Pharmacokinetics and Safety of Single-Dose Wafermine™ (Ketamine Sublingual Wafer) in Healthy Subjects

Официальное название

An Open-Label, Three-Period Crossover Study to Evaluate the Pharmacokinetics and Safety of Single-Dose Wafermine™ (Ketamine Sublingual Wafer) in Healthy Male and Female Subjects Under Fasting Conditions

Обзор

This is a Phase 1, open-label, three-period crossover study evaluating the pharmacokinetics and safety of single-dose Wafermine™ (ketamine sublingual wafer) at dose levels of 25 mg, 50 mg, and 75 mg in healthy adult participants under fasting conditions. Participants will receive all three dose levels in a fixed ascending sequence during a single inpatient admission, with washout periods between doses. Pharmacokinetic sampling will be conducted over 36 hours following each dose.

Подробное описание

This study is designed to characterize the pharmacokinetic profile of ketamine and its metabolite norketamine following sublingual administration of Wafermine™. Each participant will receive three single-dose treatments (25 mg, 50 mg, and 75 mg) administered in a fixed ascending sequence across three treatment periods.

All treatment periods will occur during a single inpatient stay. Participants will undergo a minimum 10-hour fast prior to dosing. Each dosing period will be separated by a washout period of at least 48 hours. Serial blood samples will be collected up to 36 hours post-dose in each period.

Safety and tolerability will be assessed through monitoring of adverse events, vital signs, electrocardiograms, clinical laboratory tests, and local tolerability assessments.

Вмешательства

• Препарат Wafermine™ (ketamine sublingual wafer)
  Single-dose sublingual administration of Wafermine™ at dose levels of 25 mg, 50 mg, and 75 mg under fasting conditions.

Первичные конечные точки

• Peak Plasma Concentration (Cmax) of Ketamine and Norketamine [Срок оценки: From pre-dose through the last measurable concentration, with plasma samples collected up to 36 hours post-dose.]
• Terminal Elimination Half-Life (t½) of Ketamine and Norketamine [Срок оценки: From pre-dose through the last measurable concentration, with plasma samples collected up to 36 hours post-dose.]
• Time to Peak Plasma Concentration (Tmax) of Ketamine and Norketamine [Срок оценки: Pre-dose to 36 hours post-dose]
• Area Under the Plasma Concentration-Time Curve (AUC) of Ketamine and Norketamine [Срок оценки: From pre-dose through the last measurable concentration, with plasma samples collected up to 36 hours post-dose.]

Вторичные конечные точки (12)

• Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs) [Срок оценки: From first dose through end of study/follow-up (~10 days)]
• Vital Signs: Change From Baseline in Systolic Blood Pressure [Срок оценки: From first dose through End of study/ follow-up, approximately 10 days]
• Vital Signs: Change From Baseline in Diastolic Blood Pressure [Срок оценки: From first dose through end of study/ follow-up, approximately 10 days]
• Vital Signs: Change from Baseline in Heart Rate [Срок оценки: From first dose through End of study/ follow-up, approximately 10 days]
• Vital Signs: Change From Baseline in Respiratory Rate [Срок оценки: From first dose through end of study/follow-up, approximately 10 days]
• Vital Signs: Change From Baseline in Tympanic Temperature [Срок оценки: From first dose through end of study/follow-up, approximately 10 days]
• Vital Signs: Change From Baseline in Oxygen Saturation [Срок оценки: From first dose through end of study/follow-up, approximately 10 days]
• Number of Participants with Clinically Significant Vital Sign Abnormalities [Срок оценки: From first dose through end of study/follow-up, approximately 10 days]
• 12-lead Electrocardiogram Readings: Change from Baseline in PR Interval [Срок оценки: Baseline through end of study/follow-up (assessed up to 6 weeks)]
• 12-lead Electrocardiogram Readings: Change from Baseline in QRS Duration [Срок оценки: Baseline through end of study/follow-up (assessed up to 6 weeks)]
• 12-lead Electrocardiogram Readings: Change from Baseline in QT Interval [Срок оценки: Baseline through end of study/follow-up (assessed up to 6 weeks)]
• 12-lead Electrocardiogram Readings: Change From Baseline in QTcF Interval [Срок оценки: Baseline through end of study/follow-up (assessed up to 6 weeks)]

Критерии участия

Критерии включения

• Clinically healthy participants (male and female) aged ≥ 18 to ≤ 65 years at the time of signing the informed consent.
• Research participants with no history of clinically significant cardiac, endocrine, gastrointestinal, hematological, hepatic, immunological, metabolic, urological, pulmonary, neurological, dermatological, or renal diseases or comorbidity of significance at the discretion of the Principal Investigator (or his/her delegate). The following medical history are permitted at the discretion of the Principal Investigator: history of childhood asthma; prior history of cholecystectomy; history of eczema with no use of steroid creams for 3 months prior to screening; history of fully resolved gestational diabetes; current or history of ADHD, anxiety or antidepression ( stable condition with no use of antidepressants 6 months prior to screening)
• Be able and willing to read, understand, sign, and date the Informed Consent Form prior to entering the study.
• Have adequate venous access for blood sampling.
• Female participants are eligible only if all the following contraceptive requirements are met:

These requirements also apply to ova donation.

• Women of non-childbearing potential (WONCBP) are not required to use contraception and are defined as women who meet at least one of the following criteria:

• Have undergone surgical sterilisation (e.g., hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), or
• Are postmenopausal, defined as at least 12 consecutive months of amenorrhea without an alternative medical cause, with confirmation by follicle-stimulating hormone (FSH) levels at screening, where required.
• Women of childbearing potential (WOCBP) must agree to use highly effective methods of contraception, defined as methods with a failure rate of <1% per year when used consistently and correctly, from screening until at least 33 days after the last administration of the investigational product.

Acceptable highly effective methods of contraception include:

• Combined (estrogen- and progestogen-containing) hormonal contraception (oral, intravaginal) associated with inhibition of ovulation
• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable)
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Sexual abstinence, provided this is the participant's usual and preferred lifestyle
• Not breastfeeding
• Be willing to complete all study procedures, safety laboratory tests, lifestyle considerations, restrictions, and other study procedures. Participants of childbearing potential will be eligible only if they have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day -1 of each study period, agree to avoid pregnancy for the duration of the study, and are not breastfeeding
• Male condom use is required in addition to hormonal contraception or other user-dependent methods, where applicable.

Unacceptable Contraceptive Methods (Do Not Meet Requirements)

• Condoms alone
• Double barrier method
• Female condoms
• Female diaphragms
• Dermal patches
• Withdrawal / coitus interruptus
• Cycle tracking
• Periodic abstinence
• Male contraceptive Requirements These requirements also apply to sperm donation;

• Male participants must agree to use effective contraception or to remain abstinent (provided this is their usual and preferred lifestyle) from screening until at least 33 days after the last administration of the investigational product.
• Male participants must also agree not to donate sperm during this period.
• Surgically sterilized males are defined as:

• Bilateral orchidectomy: no contraceptive requirements .
• Bilateral vasectomy or documented azoospermia (≥90 days post-procedure): condom use is required only during intercourse with women of childbearing potential (WOCBP)
• For non-sterilized males, the following contraceptive requirements apply:

o Use of a male condom in combination with a highly effective method of contraception used by the female partner (WOCBP), as defined above

• The following are also considered acceptable:

• Same-sex relationships/intercourse only (no contraception required)
• Abstinence, provided this is the participant's usual and preferred lifestyle
• Body mass index between 18.5-30.0kg/m2 (inclusive) index.
• Deemed able to read and understand English in order to communicate with research staff and complete protocol required questionnaires and forms.

Критерии исключения

Medical history

• Research participants with inflammatory or ulcerative disease in the oral cavity that may affect the absorption of the sublingual presentation.
• History of allergic reactions, anaphylactic reactions, severe systemic hypersensitivity, or any allergic reaction that, in the opinion of the Principal Investigator or his or her delegate, is likely to be exacerbated by the study drug.
• History of hypersensitivity to ketamine or any of the WafermineTM excipients.
• Elective procedures or surgeries scheduled after signing the Informed Consent Form and until the safety follow-up call \[3 days ± 1 day after the 36.0-hour third period is taken\].
• History of gastric bypass surgery/bariatric surgery or other gastrointestinal surgery or condition that may affect gastric emptying or absorption of the study drug.
• A history of 6 previous months of psychiatric disorders (schizophrenia, anxiety, acute psychosis, depression). A clinically significant history of psychiatric disorders (including but not limited to: schizophrenia, anxiety, acute psychosis, depression). Resolved psychiatric disorders (>6 months before screening) may be included at the discretion of the Investigator or delegate).

Risk of infection

• Positive serology for hepatitis C virus (HCV), hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
• Presence of chronic, recurrent, or severe infection (e.g., pneumonia, sepsis) at the discretion of the Principal Investigator, within 90 days prior to the screening visit and between the screening visit and Day -1.
• Presence of symptoms of bacterial, fungal, or viral infection (including upper respiratory tract infection) within 14 days prior to the screening visit and between screening and Day -1. Participants with local fungal infection (e.g., candidiasis, ringworm, tinea pedis) are eligible for reevaluation after successful treatment of the infection.
• History of clinically significant condition involving the bladder or urinary tract, including frequent urinary tract infections (e.g. > 2 per year), or current symptoms of bladder irritation such as frequent or urgent need to urinate or burning with urination.
• Any immunization or vaccine administered within 30 days prior to Day 1. Laboratory assessment and results
• Abnormal and clinically significant results at the discretion of the Principal investigator (or his/her delegate) in the laboratory tests and electrocardiogram of the screening visit. Laboratory values out of range and determined to be not clinically significant at the discretion of the Principal Investigator or his/her delegate may be repeated on one occasion, the subject may be enrolled if the repeated value is within the normal range.
• Participants with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin values ≥1.5 × upper limit of normal (ULN) at screening.

Pre-medicated and concomitant medications

• Participation in any other investigational study with drugs, biologics, medical devices, or treatment with an investigational product or therapy approved for investigational use within the 30 days prior to or 5 half-lives, whichever is greater, by Day -1.
• Use of any Over-The-Counter (OTC)/non-prescribed drugs including vitamins, minerals, supplements or herbal medicines within 1 week of Period 1 study drug administration, or intake of prescribed drugs within 2 weeks of Period 1 study drug administration (or longer if the medication has a half-life long enough to potentially expose the healthy participant to any significant systemic exposure).

\[Exception: hormone replacement therapy and oral contraceptives in female participants is allowed.\]

• Use of drugs with enzyme-inducing properties (such as rifampicin and St John's Wort) or any drug known to be either a moderate or strong inhibitor of CYP3A4 or CYP2B6 within 3 weeks or 5 half-lives, whichever is greater, prior to treatment period 1 and throughout the study.

Others

• History of abuse or dependence on alcohol or illegal/recreational drugs during the development of the study.
• Positive results on the urine drug screen or breath alcohol test at screening and/or pre-dose. \[Exception: a positive result on the urinary drug screen at screening only is allowed at the discretion of the Investigator provided the result can be reliably explained by recent medication and/or dietary history.\]
• Current or recent use of tobacco or nicotine-containing products, defined as:

• Any smoking or nicotine use (cigarettes, e-cigarettes, vaping, chewing tobacco, etc.) within 30 days prior to screening, or
• History of regular (daily) smoking, or
• Casual/social smoking (>5 cigarettes or equivalent per week on average in the past 6-12 months)
• Participants with history of occasional smoking (≤5 cigarettes/week) may be considered if they can commit to full abstinence during the entire study period including from screening through inpatient stays, and pass all other eligibility criteria (at the discretion of the Principal Investigator).
• Alcohol consumption 24 hours prior to Day -1.
• Habitual alcohol consumption > 14 units per week for men and > 10 units per week for women. One unit is equivalent to 250 mL of beer, 25 mL of hard liquor, or 125 mL of wine.
• Intake of beverages containing xanthines (coffee, tea, chocolate, cocoa, , cola) or charcoal-roasted foods 24 hours prior to Day -1.
• Habitual consumption of more than 4 caffeinated beverages in a period of 24 hours.
• Blood donation of one unit (approximately 450-500 mL) within the last 30 days prior to screening will be exclusionary.
• Strenuous physical exercise (e.g., heavy lifting, weight training, calisthenics, and aerobic exercise) within 48 hours prior to Day-1. Walking at a normal pace is allowed.
• Unwillingness or inability to comply with the requirements of the protocol.
• Other unspecified reasons that, at the discretion of the Principal Investigator or the Sponsor, determine that the subject is not suitable for inclusion.
• Participants who had been hospitalized in the 6 months prior to the screening visit.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Не применимо

Модель

Перекрёстный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Австралия · 1 центр

• Q-Pharm Pty Ltd. — Brisbane

Идентификаторы

NCT: NCT07691372 · KET004

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗