| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 assess the effect and tolerability of adding OSU6162 to ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI) in patients with SSRI/SNRI-resistant depression. |
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| E.2.2 | Secondary objectives of the trial |
A. To assess the effect of adding OSU6162 or placebo to ongoing treatment with SSRI/SNRI in patients with major depression.
i) on response and remission as reflectedby the total score of the Bech 6-item rating scale,
ii) on symptoms of depression, fatigue and anhedonia assessed using other inventories than
the Bech 6-item rating scale,
iii) on symptom rating after exclusion of subjects not displaying fatigue at baseline, and iv) on serum biomarkers.
B. To evaluate the safety of OSU6162. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent.
2. Age: 25-65 on the day of screening.
3. Meeting DSM-5 criteria for major depressive disorder as confirmed by the Mini International Neuropsychiatric Interview (MINI).
4. A symptom-free period preceding the current episode within the past two years confirmed at interview.
5. Not significantly improved, as judged by both doctor and patient, after having been treated with citalopram, escitalopram, paroxetine, sertraline, fluoxetine, duloxetine, or venlafaxine for at least 6 weeks.
6. Displaying a sum score of MADRS ≥22.
7. In women of childbearing potential (WOCBP): negative result of a pregnancy test and a method of contraception with a failure rate of less than 1 %. Contraception must be used during the treatment and follow-up period. Acceptable forms of contraception are:
a) Use of combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation
- oral
- intravaginal
- transdermal
b) progestogen-only hormonal contraception associated with inhibition of ovulation:
- oral
- injectable
- implantable
c) Placement of intrauterine device (IUD) or intrauterine hormone releasing system (IUS)
d) Bilateral tubal occlusion or ligation
e) Vasectomised partner (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate and provided that male partner is the sole sexual partner of the WOCBP trial participant).
f) Sexual abstinence.
8. Male patients must agree to use condoms during the study and for 2 weeks after the end of the study/last dose of IMP, unless their partner is using a highly efficient method of contraception, as described above.
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| E.4 | Principal exclusion criteria |
1. Meeting MINI criteria at interview for suicidality, manic episode, hypomanic episode, bipolar I, bipolar II, bipolar unspecified, bipolar I with psychotic symptoms, panic disorder (current), agoraphobia, social anxiety (social phobia), obsessive compulsive disorder, posttraumatic stress disorder, alcohol dependency, alcohol abuse, substance dependency (non-alcoholic), substance abuse (non-alcoholic), psychotic disorders, mood disorders with psychotic features, anorexia nervosa, bulimia nervosa, anorexia nervosa binge eating / purging type, generalised anxiety disorder, or antisocial personality disorder. Meeting MINI criteria at interview for generalised anxiety disorder, obsessive compulsive disorder or social anxiety (social phobia), unless the present symptoms can predominantly be attributed to a diagnosis of major depressive disorder.
2. A history of substance/alcohol abuse within 2 years prior to screening.
3. A previous diagnosis of a personality disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder, or intellectual disability.
4. Any other previously diagnosed or suspected CNS disorder that according to the investigator renders the patient unsuitable for participation in the trial.
5. Any factor that according to the investigator renders it unlikely that the patient will comply with the instructions regarding treatment, visits etc.
6. Any somatic illness that according to the investigator renders the patient unsuitable for participation in the trial.
7. Any signs or symptoms of somatic illness resulting from assessment of vital signs, physical examination, clinical laboratory tests and 12-lead ECG that according to the investigator renders the patient unsuitable for participation for safety reasons, including a QTc-time on ECG exceeding 450 ms in men and 460 ms in women.
8. Any change in dosage of said SSRI/SNRI within 4 weeks prior to screening or at any time during the course of the trial.
9. Treatment with any other psychoactive drug than said SSRI/SNRI with the exception of using mirtazapine up to 15 mg for sleep, occasional use of benzodiazepines and benzodiazepine-like anxiolytics or hypnotics and occasional use of antihistaminergic sedatives (without anti-dopaminergic effects) within 4 weeks prior to screening and at any time during the course of the trial.
10. Patients who are receiving concomitant therapy with potent cytochrome P450 enzyme inhibitors (e.g., bupropion, fluvoxamin, ketoconazol, itraconazole, telitromycin, clarithromycin, protease inhibitors, quinidine, and terbinafine).
11. Ongoing treatment with drugs with a narrow therapeutic window where either lower or higher serum levels are potentially harmful (including but not limited to warfarin along with other anticoagulants, digoxin along with other antiarrythmics, anticonvulsants prescribed for treatment of epilepsy, cyclosporine, immunosuppressants, and lithium).
12. Current treatment with any prescribed or OTC drug that according to the investigator renders the subject unsuitable for participation in the trial.
13. Previous intake of OSU6162.
14. Current participation in another clinical trial.
15. Nursing women.
16. Substudy only: Relative and/or absolute contraindications to lumbar puncture and functional Magnetic Resonance Imaging (fMRI), as per clinical practice.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline with respect to the total score of the investigatorrated Bech 6-item subscale of the Hamilton Depression Rating Scale (HDRS) at endpoint. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1) Number of participants displaying clinical response defined as ≥50% reduction in the total score of the investigator-rated Bech 6-item subscale of the HDRS at endpoint.
2) Number of participants displaying clinical remission defined as a sum rating of ≤4 in the total score of the investigator-rated Bech 6-item subscale of the HDRS at endpoint (investigator rating).
3) Change from baseline with respect to investigator-rated item 1 (depressed mood) of the HDRS (9).
4) Change from baseline with respect to the total score of the investigator-rated HDRS at endpoint (17 items).
5) Change from baseline with respect to the total score of the investigator-rated Montgomery Åsberg Depression Rating Scale (MADRS) at endpoint.
6) Change from baseline with respect to the total score of the investigator-rated Clinical Global Impression - Severity scale (CGI-S) at endpoint.
7) Investigator rating of the Clinical Global Impression - Change scale (CGI-C) at endpoint.
8) Change from baseline with respect to the total score of the patient rated Fatigue Severity Scale (FSS) at endpoint.
9) Change from baseline with respect to the total score of the patient rated MADRS (self) at endpoint.
10) Change from baseline with respect to the total score of the patient rated Snaith-Hamilton Pleasure Scale (SHAPS) at endpoint.
11) Patient rating of the Global Rating of Change Scale (GRC) at endpoint.
12) Change from baseline with respect to the total score of the Bech 6- item subscale of the HDRS at endpoint in patients displaying a sum rating of ≥36 at the Fatigue Severity Scale at baseline.
13) Patient rating of the Global Rating of Change Scale (GRC) at endpoint in patients displaying a sum rating of ≥36 at the Fatigue Severity Scale at baseline.
14) Baseline, and change from baseline to endpoint, with respect to serum and cerebrospinal fluid levels of a number of possible markers of depression including C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), brain-derived neurotrophic factor (BDNF), and interleukin-6 (IL-6). In substudy only: Homovanillic acid and other biomarkers associated with dopamine and serotonin.
15) Possible association between baseline levels and outcome, as well as changes from baseline to endpoint, with respect to cerebrospinal fluid levels of a number of possible markers of depression including C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), brain-derived neurotrophic factor (BDNF), and interleukin-6 (IL-6), as well as with respect to monoamines and monoamine metabolites (Substudy only.)
16) Number of participants with individual AEs and individual SAEs throughout the trial.
17) Serum levels of OSU6162 at endpoint and of the prescribed SSRI/SNRI at endpoint as compared to screening.
18) Baseline and treatment-associated change in reward-related striatal activity per fMRI-assessment. (Substudy 1).
19) Brain signal variability per fMRI-assessment. (Substudy 1).
20) Probabilistic Reward Task (TRL). (Substudy 2). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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