Clinical Study of Efficacy and Safety of Raphamin in the... | NCT04918771

Status Module

Description Module

Detailed Description

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".

Arms/Interventions Module

Label	Type	Description	Intervention Names
Raphamin	Experimental	Tablet for oral use.	Drug: Raphamin
Placebo	Placebo Comparator	Tablet for oral use.	Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Raphamin	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Time to Resolution of Acute Respiratory Viral Infection (ARVI) Symptoms (ARVI, Confirmed by Polymerase Chain Reaction (PCR)).	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 7 nasal/throat/chest symptoms (runny nose, nasal congestion, sneezing, hoarseness, sore throat, cough, pain/heaviness in chest) 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. So the range of TSS was from "0" to "42". The TSS higher score is the worse outcome.	14 days of observation

Secondary Outcomes

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 (Total symptoms score). TSS is calculated as a sum of scores for 14 different symptoms. 13 of them are different ARVI manifestations, each of them is evaluated on a scale: 0 (none), 1 (mild), 2 (moderate), 3 (severe). 14th symptom is body temperature (temp) which is converted to its score using following rules: if temp <= 37.3 then score = 0 (none) if 37.3 < temp <= 38.0 then score = 1 (mild) if 38.0 < temp <= 39.0 then score = 2 (moderate) if 39.0 < temp then score = 3 (severe) So it is 14 symptoms and the score for each of them varies between 0 and 3. Minimum TSS is 0, maximum is 42 (higher TSS score is worse). AUC is calculated for all timepoints available for patient.

Eligibility Module

Eligibility Criteria

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).

Facility	Status	City	State	ZIP	Country	Contacts
Kazan State Medical University		Kazan'		420012	Russia
Llc "Medlight"

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Raphamin	Tablet for oral use. Raphamin: 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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Nov 10, 2020

Arm/Group Information

ID	Title	Description
BG000	Raphamin	Tablet for oral use. Raphamin: 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.
BG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	OG0003.3± 1.7 OG0014.4± 2.6

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Mean time to resolution of ARVI symptoms	t-test, 2 sided		0.0003		Mean Difference (Final Values)	1.09			2-Sided	95	0.51	1.67					Superiority

Secondary

Severity of ARVI (Clinically Diagnosed and/or PCR-confirmed).

The outcome measure is based on the area under the curve (AUC) for the TSS (Total symptoms score).

TSS is calculated as a sum of scores for 14 different symptoms. 13 of them are different ARVI manifestations, each of them is evaluated on a scale: 0 (none), 1 (mild), 2 (moderate), 3 (severe). 14th symptom is body temperature (temp) which is converted to its score using following rules:

if temp <= 37.3 then score = 0 (none) if 37.3 < temp <= 38.0 then score = 1 (mild) if 38.0 < temp <= 39.0 then score = 2 (moderate) if 39.0 < temp then score = 3 (severe) So it is 14 symptoms and the score for each of them varies between 0 and 3. Minimum TSS is 0, maximum is 42 (higher TSS score is worse). AUC is calculated for all timepoints available for patient.

Two subpopulations were analysed:

Patients with clinically diagnosed and/or PCR-confirmed ARVI.
Patients with PCR-confirmed ARVI strictly.

Posted

Mean

Standard Deviation

scores on a scale*days

Day1 through Day6 of the treatment and observation

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001

Secondary

Percentage of Patients With Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed).

Posted

Count of Participants

Participants

14 days of observation

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.

Secondary

Time to Resolution of ARVI Symptoms (Clinically Diagnosed and/or PCR-confirmed).

Posted

Mean

Standard Deviation

day

14 days of observation

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.

Secondary

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.

Posted

Count of Participants

Participants

14 days of observation

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001	Placebo

Secondary

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.

Posted

Mean

Standard Deviation

number of doses

3 days of therapy

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.

Units	Counts
Participants	OG000

Secondary

Percentage of Patients Reporting Worsening of Illness.

Outcome Measure is based on the rates of Complications that require the use of antibiotics or hospitalization.

Posted

Count of Participants

Participants

Day 4 through day 14 of the treatment and observation period

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.

Units	Counts
Participants	OG000

Secondary

Occurrence and Type of Adverse Events (AE) During the Treatment. AE Severity.

The intensity (severity) of adverse events.
Causal relationship of AEs to the sudy drug.
Outcome of AEs. Based on medical records.

Posted

Number

number of cases

14 days of observation

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.

Units	Counts
Participants	OG000

Secondary

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).

Only non-missing values were analyzed, so numbers analyzed are a bit lower then overall number of participants for visits 2 and 3.

Posted

Mean

Standard Deviation

beats per minute

Day 1 through day 7 of the treatment and observation period.

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.

Units	Counts
Participants

Secondary

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).

Only non-missing values were analyzed, so numbers analyzed are a bit lower then overall number of participants for visits 2 and 3.

Posted

Mean

Standard Deviation

breaths per minute

Day 1 through day 7 of the treatment and observation period.

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.

Units	Counts

Secondary

Changes in Vital Signs: Blood Pressure in Units of Millimeters of Mercury (mmHg).

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).

Only non-missing values were analyzed, so numbers analyzed are a bit lower then overall number of participants for visits 2 and 3.

Posted

Mean

Standard Deviation

mmHg

Day 1 through day 7 of the treatment and observation period.

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.

Units	Counts
Participants

Secondary

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.

Posted

Count of Participants

Participants

Day 1 through day 7 of the treatment and observation period.

ID	Title	Description
OG000	Raphamin	Tablet for oral use. Raphamin: 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.
OG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.

Units	Counts
Participants

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Raphamin	Tablet for oral use. Raphamin: 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.	0	206	1	206	6	206
EG001	Placebo	Tablet for oral use. Placebo: Oral administration - not with food. Placebo using Raphamin scheme.	0	214	0	214	5	214

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Adenoiditis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 events0 affected206 at risk EG0011 events1 affected214 at risk
Bacterial superinfection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 events1 affected206 at risk EG0010 events0 affected214 at risk
Viral upper respiratory tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 events1 affected206 at risk EG0010 events0 affected214 at risk
Coronavirus infection COVID-19	Infections and infestations	MedDRA	Systematic Assessment	EG0000 events0 affected206 at risk EG0011 events1 affected214 at risk
Increased percentage of monocytes	Investigations	MedDRA	Systematic Assessment	EG0001 events1 affected206 at risk EG0010 events0 affected214 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 events0 affected206 at risk EG0011 events1 affected214 at risk
Anemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 events0 affected206 at risk EG0011 events1 affected214 at risk
Lymphadenopathy	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 events0 affected206 at risk EG0011 events1 affected214 at risk
Dizziness	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 events1 affected206 at risk EG0010 events0 affected214 at risk
Loss of consciousness	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 events1 affected206 at risk EG0010 events0 affected214 at risk
Pallor	Vascular disorders	MedDRA	Systematic Assessment	EG0001 events1 affected206 at risk EG0010 events0 affected214 at risk
Flu	Infections and infestations	MedDRA	Systematic Assessment	EG0001 events1 affected206 at risk EG0011 events1 affected214 at risk