Clinical Study of Efficacy and Safety of Raphamin in the Treatment of ARVI in Children 12-18 Years Old

Study Overview
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Brief Summary
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The multicenter double-blind placebo-controlled randomized in parallel-group. The objective of this study is to evaluate efficacy and safety of Raphamin in the treatment of acute respiratory viral infection (ARVI) in children aged 12-18 years old.

Detailed Description
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Design: a multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial. The study will enroll outpatient subjects of either gender aged 12-18 old years with clinical manifestations of acute respiratory viral infection (ARVI) within the first days after the onset of the disease. The patients will be recruited during seasonal ARVI morbidity. Collection of history, thermometry, objective examination, laboratory tests, recording concomitant therapy will be made after parent/adoptive parent signing information sheet and informed consent form for the child participation in the clinical study, for children ≥14 years old after signing patient information sheet and informed consent form for children ≥14 years old to participate in the clinical study. The severity of ARVI symptoms will be evaluated with a 4-point scale. The nasopharyngeal swabs for PCR diagnosis and verification of respiratory viruses will be performed prior to therapy to confirm the viral etiology of ARVI. To rule out the infection caused by the new coronavirus COVID-19 (Coronavirus disease 2019), a rapid test for SARS-CoV-2 antigen will be made. In case of a positive SARS-CoV-2 test, the physician will act in accordance with the current version of the RF MoH Temporary methodological recommendations Prevention, diagnosis, and therapy of new coronavirus infection (COVID-19). 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: patients of group 1 will take Raphamin according to the dosage regimen for 5 days; patients of group 2 will take Placebo using Raphamin 5-day regimen. The study will use an electronic patient diary (EPD) for recording morning and evening axillary body temperature (using a classic mercury-free thermometer) and disease symptoms (Symptom Severity Score). Besides, antipyretic dosing (if applicable) and any deterioration in a patient's condition (if applicable, for safety evaluation/AE documentation) will also be recorded in a patient diary. The investigator will provide instructions on filling the diary. At Visit 1 the parent/adoptive parent together with an investigator will record ARVI symptom severity and body temperature in the diary. Patients will be observed for 14 days (screening, randomization - up to 1 day, treatment period - 5 days, follow-up - up to 2 days; deferred phone visit - day 14). During the treatment and follow-up period the patients/physicians will make 3 visits and the fourth phone visit will be scheduled additionally: 1) visits by physician/patient - on Days 1, 5, and 7 (Visits 1, 2, and 3) - in a study center or at home; 2) phone visit (Visit 4) - on Day 14. At Visits 2 and 3, the investigator will perform an objective examination, document changes in the symptoms and concomitant medications, and check patient diaries. At Visit 3 laboratory tests will be performed and compliance will be checked. Phone visit will be performed to interview parents/adoptive parents about the patient's condition, presence/absence of secondary bacterial/viral complications, and use of antibiotics. During the study, symptomatic therapy and therapy for their co-morbidities are allowed with the exception of the drugs indicated in the section Prohibited Concomitant Treatment.

Official Title
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Multicenter Double Blind Placebo-controlled Parallel-group Randomized Clinical Study of Efficacy and Safety of Raphamin in the Treatment of Acute Respiratory Viral Infection in Children Aged 12-18 Years Old

Conditions
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Acute Respiratory Viral Infection

Intervention / Treatment
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* Drug: Raphamin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of either gender aged 12 to 18 years. Diagnosis of ARVI based on medical examination: axillary temperature ≥ 37.8°C at examination + non-specific flu-like symptoms score ≥4, nasal/throat/chest symptom score ≥2. The first 24 hours after ARVI onset. Contraceptive measures by sexually active adolescents of both genders during the study. Patient information sheet (informed consent form) signed by one parent/adoptive parent of the patient and there is also a signed patient information sheet (informed consent form) for children aged 14 and over. Exclusion Criteria: Clinical symptoms of severe influenza/ARVI requiring hospitalization. Positive SARS-CoV-2 (COVID-19/Coronavirusdisease2019) antigen test. Suspected pneumonia, bacterial infection (including otitis media, sinusitis, urinary tract infection, meningitis, sepsis, etc.) requiring administration of antibiotics from the first day of illness. Suspected initial manifestations of diseases with symptoms similar to ARVI at onset (other infectious diseases, flu-like syndrome at the onset of systemic connective tissue diseases, and other pathology). Patients requiring antiviral medication prohibited within the study. Medical history of primary and secondary immunodeficiency. Medical history/suspicion of oncology of any localization (except for benign neoplasms). Aggravation or decompensation of chronic diseases (diabetes mellitus, infantile cerebral paralysis, cystic fibrosis, primary ciliary dyskinesia, bronchopulmonary dysplasia, respiratory and ENT congenital defects, etc.) affecting a patient's ability to participate in the clinical trial. Malabsorption syndrome, including congenital or acquired lactase or other disaccharidase deficiency, galactosemia. Allergy/ hypersensitivity to any component of the study drugs used in the treatment. Pregnancy. Breast-feeding. Use of medications specified in the section Prohibited Concomitant Therapy within two weeks prior to inclusion in the study. Patients whose parents/adopters, from the investigator's point of view, will not comply with the observation requirements during the study or follow the procedure for taking the study drugs. Medical history of mental diseases of the patient or their parent(s)/adoptive parents. Participation in other clinical trials for 3 months prior to enrollment in this study. Patient's parents/adopters 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). The patient's parent/adopter 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).

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Raphamin<br>Tablet for oral use. | Drug: Raphamin<br>* Oral administration - not with food. Keep the tablet in the mouth until it is completely dissolved. On the 1st day of treatment, 8 tablets are taken according to the following scheme: 1 tablet every 30 minutes in the first 2 hours (a total of 5 tablets in 2 hours), then during the same day, take another 1 tablet 3 times at regular intervals. On the 2nd day and then take 1 tablet 3 times a day. The duration of treatment is 5 days.<br>|
| Placebo Comparator: Placebo<br>Tablet for oral use. | Drug: Placebo<br>* Oral administration - not with food. Placebo using Raphamin scheme.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to resolution of ARVI symptoms (PCR-confirmed). | Outcome Measure is evaluated on the basis of ARVI, confirmed by Polymerase chain reaction (PCR), i.e virus detection. ARVI's resolution criteria: temperature ≤37.3°С + total symptom score (TSS) ≤2. Axillar temperature, 6 flu-like nonspecific symptoms (headache, chills, sweating, weakness, muscle pain, drowsiness), and 6 nasal/throat/chest symptoms (runny nose, nasal congestion, sneezing, hoarseness, sore throat, cough) are registered for TSS according to the 4-point scale for each of them (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). To calculate TSS absolute axillar temperature (in degrees Celsius) are converted to relative units (or points) using the following scale: ≤37.3 С=0 points; 37.4-38.0 С=1 point; 38.1-39.0 С=2 points; ≥39.1 С=3 points. The range of TSS is from 0 to 39. | 14 days of observation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of ARVI (Clinically Diagnosed and/or PCR-confirmed). | The outcome measure is based on the area under the curve (AUC) for the TSS. AUC is calculated between 6 points (by TSS for every 6 days of the treatment and observation). The minimum value for the AUC is 0 and the maximum value was 234 units (day*score). Higher TSS and AUC scores meant worse results. | On days 1- 6 of the observation | 
| Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | ARVI's resolution criteria: temperature ≤37.3°С + total symptom score (TSS) ≤2. Axillar temperature, 6 flu-like nonspecific symptoms (headache, chills, sweating, weakness, muscle pain, drowsiness) and 6 nasal/throat/chest symptoms (runny nose, nasal congestion, sneezing, hoarseness, sore throat, cough) were registered for TSS according to the 4-point scale for each of them (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). To calculate TSS absolute axillar temperature (in degrees Celsius) was converted to relative units (or points) using the following scale: ≤37.3 С=0 points; 37.4-38.0 С=1 point; 38.1-39.0 С=2 points; ≥39.1 С=3 points. The range of TSS was from 0 to 39. | 14 days of observation | 
| Time to Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed). | Acute Respiratory Viral Infection (ARVI) Symptoms resolution criteria: temperature ≤37.3°С + total symptom score (TSS) ≤2. Axillar temperature, 6 flu-like nonspecific symptoms (headache, chills, sweating, weakness, muscle pain, drowsiness), and 6 nasal/throat/chest symptoms (runny nose, nasal congestion, sneezing, hoarseness, sore throat, cough) are registered for TSS according to the 4-point scale for each of them (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). To calculate TSS absolute axillar temperature (in degrees Celsius) is converted to relative units (or points) using the following scale: ≤37.3 С=0 points; 37.4-38.0 С=1 point; 38.1-39.0 С=2 points; ≥39.1 С=3 points. The range of TSS was from 0 to 39. | 14 days of observation | 
| Percentage of Patients With Resolution of ARVI Symptoms (PCR-confirmed). | Outcome Measure is based on the Percentage of Patients With Resolution of ARVI, confirmed by Polymerase chain reaction (PCR), i.e virus detection. Acute Respiratory Viral Infection (ARVI) Symptoms resolution criteria: temperature ≤37.3°С + total symptom score (TSS) ≤2. Axillar temperature, 6 flu-like nonspecific symptoms (headache, chills, sweating, weakness, muscle pain, drowsiness), and 6 nasal/throat/chest symptoms (runny nose, nasal congestion, sneezing, hoarseness, sore throat, cough) are registered for TSS according to the 4-point scale for each of them (0 = no symptom; 1 = mild symptom; 2 = moderate symptom; 3 = severe symptom). To calculate TSS absolute axillar temperature (in degrees Celsius) is converted to relative units (or points) using the following scale: ≤37.3 С=0 points; 37.4-38.0 С=1 point; 38.1-39.0 С=2 points; ≥39.1 С=3 points. The range of TSS was from 0 to 39. | 14 days of observation | 
| Dosing Frequency of Antipyretics. | Outcome Measure is based on the rates of antipyretic use per patient during days 1 to 3 of therapy according to the electronic patient diary. | On days 1- 3 of therapy | 
| Percentage of Patients Reporting Worsening of Illness. | Outcome Measure is based on the rates of Complications that require the use of antibiotics or hospitalization. | From day 4 to day 14 of the observation period | 
| Occurrence and Characteristics of Adverse Events (AEs). | Severity of AEs, its causal relationship to the study drug, and outcomes. | From day 1 to day 7 of the treatment and observation period. | 
| Changes in Vital Signs: Pulse Rate/Heart Rate in Beats per minute (bpm). | The outcome measure is based on the medical records. The patient's heart rate (heart rate) is measured by the physician in every visit (on days 1, 5, and 7). | From day 1 to day 7 of the treatment and observation period. | 
| Changes in Vital Signs: Respiration Rate/Breathing Rate in breaths per minute. | Outcome Measure is based on the medical records. The patient's respiration rate (breathing rate) is measured by physician in every visit (on days 1, 5, and 7). | From day 1 to day 7 of the treatment and observation period. | 
| Changes in Vital Signs: Blood Pressure in units of millimeters of mercury (mm Hg). | Outcome Measure is based on the medical records. The patient's blood pressure is measured by the physician in every visit (on days 1, 5, and 7). | From day 1 to day 7 of the treatment and observation period. | 
| Percentage of Patients With Clinically Relevant abnormal laboratory findings. | Outcome Measure is based on the Hematology, blood chemistry, and urinalysis parameters, which are beyond the reference values at the end of treatment. | From day 1 to day 7 of the treatment period. |