E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
To unravel the neural correlates of the interaction between positive expectation (high/low) and single dose antidepressant treatment (verum/placebo) with esketamine in patients with major depressive disorder |
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E.1.1.1 | Medical condition in easily understood language |
To unravel the interaction between positive expectation and single dose antidepressant treatment with esketamine in patients with major depressive disorder
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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 | SOC |
E.1.2 | Classification code | 10037175 |
E.1.2 | Term | Psychiatric disorders |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10081270 |
E.1.2 | Term | Major depressive disorder |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10057840 |
E.1.2 | Term | Major depression |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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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 |
Major depressive disorder (MDD) is highly prevalent (8-15%), severely disabling and associated with enormous socioeconomic impact. Antidepressant medication for the treatment of MDD has proven effective in randomized controlled trials (RCTs), however, placebo response is substantial and has been increasing over the last 3 decades. In this double-blind, randomized, controlled parallel-group, 4-arm, monocenter trial project we will employ the factors ‘treatment’ (intravenous esketamine / placebo, single application) and verbally induced ‘expectation’ (high / low) combined with functional magnetic resonance imaging (fMRI, resting state, emotion and reward processing paradigms, on the same day as the esketamine/placebo treatment) to investigate the psychological and neural mechanisms underlying the antidepressant effects of expectation, and how these interact with the pharmacological effects of esketamine. |
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E.2.2 | Secondary objectives of the trial |
Not appicable See secondery endpoints below |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. a current depressive episode lasting at least four weeks 2. an initial score of at least 7 (corresponding to a mild degree of depression) on the Montgomery Åsberg Depression Rating Scale (MADRS) 3. Negative serum pregnancy test in women of childbearing potential. 4. Patients with reproductive potential must agree to maintain highly effective methods of contraception by practicing abstinence or by using at least two methods of birth control from the date of consent through the end of the study. If abstinence could not be practiced, a combination of hormonal contraceptive (oral, injectable, or implants) and a barrier method (condom, diaphragm with a vaginal spermicidal agent) has to be used.
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E.4 | Principal exclusion criteria |
1. psychotic symptoms (ascertained using SCID-5 Interview measured by module A-E) 2. acute suicidality (clinical assessment by study physician) 3. hypertension > 180/100 mmHg (according to resting blood pressure, as assessed by study physician using blood pressure measurement) 4. hyperthyroidism that has not been sufficiently treated (clinical history by study physician and current thyroid parameters will have to be within the following ranges: TSH 0,34-5,6 mU/l, fT3 3,2-6,9 pmol/l, fT4 7,5-21 pmol/l) 5. severe hepatic impairment (clinical history by study physician and current liver parameters will have to be within the following ranges: serum albumin < 2,8 g/dl serum bilirubin > 3,0mg/dl, prothrombin time < 40 % or INR > 2,3) 6. hypersensitivity to the active substance of esketamine or to any of the excipients listed in section 6.1 of the SmPC (clinical history by study physician) 7. unstable angina or myocardial infarction in the last 6 months (clinical history by study physician) 8. Myocardial failure (clinical history and physical examination by study physician) 9. Glaucoma or perforating eye injuries (clinical history by study physician) 10. patients will be excluded if they have any drug or alcohol dependency/abuse within the previous three months or if they are under acute influence of alcohol (clinical assessment by study physician and alcohol breath test) 11. any contraindications for MRI, i.e. non-removable medical devices (such as pacemakers, insulin pumps, implantable drug infusion pumps etc) or metal devices /foreign bodies (such as aneurysm clips, metal splinters in the eye , intrauterine devices etc) and pregnancy (clinical assessment by study physician and serum pregnancy test) 12. medical conditions likely to affect brain anatomy or physiology (clinical assessment by study physician) 13. age <18 or > 65 years 14. inability to provide written informed consent 15. Breastfeeding (clinical history by study physician) 16. simultaneous participation in other clinical trials if not permitted by the Principal Investigator 17. Patients for whom an elevated blood pressure or an increased intracranial pressure represents a serious risk will be excluded (clinical history and blood pressure measurement by study physician) 18. Patients with manifest ischemic heart diseases will be excluded (clinical history by study physician) 19. Increased intracranial pressure (clinical history by study physician) 20. Severe psychological disorders other than depression (Structured Clinical Interview for DSM-5 (SCID-5) measured by module A-E) 21. Concomitant therapy with Xanthin-derivates and ergometrin (clinical history by study physician) 22. Treatment with strong inhibitors or inducers of CYP3A4 (for example, but not exclusively, HIV protease inhibitors, Macrolide antibiotics, Azole antifungals, Carbamazepine, Phenobarbital; clinical history by study physician) 23. Diazepam treatment (clinical history by study physician)
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E.5 End points |
E.5.1 | Primary end point(s) |
Brain activation in networks implicated in (i) reward and (ii) emotion processing, (iii) placebo and (iv) antidepressant treatment response in MDD and (v) the pathophysiology of MDD (in particular the ventromedial prefrontal cortex [VMPFC], rostral anterior cingulate cortex (rACC), amygdala and hippocampus). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The evaluation will performed during one single day (visit 1) |
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E.5.2 | Secondary end point(s) |
• Behavioural reaction times and hit rates in the Monetary Incentive Delay task. •Changes in depressive symptoms (self-rating beck depression inventory [BDI-II], expert rating Montgomery Åsberg Depression Rating Scale [MADRS]) in response to high vs. low expectation and placebo vs. esketamine. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The evaluation will performed 4 hours, 2, 3 and 6 days after visit 1 |
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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 | No |
E.6.5 | Efficacy | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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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End of the study is defined as "Last patient Out" and database closure. |
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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 | |
E.8.9.1 | In the Member State concerned months | 39 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 39 |