Clinical Trial of the Safety and Tolerability of MMH-522 in Healthy Volunteers

Screening (Days -7-0, Visit 0) After signing a patient information sheet (PIS) and an informed consent form (ICF), the participant undergoes a screening examination on an outpatient basis (Days -7-0): medical history collection, physical examination (height, weight, vital signs: blood pressure, heart rate, body temperature, saturation)), pregnancy test, 12-lead ECG, breath alcohol test, laboratory tests (express urine analysis for drugs and medications, general blood and urine tests, blood chemistry, coagulation test, platelet aggregation test, HIV test, RPR test, HBsAg, HCV), determination of compliance with the inclusion/non-inclusion criteria. If the participant meets the inclusion criteria/does not meet the non-inclusion criteria, he or she is included in the study. The screening period lasts no more than 7 days.

Hospital admission (Day 1, Visit 1.1-1.3) A participant who has passed screening, meets the inclusion criteria, and does not meet the non-inclusion criteria will be admitted to the hospital on Day 1. Admission will take place from 8:00 to 9:00, admission to the hospital on the evening before is allowed (at the discretion of the test facility staff and with the consent of the participant). During hospital admission, the trial participant undergoes an objective examination prior to administration of the study drug, including measuring body weight, vital signs, a breath alcohol test, a 12-lead ECG, a urine express analysis for drugs and medications, a pregnancy test, and blood sampling for the development of methods for detecting the active components of the MMH-522 drug.

The first dose of MMH-522 is administered in the hospital under the supervision of medical staff at 10:00 (±20 min) on Day 1. The investigator assesses local tolerability of the drug immediately after administration and 15 minutes after administration of the study drug (SD), assesses subjective sensations after administration of the SD. In case of gagging or spitting out the drug, the participant repeats the attempt to take the test drug. A total of up to 3 attempts are allowed. Failure to take the drug will be recorded in the primary documents, and the participant will be excluded from the study and replaced by another participant (a replacement participant).

One hour after the first administration of the study drug, the investigator repeats the objective examination, measures vital signs, performs a 12-lead ECG, and assesses the safety of the test therapy (record any possible AEs).

The 2nd, 3rd and 4th doses of the study drug on Day 1 will be administered at 14:00 (±20 min), 18:00 (±20 min) and 22:00 (±20 min), respectively. The investigator will assess local tolerability of the drug immediately after administration and 15 minutes after each administration of the SD, assess subjective sensations after administration of the SD.

Within 24 hours of administering the first dose of the study drug, the participant is monitored by medical staff; the investigator assesses the safety of the study therapy (records possible AEs).

At 24 hours (±30 min) after administration of the first dose of the study drug, a repeat examination is performed, including a physical examination with assessment of vital signs, 12-lead ECG, laboratory tests (complete blood count and urine analysis, blood biochemistry, coagulation tests, platelet aggregation test), blood sampling for the development of methods for detecting the active components of MMH-522. The investigator assesses the safety of the study therapy (records possible AEs). The duration of hospital stay for conducting the research procedures will be no more than 28 hours on Days 1-2 (approximately from 8:00 on Day 1 to 12:00 on Day 2), and the duration of the visit on Day 8 will be no more than 3 hours. Participants will receive the same menu during their stay in the hospital.

Drug administration period (Days 2-7) At 8:00 am (±20 min) on Day 2, the study drug is administered under the supervision of medical staff. The investigator assesses local tolerability of the drug immediately after administration and 15 minutes after administration of the SD. Starting with the daytime administration of the study drug on Day 2 and up to and including Day 7, the participant independently takes the drug 4 times a day, approximately at equal intervals in the morning (8:00-9:00 am), afternoon (12:00-1:00 and 16:00-17:00), and evening (20:00-21:00), indicating the exact time of administration of the study drug in the electronic participant diary (EPD), and recording any deterioration of their condition in the EPD; the physician monitors completion of the diary. The participant takes the study drug for a total of 7 days.

Final visit (Day 8, Visit 2) On Day 8, the hospital visit is scheduled for approximately 8:00 to 9:00. The participant visits the hospital fasting, and the investigator performs a physical examination, oral cavity examination, assesses subjective sensations after administration of the SD, measures vital signs, performs a breath alcohol test, 12-lead ECG, and laboratory tests (express urine analysis for drugs and medications, general blood and urine tests, blood chemistry, coagulation test, platelet aggregation test), blood sampling for developing methods for detecting active components of MMH-522; assesses compliance. The investigator assesses the safety of the study therapy (records possible AEs). If necessary, participants may be supervised after completion of all research procedures on Day 8 for up to 1 hour.

Unscheduled visit It is conducted in the event of an AE. The study participant is invited to visit the medical center. The investigator collects complaints, performs a physical examination, oral cavity examination, assesses subjective sensations after administration of the SD, measures vital signs. During the visit, the investigator decides on the further tactics regarding continued participation in the study and the need to prescribe AE therapy on an outpatient or inpatient basis. The participant may enter data on the AE that has occurred in the EPD or report it to the physician.

Early termination visit A participant who meets at least one withdrawal criterion is considered to have terminated their participation in the trial early. During the visit, the final visit procedures are performed, including an objective examination, measurement of vital signs, a breath alcohol test, 12-lead ECG, laboratory tests (express urine test for drugs and medications, general clinical blood and urine tests, blood chemistry test, coagulation test, platelet aggregation test), blood sampling for the development of methods for detecting the active components of MMH-522. The investigator indicates the date of termination of participation in the primary documentation and CRF, the date of the last administration of the study drug, notes the fact of early termination of participation in the study, the day of the participant's early exclusion from the study, the reason, and information about the return of the drug.

Monitoring of MMH-522 administration outside of the participants' stay in the hospital All participants will receive a reminder to take the study drug daily (Days 2-7) four times a day at 7:50, 11:50, 15:50, and 19:50. If a participant does not enter information about taking the SD into the EPD before the established periods, the participant and the investigator will receive a repeat reminder.

After each dose of MMH-522, the participant records the exact time of administration in the EPD. The investigator monitors the administration of MMH-522 by analyzing the records in the EPD. If there is no record of MMH-522 administration, the investigator contacts the participant to clarify the reason for not taking the study drug and, if the participant continues to participate in the trial, reminds them of the need to take MMH-522.

Stages of the trial The trial will be conducted in four stages. The stages will be carried out sequentially. Each subsequent stage will begin after the completion of the previous one and the conclusion of the Independent Committee for Monitoring Safety and Patient Data (ICMSPD ) on the safety and tolerability of the course administration at stages 1-4; upon completion of stage 4, a report on the phase I trial will be prepared.

The criteria for transition to the next stage are as follows:

Absence of severe AEs (grade 3 and above, CTCAE 5.0, Appendix 1) related to the cardiovascular system, gastrointestinal tract, skin and subcutaneous adipose tissue, laboratory abnormalities (in clinical and biochemical blood tests) associated with the administration of the study drug, severe life-threatening allergic reactions (generalized urticaria, angioedema, anaphylaxis) requiring intensive care.

In the event of one severe grade AE at each stage (grade 3 and above, CTCAE 5.0) related to the study drug, and AEs related to the study drug that led to the participant's early withdrawal from the study, as well as when new data appear indicating any changes in the benefit-risk ratio, an unscheduled meeting of the ICMSPD is held and a decision is made on the further tactics for conducting/completing the trial. If a decision is made to continue the trial, the current stage is repeated with three more participants.

Participants are screened separately before each stage. Stage 1 Course administration, single dose: 1 tablet of MMH-522 4 times a day for 7 days. The duration of hospital stay for conducting research procedures will be no more than 28 hours on Days 1-2 (approximately from 8:00 on Day 1 to 12:00 on Day 2), the duration of the visit on Day 8 will be no more than 3 hours. Three participants will be included in the dosing.

Stage 2 Course administration, single dose: 2 tablets of MMH-522 (consecutive administration of tablets without interruption is allowed) 4 times a day for 7 days. The duration of hospital stay for conducting research procedures will be no more than 28 hours on Days 1-2 (approximately from 8:00 on Day 1 to 12:00 on Day 2), the duration of the visit on Day 8 will be no more than 3 hours. Three participants will be included in the dosing.

Stage 3 Course administration, single dose: 3 tablets of MMH-522 (consecutive administration of tablets without interruption is allowed) 4 times a day for 7 days. The duration of hospital stay for conducting research procedures will be no more than 28 hours on Days 1-2 (approximately from 8:00 on Day 1 to 12:00 on Day 2), the duration of the visit on Day 8 will be no more than 3 hours. Three participants will be included in the dosing.

Stage 4 Repeat study of the maximum tolerated dosage regimen of MMH-522 for 7 days. The duration of hospital stay for conducting research procedures will be no more than 28 hours on Days 1-2 (approximately from 8:00 on Day 1 to 12:00 on Day 2), the duration of the visit on Day 8 will be no more than 3 hours. Three participants will be included in the dosing at stage 4.

For each stage, replacement participants who have successfully completed the screening procedures will be invited along with the main participants. If one of the participants is unable to be admitted to the hospital and participate in the trial for any reason, the replacement participant becomes a full participant in the study and undergoes all procedures according to the protocol. If all planned participants of the relevant stage are admitted to the hospital and receive the first dose of the study drug, the replacement participant will be excluded from the study.

Blood sampling for the development of methods for detecting the active components of MMH-522 will be performed three times on an empty stomach: 1) on Day 1 before administering the first dose of the study drug, 2) 24 hours (±30 min) after the start of administering the study drug, 3) 7 days after therapy with the study drug.

Then, blood serum is frozen for subsequent storage and transportation at -200С to the laboratory of the clinical trial Sponsor.

Inclusion criteria

• Males and females aged 18 to 45 years.
• A diagnosis of "healthy" was established by the examining physician based on a medical assessment , including medical history, vital signs, an objective examination, a 12-lead electrocardiogram, and laboratory test results.
• The body mass index ranges from 18.5 to 30 kg/m2 with a body weight over 50 kg.
• Availability of a participant information sheet and informed consent form for participation in the clinical trial, signed by the participant.
• Participants who agreed to use a reliable method of contraception during the study (for men and women of reproductive potential).

Exclusion criteria

• A history of significant diseases, in the investigator's opinion, that may interfere with achieving the study's objectives: renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, hematological, endocrine, or neurological diseases.
• Any condition that may affect the absorption of the drug in the oral cavity or gastrointestinal tract (e.g., gastric resection or other gastrointestinal surgery other than appendectomy).
• Hypersensitivity to any component of the drug used in treatment; a history of anaphylactic reactions to drugs or general allergic reactions that, in the opinion of the investigator, may affect the outcome of the study.
• Abnormalities in laboratory blood and urine tests (general clinical, biochemical, coagulogram, platelet aggregation parameters).
• Abnormal in vital signs parameters: systolic blood pressure <90 mmHg or >139 mmHg; diastolic blood pressure <60 mmHg or >89 mmHg; heart rate <50 bpm or >99 bpm, body temperature >37.0, saturation <95%.
• Any abnormal ECG changes, including HR < 50 or > 99 bpm, mean corrected PQ < 120 or > 200 ms, QT (QTcF) > 450 ms, QRS < 60 or > 120 ms. Abnormal PQRST patterns.
• Donor blood donation (450 ml of blood or more) less than 3 months before the start of the study.
• Participation in other clinical trials within 3 months prior to inclusion in the study.
• Regular alcohol consumption exceeding 10 units of alcohol per week (where each unit is approximately equal to 25 ml of spirits or 250 ml of beer) during the 6 months prior to taking the study drug.
• Positive breath alcohol test.
• Smoking cigarettes, cigars, e-cigarettes, or vapes within 3 months prior to taking the study drug.
• A positive urine rapid test for narcotics and drugs (amphetamine, barbiturates, benzodiazepines, cocaine, marijuana, methadone, methamphetamine, morphine, MDMA (ecstasy), tricyclic antidepressants).
• Positive test results for hepatitis B, C, HIV, or syphilis.
• Participants who, in the investigator's judgment, will not comply with the study drug administration instructions.
• Pregnancy, breastfeeding, or childbirth less than 3 months prior to study entry.
• A participant is a member of the center's research staff directly involved in the study and is an immediate family member of the researcher. Immediate family members are defined as spouses, parents, children, or siblings, regardless of whether they are biological or adopted.
• The participant is employed by NPF MATERIA MEDICA HOLDING LLC, i.e., is an employee of the company, a temporary contract worker, or an appointed official responsible for the conduct of the study, or their immediate family member.