Clinical Trial of Efficacy and Safety of Raphamin in the Treatment of Coronavirus Disease 2019 in Outpatients

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

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.

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".

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, upper respiratory infection symptoms, SpO2 ≥ 95%, no symptoms of moderate or severe forms.
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 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.
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 trial.
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 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 relative 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.