| 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 |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012378 |
| E.1.2 | Term | Depression |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| 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 determine the efficacy of 2 doses (30 mg and 60 mg) of intravenous (IV) PCN-101 compared with placebo in improving depressive symptoms in subjects with TRD. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the proportion of subjects with a response (defined as ≥ 50% improvement in MADRS total score from predose).
• To assess the proportion of subjects with remission (defined as MADRS total score ≤ 10).
• To define changes in Hamilton Depression Rating Scale (HAM-D).
• Generalized Anxiety Disorder 7-Item (GAD-7).
• Clinical Global Impression - Severity (CGI-S) and Clinical Global Impression - Improvement (CGI-I).
• Quick Inventory of Depressive Symptomatology - 16 Items (QIDS-SR-16).
• European Quality - 5 Dimensions - 3 Levels (EQ-5D-3L).
• To determine the safety and tolerability of 2 doses of PCN-101 administered IV in subjects with TRD compared with placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects are eligible to be included in the study only if all of the following criteria apply:
1. Be capable of giving and give signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol.
2. Be male or female 18 to 65 years of age inclusive at the time of signing the ICF.
3. Weigh ≥ 50 kg and have a body mass index (BMI) ≥ 18 and ≤ 35.
4. Have a diagnosis of recurrent major depressive disorder (MDD) without psychotic features per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), confirmed by the
Mini-International Neuropsychiatric Interview (MINI).
5. Have an HAM-D total score > 20 at screening and baseline (Day -1).
6. Have an inadequate response to at least 2 antidepressants in the current episode of depression that were each given for ≥ 6 weeks at an adequate dose as defined by the Massachusetts General Hospital
Antidepressant Response Questionnaire (MGH-ATRQ).
7. Must be on stable oral antidepressant treatment without a dose change for at least 30 days before screening (a missed dose, or reasonable number of missed doses per Investigator’s discretion, in that period does not exclude a subject).
8. A male subject must be medically confirmed sterile for at least 6 months prior to screening or agree to use highly effective contraception (see Protocol Appendix 5) during the treatment period and for at least 3 months after the last dose of study treatment and refrain from donating sperm during this period. If a male with a partner who is of childbearing potential (OCBP) is included, his partner also needs to use highly effective birth control measures.
9. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
• Not of childbearing potential (see Protocol Appendix 5).
• A subject OCBP who agrees to follow the highly effective contraceptive guidance (see Protocol Appendix 5) on highly effective birth control measures during the treatment period and for at least 3 months after the last dose of study treatment and refrain from donating eggs during this period.
10. Be medically stable on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening. If there are abnormalities, the subject may be included only if the
Investigator judges the abnormalities not to be clinically important. This determination must be recorded in the subject's source documents and initialed and dated by the Investigator. |
|
| E.4 | Principal exclusion criteria |
1. History of, or current signs and symptoms of, diseases or conditions that could prevent, limit, or confound the protocol specified assessments.
2. History of moderate or severe head trauma or other neurological disorders (including a diagnosis of epilepsy or has had a seizure in
the last 6 months), neurodegenerative disorder or systemic medical diseases that are, in the opinion of the Investigator, likely to interfere with the conduct of the study or confound the study assessments.
3. Has a primary DSM-V diagnosis of current MDD with psychotic features, panic disorder, obsessive compulsive disorder, posttraumatic stress disorder, anorexia nervosa, or bulimia nervosa.
4. Has a current or prior DSM-V diagnosis of a primary psychotic disorder (eg, schizophrenia), bipolar or related disorders (confirmed by the MINI), intellectual or autism spectrum disorder, or borderline
personality disorder.
5. Has any significant disease or disorder that, in the opinion of the Investigator, may either put the subject at risk because of
participation in the study, influence the results of the study.
6. Has uncontrolled hypertension, despite medication, at Screening (systolic blood pressure [SBP]> 160 mm Hg or diastolic blood pressure [DBP] > 90 mm Hg) or any past history of hypertensive
crisis.
7. Has an abnormal ECG of clinical relevance at screening or baseline (Day -1).
8. Has known history of, or positive serology for HIV; has a positive hepatitis B surface antigen, and/or confirmed current hepatitis C infection (positive HCV antibody confirmed with reflex HCV ribonucleic acid [RNA] test).
9. Has a history of malignancy within the 5 years prior to screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or a malignancy that in the opinion of
the Investigator, with concurrence with the Sponsor's Medical Monitor, is considered to have minimal risk of recurrence).
10. Has homicidal ideation/intent per the Investigator’s clinical judgment; or has suicidal ideation with some intent to act within 1 month prior to the start of screening per the Investigator’s clinical
judgment or based on the C-SSRS, corresponding to a response of “Yes” on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific
plan and intent); or a history of suicidal behavior within the past year prior to the start of the screening/prospective observational phase.
11. Has had major surgery (eg, requiring general or local anesthesia) within the 4 weeks before screening, or will not have fully recovered from surgery or planned surgery during the time the subject is
expected to participate in the study.
12. Has moderately impaired hepatic function at screening, defined as serum ALT or AST > 2 × upper limit of normal (ULN) or total bilirubin (TBL) > 2 × ULN.
13. Has received any disallowed therapies (see Protocol Section 6.5 for further details).
14. Has initiated psychotherapy (eg, Cognitive Behavior Therapy, Interpersonal Psychotherapy, Psychodynamic Psychotherapy other than psycho-education, or acupuncture within the past 90 days
of screening. Patients planning to initiate individual or group therapy during the study are also not eligible.
15. Has received electroconvulsive therapy, transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation, or other brain stimulation treatment within the past 4 weeks or currently used
as either an acute or maintenance treatment of depression.
16. Has received any investigational product (IP) within 30 days or 5 half-lives prior to dosing with PCN-101.
17. Has a history of substance abuse (drug or alcohol) or dependence (except nicotine or caffeine) within the previous 6 months prior to the screening visit.
• Has a positive urine drug screen for ketamine, opiates, cocaine, barbiturates, and/or amphetamine/methamphetamine or positive alcohol screen at Screening or Day -1.
• Subjects who have a positive test result at screening due to prescribed opiates or amphetamines may be permitted to continue the screening phase if the prohibited medication is discontinued at
least 1 week or 5 half-lives, whichever is longer, before the first dose of study medication.
18. Has a history of previous nonresponse to ketamine, R-ketamine or S-ketamine, or has received 8 or more doses of the same in their lifetime.
19. Has a previous history of intolerance to ketamine, R-ketamine, or S-ketamine.
20. History of abuse of ketamine, R-ketamine, S-ketamine, or phencyclidine.
21. Subjects should not consume grapefruit, grapefruit juice, or Seville orange -related products for 72 hours before IP administration and throughout the study.
22. Has the presence of clinically relevant long-term COVID-19 symptoms or current signs of COVID-19.
23. COVID-19 vaccination is allowed as long as the doses are administered ≥ 30 days before study drug administration. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in MADRS total score assessed at 24 hours after the start of the infusion. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 hours after the start of the infusion. |
|
| E.5.2 | Secondary end point(s) |
• Change from baseline in MADRS total score at 2 hours, 4 hours,
7 days, and 14 days after the start of the infusion.
• Proportion of subjects with ≥ 50% improvement in MADRS total score at 24 hours, 7 days, and 14 days after start of infusion.
• Proportion of subjects with a MADRS total score ≤ 10 at 24 hours, 7 days, and 14 days after start of infusion.
• Changes in HAM-D on Day 8 and Day 15 after start of infusion.
• Change from baseline in QIDS-SR-16 by visit.
• Change from baseline in GAD-7 by visit.
• Change from baseline in EQ-5D-3L by visit.
• Change from baseline in CGI S by visit and CGI I (calculated from
predose CGI S). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 24 hours after the start of the infusion. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 6 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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