| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment-resistant depression |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment-resistant depression is defined as the intake of 2 different anti-depressant medications for a sufficient length of time at an adequate dose without an adequate improvement of the depression |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To explore the efficacy of KET01 (120 mg or 240 mg) administered once daily (OD) as add-on therapy to standard treatment compared to placebo with respect to improvement of depressive symptoms assessed by change in Montgomery–Åsberg Depression Rating Scale (MADRS) total score in subjects with major depressive disorder (MDD), fulfilling criteria for treatment-resistant depression (TRD). |
|
| E.2.2 | Secondary objectives of the trial |
1. To investigate the efficacy of add-on KET01 treatment (120 mg OD or 240 mg OD) compared to placebo in subjects with TRD.
2. To investigate the safety and tolerability of add-on KET01 treatment (120 mg OD or 240 mg OD) compared to placebo in
subjects with TRD.
3. To evaluate population pharmacokinetics of ketamine and its metabolites (norketamine and hydroxynorketamine). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to comprehend and willing to sign an informed consent form and to comply with all aspects of the trial.
2. Subjects aged ≥ 18 and ≤ 65 years.
3. Body mass index (BMI) ≥ 18 and ≤ 35 kg/m2.
4. Primary diagnosis of MDD meeting Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria and one of the following episode characteristics:
a.MDD, single episode, moderate (F32.1)
b.MDD, recurrent, moderate (F33.1)
The diagnosis of MDD has to be confirmed by the Mini International Neuropsychiatric Interview (MINI) 7.0.2.
5. Current episode of MDD (≤ 24 months) fulfilling the criteria of TRD, i.e. less than 50% improvement in at least 2 different optimised antidepressant treatment periods (each for at least 6 weeks) within the current episode and before Visit 1 as confirmed by the TreatmentResistant Depression Checklist (TRD-C).
6. Stable antidepressant treatment for at least 6 weeks before Visit 1 until FU visit.
7. Duration of the current episode of MDD ≤ 24 months.
8. HAM-D17 score ≥ 19.
9. For females of childbearing potential: Must be willing to undergo pregnancy tests and will be required to use highly effective contraceptive measures from the time of informed consent until 28 days after last IP intake.
10. For male subjects with a partner of childbearing potential: Must be willing to use adequate contraceptive measures (barrier method) or practice sexual abstinence (if this is in line with the preferred and usual lifestyle of the subject) from the time of informed consent until 28 days after last IP intake.
CZ-1. Valid only in Czech Republic: Subject has a caregiver during the course of the clinical trial, who will have the following responsibilities: To accompany the patient during the informed consent procedure to ensure he/she is fully informed about conditions of the patient's participation in the trial, to be in personal contact with the subject on at least 5 days per week and to support the subject during the trial participation, as needed. The caregiver does not have the authority to express legally relevant consent to the subject's trial participation. The caregiver is willing to confirm his/her responsibilities by signing the informed consent form.
Inclusion criteria at Visit 2a:
11. Outpatient.
12. HAM-D17 score ≥ 19. |
|
| E.4 | Principal exclusion criteria |
1. Known hypersensitivity or intolerance to ketamine or any of the excipients.
2. Inability to swallow the IP whole.
3. For females: Pregnant or lactating.
4. Significant risk of suicide, defined as (1) suicidal ideation endorsed by a response of ‘yes’ on items 4 or 5 of the C-SSRS (2) suicidal behaviour within the past year, or (3) clinical identification of a significant suicidal risk during the interview.
5. Currently ongoing psychiatric and neurological concomitant condition of:
a. MDD, single episode, severe, with psychotic features (F32.3), or MDD, single episode, severe, without psychotic features (F32.2), MDD, recurrent, severe, without psychotic features (F33.2) or MDD, recurrent, severe with psychotic features (F33.3).
b. Schizophrenia spectrum and other psychotic disorders (F21, F22, F23, F20.81, F20.9, F25.0, F25.1, F06.0, F06.1, F06.2, F28 and F29) or bipolar disorder (F31), other mental disorder due to known physiological condition (F06). Subjects with first-degree relatives (parents, brothers, sisters or children) with psychotic or bipolar disorders are also not considered eligible.
c. Paranoid or schizoid personality disorder (ICD-10-CM: F60.0, F60.1, F21 / DSM-5: 301.0, 301.20).
d. Antisocial, borderline, histrionic or narcissistic personality disorder (ICD-10-CM: F60.2, F60.3, F60.4, F60.81 / DSM-5: 301.7, 301.83, 301.50, 301.81).
e. Moderate to severe intellectual disability / mental retardation, e.g. due to neurodevelopmental disorders, neurocognitive or neurodegenerative disorders or autism spectrum disorder (ICD-10-CM: F71, F72, F73, F84 / DSM-5: 318.0, 318.1, 318.2, 299.00).
6. Known or suspected lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system (CNS) disorder, epilepsy (excluding uncomplicated childhood febrile seizures with no sequelae) or any other disease/procedure/accident/intervention which, according to the investigator is deemed associated with significant injury to or malfunction of the CNS.
7. History of significant head trauma within the past 2 years prior to Visit 1.
8. History of cerebrovascular event (e.g. stroke, prolonged ischaemic neurologic deficit [PRIND], transient ischaemic attack) and/or known or suspected cardiac disease (e.g. unstable angina, congestive heart failure, tachyarrhythmia or myocardial infarction).
9. Clinically significant abnormal electrocardiogram findings at Visit 1 which may jeopardize subject’s safety according to the investigator.
10. Family history of sudden cardiac death in first-degree relatives.
11. Untreated or uncontrolled hypertension (after 5 minutes of rest, systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 90 mmHg).
12. Laboratory findings suggesting impaired hepatic function or liver cirrhosis i.e. gammaglutamyl transferase (GGT), alkaline phosphatase (AP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values > 2x the upper limit of normal (ULN) or total bilirubin > 1.5 times the ULN at Visit 1. Subjects with an isolated increase of indirect
bilirubin not previously documented as a diagnosis of Gilbert’s syndrome must be discussed with the medical monitor.
13. Known hepatitis B or C.
14. Estimated Glomerular Filtration Rate (eGFR) < 60 mL/min/1.73 m2 or creatinine > 200 µmol/L at Visit 1 or ongoing dialysis or kidney transplants.
15. Uncontrolled diabetes mellitus within the 3 months prior to Visit 1 and/or a haemoglobin A1c (HbA1c) value > 8.0% at Visit 1.
16. Hyperthyroidism.
17. Uncontrolled hypothyroidism i.e. not at stable treatment with thyroid hormones (triiodothyronine/thyroxine [T3/T4]) within the 6 weeks before Visit 1 until FU visit or abnormal thyroid stimulating hormone (TSH) and free thyroxine (fT4) values at Visit 1.
18. History (within 5 years before Visit 1) of complicated cystitis.
19. Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the trial, or jeopardise the conduct of the trial according to the protocol.
20. Previous administration of ketamine (including known or suspected ketamine-anaesthesia) or esketamine within 1 year before Visit 1.
21. Prohibited prior and concomitant therapies and medication.
22. History of moderate to severe alcohol use disorder or substance use disorder except nicotine and caffeine, within 6 months before Visit 1 or a positive drug abuse test except for allowed medication prescribed for a medical condition.
23. Use of any IP or investigational medical device, currently or within the 6 months before Visit 1, or participation in ≥ 2 MDD or other psychiatric clinical trials within 1 year before Visit 1.
24. Employees of the investigator, trial centre, sponsor, clinical research organisation or trial consultants and their family members.
25. Persons committed to an institution by virtue of an order issued either by the judicial or other authorities. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from baseline at Visit 2a to Visit 6/ early discontinuation visit
(EDV) in MADRS total score. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of responders (response will be defined by at least 50% reduction in the MADRS total score) at each post-baseline visit.
2. Proportion of remitters (remission will be defined by a MADRS total score ≤ 10) at each post-baseline visit.
3. Change in the MADRS total score from baseline at Visit 2a to Visit 2b at 7 hours after IP intake, Visits 3, 4 and 5.
4. Change in the MADRS total score from baseline at Visit 2a to FU visit and from Visit 6/EDV to FU visit.
5. Change in Hamilton Depression Rating Scale 17-item version (HAM-D17) total score from baseline at Visit 2a to Visit 6/EDV.
6. Change in HAM-D17 total score from baseline at Visit 2a to FU visit and from Visit 6/EDV to FU visit.
7. Change in Clinical Global ImpressionSeverity (CGI-S) from baseline at Visit 2a to Visit 6/EDV.
8. Change in CGI-S from baseline at Visit 2a to FU visit and from Visit 6/EDV to FU visit.
9. Change in Quick Inventory of Depressive Symptomatology (16-Item) (Self-Report) (QIDS-SR16) from baseline at Visit 2a to Visit 6/EDV.
10. Change in QIDS-SR16 from baseline at Visit 2a to FU visit and from Visit 6/EDV to FU visit.
11. Change in Generalized Anxiety Disorder Scale-7 (GAD-7) from baseline at Visit 2a to Visits 3, 4, 5 and Visit 6/EDV.
12. Change in GAD-7 from baseline at Visit 2a to FU visit and from Visit 6/EDV to FU visit.
13. Change in Short-Form 36 Health Survey, version 2 (SF-36v2) health survey questionnaire from baseline at Visit 2a to
Visit 6/EDV.
14. Change in SF-36v2 questionnaire from baseline at Visit 2a to FU visit and from Visit 6/EDV to FU visit.
15. Change in Sheehan Disability Scale (SDS) from baseline at Visit 2a to Visit 6/EDV.
16. Change in SDS from baseline at Visit 2a to FU visit and from Visit 6/EDV to FU visit.
17. Change in Pittsburgh Sleep Quality Index (PSQI) from baseline at Visit 2a to Visit 6/EDV.
18. Change in PSQI from baseline at Visit 2a to FU visit and from Visit 6/EDV to FU visit.
19. Change in Sleep Quality Scale (SQS) from baseline at Visit 2a to Visit 6/EDV.
20. Change in SQS from baseline at Visit 2a to FU visit and from Visit 6/EDV to FU visit.
21. Change in Clinician Administered Dissociative States Scale (CADSS) from baseline at Visit 2a to Visit 2b at 1, 4 and
7 hours after IP intake, Visits 3, 4, 5 and Visit 6/EDV.
22. Change in Karolinska Sleepiness Scale (KSS) from baseline at Visit 2a to Visit 2b at 1, 4 and 7 hours after IP intake, Visits 3, 4, 5 and Visit 6/EDV.
23. Clinically relevant changes in vital signs from baseline at Visit 2b before IP intake to Visit 2b at 1, 4 and 7 hours after IP intake, Visits 3, 4, 5, 6/EDV and FU visit.
24. Clinically relevant changes in safety laboratory parameters from baseline at Visit 2b before IP intake to Visits 4, 5, 6/EDV and FU visit.
25. Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS) at Visit 6/EDV and FU visit.
26. Adverse events, including findings from physical examination.
27. Suicidality, assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) at Visits 3, 4, 5, 6/EDV and FU visit.
28. Population pharmacokinetics of ketamine and its metabolites at baseline (Visit 2b before IP intake) and Visit 2b at 7 hours after IP intake, Visits 3, 4, 5 and Visit 6. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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