Safety, Tolerability, and Pharmacokinetic Parameters of Grammidin With Anesthetic, a Metered Spray in Healthy Volunteers

Phase 1

Recruiting

• Conditions: Pharyngitis
• Interventions: Drug: Grammidin with anesthetic neo; Drug: Grammidin with anesthetic, a metered spray for local application

• Registration Number: NCT06857890
• Lead Sponsor: Valenta Pharm JSC

Brief Summary

Study of the safety, tolerability, and pharmacokinetic parameters of the investigational drug Grammidin with anesthetic, a metered spray for local application, compared to Grammidin with anesthetic neo, lozenges for dissolution upon single use in healthy volunteers.

Detailed Description

Not available

Study Timeline

• Study Start: 2024-12-09
• Status Verified: 2025-02
• Study First Submitted: 2025-02-17
• Study First Submitted QC: 2025-02-27
• Last Update Submitted: 2025-02-27
• Study First Posted: 2025-03-05
• Last Update Posted: 2025-03-05
• Primary Completion: 2026-12-01
• Study Completion: 2026-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

1. Voluntarily and personally signed informed consent form by a healthy volunteer to participate in the study before any study procedures are conducted;
2. Men and women aged 18 to 45 years (inclusive);
3. Verified diagnosis of "healthy" (absence of deviations based on clinical, laboratory, and instrumental examination methods specified in the protocol);
4. Blood pressure (BP) level: systolic blood pressure (SBP) from 99 to 129 mm Hg (inclusive), diastolic blood pressure (DBP) from 70 to 89 mm Hg (inclusive);
5. Heart rate (HR) from 60 to 89 beats per minute (inclusive);
6. Respiratory rate (RR) from 12 to 20 breaths per minute (inclusive);
7. Body temperature from 36.0°C to 36.9°C (inclusive);
8. Body mass index (BMI) between 18.5 kg/m² and 30 kg/m², with a minimum body weight of ≥ 55 kg for men and ≥ 45 kg for women;
9. Consent to use adequate contraceptive methods throughout the study and for 30 days after its completion, with a negative urine pregnancy test result for women with preserved reproductive potential.

Non-Inclusion Criteria:

1. History of significant allergic reactions;
2. Hypersensitivity to active and/or excipient substances in the investigational drug and comparator drug in the medical history;
3. Drug intolerance to active and/or excipient substances in the investigational drug and comparator drug in the medical history;
4. Chronic diseases of the kidneys, liver, gastrointestinal tract (GIT), cardiovascular, lymphatic, respiratory, nervous, endocrine, musculoskeletal, urogenital, and immune systems, as well as skin, hematopoietic organs, and the eye;
5. Erosive-ulcerative lesions of the oral mucosa (aphthous stomatitis, mechanical injuries due to dental diseases, herpes outbreaks, and any other diseases or conditions leading to disruption of the integrity of the oral mucosa);
6. Surgical interventions on the GIT in the medical history (except for appendectomy performed at least 1 year prior to screening);
7. Diseases/conditions that, in the investigator's opinion, may affect the absorption, distribution, metabolism, or excretion of the investigational drugs;
8. Acute infectious diseases less than 4 weeks before screening;
9. Use of medications (drugs) that significantly affect hemodynamics and drugs affecting liver function (barbiturates, omeprazole, cimetidine, etc.) less than 2 months before screening;
10. Regular use of medications less than 2 weeks before screening and single use of medications less than 7 days before screening (including over-the-counter medications, vitamins, dietary supplements, herbal medicines);
11. Donating blood or plasma less than 3 months before screening;
12. Use of hormonal contraceptives (in women) less than 2 months before screening;
13. Use of depot injections of any medications less than 3 months before screening;
14. Pregnancy or lactation; positive urine pregnancy test result for women with preserved reproductive potential;
15. Women with preserved reproductive potential who have had unprotected sexual contact within 30 days prior to taking investigational drugs with an unsterilized partner;
16. Participation in another clinical study less than 3 months prior to screening or concurrently with this study;
17. Consumption of more than 10 alcohol units per week (1 unit of alcohol is equivalent to 500 ml of beer, 200 ml of wine, or 50 ml of strong alcoholic beverages) in the last month before inclusion in the study or a history of alcoholism, drug addiction, or substance abuse;
18. Smoking more than 10 cigarettes per day currently or smoking that amount in the past 6 months prior to screening; unwillingness to refrain from smoking during hospitalization;
19. Consumption of alcohol, caffeine, and xanthine-containing products within 7 days prior to taking investigational drugs;
20. Consumption of citrus fruits, cranberries, rose hips and products containing them, or preparations/products containing St. John's wort within 7 days prior to taking investigational drugs;
21. Dehydration due to diarrhea, vomiting, or other causes within the last 24 hours prior to taking investigational drugs;
22. Positive blood test for antibodies to human immunodeficiency virus (HIV) types 1 and 2, antibodies to Treponema pallidum antigens, hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus antigens during screening;
23. Positive rapid test for coronavirus disease 2019 (COVID-19) during screening;
24. ECG abnormalities in medical history and/or during screening;
25. Positive urine test for narcotic substances and potent medications during screening;
26. Positive breath alcohol test result during screening;
27. Planning hospitalization during the study period for any reason other than hospitalization specified in this protocol;
28. Inability or unwillingness to comply with protocol requirements, perform procedures prescribed by the protocol, or adhere to dietary and activity restrictions;
29. Belonging to a vulnerable group of volunteers: students from higher and secondary medical, pharmaceutical and dental educational institutions, junior staff from clinics and laboratories, employees of pharmaceutical companies, military personnel and prisoners, individuals in nursing homes, low-income and unemployed individuals, representatives of national minorities, homeless individuals, refugees, individuals under guardianship or custody, individuals unable to provide consent as well as law enforcement personnel;
30. Dental procedures performed less than 3 weeks prior to screening;
31. Other conditions that in the opinion of the Investigator may prevent volunteer inclusion in the study or lead to premature withdrawal from the study including adherence to fasting or special diets (e.g., vegetarianism, veganism, salt restriction) or special lifestyles (night work, extreme physical exertion).

Exclusion Criteria

1. Withdrawal of the volunteer from further participation in the study;
2. Non-compliance by the volunteer with the study participation rules (missed study procedures, self-administration of drugs prohibited in the study, violation of dietary and lifestyle restrictions, etc.);
3. Emergence of reasons/situations during the study that threaten the safety of the volunteer (e.g., hypersensitivity reactions, etc.);
4. Volunteers selected for participation in the study who do not meet inclusion/exclusion criteria;
5. Development of a severe adverse event (SAE) in the volunteer during the study;
6. The volunteer undergoes or requires treatment that may affect the pharmacokinetic parameters (PKP) of the investigational drugs;
7. Missed collection of 2 or more consecutive blood samples or 3 or more blood samples within one study period;
8. Occurrence of vomiting/diarrhea within 6 hours after taking the investigational drug;
9. Positive urine test for narcotic substances and potent medications;
10. Positive breath test for alcohol vapors;
11. Positive pregnancy test result in women;
12. Positive COVID-19 test result;
13. Emergence of other reasons during the study that prevent conducting the study according to the protocol.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
RT sequence: Grammidin with anesthetic neo followed by Grammidin with anesthetic	Grammidin with anesthetic neo	RT sequence where R is Grammidin with anesthetic neo, lozenges, and T is Grammidin with anesthetic, a metered spray for local application
RT sequence: Grammidin with anesthetic neo followed by Grammidin with anesthetic	Grammidin with anesthetic, a metered spray for local application	RT sequence where R is Grammidin with anesthetic neo, lozenges, and T is Grammidin with anesthetic, a metered spray for local application
TR sequence: Grammidin with anesthetic followed by Grammidin with anesthetic neo	Grammidin with anesthetic neo	TR sequence where T is Grammidin with anesthetic, a metered spray for local application, and R is Grammidin with anesthetic neo, lozenges
TR sequence: Grammidin with anesthetic followed by Grammidin with anesthetic neo	Grammidin with anesthetic, a metered spray for local application	TR sequence where T is Grammidin with anesthetic, a metered spray for local application, and R is Grammidin with anesthetic neo, lozenges

Primary Outcome Measures

Name	Time	Method
Pharmacokinetics - Cmax	From 0 to 24 hours after each drug intake.	Maximum plasma concentration (Cmax) of gramicidin S, oxybuprocaine hydrochloride, and cetylpyridinium chloride. The same analytes would be used for other pharmacokinetic measures listed below.
Pharmacokinetics - tmax	From 0 to 24 hours after each drug intake.	Time to reach Cmax (tmax)
Pharmacokinetics - AUC0-t	From 0 to 24 hours after each drug intake.	Area under the plasma concentration-time curve from time 0 to t (AUC0-t)
Pharmacokinetics - AUC0-inf	From 0 hours after each drug intake (extrapolated to infinity)	Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf)
Pharmacokinetics - AUCextr	From 0 hours after each drug intake (extrapolated to infinity)	Extrapolated AUC defined as (AUC0-inf - AUC0-t)/AUC0-inf
Pharmacokinetics - t1/2	From 0 to 24 hours after each drug intake.	Elimination half-life (t1/2)
Pharmacokinetics - kel	From 0 to 24 hours after each drug intake.	Elimination constant (kel)
Pharmacokinetics - MRT	From 0 to 24 hours after each drug intake.	Mean residence time (MRT)
Pharmacokinetics - Vd	From 0 to 24 hours after each drug intake.	Volume of distribution
Pharmacokinetics - CL	From 0 to 24 hours after each drug intake.	Clearance (CL)
Pharmacokinetics - number of terminal timepoints	From 0 to 24 hours after each drug intake.	Number of points in the terminal logarithmic phase used to estimate the terminal elimination rate constant

Secondary Outcome Measures

Name	Time	Method
Adverse event type	From screeninig (days -14 to -1) to the end of study (day 15 ± 1)	Adverse events will be assessed by complaints, results of physical examination, results of heart rate and blood pressure assessment, results of respiratory rate assessment, body temperature, laboratory monitoring (clinical blood count, biochemical blood count, urinalysis), electrocardiography; adverse events will be classified in accordance to MedDRA.
Adverse event number	From screeninig (days -14 to -1) to the end of study (day 15 ± 1)	Number of adverse events registered during the study
Adverse event severety	From screeninig (days -14 to -1) to the end of study (day 15 ± 1)	Severity of adverse events registered during the study
Drop-outs associated with adverse events	From screeninig (days -14 to -1) to the end of study (day 15 ± 1)	The number of cases of early termination of participation in the study due to the development of adverse events and/or serious adverse events associated with the study drug
Safety and Tolerability: volunteer complaints	From screeninig (days -14 to -1) to the end of study (day 15 ± 1)	Description of complaints, recieved from volunteer
Safety and Tolerability: physical examination results - cardiovascular system	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	An assessment of the condition of the cardiovascular system on physical examination (normal condition or list of abnormal conditions, if any)
Safety and Tolerability: physical examination results - respiratory system	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	An assessment of the condition of the respiratory system on physical examination (normal condition or list of abnormal conditions, if any)
Safety and Tolerability: physical examination results - digestive tract	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	An assessment of the condition of the digestive tract on physical examination (normal condition or list of abnormal conditions, if any)
Safety and Tolerability: physical examination results - endocrine system	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	An assessment of the condition of the endocrine system on physical examination (normal condition or list of abnormal conditions, if any)
Safety and Tolerability: physical examination results - musculoskeletal system	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	An assessment of the condition of the musculoskeletal system on physical examination (normal condition or list of abnormal conditions, if any)
Safety and Tolerability: physical examination results - nervous system	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	An assessment of the condition of the nervous system on physical examination (normal condition or list of abnormal conditions, if any)
Safety and Tolerability: physical examination results - sensory systems	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	An assessment of the condition of the sensory systems on physical examination (normal condition or list of abnormal conditions, if any)
Safety and Tolerability: physical examination results - skin/visible mucous membranes	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	An assessment of the condition of the skin/visible mucous membranes on physical examination (normal condition or list of abnormal conditions, if any)
Safety and Tolerability: vital signs - systolic blood pressure	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	Systolic blood pressure (SBP, mmHg)
Safety and Tolerability: vital signs - diastolic blood pressure	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	Diastolic blood pressure (DBP, mmHg)
Safety and Tolerability: vital signs - heart rate	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	Heart rate (HR, bpm)
Safety and Tolerability: 12-lead electrocardiogram (ECG) - heart rate	Screeninig (days -14 to -1), day 1, 2, 8, 9, 15 ± 1	12-lead ECG (I, II, III, aVR-enhanced unipolar abduction from the right arm , aVL-enhanced unipolar abduction from the left arm, aVF - enhanced unipolar abduction from the left leg, V1-V6) taken while lying down: heart rate (beats per minute)
Safety and Tolerability: vital signs - body temperature (Celsius temperature scale)	Screeninig (days -14 to -1), day -1 to 2, day 7 to 9, day 15 ± 1	Body temperature (Celsius temperature scale)
Safety and Tolerability: 12-lead electrocardiogram (ECG) - PQ interval	Screeninig (days -14 to -1), day 1, 2, 8, 9, 15 ± 1	12-lead ECG (I, II, III, aVR-enhanced unipolar abduction from the right arm , aVL-enhanced unipolar abduction from the left arm, aVF - enhanced unipolar abduction from the left leg, V1-V6) taken while lying down: PQ interval (is the period, measured in milliseconds, that extends from the beginning of the P wave (the onset of atrial depolarization) until the beginning of the QRS complex)
Safety and Tolerability: 12-lead electrocardiogram (ECG) - QRS complex	Screeninig (days -14 to -1), day 1, 2, 8, 9, 15 ± 1	12-lead ECG (I, II, III, aVR-enhanced unipolar abduction from the right arm , aVL-enhanced unipolar abduction from the left arm, aVF - enhanced unipolar abduction from the left leg, V1-V6) taken while lying down: QRS complex (the QRS complex is the combination of three of the graphical deflections seen on a typical electrocardiogram)
Safety and Tolerability: 12-lead electrocardiogram (ECG) - corrected QT interval	Screeninig (days -14 to -1), day 1, 2, 8, 9, 15 ± 1	12-lead ECG (I, II, III, aVR-enhanced unipolar abduction from the right arm , aVL-enhanced unipolar abduction from the left arm, aVF - enhanced unipolar abduction from the left leg, V1-V6) taken while lying down: corrected QT interval (distance from the beginning of the QRS complex to the end of the T wave)
Safety and Tolerability: clinical blood test - hemoglobin	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Hemoglobin (g/L)
Safety and Tolerability: clinical blood test - hematocrit	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Hematocrit (%)
Safety and Tolerability: clinical blood test - red blood cell count	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Red blood cell count (cells/L)
Safety and Tolerability: clinical blood test - platelet count	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Platelet count (cells/L)
Safety and Tolerability: clinical blood test - leukocyte count	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Leukocyte count (cells/L)
Safety and Tolerability: clinical blood test - erythrocyte sedimentation rate	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Erythrocyte sedimentation rate (mm/h)
Safety and Tolerability: clinical blood test - myelocytes	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Leukocyte formula (myelocytes, %)
Safety and Tolerability: clinical blood test - band neutrophils	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Leukocyte formula (band neutrophils, %)
Safety and Tolerability: clinical blood test - segmented neutrophils	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Leukocyte formula (segmented neutrophils, %)
Safety and Tolerability: clinical blood test - eosinophils	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Leukocyte formula (eosinophils, %)
Safety and Tolerability: clinical blood test - basophils	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Leukocyte formula (basophils, %)
Safety and Tolerability: clinical blood test - monocytes	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Leukocyte formula (monocytes, %)
Safety and Tolerability: clinical blood test - lymphocytes	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Leukocyte formula (lymphocytes, %)
Safety and Tolerability: urinalysis - specific gravity	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Specific gravity of the urine
Safety and Tolerability: urinalysis - color	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Color of the urine
Safety and Tolerability: urinalysis - transparency	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Transparency of the urine
Safety and Tolerability: urinalysis - pH	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	pH of the urine
Safety and Tolerability: urinalysis - protein	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Protein concentration (g/L)
Safety and Tolerability: urinalysis - glucose	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Glucose concentration (mmol/L)
Safety and Tolerability: urinalysis - red blood cells	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Red blood cell content (number in sight)
Safety and Tolerability: urinalysis - white blood cells	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	White blood cell content (number in sight)
Safety and Tolerability: urinalysis - epithelial cells	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Epithelial cell content (number in sight)
Safety and Tolerability: urinalysis - casts	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Presence of casts (Yes/No)
Safety and Tolerability: urinalysis - mucus	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Presence of mucus (Yes/No)
Safety and Tolerability: urinalysis - bacteria	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Presence of bacteria (Yes/No)
Safety and Tolerability: urinalysis (microscopy)	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Microscopy of urine sediment is performed if it is present
Safety and Tolerability: blood chemistry - glucose	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Glucose concentration (mmol/L)
Safety and Tolerability: blood chemistry - cholesterol	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Total cholesterol concentration (mmol/L)
Safety and Tolerability: blood chemistry - protein	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Total protein concentration (g/L)
Safety and Tolerability: blood chemistry - bilirubin	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Total bilirubin concentration (micromol/L)
Safety and Tolerability: blood chemistry - creatinine	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Creatinine concentration (micromol/L)
Safety and Tolerability: blood chemistry - alkaline phosphatase	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Alkaline phosphatase activity (U/L)
Safety and Tolerability: blood chemistry - alanine transaminase	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Alanine transaminase activity (U/L)
Safety and Tolerability: blood chemistry - aspartate transaminase	Screeninig (days -14 to -1), day 2, 9, 15 ± 1	Aspartate transaminase activity (U/L)

Trial Locations

Locations (1)

Separate Medical Unit "CoMed" (LLC "Ligand Research"); 🇷🇺 Moscow, Russian Federation