Acute Respiratory Viral Infections
Conditions
Brief summary
Purpose of the study: • To obtain additional data on the efficacy and safety of Anaferon in the treatment of acute respiratory viral infections.
Detailed description
Design: a multicenter, double-blind, placebo-controlled, parallel-group randomized trial. The study will enroll patients of either gender aged 18-70 years old with clinical manifestations of ARVI within the first day after the onset of the disease. Signed information sheet for patient will be obtained from all participants prior to the screening procedures. Medical history, concomitant medication, thermometry, patient examination by a doctor, assessment of ARVI symptoms severity will be performed at screening visit. The nasopharyngeal swabs will be performed for Real-time reverse transcription polymerase chain reaction (PCR) assay to confirm viral etiology of ARVI and to verify respiratory viruses prior to the therapy. If a patient meets all inclusion criteria and does not have any exclusion criteria, at Visit 1 (Day 1) he/she will be randomized into one of two groups: the 1st group patients will take Anaferon according to the dosage regimen until the end of the study; the 2nd group patients will take Placebo according to Anaferon dosage regimen until the end of the study. The patients will be provided with a patient diary (paper or electronic) where daily they will record axillary body temperature (using a Geratherm Classic thermometer) and each ARVI symptom severity twice a day (in the morning and in the evening). In addition, antipyretic administration (if applicable) as well as any possible worsening of the patient's condition (if applicable, for safety evaluation/AEs documentation) will also be recorded in a patient diary. An investigator will provide the instructions on filling out the diary and will help the patient to make first records of ARVI symptom severity and body temperature in the diary. Patients are observed up for 7 days (screening, randomization - 1 day, study therapy - 5 days, follow-up period - 2 days). During treatment and follow-up period two visits are scheduled (at home or at the study site) on days 5 (Visit 2) and day 7 (Visit 3). At Visits 2 and 3, the investigator will carry out physical examination, record dynamics of ARVI symptoms and concomitant therapy and check patient diaries. Treatment compliance will be evaluated at Visit 3. During the study, symptomatic therapy and therapy for underlying chronic conditions are allowed with the exception of the drugs indicated in the section Prohibited Concomitant Treatment.
Interventions
DRUGAnaferon
Oral administration.
DRUGPlacebo
Oral administration.
Sponsors
Materia Medica Holding
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 70 Years
Healthy volunteers
No
Inclusion criteria
1. Patients of either gender aged 18-70 years. 2. Diagnosis of acute respiratory viral infection (ARVI) based on medical examination: axillary temperature ≥ 37,8 ° C at examination + non-specific/flu-like symptom score ≥4, nasal/throat/chest symptom score ≥2. 3. The first 24 hours after ARVI onset. 4. Seasonal rise in ARVI incidence. 5. Patients giving their consent to use reliable contraception during the study. 6. Signed patient information sheet (informed consent form).
Exclusion criteria
1. Suspected pneumonia, bacterial infection (including otitis media, sinuitis, urinary tract infection, meningitis, sepsis, etc.), requiring the administration of antibacterial drugs from the first day of the disease. 2. Suspected initial manifestations of diseases with symptoms similar to ARVI at onset (other infectious diseases, flu-like syndrome at the onset of systemic diseases of connective tissue, oncohaematological and other diseases). 3. Clinical symptoms of severe influenza/ARVI requiring hospitalization. 4. Subjects requiring concurrent antiviral products forbidden by the study. 5. Medical history of primary and secondary immunodeficiency. 6. Oncologic conditions /suspected oncologic conditions. 7. Aggravation or decompensation of chronic diseases affecting a patient's ability to participate in the clinical trial. 8. Impaired glucose tolerance, diabetes mellitus. 9. Malabsorption syndrome, including congenital or acquired lactase or other disaccharidase deficiency, galactosemia. 10. Allergy/ hypersensitivity to any component of the study drug. 11. Pregnancy, breast-feeding; childbirth less than 3 months prior to the inclusion in the trial, unwillingness to use contraceptive methods during the trial. 12. Consumption of narcotics, alcohol \> 2 alcohol units per day, mental diseases. 13. Course administration of the drug products specified in the section Prohibited Concomitant Therapy within two weeks prior to inclusion in the study. 14. Patients who will not fulfill the requirements during the study or follow the order of administration of the studied drug products, from the Investigator's point of view. 15. Participation in other clinical trials for 3 months prior to enrollment in this study. 16. Patients who are related to any of the on-site research personnel directly involved in the study or are an immediate relative of the investigator. 'Immediate relative' means husband, wife, parent, son, daughter, brother, or sister (regardless of whether they are natural or adopted). 17. Patients who work for OOO NPF Materia Medica Holding (i.e. the company's employees, temporary contract workers, designated officials responsible for carrying out the research or any immediate relatives of the aforementioned).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Resolution of Acute Respiratory Viral Infection (ARVI) Symptoms. | On days 1-7 of the observation period. | Based on a patient diary. ARVI is clinically diagnosed and/or Real-time reverse transcription polymerase chain reaction (PCR) confirmed. Criteria of resolution of ARVI symptoms: body/axillary temperature ≤37.30С for 24 hours (without subsequent increase within the observation period) + absence/presence of general ARVI symptoms with ≤2 points of Total Severity (TS) score according to the 4-point scale for each of 14 ARVI symptoms (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). ARVI symptoms are body temperature, 6 nonspecific/flu-like symptoms, and 7 nasal/throat and chest symptoms. Absolute body temperature (in degrees Celsius) is converted to arbitrary units (or scores) using the following scale: ≤37.30С=0 points; 37.4-38.00С=1 point; 38.1-39.00С=2 points; ≥39.10С=3 points. TS ranges from 0 to 42 (higher scores mean a worse outcome). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | On day 2, 3, 4, 5, and 6. | Based on patient diary data. Criteria of resolution of ARVI symptoms: body/axillary temperature ≤37.30С for 24 hours (without subsequent increase within the observation period) + absence/presence of general ARVI symptoms with ≤2 points of Total Severity (TS) score according to the 4-point scale for each of 14 ARVI symptoms (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). ARVI symptoms are body temperature, 6 nonspecific/flu-like symptoms, and 7 nasal/throat and chest symptoms. Absolute body temperature (in degrees Celsius) is converted to arbitrary units (or scores) using the following scale: ≤37.30С=0 points; 37.4-38.00С=1 point; 38.1-39.00С=2 points; ≥39.10С=3 points. TS ranges from 0 to 30 (higher scores mean a worse outcome). |
| Time to Resolution of ARVI (PCR-confirmed) Symptoms. | On days 2-6 of the observation period. | Based on patient diary data. Criteria of resolution of ARVI symptoms: body/axillary temperature ≤37.30С for 24 hours (without subsequent increase within the observation period) + absence/presence of general ARVI symptoms with ≤2 points of Total Severity (TS) score according to the 4-point scale for each of 14 ARVI symptoms (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). ARVI symptoms are body temperature, 6 nonspecific/flu-like symptoms, and 7 nasal/throat and chest symptoms. Absolute body temperature (in degrees Celsius) is converted to arbitrary units (or scores) using the following scale: ≤37.30С=0 points; 37.4-38.00С=1 point; 38.1-39.00С=2 points; ≥39.10С=3 points. TS ranges from 0 to 42 (higher scores mean a worse outcome). |
| ARVI Severity. | On days 1-6 of the observation period. | ARVI severity is assessed using the Area under the curve (AUC) for the Total Symptom (TS) score for 6 days of the treatment and observation. TS score is calculated every day according to the 4-point scale for each of 14 ARVI symptoms (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). ARVI symptoms are body temperature, 6 nonspecific/flu-like symptoms, and 7 nasal/throat and chest symptoms. Absolute body temperature (in degrees Celsius) is converted to arbitrary units (or scores) using the following scale: ≤37.30С=0 points; 37.4-38.00С=1 point; 38.1-39.00С=2 points; ≥39.10С=3 points. TS ranges from 0 to 42 (higher scores mean a worse outcome). AUC is calculated between 6 points (by TS for every 6 days of the treatment and observation). AUC is calculated using integration with given limits (TS score). The minimum value for the AUC is 0 and the maximum value is 252 units (day\*score). The higher score means a worse outcome (ARVI severity). |
| Dosing Frequency of Antipyretics if Indicated. | On day 1, 2, and 3. | Based on patient diary data. Dosing frequency is calculated as the number of antipyretic doses per 1 patient in a day. |
| The Percentage of Patients Requiring Administration of Antibiotics. | On days 4-7 of the observation period. | Based on medical records. This Outcome Measure is calculated as the number of patients who were administered antibiotics for the treatment of secondary bacterial complications. |
| Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | On day 2, 3, 4, 5, and 6. | Based on patient diary data. ARVI is PCR confirmed. Criteria of resolution of ARVI symptoms: body/axillary temperature ≤37.30С for 24 hours (without subsequent increase within the observation period) + absence/presence of general ARVI symptoms with ≤2 points of Total Severity (TS) score according to the 4-point scale for each of 14 ARVI symptoms (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). ARVI symptoms are body temperature, 6 nonspecific/flu-like symptoms, and 7 nasal/throat and chest symptoms. Absolute body temperature (in degrees Celsius) is converted to arbitrary units (or scores) using the following scale: ≤37.30С=0 points; 37.4-38.00С=1 point; 38.1-39.00С=2 points; ≥39.10С=3 points. TS ranges from 0 to 30 (higher scores mean a worse outcome). |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Anaferon 1 tablet per administration. Day 1: 1 tablet every 30 minutes for the first 2 hours, followed by 3 more tablets taken at regular intervals through the rest of the day.
Days 2-5: 1 tablet 3 times a day. The drug is taken out of the meal (in the interval between meals or 15-30 minutes before eating), keep the tablet in the mouth, without swallowing, until completely dissolved.
Anaferon: Oral administration. | 103 |
| Placebo Placebo using Anaferon regimen until the end of the study.
Placebo: Oral administration. | 100 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Violation of inclusion criteria | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Anaferon |
|---|---|---|---|
| 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 | 100 Participants | 203 Participants | 103 Participants |
| Age, Continuous | 37.8 years STANDARD_DEVIATION 11.9 | 38.5 years STANDARD_DEVIATION 12.7 | 39.1 years STANDARD_DEVIATION 13.4 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Russia | 100 participants | 203 participants | 103 participants |
| Sex: Female, Male Female | 73 Participants | 139 Participants | 66 Participants |
| Sex: Female, Male Male | 27 Participants | 64 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 104 | 0 / 100 |
| other Total, other adverse events | 5 / 104 | 5 / 100 |
| serious Total, serious adverse events | 0 / 104 | 0 / 100 |
Outcome results
Primary
Time to Resolution of Acute Respiratory Viral Infection (ARVI) Symptoms.
Based on a patient diary. ARVI is clinically diagnosed and/or Real-time reverse transcription polymerase chain reaction (PCR) confirmed. Criteria of resolution of ARVI symptoms: body/axillary temperature ≤37.30С for 24 hours (without subsequent increase within the observation period) + absence/presence of general ARVI symptoms with ≤2 points of Total Severity (TS) score according to the 4-point scale for each of 14 ARVI symptoms (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). ARVI symptoms are body temperature, 6 nonspecific/flu-like symptoms, and 7 nasal/throat and chest symptoms. Absolute body temperature (in degrees Celsius) is converted to arbitrary units (or scores) using the following scale: ≤37.30С=0 points; 37.4-38.00С=1 point; 38.1-39.00С=2 points; ≥39.10С=3 points. TS ranges from 0 to 42 (higher scores mean a worse outcome).
Time frame: On days 1-7 of the observation period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anaferon | Time to Resolution of Acute Respiratory Viral Infection (ARVI) Symptoms. | 4.1 days | Standard Deviation 1.6 |
| Placebo | Time to Resolution of Acute Respiratory Viral Infection (ARVI) Symptoms. | 4.5 days | Standard Deviation 1.5 |
p-value: 0.032Wilcoxon (Mann-Whitney)
Secondary
ARVI Severity.
ARVI severity is assessed using the Area under the curve (AUC) for the Total Symptom (TS) score for 6 days of the treatment and observation. TS score is calculated every day according to the 4-point scale for each of 14 ARVI symptoms (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). ARVI symptoms are body temperature, 6 nonspecific/flu-like symptoms, and 7 nasal/throat and chest symptoms. Absolute body temperature (in degrees Celsius) is converted to arbitrary units (or scores) using the following scale: ≤37.30С=0 points; 37.4-38.00С=1 point; 38.1-39.00С=2 points; ≥39.10С=3 points. TS ranges from 0 to 42 (higher scores mean a worse outcome). AUC is calculated between 6 points (by TS for every 6 days of the treatment and observation). AUC is calculated using integration with given limits (TS score). The minimum value for the AUC is 0 and the maximum value is 252 units (day\*score). The higher score means a worse outcome (ARVI severity).
Time frame: On days 1-6 of the observation period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anaferon | ARVI Severity. | 104.6 day*score | Standard Deviation 43.5 |
| Placebo | ARVI Severity. | 114.3 day*score | Standard Deviation 45.7 |
p-value: 0.11Wilcoxon (Mann-Whitney)
Secondary
Dosing Frequency of Antipyretics if Indicated.
Based on patient diary data. Dosing frequency is calculated as the number of antipyretic doses per 1 patient in a day.
Time frame: On day 1, 2, and 3.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anaferon | Dosing Frequency of Antipyretics if Indicated. | Day 1 | 0.4 doses | Standard Deviation 0.6 |
| Anaferon | Dosing Frequency of Antipyretics if Indicated. | Day 2 | 0.2 doses | Standard Deviation 0.4 |
| Anaferon | Dosing Frequency of Antipyretics if Indicated. | Day 3 | 0.1 doses | Standard Deviation 0.3 |
| Placebo | Dosing Frequency of Antipyretics if Indicated. | Day 1 | 0.4 doses | Standard Deviation 0.6 |
| Placebo | Dosing Frequency of Antipyretics if Indicated. | Day 2 | 0.2 doses | Standard Deviation 0.4 |
| Placebo | Dosing Frequency of Antipyretics if Indicated. | Day 3 | 0.1 doses | Standard Deviation 0.3 |
Comparison: Day 1 comparison.p-value: 0.89Wilcoxon (Mann-Whitney)
Comparison: Day 2 comparison.p-value: 0.75Wilcoxon (Mann-Whitney)
Comparison: Day 3 comparison.p-value: 0.34Wilcoxon (Mann-Whitney)
Secondary
Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed).
Based on patient diary data. Criteria of resolution of ARVI symptoms: body/axillary temperature ≤37.30С for 24 hours (without subsequent increase within the observation period) + absence/presence of general ARVI symptoms with ≤2 points of Total Severity (TS) score according to the 4-point scale for each of 14 ARVI symptoms (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). ARVI symptoms are body temperature, 6 nonspecific/flu-like symptoms, and 7 nasal/throat and chest symptoms. Absolute body temperature (in degrees Celsius) is converted to arbitrary units (or scores) using the following scale: ≤37.30С=0 points; 37.4-38.00С=1 point; 38.1-39.00С=2 points; ≥39.10С=3 points. TS ranges from 0 to 30 (higher scores mean a worse outcome).
Time frame: On day 2, 3, 4, 5, and 6.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Anaferon | Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Day 3 | 11 Participants |
| Anaferon | Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Day 5 | 57 Participants |
| Anaferon | Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Day 4 | 39 Participants |
| Anaferon | Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Day 6 | 76 Participants |
| Anaferon | Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Day 2 | 0 Participants |
| Placebo | Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Day 6 | 64 Participants |
| Placebo | Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Day 2 | 0 Participants |
| Placebo | Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Day 3 | 6 Participants |
| Placebo | Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Day 4 | 25 Participants |
| Placebo | Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Day 5 | 43 Participants |
p-value: 0.0012Cochran-Mantel-Haenszel
p-value: 0.98Breslow-Day test
Secondary
Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed).
Based on patient diary data. ARVI is PCR confirmed. Criteria of resolution of ARVI symptoms: body/axillary temperature ≤37.30С for 24 hours (without subsequent increase within the observation period) + absence/presence of general ARVI symptoms with ≤2 points of Total Severity (TS) score according to the 4-point scale for each of 14 ARVI symptoms (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). ARVI symptoms are body temperature, 6 nonspecific/flu-like symptoms, and 7 nasal/throat and chest symptoms. Absolute body temperature (in degrees Celsius) is converted to arbitrary units (or scores) using the following scale: ≤37.30С=0 points; 37.4-38.00С=1 point; 38.1-39.00С=2 points; ≥39.10С=3 points. TS ranges from 0 to 30 (higher scores mean a worse outcome).
Time frame: On day 2, 3, 4, 5, and 6.
Population: From all patients with ARVI only 79 have ARVI (PCR-confirmed), including 41 patient in Anaferon group and 38 patient in Placebo group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Anaferon | Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Day 3 | 7 Participants |
| Anaferon | Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Day 5 | 29 Participants |
| Anaferon | Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Day 4 | 22 Participants |
| Anaferon | Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Day 6 | 35 Participants |
| Anaferon | Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Day 2 | 0 Participants |
| Placebo | Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Day 6 | 23 Participants |
| Placebo | Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Day 2 | 0 Participants |
| Placebo | Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Day 3 | 4 Participants |
| Placebo | Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Day 4 | 10 Participants |
| Placebo | Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Day 5 | 14 Participants |
p-value: <0.0001Cochran-Mantel-Haenszel
p-value: 0.75Breslow-Day test
Secondary
The Percentage of Patients Requiring Administration of Antibiotics.
Based on medical records. This Outcome Measure is calculated as the number of patients who were administered antibiotics for the treatment of secondary bacterial complications.
Time frame: On days 4-7 of the observation period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anaferon | The Percentage of Patients Requiring Administration of Antibiotics. | 4 Participants |
| Placebo | The Percentage of Patients Requiring Administration of Antibiotics. | 5 Participants |
p-value: 0.75Fisher Exact
Secondary
Time to Resolution of ARVI (PCR-confirmed) Symptoms.
Based on patient diary data. Criteria of resolution of ARVI symptoms: body/axillary temperature ≤37.30С for 24 hours (without subsequent increase within the observation period) + absence/presence of general ARVI symptoms with ≤2 points of Total Severity (TS) score according to the 4-point scale for each of 14 ARVI symptoms (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). ARVI symptoms are body temperature, 6 nonspecific/flu-like symptoms, and 7 nasal/throat and chest symptoms. Absolute body temperature (in degrees Celsius) is converted to arbitrary units (or scores) using the following scale: ≤37.30С=0 points; 37.4-38.00С=1 point; 38.1-39.00С=2 points; ≥39.10С=3 points. TS ranges from 0 to 42 (higher scores mean a worse outcome).
Time frame: On days 2-6 of the observation period.
Population: From all patients with ARVI only 79 have ARVI (PCR-confirmed), including 41 patient in Anaferon group and 38 patient in Placebo groupe.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anaferon | Time to Resolution of ARVI (PCR-confirmed) Symptoms. | 3.6 days | Standard Deviation 1.5 |
| Placebo | Time to Resolution of ARVI (PCR-confirmed) Symptoms. | 4.6 days | Standard Deviation 1.5 |
p-value: 0.007Wilcoxon (Mann-Whitney)