E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Therapy resistant depression |
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E.1.1.1 | Medical condition in easily understood language |
Depression without sufficient response to antidepressant medication |
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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 |
Effectiveness of a single i.v. application of the NMDA antagonist ketamine at subanaesthetic doses will be tested The study will extend prior reports of open label studies in exploratory sample sizes to a double blinded placebo controlled study on a larger sample of 40 patients.
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E.2.2 | Secondary objectives of the trial |
Prediction of treatment response by severity of abnormal resting state fMRI in pregenual cingulate cortex (pgACC) will be tested as a secondary endpoint. Regional homogeneity (ReHo) and functional connectivity (fc) of the pgACC are tested to predict treatment response to ketamine. This biomarker will be tested on MRI conditions that are available in a standard clinical environment.
Changes of glutamine concentrations after injection will be monitored using MR spectroscopy. Effects of ketamine on metabolite concentrations will be compared in healthy controls and patients. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria: patients (age 18-55) with recurrent major depressive disorder for at least 5 years on a stable regimen of psychotropic medications for > 6 weeks before study entry, Hamilton Depression Rating Scale (HAMD, 21 item) scores ≥ 18, with failed responses to at least 2 previous adequate (guideline conform) treatment attempts during the recent episode.
Treatment resistance is defined by 1) unsuccessful adequate trials ( >6 weeks at maximum recommended or tolerated dose) of primary antidepressant drugs from at least three different classes; 2) unsuccessful adequate trials ( > 4 weeks) of augmentation/combination strategies using a primary antidepressant with at least two other different agents; Treatment resistance will be quantified after inclusion using the Antidepressant Treatment History Form (ATHF).
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E.4 | Principal exclusion criteria |
Exclusion criteria include pregnancy, history of psychotic symptoms, increased intraorbital pressures, known neurological comorbidities, cardiac exclusion criteria include arterial hypertension, arythmia, congenital heart failures, hearth insufficience (NYHA II or higher) and coronary heart disease. Further exclusion criteria consist of any history of substance abuse or psychiatric comorbidities requiring additional treatment, known adverse responses during previous surgical procedures requiring anaesthesia such as delirium. Specific MR exclusion criteria comprise metal implants, claustrophobia, tattoos and tinnitus. |
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E.5 End points |
E.5.1 | Primary end point(s) |
improvement on HAMD scores |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 hours after ketamine infusion |
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E.5.2 | Secondary end point(s) |
Secondary endpoint 1: Predictive value of pretreatment regional homogeneity (ReHo), glutamine concentration and functional connectivity (FC) of pgACC for treatment response to ketamine in patients.
Secondary endpoint 2: acute and sustained changes of glutamine concentrations after administration compared to baseline |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
secondary endpoint 1: pretreatment MR measurement and HAMD after 24 hours secondary endpoint 2: MR measurements pretreatment, 60 mins post infusion and after 24hours |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
molecular neuroscience - insight on glutamatergic dysbalance in treatment resistant depression |
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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 | No |
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
| 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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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 | 18 |
E.8.9.1 | In the Member State concerned days | |