A Study of the Safety, Tolerability, and Pharmacokinetics of Single-Dose DMI019 Nasal Spray in Healthy Participants
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 48
- 主要终点
- Number of Participants With Clinically Significant Changes in Vital Signs
研究概览
简要总结
This Phase 1a, single-center, randomized study will evaluate the safety, tolerability, pharmacokinetics, and relative bioavailability of single-dose DMI019 nasal spray in healthy participants. Approximately 48 healthy male and female participants will be enrolled. The study includes an open-label, two-period crossover part comparing DMI019 nasal spray with oral emedastine difumarate sustained-release capsules, and a double-blind, placebo-controlled, dose-escalation part evaluating three dose levels of DMI019 nasal spray.
详细描述
This is a Phase 1a, single-center, randomized, single-dose study in approximately 48 healthy male and female participants. The primary objective is to evaluate the safety and tolerability of DMI019 nasal spray following a single dose. The secondary objectives are to characterize the pharmacokinetics of emedastine and to evaluate the relative bioavailability of DMI019 nasal spray compared with oral emedastine difumarate sustained-release capsules.The study consists of four cohorts: Part A and Cohorts B, C, and D.Part A will enroll approximately 12 participants and will use a randomized, open-label, two-period, two-sequence crossover design. Participants will be randomized in a 1:1 ratio to the TR or RT treatment sequence. In separate treatment periods, each participant will receive a single intranasal dose of DMI019 nasal spray 0.4 mg and a single oral dose of emedastine difumarate sustained-release capsule 2 mg under fasting conditions. The two treatment periods will be separated by a 7-day washout period. Part A will assess the relative bioavailability and pharmacokinetic profiles of the two formulations.Cohorts B, C, and D will enroll approximately 36 participants, with 12 participants in each cohort. These cohorts will use a randomized, double-blind, placebo-controlled, parallel-group, sequential dose-escalation design. Within each cohort, participants will be randomized in a 5:1 ratio to receive a single intranasal dose of DMI019 nasal spray or matching placebo under fasting conditions. The planned DMI019 dose levels are 0.8 mg in Cohort B, 1.6 mg in Cohort C, and 2.4 mg in Cohort D. Dose escalation to the next cohort will occur only after the available safety, tolerability, and pharmacokinetic data from the preceding cohort have been reviewed by the investigator and sponsor and no unacceptable safety risk has been identified.Blood samples for pharmacokinetic analysis will be collected before dosing and for up to 48 hours after dosing. Pharmacokinetic parameters will include maximum observed plasma concentration, time to maximum plasma concentration, area under the plasma concentration-time curve, terminal elimination rate constant, terminal elimination half-life, apparent clearance, apparent volume of distribution, mean residence time, and other relevant parameters.Safety and tolerability will be evaluated based on adverse events, vital signs, physical examinations, nasal examinations, clinical laboratory tests, and 12-lead electrocardiograms. Participants with unresolved adverse events will be followed until the event has resolved, stabilized, or received an adequate clinical explanation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants who fully understand the study, voluntarily agree to participate, and provide written informed consent before any study-related procedures are performed.
- •Chinese male or female participants aged 18 to 45 years, inclusive.
- •Male participants with a body weight of at least 50.0 kg and female participants with a body weight of at least 45.0 kg, with a body mass index (BMI) of 18.5 to 28.0 kg/m², inclusive.
- •From the time of signing the informed consent form until 3 months after the last administration of the study intervention, the participant and the participant's partner must have no plans for pregnancy, sperm donation, or egg donation. Participants must agree to use at least one non-pharmacological method of contraception from the time of signing informed consent until the last pharmacokinetic blood sample is collected and to use an effective method of contraception for 3 months after the last administration of the study intervention.
- •Participants who are able to communicate effectively with the investigator, correctly use the nasal spray device after training, and understand and comply with all study requirements.
排除标准
- •Known hypersensitivity to the study intervention or any of its components, or a history of severe allergic constitution, defined as known allergy to three or more drugs or foods.
- •Inability to comply with the standardized dietary requirements of the study.
- •Inability to tolerate venipuncture or a history of fainting associated with needles or blood.
- •A history or current presence of a clinically significant disease of the cardiovascular, endocrine, neurological, gastrointestinal, respiratory, urinary, ophthalmological, hematological, immunological, psychiatric, or metabolic system, including hypokalemia, atopic allergic disease, psychiatric disorders, or disorders of brain function, that in the investigator's judgment makes the participant unsuitable for the study.
- •A history of hypertension or hypotension, including orthostatic hypotension.
- •A clinically significant nasal medical history, disease, or abnormality that, in the investigator's judgment, may affect administration or absorption of the study intervention, including:
- •A history of persistent nasal congestion, rhinorrhea, epistaxis, or similar symptoms;
- •A history of nasal surgery, nasal trauma, severe rhinitis, or severe sinusitis that may affect drug absorption;
- •Any other structural abnormality of the nasal cavity or abnormality of the nasal mucosa that may affect drug absorption.
- •Major surgery within 6 months before screening or planned surgery during the study, except for appendectomy or hernia repair.
- •Clinically significant abnormalities identified at screening through physical examination, vital signs, 12-lead electrocardiogram, posteroanterior chest X-ray, or laboratory testing, including hematology, urinalysis, serum chemistry, coagulation tests, or testing for transfusion-transmitted infections. This includes alanine aminotransferase, aspartate aminotransferase, or gamma-glutamyl transferase above the upper limit of normal; total bilirubin greater than 1.2 times the upper limit of normal; or serum creatinine greater than 1.2 times the upper limit of normal.
- •Uncontrolled ventricular arrhythmia at screening; corrected QT interval using Fridericia's formula (QTcF) of at least 450 milliseconds in male participants or at least 460 milliseconds in female participants; a history of long QT syndrome; or any concomitant condition that may prolong the QT interval.
- •Consumption of more than 5 cups per day of tea, coffee, or other caffeine-containing beverages within 3 months before screening, with each cup defined as approximately 200 mL.
- •Consumption within 48 hours before the first administration of the study intervention of a special diet or products that may affect drug absorption, distribution, metabolism, or excretion, including grapefruit or grapefruit-containing products, chocolate, caffeine-containing products, or foods rich in xanthines such as animal liver; strenuous exercise during this period; or any other factor that may affect drug pharmacokinetics.
- •Use within 30 days before the first administration of the study intervention of any drug known to induce or inhibit hepatic drug metabolism. Examples include inducers such as barbiturates, carbamazepine, phenytoin, glucocorticoids, and omeprazole, and inhibitors such as selective serotonin reuptake inhibitors, cimetidine, diltiazem, macrolides, nitroimidazoles, sedative-hypnotics, verapamil, fluoroquinolones, and antihistamines.
- •Pregnant or breastfeeding women.
- •Use of any prescription drug, over-the-counter drug, traditional Chinese medicine, herbal product, dietary supplement, or health product within 14 days before the first administration of the study intervention.
- •Habitual smoking, smoking at least 5 cigarettes per day within 3 months before screening, a positive nicotine test at screening, or inability to abstain from smoking throughout the study.
- •Consumption of more than 14 standard units of alcohol per week within 6 months before screening, where one standard unit contains 14 g of alcohol and is approximately equivalent to 360 mL of beer, 45 mL of 40% spirits, or 150 mL of wine; a positive alcohol breath test before the first administration of the study intervention; or inability to abstain from alcohol throughout the study.
- •A history of drug abuse within 1 year before screening, including abuse of cannabis, benzodiazepines, ketamine, morphine, cocaine, methamphetamine, barbiturates, or tricyclic antidepressants, or a positive urine drug screen.
- •Participation in another clinical study involving administration of an investigational drug or use of an investigational device within 3 months before screening.
- •Donation or loss of at least 400 mL of blood within 3 months before screening; planned donation of blood or blood components during the study or within 3 months after study completion; receipt of a live attenuated vaccine within 28 days before the first administration of the study intervention; receipt of an inactivated vaccine within 14 days before the first administration; or planned vaccination during the study.
- •Any other medical or psychological condition that, in the investigator's judgment, may expose the participant to excessive risk, interfere with compliance with the protocol, or affect the participant's ability to complete the study.
研究组 & 干预措施
Part A: TR Sequence
Participants will receive a single intranasal dose of DMI019 nasal spray 0.4 mg under fasting conditions in Period 1, followed by a 7-day washout period, and then a single oral dose of emedastine difumarate sustained-release capsule 2 mg under fasting conditions in Period 2.
干预措施: DMI019 Nasal Spray 0.4 mg (Drug)
Part A: TR Sequence
Participants will receive a single intranasal dose of DMI019 nasal spray 0.4 mg under fasting conditions in Period 1, followed by a 7-day washout period, and then a single oral dose of emedastine difumarate sustained-release capsule 2 mg under fasting conditions in Period 2.
干预措施: Emedastine Difumarate Sustained-Release Capsule 2 mg (Drug)
Part A: RT Sequence
Participants will receive a single oral dose of emedastine difumarate sustained-release capsule 2 mg under fasting conditions in Period 1, followed by a 7-day washout period, and then a single intranasal dose of DMI019 nasal spray 0.4 mg under fasting conditions in Period 2.
干预措施: DMI019 Nasal Spray 0.4 mg (Drug)
Part A: RT Sequence
Participants will receive a single oral dose of emedastine difumarate sustained-release capsule 2 mg under fasting conditions in Period 1, followed by a 7-day washout period, and then a single intranasal dose of DMI019 nasal spray 0.4 mg under fasting conditions in Period 2.
干预措施: Emedastine Difumarate Sustained-Release Capsule 2 mg (Drug)
Part B: DMI019 Nasal Spray 0.8 mg
Participants will receive a single intranasal dose of DMI019 nasal spray 0.8 mg under fasting conditions. The dose will be administered as four sprays of the 0.2 mg/spray formulation, with two sprays administered into each nostril and an interval of approximately 30 seconds between consecutive sprays into the same nostril.
干预措施: DMI019 Nasal Spray 0.8 mg (Drug)
Part B: Placebo
Participants will receive a single intranasal dose of matching DMI019 nasal spray placebo under fasting conditions according to the administration schedule used for Part B.
干预措施: DMI019 Nasal Spray Placebo (Drug)
Part C: DMI019 Nasal Spray 1.6 mg
Participants will receive a single intranasal dose of DMI019 nasal spray 1.6 mg under fasting conditions. The dose will be administered as four sprays of the 0.4 mg/spray formulation, with two sprays administered into each nostril and an interval of approximately 30 seconds between consecutive sprays into the same nostril.
干预措施: DMI019 Nasal Spray 1.6 mg (Drug)
Part C: Placebo
Participants will receive a single intranasal dose of matching DMI019 nasal spray placebo under fasting conditions according to the administration schedule used for Part C.
干预措施: DMI019 Nasal Spray Placebo (Drug)
Part D: DMI019 Nasal Spray 2.4 mg
Participants will receive a single intranasal dose of DMI019 nasal spray 2.4 mg under fasting conditions. The dose will be administered as six sprays of the 0.4 mg/spray formulation, with three sprays administered into each nostril and an interval of approximately 30 seconds between consecutive sprays into the same nostril.
干预措施: DMI019 Nasal Spray 2.4 mg (Drug)
Part D: Placebo
Participants will receive a single intranasal dose of matching DMI019 nasal spray placebo under fasting conditions according to the administration schedule used for Part D.
干预措施: DMI019 Nasal Spray Placebo (Drug)
结局指标
主要结局
Number of Participants With Clinically Significant Changes in Vital Signs
时间窗: From screening through approximately 48 hours after the final study dose.
Vital sign assessments will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and body temperature. The number of participants with clinically significant abnormalities or worsening from baseline will be summarized by treatment and dose group.
Incidence and Severity of Adverse Events
时间窗: From signing informed consent through Day 11 for Part A and through Day 7 for Parts B-D; unresolved adverse events will be followed until resolution, stabilization, or adequate clinical explanation.
The number and percentage of participants with adverse events, treatment-related adverse events, serious adverse events, and treatment-related serious adverse events will be summarized by treatment and dose group. Adverse events will be assessed for severity, seriousness, outcome, and relationship to the study intervention.
Number of Participants With Clinically Significant Physical Examination Abnormalities
时间窗: From screening through the end-of-study assessment, approximately 48 hours after the final study dose.
Physical examinations will include assessments of the skin, mucous membranes, lymph nodes, head, neck, chest, abdomen, spine and extremities, and nervous system. Clinically significant new abnormalities or worsening of pre-existing findings will be summarized.
Number of Participants With Clinically Significant Nasal Examination Abnormalities
时间窗: From screening through the end-of-study assessment, approximately 48 hours after the final study dose.
Nasal examinations will be performed to identify clinically significant nasal symptoms, mucosal abnormalities, or other abnormal findings. Instrument-assisted examination using a nasal speculum may be performed when considered necessary.
Number of Participants With Clinically Significant Clinical Laboratory Abnormalities
时间窗: From screening through the end-of-study assessment, approximately 48 hours after the final study dose.
Clinical laboratory evaluations will include hematology, urinalysis, serum chemistry, and coagulation tests. The number of participants with clinically significant post-baseline abnormalities, shifts from normal to abnormal, or worsening of pre-existing abnormalities will be summarized by treatment and dose group.
Number of Participants With Clinically Significant Twelve-Lead Electrocardiogram Abnormalities
时间窗: From screening through 48 hours after the final study dose.
The number and percentage of participants with clinically significant abnormalities or worsening from baseline in twelve-lead electrocardiogram findings will be summarized by treatment group. Each participant will be counted once if at least one clinically significant electrocardiogram abnormality is identified.
次要结局
- Maximum Observed Plasma Concentration of Emedastine(Pre-dose through 48 hours after dosing.)
- Time to Maximum Observed Plasma Concentration of Emedastine(Pre-dose through 48 hours after dosing.)
- Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Concentration(Pre-dose through 48 hours after dosing.)
- Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity(Pre-dose through 48 hours after dosing.)
- Percentage of AUC Extrapolated From the Last Quantifiable Concentration to Infinity(Pre-dose through 48 hours after dosing.)
- Time of the Last Quantifiable Plasma Concentration of Emedastine(Pre-dose through 48 hours after dosing.)
- Terminal Elimination Rate Constant of Emedastine(Pre-dose through 48 hours after dosing.)
- Terminal Elimination Half-Life of Emedastine(Pre-dose through 48 hours after dosing.)
- Apparent Total Clearance of Emedastine(Pre-dose through 48 hours after dosing.)
- Apparent Volume of Distribution During the Terminal Phase(Pre-dose through 48 hours after dosing.)
- Mean Residence Time of Emedastine(Pre-dose through 48 hours after dosing.)
- Relative Bioavailability of DMI019 Nasal Spray Compared With Emedastine Difumarate Sustained-Release Capsule(Pre-dose through 48 hours after dosing in each treatment period of Part A.)
研究者
Guoping Yang
Professor of Clinical Pharmacology
The Third Xiangya Hospital of Central South University