None listed
Conditions
Brief summary
This study aims to find out how safe and well-tolerated a new oral form of esketamine, called GM-28K, is when taken by healthy adults. Esketamine is a medicine that affects certain brain pathways involved in mood regulation and is already used in other forms to treat depression. GM-28K has been developed as a capsule taken by mouth, which may provide a simpler and more comfortable way to deliver the medicine compared to the existing nasal spray or injection forms. In this study, participants will receive a single dose of GM-28K or a placebo capsule (which does not contain active medicine). The main goal is to check for any side effects and to understand how the body processes the medicine by measuring its levels in the blood and urine over time. The results will help determine a safe dose range for future studies in people with depression or other conditions that may benefit from this treatment.
Interventions
The investigational intervention being studied is GM-28K, an oral capsule formulation containing esketamine hydrochloride as the active ingredient. Esketamine is the S-enantiomer of ketamine, a non-competitive NMDA receptor antagonist with established antidepressant activity. GM-28K has been developed by Grey Matter Pharma Pty Ltd as a novel oral formulation designed as an alternative to the currently approved intranasal or intravenous esketamine products used for treatment-resistant depression.
The investigational intervention being studied is GM-28K, an oral capsule formulation containing esketamine hydrochloride as the active ingredient. Esketamine is the S-enantiomer of ketamine, a non-competitive NMDA receptor antagonist with established antidepressant activity. GM-28K has been developed by Grey Matter Pharma Pty Ltd as a novel oral formulation designed as an alternative to the currently approved intranasal or intravenous esketamine products used for treatment-resistant depression. Each capsule contains 50 mg of esketamine hydrochloride together with standard pharmaceutical excipients including microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and colloidal silicon dioxide. The capsule shell consists of gelatin, titanium dioxide as an opacifier, and iron oxide as an optional colourant. This first-in-human, single-ascending-dose study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GM-28K following single oral administration in healthy adult participants. Participants will receive a single oral dose of GM-28K ranging from 50 mg to a maximum of 300 mg, depending on their assigned cohort. Dosing occurs once only on Day 1, following an overnight fast of at least ten hours, with no repeat or maintenance dosing. All participants remain under observation in the clinical research unit for up to twelve hours post-dose, with follow-up visits on Day 2 and Day 7 for safety and PK/PD assessments. Two sentinel participants (one active and one placebo) are dosed initially per cohort; after at least 24 hours of safety review, the remaining participants in that cohort are dosed. Dose escalation to subsequent cohorts proceeds only after approval by an independent Safety Review Committee based on review of cumulative safety, tolerability, and pharmacokinetic data. The investigational product is administered orally under direct supervision by qualified research staff at a single Phase 1 clinical research unit in Australia. Each capsule is swallowed with water, and all study activities including dosing, safety monitoring, ECGs, clinical laboratory testing, and PK/PD sampling are conducted in-clinic by medically trained personnel. Dosing fidelity and accountability are fully maintained because administration occurs under direct observation. The GM-28K capsules and matching placebo are manufactured and packaged in accordance with GMP standards at Syntro Health, Richmond VIC, Australia. Study will consist of up to 5 cohorts (3 pre-determined cohorts and 2 optional cohorts) Cohort A1: 50 mg (1 × 50 mg capsule) Cohort A2: 100 mg (2 × 50 mg capsules) Cohort A3: Dose to be determined (TBD) following Safety Review Committee (SRC) evaluation of safety/pharmacokinetics in earlier cohorts Optional Cohort A4: TBD Optional Cohort A5: TBD A maximum planned dose of up to 300 mg may be evaluated. Each cohort includes 8 participants (6 active, 2 placebo), with sentinel dosing (1 active, 1 placebo) followed by dosing of remaining participants more than or equal to 24 hours later pending safety review. For the optional cohorts, the doses will be determined by the independent Safety Review Committee (SRC) based on blinded review of cumulative safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) data from the preceding cohorts. After completion of each dose level, the SRC evaluates data up to at least 24 hours post-dose for a minimum of 7 participants in that cohort, together with full data from earlier cohorts, to establish a safe and appropriate dose for the next cohort. Dose selection for optional cohorts A4 and A5 will therefore be informed by the systemic exposure of esketamine and its metabolites observed in earlier cohorts, ensuring dose progression remains within pre-specified boundaries: the total dose must not exceed 300 mg and dose increments must not exceed a 3-fold increase from the previous cohort. Progression to any optional cohort will only occur if the SRC authorises continuation following their review. A new cohort cannot be initiated until the clinical portion of the preceding cohort is complete and the SRC confirms that predefined dose-escalation criteria have been met. Escalation will not proceed if any stopping rules are triggered, including the occurrence of drug-related serious adverse events, multiple severe or clinically significant drug-related adverse events, or clinically meaningful abnormalities in vital signs, ECGs, or laboratory parameters in the preceding cohort. If no stopping rules are met, the SRC may approve escalation to the next planned or adjusted dose, repeat a cohort, or adopt a more conservative dosing increment. This approach ensures that the optional cohorts are only activated if safety, tolerability and PK/PD findings support further evaluation at higher or intermediate dose levels.
Sponsors
Grey Matter Pharma Pty Ltd
Study design
Allocation
Randomised controlled trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male or female, non-smoker (no use of tobacco or nicotine products within 6 months prior to first dose) 2. Aged more than or equal to 18 and less than or equal to 55 years (inclusive) at screening 3. BMI more than 18.0 and less than 32.0 kg/m2 and body weight more than or equal to 50.0 kg. 4. Participant is judged by the Investigator to be in generally good health on the basis of medical history, physical examination, or clinical laboratory results during the screening. 5. Pulse between 45 and 100 beats per minute (bpm) at screening (inclusive) 6. Seated systolic BP between 90 and 160 mmHg, diastolic BP between 50 and 95 mmHg inclusive, at screening. For the purpose of qualifying any given participant for study participation, out-of-range vital signs may be repeated once. 7. No known history or family history of schizophrenia or other psychotic illness; history or presence of severe personality disorder or other significant psychiatric history or mental illness (in the opinion the Investigator). 8. Must have hepatic and renal clinical laboratory test results (ALT, AST, total bilirubin and eGFR) within a laboratory defined normal range. 9. Must not be pregnant, breastfeeding (non-lactating), or planning pregnancy. 10. Female participants must have negative serum hCG pregnancy test at screening and negative urine test at check-in. 11. Females of childbearing potential who are sexually active with a non-sterile male partner (sterile male partners are defined as men vasectomised at least 6 months prior to the first study drug administration) must be willing to use one of the following acceptable contraceptive methods throughout the study and for at least 3 months after the last study drug administration: a. Simultaneous use of intrauterine contraceptive device without hormone release system placed at least 4 weeks prior to the first study drug administration; or intrauterine contraceptive device with hormone release system placed at least 12 weeks prior to first study drug administration; or oral hormonal contraceptives (minimum 12 week use without issue), and a condom for the male partner. Other hormonal contraceptives such as depot are allowed. 12. Females of non-childbearing potential must be: a. Post-menopausal (absence of menses for at least 12 months prior to the first study drug administration) with confirmation of the post menopausal status by documented FSH level more than or equal to 40 mIU/mL; or b. Surgically sterile (complete hysterectomy or bilateral oophorectomy at least 3 months prior to the first study drug administration). 13. Female participants must be willing not to donate ova for 30 days after the last dose 14. All male participants (including men who have had a vasectomy) must agree to use a condom from the first dose and for 90 days after the last dose. 15. Male Patients who are not vasectomised for at least 3 months prior to dosing and who are sexually active with a female partner of childbearing potential must be willing to use one of the following acceptable contraceptive methods from the first dose and for 90 days after the last dose: a. Simultaneous use of condom and established use of oral, injected or implanted hormonal contraceptive or placement of intrauterine device (IUD) or intrauterine system (IUS) for the female partner; 16. Male participants must be willing not to donate sperm for 90 days after the last dose. 17. Willing and able to adhere to all study requirements, including willingness to remain in the study unit for the entire duration of the confinement period. 18. Able to understand the study procedures and provide signed and dated participant informed consent form (PICF) to participate in the study prior to screening.
Exclusion criteria
1. History of any clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, or cardiovascular disease or other condition which would jeopardize safety or impact validity of results (in the opinion the Investigator). 2. History of severe allergic or anaphylactic reactions, known intolerance, allergy or hypersensitivity reactions to Esketamine 3. History of coronary disease, peripheral vascular disease, cerebrovascular accident, transient ischemic attack, uncontrolled hypertension or signs/symptoms of ischemic heart disease. 4. Participant has any documented history of, or currently active, seizure disorder or history of clinically significant head injury or history of intracerebral hemorrhage 5. Has undergone surgery requiring or has received (for any reason) anesthetic within 30 days of Day 1, or has planned surgery during the study 6. Participant has an active malignancy of any type or has been diagnosed with cancer within 5 years prior to screening (excluding squamous or basal cell carcinoma of the skin). 7. Any laboratory test results deemed clinically significant by the Investigator or positive test serology test results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antigen and antibody at screening. 8. Clinically significant ECG abnormalities (Fridericia’s corrected QT interval [QTcF] more than 450 ms for males and more than 470 ms for females), PR more than 210 ms, QRS interval more than 120 ms at screening. 9. Clinically significant bradycardia or tachycardia defined as resting heart rate (HR) less than 40 bpm or more than 100 bpm, respectively. 10. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels more than 1.50 times the upper limit of normal at screening. 11. Positive urine drug screen, urine cotinine and urine alcohol test prior dosing. Testing for any out-of-range laboratory tests (ex.criteria # 8-11) values may be repeated once at the discretion of the Investigator. 12. Known allergic reactions to any excipient in the formulations. 13. History of significant drug abuse such as cocaine, phencyclidine (PCP), crack, opioid derivatives including heroin, and amphetamine derivatives within 1 year prior to screening. 14. Use of marijuana (directly or indirectly) within 90 days prior to drug administration and during the course of the study. 15. History of significant alcohol abuse within 1 year prior to screening or regular use of alcohol within 6 months prior to the screening visit that exceeds 14 units of alcohol per week (1 unit equal to 150 mL of wine, 375 mL of mid strength beer, or 30 mL of distilled alcohol 40%). 16. Use of medications for the timeframes specified below, with the exception of medications exempted by the Investigator on a case-by-case basis because they are judged unlikely to affect the PK profile of the study drug or participant safety (e.g., topical drug products without significant systemic absorption): a. Prescription medications (except for non-hormonal contraceptives) within 14 days prior to the first dose until end of the study. b. Monoamine oxidase inhibitors (MAOIs) within 28 days prior to dosing. c. Over-the-counter products and natural health products (including herbal remedies such as St. John’s wort, homeopathic and traditional medicines), and antacid preparations within 14 days prior to the first dose up to end of study. Vitamins used as nutritional supplements in non-therapeutic doses (judged by the qualified Investigator or designee) may be accepted, but they must be stopped at least 48 hours before dosing and during the study. d. Any drugs known to induce or inhibit hepatic and renal drug metabolism within 30 days prior to the first dose and during the study. e. Any drugs that have a significant impact on the CNS including benzodiazepines (e.g., Diazepam, Alprazolam, Lorazepam), Antipsychotic medications (e.g., Haloperidol, Risperidone, Quetiapine), Antidepressants (e.g., Sertraline, Fluoxetine, Escitalopram), Antiepileptic drugs (e.g., Phenytoin, Carbamazepine, Valproate) or Sedative-hypnotics (e.g., Zolpidem, Zopiclone, Eszopiclone) within 30 days prior to the first dose and during the study. f. Use of macrolide antibiotics (e.g., Erythromycin), azole antifungal agents (e.g., Ketoconazole) or protease inhibitors (e.g., Ritonavir) within 30 days of Day 1. 17. Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to the first dose, administration of a biological product in the context of a clinical research study within 90 days prior to the first dose, or concomitant participation in an investigational study involving no drug or device administration. 18. Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of whole blood within 56 days prior to Day -1. 19. Any reason which, in the opinion of the Investigator, would compromise the participant from participating in the study
Outcome results
None listed