symptoms: sneezing, nasal obstruction, nasal discharge, sore throat, cough, headache, chilliness, and malaise.
Time frame: Day 0-10
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| ColdZyme | Lower Daily Total Symptom Score | Day 3 | 4.6 score on a 5 graded scale (0-4) | Standard Error 0.8 |
| ColdZyme | Lower Daily Total Symptom Score | Day 6 | 3.7 score on a 5 graded scale (0-4) | Standard Error 0.7 |
| ColdZyme | Lower Daily Total Symptom Score | Day 2 | 4.0 score on a 5 graded scale (0-4) | Standard Error 0.8 |
| ColdZyme | Lower Daily Total Symptom Score | Day 7 | 3.3 score on a 5 graded scale (0-4) | Standard Error 0.8 |
| ColdZyme | Lower Daily Total Symptom Score | Day 4 | 5.3 score on a 5 graded scale (0-4) | Standard Error 0.8 |
| ColdZyme | Lower Daily Total Symptom Score | Day 8 | 3.2 score on a 5 graded scale (0-4) | Standard Error 0.9 |
| ColdZyme | Lower Daily Total Symptom Score | Day 1 | 1.5 score on a 5 graded scale (0-4) | Standard Error 0.5 |
| ColdZyme | Lower Daily Total Symptom Score | Day 9 | 3.0 score on a 5 graded scale (0-4) | Standard Error 0.9 |
| ColdZyme | Lower Daily Total Symptom Score | Day 5 | 4.3 score on a 5 graded scale (0-4) | Standard Error 0.8 |
| ColdZyme | Lower Daily Total Symptom Score | Day 10 | 2.6 score on a 5 graded scale (0-4) | Standard Error 0.9 |
| ColdZyme | Lower Daily Total Symptom Score | Day 0 | 0.9 score on a 5 graded scale (0-4) | Standard Error 0.3 |
| Placebo | Lower Daily Total Symptom Score | Day 10 | 3.1 score on a 5 graded scale (0-4) | Standard Error 0.9 |
| Placebo | Lower Daily Total Symptom Score | Day 0 | 0.2 score on a 5 graded scale (0-4) | Standard Error 0.3 |
| Placebo | Lower Daily Total Symptom Score | Day 1 | 1.4 score on a 5 graded scale (0-4) | Standard Error 0.5 |
| Placebo | Lower Daily Total Symptom Score | Day 2 | 4.3 score on a 5 graded scale (0-4) | Standard Error 0.8 |
| Placebo | Lower Daily Total Symptom Score | Day 3 | 5.4 score on a 5 graded scale (0-4) | Standard Error 0.8 |
| Placebo | Lower Daily Total Symptom Score | Day 4 | 5.5 score on a 5 graded scale (0-4) | Standard Error 0.8 |
| Placebo | Lower Daily Total Symptom Score | Day 5 | 4.5 score on a 5 graded scale (0-4) | Standard Error 0.8 |
| Placebo | Lower Daily Total Symptom Score | Day 6 | 3.7 score on a 5 graded scale (0-4) | Standard Error 0.7 |
| Placebo | Lower Daily Total Symptom Score | Day 7 | 3.9 score on a 5 graded scale (0-4) | Standard Error 0.8 |
| Placebo | Lower Daily Total Symptom Score | Day 8 | 3.3 score on a 5 graded scale (0-4) | Standard Error 0.9 |
| Placebo | Lower Daily Total Symptom Score | Day 9 | 2.9 score on a 5 graded scale (0-4) | Standard Error 0.9 |
Secondary
Lower Level of Proinflammatory Proteins
Nasal samples will be analysed for the quantity of IL-6 (Interleukin 6), IL-8 and IFNα (Interferon alpha).
Time frame: 11 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ColdZyme | Lower Level of Proinflammatory Proteins | IL-6 | 273.93 pg*day/mL | Standard Deviation 641.76 |
| ColdZyme | Lower Level of Proinflammatory Proteins | IL-8 | 1863.36 pg*day/mL | Standard Deviation 1597.92 |
| ColdZyme | Lower Level of Proinflammatory Proteins | IFNα | 101.24 pg*day/mL | Standard Deviation 66.65 |
| Placebo | Lower Level of Proinflammatory Proteins | IL-6 | 254.45 pg*day/mL | Standard Deviation 494.69 |
| Placebo | Lower Level of Proinflammatory Proteins | IL-8 | 2057.59 pg*day/mL | Standard Deviation 1792.9 |
| Placebo | Lower Level of Proinflammatory Proteins | IFNα | 101.15 pg*day/mL | Standard Deviation 73.54 |
Secondary
Prevention of Asymptomatic URTI
Asymptomatic URTI will be assessed by quantification of viral load at peak day (day with highest viral load measured by oropharyngeal swab). Will be assessed by quantification of viral load at peak day (day with highest viral load). A subject is considered to be a success if the viral load is not different from the base-line value (from day 0). Otherwise will the subject be classified as a failure to prevent asymptomatic URTI.
Time frame: 11 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ColdZyme | Prevention of Asymptomatic URTI | Yes (success if viral load in oropharyngeal swab is 0 in peak day | 5 Participants |
| ColdZyme | Prevention of Asymptomatic URTI | No | 18 Participants |
| Placebo | Prevention of Asymptomatic URTI | Yes (success if viral load in oropharyngeal swab is 0 in peak day | 8 Participants |
| Placebo | Prevention of Asymptomatic URTI | No | 15 Participants |
Secondary
Prevention of Symptomatic URTI (Upper Respiratory Tract Infection)
Reduction of number of days having a total symptom severity score of 6 or higher using a 5-graded Jackson scale, in relation to placebo. Will be assessed by the severity of cold symptoms quantified by the modified method of Jackson at peak day (day with highest score). A subject is considered to be a success if the total symptom score is below 6. Otherwise will the subject be classified as a failure to prevent symptomatic URTI.
Time frame: 11 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ColdZyme | Prevention of Symptomatic URTI (Upper Respiratory Tract Infection) | No (Success if total symptom score is below 6 on peak day) | 21 Participants |
| ColdZyme | Prevention of Symptomatic URTI (Upper Respiratory Tract Infection) | Yes (Success if total symptom score is below 6 on peak day) | 2 Participants |
| Placebo | Prevention of Symptomatic URTI (Upper Respiratory Tract Infection) | No (Success if total symptom score is below 6 on peak day) | 16 Participants |
| Placebo | Prevention of Symptomatic URTI (Upper Respiratory Tract Infection) | Yes (Success if total symptom score is below 6 on peak day) | 7 Participants |
Post Hoc
Area Under the Curve (AUC) for Day 3-10 in the Oropharyngeal Samples of Viral Load
Time frame: Day 3, 4, 5, 7, 10
Population: Subjects with no viral load during the study excluded
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ColdZyme | Area Under the Curve (AUC) for Day 3-10 in the Oropharyngeal Samples of Viral Load | 6.6 copies*day/mL | Standard Deviation 7.41 |
| Placebo | Area Under the Curve (AUC) for Day 3-10 in the Oropharyngeal Samples of Viral Load | 11.30 copies*day/mL | Standard Deviation 6.17 |
p-value: 0.0232Exact Wilcoxon rank sum test
Post Hoc
Number of Days With Asymptomatic Cold (Nasal Sample)
Time frame: 11 days
Population: Subjects with no viral load during the study excluded
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ColdZyme | Number of Days With Asymptomatic Cold (Nasal Sample) | 3.0 Days with asymptomatic cold | Standard Deviation 1.5 |
| Placebo | Number of Days With Asymptomatic Cold (Nasal Sample) | 4.0 Days with asymptomatic cold | Standard Deviation 1.5 |
Post Hoc
Number of Days With Asymptomatic Cold (Oropharyngeal Sample)
Time frame: 11 days
Population: Subjects with no viral load during the study excluded
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| ColdZyme | Number of Days With Asymptomatic Cold (Oropharyngeal Sample) | 1.0 Days with asymptomatic cold | Standard Deviation 1 |
| Placebo | Number of Days With Asymptomatic Cold (Oropharyngeal Sample) | 2.0 Days with asymptomatic cold | Standard Deviation 1 |
Post Hoc
Number of Days With Symptomatic Cold
Time frame: 11 days
Population: Subjects with no symptomatic cold during the study excluded
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| ColdZyme | Number of Days With Symptomatic Cold | 3.0 Days with symptomatic cold | Standard Deviation 2.1 |
| Placebo | Number of Days With Symptomatic Cold | 6.5 Days with symptomatic cold | Standard Deviation 2.7 |