Clinical Trial of the Safety and Tolerability of the Drug MMH-450 in Healthy Volunteers

Open-label, Non-comparative, Non-randomized Clinical Trial of the Safety and Tolerability of the Drug MMH-450 in Healthy Volunteers

Open-label, non-comparative, non-randomized clinical trial of the safety and tolerability of the drug MMH-450 in healthy volunteers

Design: open-label, non-comparative, non-randomized clinical trial consisting of 4 consecutive stages.

The study will include healthy volunteers (hereinafter referred to as 'participants') of both sexes aged 18 to 45 years who meet the inclusion criteria and do not meet the exclusion criteria.

Screening (Days -7-0, Visit 0). After signing the participant information sheet and informed consent form (ICF), the study participant undergoes a screening examination on an outpatient basis (Days -7-0): medical history collection, physical examination (height, weight, vital signs, pregnancy test, 12-lead ECG, breath alcohol test, laboratory tests (rapid urine test for drugs and medications, general clinical blood and urine tests, blood chemistry, HIV test, RPR test, HBsAg, HCV), determination of compliance with inclusion/exclusion criteria. If the inclusion criteria are met/there are no exclusion criteria, the participant is included in the study. The screening period lasts no more than 7 days.

Hospital admission (Day 1, Visit 1.1-1.3). Participants who pass the screening, meet the inclusion criteria, and do not meet the exclusion criteria are admitted to the hospital on Day 1. Admission will take place from 8:00 a.m. to 1:00 p.m. (at least 8 hours before the first dose of MMH-450). During hospital admission, the study participant undergoes an objective examination prior to administration of the study drug, including measurement of body weight, vital signs, a breath alcohol test, 12-lead ECG, rapid urine test for drugs and medications, pregnancy test, blood sampling for the development of methods for detecting the active components of MMH-450, completion of the Karolinska Sleepiness Scale together with a doctor, Epworth Sleepiness Scale, TMT test (Trail Making Test).

The first dose of the study drug will be administered in the hospital under the supervision of medical staff in the evening, approximately 1 hour before bedtime (at 9:00 p.m. ±10 minutes) on Day 1. The doctor will assess the local tolerability of the drug. In case of gagging or spitting out the drug, the participant will repeat the attempt to take the study drug. A total of up to 3 attempts are allowed. Failure to take the drug will be recorded in the source documents, and the participant will be excluded from the study and replaced by another participant (a substitute participant).

One hour after taking the study drug, the doctor will repeat the objective examination, assess vital signs, perform a 12-lead ECG, and evaluate the safety of the study therapy (record any possible AEs).

Twelve hours after taking the drug, a repeat examination will be performed, including an objective examination with an assessment of vital signs, laboratory tests (general clinical blood and urine tests, biochemical blood analysis), and blood sampling to develop methods for determining the active components of study drug. The Karolinska Sleepiness Scale and TMT test are completed. The doctor assesses the safety of the study therapy (records any possible AEs). For self-administration, the participant will be given the study drug and instructions for its use. The duration of hospitalization will be no more than 28 hours (approximately from 8:00 a.m. on day 1 to 12:00 p.m. on day 2). Participants will receive the same menu during their stay in the hospital.

The study will use an electronic participant diary (EPD). On Day 1, the doctor will provide instructions on how to use the EPD. In the EPD, the participant will record any possible deterioration in their condition on a daily basis (Days 1-8), complete the Karolinska Sleepiness Scale at baseline, before taking the first dose of the study drug, 12 hours after taking it, then daily while taking the study drug (Days 2-7), and at the final visit (Day 8).

Drug administration period (Days 2-7). On Days 2-7, the participant independently takes the study drug approximately 1 hour before bedtime (at 21:00 ±10 minutes) daily, indicating the exact time of taking the study drug in the EPD, completes the Karolinska Sleepiness Scale in the EPD (on Day 2, the scale is completed twice: the first time is 12 hours after taking the first dose of the study drug during hospitalization on Day 1, and the second time is in the evening on an outpatient basis on Day 2), enters data on AEs into the EPD; the doctor monitors the completion of the diary.

Final visit (Day 8, Visit 2). On Day 8, the hospital visit is scheduled for approximately 8:00 a.m. to 1:00 p.m. The participant visits the hospital on an empty stomach, where the doctor conducts an objective examination, measures vital signs, performs a breath alcohol test, 12-lead ECG, laboratory tests (rapid urine test for drugs and medications, general clinical blood and urine tests, blood chemistry test), blood sampling to develop methods for detecting the active components of the study drug; assesses compliance; the participant, together with the doctor, completes the Karolinska Sleepiness Scale (in the EPD), the Epworth Sleepiness Scale, and the TMT test. The doctor assesses the safety of the study therapy (records possible AEs). After completing all trial procedures on Day 8, participants will be monitored for up to 1 hour, if necessary.

Unscheduled visit. It is conducted in the event of an AE. The study participant is invited to visit the medical center. The doctor collects complaints, conducts an objective examination, and measures vital signs. During the visit, the doctor decides on further tactics regarding continued participation in the trial 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 doctor.

Early termination visit. A participant who meets at least one exclusion criterion is considered to have terminated their participation in the trial early. During the visit, final visit procedures are performed, including an objective examination, measurement of vital signs, a breath alcohol test, 12-lead ECG, laboratory tests (rapid urine test for drugs and medications, general clinical blood and urine tests, blood chemistry test), blood sampling for the development of methods for detecting the active components of the study drug; the participant, together with the doctor, completes the Karolinska Sleepiness Scale, the Epworth Sleepiness Scale, and the TMT test. In the source documents and Case Report Form, the doctor indicates the date of completion of participation, 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 the study drug administration outside of the participants' stay in the hospital All participants will receive a reminder to take the study drug at 8:30 p.m. If the participant does not enter information about taking the study drug in the EPD by 9:30 p.m., the participant and the investigator will receive a repeat reminder.

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

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 receipt of the conclusion of the Independent Committee for Monitoring Safety and Patient Data (ICMSPD ) on the safety and tolerability of the course administration in 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) 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 severe grade 1 AEs (grade 3 and above, CTCAE 5.0) associated with the study drug and AEs associated with 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 study. If a decision is made to continue the study, the current stage is repeated with 3 more participants.

Participants are screened separately before each stage. Stage 1 Course administration, single dose: 1 tablet of MMH-450 once in the evening, approximately 1 hour before bedtime (at 9:00 p.m. ±10 minutes) for 7 days. The duration of hospitalization will be no more than 28 hours (approximately from 8:00 a.m. on Day 1 to 12:00 p.m. on Day 2). Three participants will be included in the dosage.

Stage 2 Course administration, single dose: 2 tablets of MMH-450 once in the evening, approximately 1 hour before bedtime (at 9:00 p.m. ±10 minutes) for 7 days. The duration of hospitalization will be no more than 28 hours (approximately from 8:00 a.m. on Day 1 to 12:00 p.m. on Day 2). Three participants will be included in the dosage.

Stage 3 Course administration, single dose: 4 tablets of MMH-450 once in the evening, approximately 1 hour before bedtime (at 21:00 ±10 minutes), for 7 days. The duration of hospitalization will be no more than 28 hours (approximately from 8:00 a.m. on Day 1 to 12:00 p.m. on Day 2). Three participants will be included in the dosage.

Stage 4 Repeat study of the maximum tolerated dosage regimen of MMH-450 approximately 1 hour before bedtime (at 9:00 p.m. ±10 minutes) for 7 days. The duration of hospitalization will be no more than 28 hours (approximately from 8:00 a.m. on Day 1 to 12:00 p.m. on Day 2). Three participants will be included in the stage 4 of the study.

For each stage, 1 replacement participant who has successfully passed the screening procedures will be invited along with the 3 participants. If one of the participants is unable to be admitted to the hospital and participate in the study 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 at the relevant stage are admitted to the hospital and receive the study drug, the replacement participant will be excluded from the study.

Blood sampling for the development of methods for determining the active components of the study drug is performed three times: 1) on Day 1 before taking the first dose of the study drug, 2) 12 hours after taking the first dose of the study drug, 3) 7 days after therapy with the study drug. The blood serum is then frozen and transported and stored at - 200С in the clinical trial Sponsor's laboratory.

Inclusion Criteria:

1. Males and females aged 18 to 45 years.
2. A diagnosis of "healthy" as determined by the study physician based on a medical assessment, including medical history, vital signs, physical examination, 12-lead electrocardiogram, and laboratory test results.
3. Participants with physiological sleep and an average daily routine (alternating 8 hours of work, 8 hours of rest (active) and 6-8 hours of sleep), with a habitual bedtime between 9:00 p.m. and 11:00 p.m.
4. Body mass index between 18.5 and 30 kg/m2 with a body weight over 50 kg.
5. Availability of a participant information sheet and an informed consent form for participation in the clinical trial signed by the participant.
6. Participants who have agreed to use a reliable method of contraception during the trial (for men and women of reproductive potential).

Exclusion Criteria:

1. The presence in the anamnesis of data on diseases that are significant, in the opinion of the investigator, which may interfere with achieving the purpose of the study: renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, hematological, endocrine or neurological diseases.
2. Any condition that may affect the absorption of the drug in the oral cavity or gastrointestinal tract (e.g., gastric resection or other surgical intervention for gastrointestinal diseases, except appendectomy).
3. Hypersensitivity to any component of the drug used in treatment; a history of anaphylactic reactions to drugs or general allergic reactions that, in the investigator's opinion, may affect the outcome of the study.
4. Abnormalities in laboratory blood and urine tests.
5. Abnormalities in vital signs: 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%.
6. Any abnormal ECG changes, including HR > 100 bpm, mean corrected PR < 100 or > 220 ms, PQ < 120 or > 200 ms, ST > 320 ms, QT (QTcF) > 450 ms, QRS > 120 ms, HR < 50 or > 99 bpm. Abnormal PQRST patterns.
7. Donor blood donation (450 ml of blood or more) less than 3 months before the start of the study.
8. Participation in other clinical trials within 3 months prior to inclusion in the study.
9. 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.
10. Positive breath alcohol test.
11. Smoking cigarettes, cigars, electronic cigarettes, or vaping within 3 months prior to taking the study drug.
12. Positive urine rapid test for narcotic and medicinal substances (amphetamine, barbiturates, benzodiazepine, cocaine, marijuana, methadone, methamphetamine, morphine, MDMA (ecstasy), tricyclic antidepressants).
13. Positive test results for hepatitis B, C, HIV infection or syphilis.
14. Unwillingness or inability to comply with lifestyle recommendations and restrictions prescribed by this protocol.
15. Participants who, in the opinion of the investigator, will not comply with the study drug administration schedule.
16. Pregnancy, breastfeeding, childbirth less than 3 months before inclusion in the study.
17. A participant is a member of the center's research staff directly involved in the study and is an immediate family member of the investigator. "Immediate family members" are defined as spouses, parents, children, or siblings, regardless of whether they are biological or adopted.
18. The participant works for the company NPF MATERIA MEDICA HOLDING LLC, i.e. is an employee of the company, a temporary contract worker, or an appointed official responsible for the implementation of the study, or their immediate family member.
19. The participant failed the screening procedure.
20. The occurrence of an adverse event requiring discontinuation of the study drug.
21. Erroneous inclusion of an ineligible participant in the study.
22. The participant's desire to terminate the study early for any reason.
23. The participant's inclusion in another clinical trial.
24. Cases not specified in the protocol, when the investigator believes that the participant's continued participation in the study would be detrimental to the participant.