Clinical trial NCT05364671
Conditions: Coronavirus Disease 2019 (COVID-19)
Sponsor: Materia Medica Holding
Start date: 2022-04-29; Completion date: 2023-08-18
Enrollment: 771 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Multicenter double-blind placebo-controlled parallel-group randomized clinical trial of efficacy and safety of Raphamin in the treatment of coronavirus disease 2019 in outpatients.

Detailed description:
Design: multicenter, double blind, placebo-controlled, parallel group randomized clinical trial.

The study enrolls outpatients of either gender aged 18-75 years with increased body temperature \> 37.5°C and other upper respiratory infection symptoms (cough, chest congestion, sore throat, nasal congestion/moderate rhinorrhea). The investigator should specify the patient's status of vaccination for COVID-19, influenza and other infections. Patients within the first four weeks after any vaccination/booster vaccination are not considered as candidates to participate in the study.

Nasopharyngeal swabs and rapid COVID-19 test are made after signing informed consent (two versions are used: 1) for patients consented for laboratory tests; 2) for patients without the consent).

Patients with a positive rapid test and presence of mild COVID-19 (upper respiratory infection symptoms, no symptoms of moderate or severe forms) within 24 hours after manifestation of the first disease symptoms are considered as candidates for the study. Oxygen saturation (SpO2) is measured by pulse oximetry in all patients (pulse oximeters are provided by the study sponsor). If SpO2 is ≥95%, a patient may be selected for the study. Baseline severity for COVID-19 symptoms is evaluated using the scoring system "Assessment of 14 Common COVID-19-Related Symptoms" (FDA, 2020). This scoring system assesses the follows symptoms:

1. Stuffy or runny nose.
2. Sore throat.
3. Shortness of breath (difficulty breathing).
4. Cough.
5. Low energy or tiredness.
6. Muscle or body aches.
7. Headache.
8. Chills or shivering.
9. Feeling hot or feverish.
10. Nausea (feeling like you wanted to throw up).
11. Vomiting.
12. Diarrhea.
13. Sense of smell.
14. Sense of taste.

Each symptom is scored individually using the following scoring values:

* Items 1-10: None = 0; Mild = 1; Moderate = 2; and Severe = 3;
* Items 11 and 12: Not at all = 0; 1-2 times = 1; 3-4 times = 2; 5 or more times = 3;
* Items 13 and 14: Sense of smell/taste same as usual = 0; Sense of smell/taste less than usual = 1; No sense of smell/taste = 2.

The minimal baseline score for COVID-19-related symptoms is defined as follows: at least two symptoms with a score of 2 or higher, with the exception of taste and smell where subjects may have a score of 1 or higher, and the absence of shortness of breath (difficulty breathing).

If more severe symptoms are presented, the patient is not included in the study. The therapeutic approach is determined by the current edition of the clinical recommendations of the Ministry of Health of the Russian Federation "Prevention, diagnosis and treatment of a new coronavirus infection (COVID-19)".

At visit 1 (Day 1), in addition to rapid COVID-19 test and SpO2 measurement, the investigator will collect complaints and medical history of the patient, perform objective examination including vital signs (blood pressure, heart rate and respiration rate), record concomitant diseases and concomitant therapy, perform nasopharyngeal smearing for further PCR for SARS-CoV-2, laboratory tests will be made (if the patient gave his/her consent for blood and urine sampling).

Patients who meet all the inclusion criteria and do not have exclusion criteria at Visit 1 (Day 1) are randomized into one of two groups: patients in group 1 receive Raphamin for 5 days; patients in group 2 receive placebo according to the Raphamin regimen.

If positive PCR test is received (confirmation of new coronavirus disease COVID-19), the patient continues to participate in the study. If PCR result is negative, the patient completes participation in the study ahead of schedule, and his further therapy is determined by the investigator in accordance with the standard of care.

Electronic patient diary (EPD) is utilized in the study where morning and evening axillary temperature records are made with the time of measurement. The sponsor provides a classical mercury-free thermometer to each patient. In addition, presence and severity of the disease symptoms according to the scoring system "Assessment of 14 Common COVID-19-Related Symptoms", antipyretics administration and probable worsening of disease duration should also be recorded in EPD. All patients are provided with paracetamol. The physician instructs the patient how to fill in the diary. The EPD is available for filling in within 28 days of participation in the study.

Overall, patients are observed for 28 days (screening and randomization up to 1 day, treatment for 5 days, follow-up till 28th day).

During the study, six visits are planned: on days 1, 3, 6, 10, 21, and 28 (visits 1, 2, 3, 4, 5, and 6). Visits 1, 3, and 4 are in person (visits to the patient or visits to the medical center) when the physician examines the patient and monitors EPD records. At visit 3, the patient's adherence to treatment is assessed and laboratory tests are performed. Visits 2, 5 and 6 are phone surveys to determine the patient's condition, presence/absence of complaints. In case of worsening of disease duration, the physician makes an extra visit. Patients with COVID-19 progression to more severe form as well as hospitalized patients are considered as reaching the study endpoints and terminate participation in the study ahead of schedule. The therapeutic approach is determined by the current edition of the clinical recommendations of the Ministry of Health of the Russian Federation "Prevention, diagnosis and treatment of a new coronavirus infection (COVID-19)".

During the study, the use of paracetamol and medicines for the treatment of concomitant diseases is allowed, with the exception of the drugs specified in the section "Prohibited concomitant treatment".

Arms: arm 1: Tablet for oral use. arm 2: Tablet for oral use.
Interventions: intervention 1: Raphamin intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet for oral use. The drug is administered not during meals. The tablet should be held in mouth until complete dissolution. On the first day, 8 tablets should be administered using the following regimen: 1 tablet every 30 minutes in the first 2 hours (5 tablets in total within 2 hours), then additionally one tablet 3 times with regular time intervals. From day 2 onwards, 1 tablet taken 3 times daily. The treatment period is 5 days. intervention 2: Tablet for oral use. The drug is administered not during meals. The tablet should be held in mouth until complete dissolution. Placebo is administered according to the Raphamin regimen.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Multicenter double-blind placebo-controlled parallel group 
randomized clinical study of efficacy and safety of Raphamin in the 
treatment of coronavirus disease 2019 in outpatient subjects 
 
 
 
 
 
Phase III 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-407-006 
Version date: 
February 09, 2022 
ClinicalTrials.gov Id: 
NCT05364671 
 


Protocol No. MMH-407-006 
09-Feb-2022 
CONFIDENTIAL  
 
Page 2 of 17 
Protocol Summary 
 
This document represents the protocol summary for the study on human patients. The study will 
be carried out in accordance with ICH GCP, Helsinki Declaration of World Medical Association, 
Rules of good clinical practice, approved by order of the Ministry of Health of the Russian 
Federation dated April 1, 2016 N 200n, , relevant requirements of the regulatory authorities as well 
as the study procedures. 
Title of Study 
Multicenter double-blind placebo-controlled parallel group randomized clinical trial of efficacy 
and safety of Raphamin in the treatment of coronavirus disease 2019 in outpatient subjects. 
Phase: III 
Sponsor: OOO «NPF "MATERIA MEDICA HOLDING», Moscow, Russia 
Protocol No. MMH-407-006 
 
Objective of the study 
• To evaluate the efficacy and safety of Raphamin in the treatment of Coronavirus Disease 2019 
in outpatient subjects. 
Endpoints  
Primary endpoint 
1. Frequency of progression of COVID-19 to a more severe level by observation day 281. 
Secondary endpoints 
1. Time to sustained clinical recovery2 from the new coronavirus infection COVID-19.  
2. Proportion of patients hospitalized during 28 days of follow-up. 
Additional endpoints 
1. Time to COVID-19 progression to more severe level within 28-day follow-up period. 
                                                 
1 Severity of COVID-19 will be assessed in accordance with the criteria presented in the current 14th version dated 27.12.2021 
Temporary Guidelines on Prevention, Diagnosis and Treatment of New Coronavirus Disease (COVID-19) (COVID-19)” of the 
Ministry of Health of the Russian Federation: 
Mild: temperature < 38.0°C, cough, chest congestion, sore throat, nasal congestion/moderate rhinorrhea, cough, weakness, 
headache, muscle pain, nausea, vomiting, diarrhea, taste loss and olfaction loss, lack of laboured breathing/lack of dyspnea, 
SpO2≥95%, lack of criteria of moderate or severe form of the disease.  
Moderate: body temperature >38.0°C; breathing rate >22/min; shortness of breath during exercise; CT (X-ray) changes, typical 
for viral lesions; SpO2 <95%; serum CRP >10 mg/L.  
Severe: HR >30/min; SpO2 ≤93%; PaO2 /FiO2 ≤300 mm Hg; reduced consciousness; agitation; unstable hemodynamics (systolic 
BP < 90 mm Hg or diastolic BP < 60 mm Hg, diuresis < 20 mL/hour); lung changes on CT (X-ray), typical for viral changes; 
arterial blood lactate >2 mmol/L; qSOFA >2. 
2 Stable clinical recovery is determined as the first day of stable clinical improvement (at least 4 consecutive days, the 
improvement day is the first of the 4) to grade 1 or 0 (for rhinitis/nasal congestion, sore throat, weakness/fatigue, muscle pain/body 
ache, headache, chill, fever, nausea, diarrhea), to grade 0 (for dyspnea/laboured breathing and vomiting) to grade ≤ 2 (for cough) 
and lack of new symptoms grade 1 using 4-point scale (“Assessment of 14 Common COVID-19 Related Symptoms”, Appendix 
1); in this case, the axillary temperature should be ≤37.30С. 


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2. Proportions of patients with negative PCR test for SARS-CoV-2 on days 6 and 10 of 
observation. 
Safety assessment  
1. Adverse events (AEs) during the therapy, AEs severity and relation to the study drug, and AEs 
outcomes.  
2. Changes in vital signs during the treatment. 
3. Percentage of patients with clinically relevant laboratory abnormalities. 
Study design  
Study design: multicenter, double blind, placebo-controlled, parallel group randomized clinical 
trial.  
The study enrolls outpatients of either gender aged 18-75 years with increased body temperature 
> 37.5°C and other symptoms of upper respiratory infection (cough, chest congestion, sore throat, 
nasal congestion/moderate rhinorrhea). The investigator should specify the patient’s status of 
vaccination for COVID-19, influenza and other infections. Patients within the first four weeks 
after any vaccination/booster vaccination are not considered as candidates to participate in the 
study.  
Nasopharyngeal swabs and rapid COVID-19 test are made after signing informed consent (two 
versions are used: 1) for patients consented for laboratory tests; 2) for patients without the consent).  
Patients with a positive rapid test and presence of mild COVID-19 (symptoms of upper respiratory 
infection, no symptoms of moderate or severe levels) within 24 hours after manifestation of the 
first symptoms of disease are considered as candidates for the study. Oxygen saturation (SpO2) is 
measured by pulse oximetry in all patients (pulse oximeters are provided by the study sponsor). If 
SpO2 is ≥95%, a patient may be selected for the study. Baseline severity of COVID-19 symptoms 
is evaluated using the scoring system «Assessing of 14 Common COVID-19-Related Symptoms» 
(FDA, 2020). This scoring system assesses the follows symptoms: 
1. 
Stuffy or runny nose. 
2. 
Sore throat. 
3. 
Shortness of breath (difficulty breathing). 
4. 
Cough. 
5. 
Low energy or tiredness. 
6. 
Muscle or body aches. 
7. 
Headache. 
8. 
Chills or shivering. 
9. 
Feeling hot or feverish. 


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10. 
Nausea (feeling like you wanted to throw up). 
11. 
Vomiting. 
12. 
Diarrhea. 
13. 
Sense of smell. 
14. 
Sense of taste. 
Each symptom is scored individually using the following scoring values: 
- Items 1–10: None = 0; Mild = 1; Moderate = 2; and Severe = 3;  
- Items 11 and 12: Not at all = 0; 1–2 times = 1; 3–4 times = 2; 5 or more times = 3;  
- Items 13 and 14: Sense of smell/taste same as usual = 0; Sense of smell/taste less than usual = 1; 
No sense of smell/taste = 2. 
The minimal baseline score for COVID-19-related symptoms is defined as follows: at least two 
symptoms with a score of 2 or higher, with the exception of taste and smell where subjects may 
have a score of 1 or higher, and the absence of shortness of breath (difficulty breathing).  
If more severe symptoms are presented, the patient is not included in the study. The therapeutic 
approach is determined by the current edition of the clinical recommendations of the Ministry of 
Health of the Russian Federation «Prevention, diagnosis and treatment of a new coronavirus 
infection (COVID-19)». 
At visit 1 (Day 1), in addition to rapid COVID-19 test and SpO2 measurement, the investigator 
collects complaints and medical history of the patient, performs objective examination including 
vital signs (blood pressure, heart rate and breathing rate), records concomitant diseases and 
concomitant therapy, performs nasopharyngeal swabs for PCR (for detection SARS-CoV-2), 
laboratory tests (if the patient gave his/her consent for blood and urine sampling).  
Patients who meet all the inclusion criteria and do not have exclusion criteria at Visit 1 (Day 1) 
are randomized into one of two groups: patients in group 1 receive Raphamin for 5 days; patients 
in group 2 receive placebo according to the Raphamin regimen.  
If positive PCR test is received (confirmation of new coronavirus disease COVID-19), the patient 
continues to participate in the study. If PCR result is negative, the patient completes participation 
in the study ahead of schedule, and his further therapy is determined by the investigator in 
accordance with the standards of care. 
Electronic patient diary (EPD) is utilized in the study, in which morning and evening axillary 
temperature records are made with the time of measurement. The sponsor provides a classical 
mercury-free thermometer to each patient. In addition, presence and severity of the disease 
symptoms according to the scoring system «Assessment of 14 Common COVID-19-Related 
Symptoms», antipyretics administration and probable worsening of disease duration should also 
be recorded in EPD. All patients are provided with paracetamol. The physician instructs the patient 


Protocol No. MMH-407-006 
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Page 5 of 17 
how to fill in the diary. The EPD is available for filling in within 28 days of participation in the 
study. 
Overall, patients are observed for 28 days (screening and randomization up to 1 day, treatment for 
5 days, follow-up till 28th day).  
During the study, six visits are planned: on days 1, 3, 6, 10, 21, and 28 (visits 1, 2, 3, 4, 5, and 6). 
Visits 1, 3, and 4 are in person (visits to the patient or visits to the medical center) when the 
physician examines the patient and monitors EPD records. At visit 3, the patient's adherence to 
treatment is assessed and laboratory tests are performed. Visits 2, 5 and 6 are phone surveys to 
determine the patient’s condition, presence/absence of complaints. In case of worsening of disease 
duration, the physician makes an extra visit. Patients with COVID-19 progression to more severe 
level as well as hospitalized patients are considered as reaching the study endpoints and terminate 
participation in the study ahead of schedule. The therapeutic approach is determined by the current 
edition of the clinical recommendations of the Ministry of Health of the Russian Federation 
«Prevention, diagnosis and treatment of a new coronavirus infection (COVID-19)». 
During the study, the use of paracetamol and medicines for the treatment of concomitant diseases 
is allowed, with the exception of the drugs specified in the section «Prohibited concomitant 
treatment». 
Inclusion and exclusion criteria 
Inclusion criteria 
1. Male and female patients aged 18-75 years old. 
2. Diagnosis of new coronavirus infection COVID-19 based on medical examination: axillary 
temperature >37.5°C, symptoms of upper respiratory infection, SpO2 ≥ 95%, no symptoms of 
moderate or severe levels. 
3. The minimal baseline score for COVID-19-related symptoms defined as follows: at least two 
symptoms with a score of 2 or higher, with the exception of taste and smell where subjects 
may have a score of 1 or higher, and the absence of shortness of breath (difficulty breathing).  
4. Positive rapid test for SARS-CoV-2 (COVID-19). 
5. The first 24 hours from the disease onset. 
6. Patients giving their consent to use reliable contraception during the study. 
7. Signed patient information sheet (informed consent form). 
Exclusion criteria 
1. Moderate and severe COVID-19. 
2. The first four weeks after any vaccination/revaccination, including against COVID-19, 
influenza, pneumococcal and other infections.  


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3. Suspected pneumonia, bacterial infection (including otitis media, sinusitis, urinary tract 
infection, meningitis, sepsis, etc.). 
4. Patients requiring medications prohibited within the study. 
5. Medical history or previously diagnosed primary and secondary immunodeficiency. 
6. Medical history/suspicion of oncology of any localization (except for benign neoplasms). 
7. Exacerbation or decompensation of chronic diseases affecting the patient's ability to 
participate in the clinical study. 
8. Malabsorption syndrome, including congenital or acquired lactase or disaccharidase 
deficiency, galactosemia. 
9. Allergy/hypersensitivity to any of the components of the medications used in the treatment. 
10. Pregnancy, breast-feeding; childbirth less than 3 months prior to the inclusion in the trial, 
unwillingness to use contraceptive methods during the study. 
11. Use of medications listed in “Prohibited concomitant therapy” within 4 weeks before the study 
entry. 
12. Patients who, from the investigator's point of view, will fail to comply with the observation 
requirements of the trial or with the intake regimen of the study drugs. 
13. Medical history of mental diseases, alcoholism or drug abuse which, according to the 
investigator's opinion, will interfere with the study procedures. 
14. Participation in other clinical trials within 3 months prior to enrollment in this study. 
15. The patient is related to the study center staff directly involved in the trial or is the immediate 
family member of the investigator. Immediate family is defined as a spouse, parents, children 
or siblings, whether natural or adopted. 
16. The patient works for OOO "NPF "MATERIA MEDICA HOLDING” i.e. is the company's 
employee, part-time employee under contract or appointed official in charge of the trial, or 
their immediate family. 
 
Criteria for Withdrawal or Termination 
1. Screening failure. 
2. Negative PCR test for SARS-CoV-2. 
3. Failure or refusal of the patient to follow the protocol. 
4. Deviation from personal visit schedule by more than 1 day. 
5. The necessity to use medications not permitted in the study. 
6. An adverse event requiring discontinuation of the study drug. 
7. Patient’s decision to withdraw early for lack of efficacy or other reasons. 
8. Pregnancy. 


Protocol No. MMH-407-006 
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9. Cases not stipulated in the protocol where the investigator decides that further participation 
may harm the patient. 
10. Eligibility error. 
11. Participation in any other clinical study. 
12. Unblinding. 
 
Number of patients 
It is planned to include 838 patients, 798 of them will be randomized which is expected to yield at 
least 712 patients (356 per Raphamin and Placebo groups) completing all the protocol procedures. 
Interim analysis 
The protocol does not schedule unblinded interim analyses. At the sponsor’s decision, blinded 
interim analysis may be carried out to specify population parameters and potential further 
specification of sample size (increase only).  
Treatment 
 
Group 1 
Name of the medicinal product: Raphamin 
Active ingredient:  affinity purified antibodies to human interferon-gamma – 10 000 UMA*, 
affinity purified antibodies to CD4 – 10 000 UMA, 
affinity purified antibodies to β2-microglobulin major histocompatibility 
complex class I – 10 000 UMA, 
affinity purified antibodies to β1-domain of major histocompatibility 
complex class II – 10 000 UMA 
* UMA – Units of Modifying Activity.   
 
Excipients: lactose monohydrate, microcrystalline cellulose, magnesium stearate          
Method of administration: Per os without food. The tablet should be held in mouth until 
completely dissolved. On the first day of treatment, take 8 tablets according to the following 
scheme: 1 tablet every 30 minutes for the first 2 hours (total 5 tablets in 2 hours), then during the 
same day take another 1 tablet 3 times at equal intervals. On the 2nd day and beyond, take 1 tablet 
3 times a day. The duration of treatment is 5 days. 
Dosage form: Tablet for oral use. 
Description: Flat, cylinder-shaped, scored beveled edge, white to off-white tablets. 
Storage conditions: At temperature below 25ºС. Keep out of the reach of children. 


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Group 2 
Name of the medicinal product: Placebo 
Active ingredient: N/A 
Excipients: lactose monohydrate, microcrystalline cellulose, magnesium stearate 
Method of administration: Per os without food. The tablet should be held in mouth until 
completely dissolved. On the first day of treatment, take 8 tablets according to the following 
scheme: 1 tablet every 30 minutes for the first 2 hours (total 5 tablets in 2 hours), then during the 
same day take another 1 tablet 3 times at equal intervals. On the 2nd day and beyond, take 1 tablet 
3 times a day. The duration of treatment is 5 days.  
Dosage form: Tablet for oral use. 
Description: Flat, cylinder-shaped, scored beveled edge, white to off-white tablets. 
Storage conditions: At temperature below 25ºС. Keep out of the reach of children. 
Treatment duration 
Raphamin/Placebo treatment duration is 5 days.  
Observation period 
Overall, the patient will be monitored for 28 days (screening, randomization - up to 1 day, 
treatment - 5 days, follow-up - up to 28 days). 
Symptomatic (Standard) treatment  
Throughout the study the patients may receive an antipyretic medication Paracetamol (provided 
by the sponsor) and other symptomatic medications (vasoconstrictive nasal agents, antitussive 
agents).  
Dosage regimens 
Paracetamol (at body temperature ≥ 38.0 ºС)   
Orally, with plenty of liquid, 1-2 hours after eating. 
Single dose is 500 (1 tablet). The maximum single dose is 1 g (2 tablets). The maximum daily dose 
is 4 g (8 tablets). The interval between doses is at least 4 hours. The patient should record 
thermometry values in EPD before taking the antipyretic drug, its name and dose. 
Prohibited concomitant therapy 
Four weeks prior to the enrollment as well as during the study (from signing of the patient 
information sheet and initiation of screening) the following medications are not allowed (ATC 
index is indicated in brackets): 
 


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1. 
Antiviral drugs (J05), as well as remdesivir, synthetic small interfering ribonucleic acid 
(siRNA) [double-stranded] (MIR 19), molnupiravir, nirmatrelvir + ritonavir, recombinant 
monoclonal antibodies (includinh sotrovimab, regdanvimab, bamlanivimab + etesivimab; 
casirivimab + imdevimab).  
2. 
Systemic antimicrobial agents (J01). 
3. 
Immunostimulants, including: 
• 
interferon inducers (acridonoacetic acid, meglumine acridone acetate/cycloferon, 
umifenovir/arbidol, kagocel, tiloron/amixin, polyadenyl acid + polyuridylic 
acid/poludan, sodium oxodihydroacridinyl acetate/neovir, lavomax, tilaxin, etc.); 
• 
interferons including recombinant interferon-alpha;  
• 
bacterial immunomodulators (including ribomunyl, sodium ribonucleate/ridostin, etc., 
sodium deoxyribonucleate/derinat, etc., IRS-19, imudon, broncho-munal, etc.); 
• 
pidotimod/immunorix;   
• 
interleukins;  
• 
synthetic immunostimulants (levamisole, alpha-glutamyl-tryptophan/thymogen, etc.);  
• 
medications containing thymus hormones.  
4. 
Preventive anti-inflammatory therapy of COVID-19 including baricitinib, tofacitinib, 
netakimab, olokizumab, levilimab, tocilizumab, sarilumab, canakinumab, anakinra, 
methylprednisolone, dexamethasone, hydrocortisone. 
5. 
Homeopathic medicines for the treatment of acute respiratory tract infections. 
6. 
Systemic (oral or parenteral) corticosteroids. 
7. 
Immunosuppressants (L04) including anakinra. 
8. 
Antineoplastic agents (L01) and antineoplastic hormonal agents (L02). 
9. 
Immune sera and immunoglobulins (J06) including anti-COVID plasma, human 
immunoglobulin against COVID-19. 
10. 
Vaccines (J07). 
11. 
Any unauthorised medicinal product. 
12. 
Drugs that previously caused hypersensitivity/ allergic reactions in patient. 
 
 
 
 
 
 
 
 


Protocol No. MMH-407-006 
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Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures 
 
Procedure/Visit 
Visit 1 
(Day 1) 
Visit 2* 
(Day 3) 
Visit 3 
(Day 6) 
Visit 4 
(Day 10) 
Visit 5* 
(Day 
21±1) 
Visit 6* 
(Day 
28±1) 
Unscheduled 
visit** 
Informed consent 
+ 
 
 
 
 
 
 
Registration of a study 
patient in the IVRS1 and 
assignment of patient ID 
+ 
 
 
 
 
 
 
Complaints collection 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Medical history 
+ 
 
 
 
 
 
 
Demographic data (gender 
and year of birth of the 
patient) 
+ 
 
 
 
 
 
 
Physical examination 
+ 
 
+ 
+ 
 
 
+ 
Thermometry 
+ 
 
+ 
+ 
 
 
+ 
Evaluation of 14 
Symptoms Associated with 
COVID-19 
+ 
 
+ 
+ 
 
 
+ 
SARS-CoV-2 rapid test 
+ 
 
 
 
 
 
 
Nasopharyngeal swabs for 
PCR 
+ 
 
+ 
+ 
 
 
 
Pulsoxymetry (SpO2) 
+ 
 
+ 
+ 
 
 
+ 
Electronic patient diary  
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Concomitant diseases and 
conditions 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Concomitant therapy 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
RANDOMIZATION 
SCREENING 
Group 1: Raphamin for 5 days. 
Follow-up period - up to day 28. 
Group 2: Placebo for 5 days. 
Follow-up period - up to day 28. 
Visit 2 
(Day 3) 
Visit 1 
(Day 1) 
28±1 days 
Visit 3 
(Day 6) 
END OF STUDY 
Visit 4  
(Day 10) 
Visits 5 and 6  
(Days 21 and 28) 
 * Unscheduled visit  
Performed in case of worsening within 28 days. 


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Procedure/Visit 
Visit 1 
(Day 1) 
Visit 2* 
(Day 3) 
Visit 3 
(Day 6) 
Visit 4 
(Day 10) 
Visit 5* 
(Day 
21±1) 
Visit 6* 
(Day 
28±1) 
Unscheduled 
visit** 
Pregnancy test 
+ 
 
 
 
 
 
 
Inclusion/exclusion criteria
+ 
 
 
 
 
 
 
Laboratory tests*** 
(for safety evaluation) 
+ 
 
+ 
 
 
 
+**** 
Randomization  
+ 
 
 
 
 
 
 
Study drug supply 
+ 
 
 
 
 
 
 
Antipyretic drug and 
thermometer supply  
+ 
 
 
 
 
 
 
Study drug accountability 
and return 
 
 
+ 
 
 
 
+**** 
Treatment compliance 
 
 
+ 
 
 
 
+**** 
Safety evaluation 
+ 
+ 
+ 
+
+
+
+ 
Visit completion 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Study completion***** 
 
 
 
 
 
+ 
+ 
1 Interactive Voice Responsible System with Web Access 
* Phone survey 
** Unscheduled visit will be performed in case of aggravation (based on EPD), at the investigator’s discretion and in case of 
early withdrawal (e.g. at the patient’s option). 
*** Include complete blood analysis and urinalysis, serum chemistry (total protein, total bilirubin, creatinine, ALT, AST, 
cholesterol, C-reactive protein). Performed with availability of signed PIS and ICF including the patient's consent for blood and 
urine sampling. 
**** If unscheduled visit is made before visit 3. 
***** In case of early withdrawal the procedure may be carried out at Visits 1-5 or at unscheduled visit.
 
Statistical Analyses 
SAS-[9.4].3 will be used for data processing and statistical calculations. 
Samples  
Total set: all patients who have signed ICF. This sample will consider all the recorded AEs, 
including those occurred prior to the study therapy. 
Safety population:  all included and randomized patients who received at least one dose of the 
study drug. This sample will be used for analysis of the study treatment safety and tolerability, 
as all adverse events identified after the study drug administration will be recorded.    
Full Analysis Set. This sample includes all enrolled patients, except for those who met at least one 
of the following events: 
1) non-compliance with inclusion / exclusion criteria; 
2) patient did not take a single dose of the study drug; 
3) lack of any data about the patient after administration of the study drug. 
This sample, the most consistent with the “Intention-to-treat” principle, will be used for 
the  Intention-to-treat analysis (ITT analysis) of the study therapy efficacy. 
                                                 
3 Holder of license: OOO “NPF “MATERIA MEDICA HOLDING”, No. 70100045. 


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Per protocol set. This sample includes all patients who completed the therapy as per the study 
protocol 
and 
completed 
all 
the 
scheduled 
visits. This 
set 
will 
be 
used 
for 
the Per Protocol analysis (PP analysis) of the study therapy efficacy. PP set will not include the 
patients with their data completely or partially invalid for analysis due to a protocol deviation. 
The list of deviations that may result in complete or partial invalidity of data is developed by a 
medical expert jointly with a biostatistician according to the study design.  
The deviations that may result in partial or complete invalidation of the study subject's data. 
1. Inappropriate distribution/supply of the study drug. 
2. Prescription of prohibited therapy. 
3. Increase or decrease in the study drug dosing by ≥ 25%. 
4. Inability to assess the patient's compliance using the formula (e.g. loss of pack with the 
product). 
5. Major discrepancies between source documents and CRF identified during monitoring or 
another authorized inspection. 
6. Violation of the procedure of obtaining informed consent. 
7. Non-compliance with the clinical study protocol procedures. 
8. Inability to collect all the patient's data used for evaluation of the study endpoints4 (e.g. lack 
of records in source documents required for verification of inclusion/exclusion criteria, 
safety and efficacy criteria). 
9. Any other protocol deviations covered by the term “major deviation”. 
Evaluation of sample size 
It is expected that out of 798 patients randomized5 712 patients will complete the study per 
protocol. Taking into consideration the expected screening failures, the informed consent should 
be obtained from 838 patients. 
The sample size was assessed on the basis of the following rules and assumptions: 
1. 
Statistical provisions. 
1.1 
the power of the statistical tests “P = (1 - β )” is assumed to be 80% (the probability 
of correct rejection of the null hypothesis is 0.8); 
1.2 
the probability of a type I error “α” is allowed to be less than 5% (the probability of 
false acceptance of an alternative hypothesis is less than 0.05); 
1.3 
the study does not plan unblinded interim analysis; 
                                                 
4 If, considering the lack of some data in primary endpoint variable, the fact of reaching the primary endpoint by the patient can 
still be determined, the patient will be eligible for PP analysis (e.g. the diary lacks some records but the time of recovery can still 
be determined). 
5 No more than 5% patients who signed PIS and ICF are expected to be screening failures for various reasons. 


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1.4 
the applied statistical tests for group comparisons are two-sided, unless stated 
otherwise; 
1.5 
the sample size is calculated based on the assumptions on the expected effect 
declared in the primary endpoint of this protocol; 
1.6 
the ratio between the sample sizes of the study drug and placebo groups is 1:1 (1 
study drug patient - 1 placebo patient);  
1.7 
statistical hypotheses: null and alternative hypotheses about the superiority of the 
study drug over placebo using the applied dosing regimen: 
primary endpoint6: 
H0: OR12 = 1 
Ha: OR12 ≠ 1 
where : OR12 – is odds ratio for an event occurrence in Raphamin and Placebo 
groups (the lower, the better). 
The following SAS program code was used to determine the required sample size: 
SAS code performed: 
proc power; 
twosamplefreq test=lrchi 
OR=0.5 
refp=0.15 
power=.8 
alpha=.04 
npergroup=.; 
run; 
1.8    Full sample size is determined using the formula:  
N = Npp / (1 – Rw), 
where  N – the final sample size;  
NPP – result of calculation in cl. 1.7, i.e. scheduled number of the patients 
completing the study per protocol;  
Rw – withdrawal rate. 
2. 
Assumptions on expected effects of the clinical study: Odds ratio for the event occurrence 
in Raphamin and Placebo groups is expected to be no more than 0.5 at population event 
frequency of at least 0.157 [32-34]. 
                                                 
6 The analysis stipulates for obligatory assessment and accounting for effects of additional factors: history of vaccination and 
age/age groups of the subjects. 
7 In assumption of reduced proportion of severe form in case of strain change (to Omicron) and based on the following sources:  


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Therefore, the number needed to compare study drug and placebo will be 712 patients for both 
groups. Given potential withdrawal of at least 15% 8 patients (RW = 0.15) during the study for 
various reasons, at least 838 subjects will be required to sign informed consent allowing to 
randomize 798 patients with 399 subjects per group (see cl. 1.8). 
Statistical criteria  
All the statistical calculations will be performed using two groups of statistical criteria:  
• parametric – to obtain effective evaluations for parameters of random values, if the 
relevant conditions of applicability of methods/models are not violated (e.g. sphericity, 
normality, proportionality of risks, etc.); 
• non-parametric – in any other cases. 
Parametric criteria 
The application of parametric criteria will be accompanied by a check of models for 
applicability (e.g. Kolmogorov-Smirnov test, Shapiro-Wilk test, etc.). 
The following parametric tests and approaches are to be used: 
1. To evaluate the differences of continuous variables obtained in one group at two 
different visits – Student’s test for matched samples. 
2. To evaluate the temporal dynamics of the compared indicators – analysis of variance 
(ANOVA) or covariance (ANCOVA) in the modification with repeated measures. 
3. In case of multiple comparisons between the groups will apply a variety of corrections 
for multiplicity (Dunnett, Tukey, Scheffe, Holm adaptive test), etc. 
4. In case of abnormal data distribution, approaches with the Generalized Linear Models 
and / or Mixed Linear Models will be used. 
5. Selection of the type of distribution, specification of the factor and covariance structures 
of the model will be made using fit-statistics such as AIC9 (Akaike information 
criterion).  
To perform the above-mentioned statistical tests and techniques, it is assumed that the 
following SAS procedures are used:  
                                                 
1) 
Weekly epidemiological update: Omicron variant of concern (VOC) – week 2 (data as of 13 January 2022) EU/EEA 
https://www.ecdc.europa.eu/en/news-events/weekly-epidemiological-update-omicron-variant-concern-voc-week-2-
data-20-january-2022 
2) 
Wolter N, Jassat W, Walaza S. et al Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in 
South Africa: a data linkage study. Lancet 2022; 399: 437-46. DOI: https://doi.org/10.1016/S0140-6736(22)00017-4 
3) 
Iuliano AD, Brunkard JM, Boehmer TK, et al. Trends in Disease Severity and Health Care Utilization During the Early 
Omicron Variant Period Compared with Previous SARS-CoV-2 High Transmission Periods - United States, December 
2020-January 
2022. 
MMWR 
Morb 
Mortal 
Wkly 
Rep 
2022; 
71(4):146-152. 
DOI: 
http://dx.doi.org/10.15585/mmwr.mm7104e4 
8 This coefficient was complex: 5% patients will be screening failures. 
9 Akaike information criterion (AIC). 


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• 
UNIVARIATE – check for normality of the compared distributions; 
• 
CORR, MEANS – calculation of descriptive statistics; 
• 
TTEST – Student t-test with all the modifications; 
• 
GLM – analysis of General Linear Models for studying temporal dynamics (ANOVA, 
ANCOVA); 
• 
GENMOD – analysis of Generalized Linear Models; 
• 
MIXED – analysis of Mixed Linear Models. 
Non-parametric criteria 
Below, there are the main types of possible comparisons with the respective criteria: 
1. To evaluate the temporal dynamics of the compared indicators – Friedman test, 
nonparametric analogue of repeated measures analysis of variance. 
2. For the frequency analysis of 2×2 cross tables – χ2-test (if the compared frequencies are 
greater than 5) or Fisher exact test (if one of the compared frequencies is less than 5). 
3. For the frequency analysis of cross tables with independent strata – Cochran–Mantel–
Haenszel test (modification of the χ2-test for multiple comparisons). 
4. For the frequency analysis of data on the presence / absence of an event or outcome during 
repeated measures (cross tables with dependent strata) – survival analysis. 
To perform the above-mentioned non-parametric statistical analysis options, it is assumed that the 
following SAS procedures are used: 
• FREQ – Friedman test, χ 2-test and / or Fisher exact test; Cochran–Mantel–Haenszel test 
• LIFETEST, PHREG – survival analysis  
• NPAR1WAY – Mann-Whitney U-test. 
Safety parameters  
Adverse events recorded during the study will be grouped into frequency tables by severity, 
seriousness and relationship with the study drug. 
Data presentation 
Descriptive statistics will be provided for each study continuous / interval variable. Numerical data 
will be presented by mean, standard deviation, min and max values (other measures of central 
tendency and variance may be provided where applicable). The data suggesting statistical 
conclusion will have the relevant confidence intervals. Extreme values (outliers) will be analyzed 
additionally. The data will be pooled according to visits. Categorical variables will be presented 
as per-visit frequency tables. 
 
 


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Appendix 1 * 
 
 
 
 
 
 
 
 


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* Assessing COVID-19-Related Symptoms in Outpatient Adult and Adolescent Subjects in 
Clinical Trials of Drugs and Biological Products for COVID-19 Prevention or Treatment. FDA. 
Guidance for Industry. September 2020.