Clinical Trial of Efficacy and Safety of Ergoferon in the Treatment of Viral Intestinal Infections in Children

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to obtain additional data on efficacy and safety of Ergoferon in the treatment of viral intestinal infections in inpatient children.

Detailed Description
-----------------
Design: a multicenter, double-blind, placebo-controlled, randomized clinical trial in parallel groups. This study will enroll subjects of both sexes aged from 6 months to 6 years who are admitted to hospital within 48 h of the onset of acute intestinal infection (AII), presumably of viral aetiology. Patients to be enrolled in the screening will be children with typical viral gastroenteritis/enteritis symptoms. The key symptom is decreased in the consistency of stools (loose or liquid) and increased in the frequency of its evacuations (at list 3 time daily). Virus detection in stool samples will be performed by polymerase chain reaction (PCR). After the parent/adopter signs a parents/adopters information sheet (Informed Consent form) for the child's participation in the clinical trial, the recording of medical history data, a medical examination including the evaluation of symptoms on the Clinical Dehydration Scale (CDS) by pediatrician, and laboratory tests will be performed during Visit 1 (Day 1). If inclusion criteria are met and non-inclusion criteria are absent (day 1), the patient will be included in the trial and randomized to administer either Ergoferon or Placebo. In addition to the standard/pathogenetic therapies, group 1 patients will take Ergoferon following a 5-day regimen, whereas group 2 patients will receive Placebo. The parents/adopters of the patient will be provided with a patient diary and instructed how to complete the diary. Before treatment stool specimens will be collected from the patients for detection and differentiation of Rotavirus A, Norovirus 2 genotype, Astrovirus, Adenovirus F, Shigella spp., enteroinvasive E.coli (EIEC), Salmonella spp., and thermophilic Campylobacter spp. using a PCR assay to diagnose the etiology of intestinal infection. In total, the patients will be monitored for 10 days (screening, randomization, treatment initiation - Day 1; the treatment on Days 1-5; observation in hospital - Day 6, and follow-up period - Day 7-10). During the treatment and inpatient observation periods (Days 1-6, Visits 1-6), the patients will be examined daily by a pediatrician, and the examination results, including the CDS scores, will be recorded in source documents. The patient's parent/adopter will complete the patient diary every day, recording the presence/absence of diarrhea signs, vomiting, and body temperature. The pediatrician will check them each time for the correctness of completion. On day 10 (after hospital discharge), Visit 7 will be done (as an in-person visit (a hospital or calling a doctor) or a distance, 'phone' visit) to interview the parents/adopters about the patient's health, presence of any complications, and use of medications (the pediatrician will use this information to complete a questionnaire). Collection of stool specimens and repeat PCR for Rotaviruses/Noroviruses/Astroviruses/Adenoviruses, Shigella spp., EIEC, Salmonella spp., and Campylobacter spp. will be performed on Days 3, 4, and 6 of inpatient observation and after discharge from the hospital (Day 10); collection of blood and urine specimens for safety tests will be carried out at baseline and before hospital discharge (day 6). The recording of the intake of study therapies and of concomitant medications as well as the assessment of compliance with and safety of the study therapies will be performed on Days 2-6 and 10. Patients who recovered while in hospital and are discharged from the unit earlier than at 5 days will undergo the procedures of Visit 6, including the collection of biological specimens for PCR (efficacy evaluation) and biochemistry, blood test and urinalysis (safety assessment). The parents/adopters will be given the blister pack with the remaining study drug so that the patient can continue the treatment.

Official Title
-----------------
International Multicenter, Double-blind, Randomized, Parallel Group Placebo-Controlled Clinical Trial of Efficacy and Safety of Ergoferon in the Treatment of Viral Intestinal Infections in Children

Conditions
-----------------
Viral Intestinal Infection

Intervention / Treatment
-----------------
* Drug: Ergoferon
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients of both gender aged from 6 months to 6 years, who have been admitted to infectious diseases unit. Diarrhea (watery diarrhea at least 3 times a day). CDS score of ≥1. The first 48 hours from the onset of the first diarrhea episode. Start of study treatment (Ergoferon/Placebo) within 12 hours after the start of the standard hospital therapy. Availability of a patient information sheet (Informed Consent form) signed by the patient's parents/adopters to confirm the child's participation in the clinical trial signed by one parent/adopter of the patient. Exclusion Criteria: Suspected bacterial intestinal infection. Suspected infectious diseases affecting other organ systems (e.g. pneumonia, meningitis, sepsis, otitis media, urinary tract infection, etc.). Severe intestinal infection. Severe dehydration (CDS score ≥7). Anuria (acute kidney injury). Medical history or prior diagnosis of serious diseases, including primary/secondary immunodeficiency, oncological disease, diabetes mellitus, infantile cerebral palsy, mucoviscidosis/cystic fibrosis etc. Exacerbation, or decompensation of chronic disease, including diseases of the digestive system that would affect the patient's ability to participate in the clinical trial. Malabsorption syndrome, including congenital or acquired lactose intolerance/lactase deficiency or any other disaccharidase deficiency and galactosemia. Allergy/ intolerance to any of the components of medications used in the treatment. Course intake of medicines listed in the section Prohibited concomitant treatment for 2 weeks prior to the enrollment in the trial. Participation in other clinical trials within 3 months prior to the enrollment in this study. Patients whose parents/adopters, from the investigator's point of view, will fail to comply with the observation requirements of the trial or with the dosing regimen of the study drugs. Patient's parents/adopters are related to the research staff of the clinical investigative site who are directly involved in the trial or are the immediate family member of the researcher. The immediate family members include husband/wife, parents, children or brothers (or sisters), regardless of whether they are natural or adopted. The patient's parent/adopter works for MATERIA MEDICA HOLDING (i.e., is the company's employee, temporary contract worker or appointed official responsible for carrying out the research) or the immediate relative.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 6 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ergoferon<br>Tablet for oral use. Dose per administration - 1 tablet per intake (outside a meal/feeding). Within the first 2 hours - 1 tablet every 30 minutes, followed by 3 more tablets at time intervals equally separated throughout the rest of the day; from day 2 to day 5 - 1 tablet 3 times daily. | Drug: Ergoferon<br> <br> |
| Placebo Comparator: Placebo<br>Tablet for oral use. Dose per administration - 1 tablet per intake (outside a meal/feeding). Within the first 2 hours - 1 tablet every 30 minutes, followed by 3 more tablets at time intervals equally separated throughout the rest of the day; from day 2 to day 5 - 1 tablet 3 times daily. | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Diarrhea Duration. | Diarrhea duration is considered as the time between receiving the first dose of investigational medicine /placebo and the normal consistency of stool pattern (to the previous stool consistency before diarrhea), i.e. time to the first loose stool which is followed by two normal consistency stools over 24 h (infants may have three episodes of loose stool over a 24-hour period), or time to ≤3 episodes of stool occurring over 24 h, at least 2 of which are normal consistency stools, or time to the absence of stools for ≥12 h which is not followed by new episodes of diarrhea (total stool frequency over 24 h - less than 3 times). | On days 1-10 of observation period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Without Diarrhea. | Based on medical records. | 48, 72 and 96 hours of the treatment. | 
| Percentage of Patients With Recovery. | Based on medical records. Recovery criteria: absence of diarrhea, vomiting, symptoms of dehydration, and increased body temperature (based on daily examinations by pediatrician). | 48, 72 and 96 hours of the treatment. | 
| Average Illness Duration. | From the enrollment to the recovery. Recovery criteria: absence of diarrhea, vomiting, symptoms of dehydration, and increased body temperature (based on daily examinations by pediatrician). | On days 1-10 of observation period. | 
| Total Clinical Dehydration Scale Score. | Based on medical records. Clinical Dehydration Scale score is more or equal 1. Note: minimum values - 0 points, maximum values - 8 points. Interpretation: 0 points - no dehydration, from 1 to 4 points - light dehydration, 5-8 points - average/severe dehydration. | 24, 48, and 72 hours of the treatment. | 
| Average Vomiting Duration (if Any). | Based on medical records. | On days 1-10 of observation period. | 
| Percentage of Patients With Negative PCR Tests. | Based on medical records. | On days 3, 4, 6 and 10 of observation period. | 
| Percentage of Patients With Worsening of Illness and/or Hospital-acquired Infection. | Based on medical records. Worsening of illness: an increase in dehydration scores and worsening of non-specific symptoms, as evidenced by a decline in general appearance, increasing fatigue and drowsiness, refusal to eat and drink, severe tachycardia/bradycardia, unstable hemodynamics, tachypnea, hypo- or hyperventilation, circulation disorders, peripheral cyanosis, sunken eyes, severe dryness of skin and mucous/tongue, poor tissue turgor, absent tears, persistent vomiting, anuria/acute kidney injury, seizure/convulsions, and meningismus. Hospital-acquired infection: a viral or bacterial infection (intestinal, respiratory or urinary tract infection, etc.) occurring after at least 48 h of hospital stay and confirmed by laboratory tests. | On days 1-10 of observation period. |