Clinical Trial of Efficacy and Safety of ММН-407 in Acute Respiratory Viral Infection

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of ММН-407 in treatment of acute respiratory viral infection (ARVI).

Detailed Description
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Design: multicenter, double blind, placebo-controlled, parallel group randomized clinical trial. The study will enroll outpatients of either gender aged 18-70 years old with clinical manifestations of ARVI within the first day after the onset of the disease during seasonal ARVI morbidity. After signing patient information sheet and informed consent form, medical history, thermometry, objective examination, laboratory tests and concomitant medication will be performed. Severity of ARVI symptoms is evaluated with 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. 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 will take MMH-407 according to the dosage regimen for 5 days; the 2nd group will take Placebo according to MMH-407 dosage regimen for 5 days. The study will use electronic patient diary for recording morning and evening axillary body temperature (measured using a mercury-free Geratherm Classic thermometer) and disease symptoms (Symptom Severity Score). Besides, antipyretic dosing (if applicable) and any aggravation 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 patient together with a doctor will record ARVI symptom severity and body temperature in the diary. Patient will be observed for 14 days (screening, randomization - Day 1, treatment period - 5 days, follow-up - up to 2 days; deferred phone visit - Day 14). During the treatment and follow-up period the patients or investigators 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 to check patient diaries. At Visit 3 compliance will be evaluated and laboratory tests will be performed. Phone visit is carried out to interview the patient about his/her 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 Trial of Efficacy and Safety of MMH-407 in the Treatment of Acute Respiratory Viral Infection

Conditions
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Viral Respiratory Infection

Intervention / Treatment
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* Drug: MMH-407
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of either gender aged 18-70 years. Diagnosis of ARVI based on medical examination: axillary temperature ≥ 38.0°C at examination + total general symptoms score ≥4, nasal/throat/chest symptoms score ≥2. The first 24 hours after ARVI onset. Patients giving their consent to use reliable contraception during the study. Signed patient information sheet (informed consent form). Exclusion Criteria: Clinical symptoms of severe influenza/ARVI requiring hospitalization. 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 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 drug. Pregnancy, breast-feeding; childbirth less than 3 months prior to the inclusion in the trial, unwillingness to use contraceptive methods during the trial. Course administration of the drug products specified in the section Prohibited Concomitant Therapy within two weeks prior to inclusion in the study. 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. Medical history of mental diseases, alcoholism or drug abuse that according to the investigator's opinion will compromise compliance with the study procedures. Participation in other clinical trials for 3 months prior to enrollment in this study. 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). 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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: MMH-407<br>Tablet for oral use. One tablet per intake. On day 1, five tablets are taken in the first 2 hours (one tablet every 30 min), followed by three more tablets regularly spaced during the rest of the day. From day 2 through 5, one tablet is administered three times daily. The drug is administered not during meals (i.e. between the meals or 15-30 minutes before meal). The tablet should be held in mouth until complete dissolution. | Drug: MMH-407<br>* Oral use.<br>* Other names: Raphamin;|
| Placebo Comparator: Placebo<br>According to the scheme of receiving MMN-407 until the end of the study. | Drug: Placebo<br>* Oral use.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Resolution of Acute Respiratory Viral Infection (ARVI) Symptoms | Outcome Measure is evaluated on the basis of the ARVI severity scale to calculate total symptom score (TSS) in patients with confirmed virus by Polymerase chain reaction (PCR). ARVI's resolution criteria: temperature ≤37.3°С + 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of ARVI (Clinically Diagnosed and/or PCR-confirmed) | Outcome Measure is based on the area under the curve (AUC) for TSS. AUC was calculated between 6 points (by TSS for every 6 days of the treatment and observation). The minimum value for the AUC was 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. | On days 3, 4, 5 and 6 of observation. | 
| Time to Resolution of Acute Respiratory Viral Infection 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) 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. | 
| Percentage of Patients With Resolution of Acute Respiratory Viral Infection (PCR-confirmed) | Outcome Measure is based on the Percentage of Patients With Resolution of Acute Respiratory Viral Infection, confirmed by Polymerase chain reaction (PCR), i.e virus detection. Acute Respiratory Viral Infection 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. | On days 3, 4, 5 and 6 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. | On days 1, 2, 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 period. | 
| Changes in Vital Signs: Blood Pressure. | Outcome Measure is based on the medical records. Blood Pressure was measured by the physician in every visit (on days 1, 5, and 7). | On days 1, 5 and 7 of the treatment period. | 
| Changes in Vital Signs: Pulse Rate (Heart Rate). | Outcome Measure is based on the medical records. Pulse Rate (Heart Rate) was measured by the physician in every visit (on days 1, 5, and 7). | On days 1, 5 and 7 of the treatment period. | 
| Changes in Vital Signs: Respiration Rate (Breathing Rate). | Outcome Measure is based on the medical records. Respiration Rate (Breathing Rate) was measured by the physician in every visit (on days 1, 5, and 7). | On days 1, 5 and 7 of the treatment period. | 
| Percentage of Patients With Clinically Relevant Laboratory Abnormalities | Outcome Measure is based on the Hematology, blood chemistry, and urinalysis parameters, which were beyond the reference values at the end of treatment. | From day 1 to day 7 of the treatment period. |