| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
20 patients with severe unipolar depression (structured clinical interview for DSM-IV and the 17-item Hamilton Depression Rating Scale), also 20 age and sex matched healthy controls.
plus 12 HC for pilot study I.
plus 10 HC for pilot study II.
plus 12 HC for pilot study III.
plus 30 HC for study sub-study.
Drop-outs will be replaced with newly recruited subjects until the number of subjects listed above have completed the study portion they are participating in according to protocol. |
20 PatientInnen mit schwerer unipolarer Depression (erfasst mit SCID und HAM-D) und 20 nach Alter und Geschlecht gematchte gesunde KontrollprobandInnen untersucht.
plus 12 gesunde Kontrollen für Pilotstudie I
plus 10 gesunde Kontrollen für Pilotstudie II
plus 12 gesunde Kontrollen für Pilotstudie III
plus 30 gesunde Kontrollen für Sub-studie
Drop-outs werden nach-rekrutiert bis die oben genannte Anzahl an ProbandInnen den jeweilige Protokollabschnitt abgeschlossen hat. |
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| E.1.1.1 | Medical condition in easily understood language |
| Severe unipolar depression |
| Schwere unipolare 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045543 |
| E.1.2 | Term | Unipolar depression |
| E.1.2 | System Organ Class | 100000004873 |
|
| 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 |
The study at hand is the first to investigate ketamine’s serotonin transporter (SERT) binding in humans, by utilizing the highly selective SERT radioligand [11C]DASB and positron emission tomography (PET). Further, investigation of severely depressed patients provides the unique opportunity to establish the relationship between ketamine’s SERT binding and its antidepressant efficacy. We aim to investigate
-Does Esketamine Hydrochloride bind the SERT?
-Does binding of Esketamine Hydrochloride to the SERT predict antidepressant response? |
Ziel dieser Studie ist es, erstmals die Bindung von Ketamin am Serotonintransporter (SERT) des Menschen in vivo zu untersuchen, da Studien mit Affen kürzlich eine hohe Bindung zeigten. Weiters soll durch den Einschluss von Patienten mit Depression und Erfassung deren Therapieansprechen die Bedeutung des SERT, der durch seine zentrale Rolle in der Depressionsbehandlung (z.B. bei Selektive Serotonin-Wiederaufnahmehemmer) einen wichtigen Angriffspunkt darstellt, für die antidepressive Wirkung von Ketamin untersucht werden.
-Bindet Esketamine Hydrochloride den SERT?
-Erlaubt das Muster der Bindung von Esketamine Hydrochloride am SERT eine Prädiktion von antidepressivem Therapieansprechen?
|
|
| E.2.2 | Secondary objectives of the trial |
| Biological mechanisms behind differences in the effects of ketamine with emphasis on genetic variants in serotonergic, glutamatergic and dopaminergic neurotransmitter systems and other important proteins with regard to pharmacodynamics (ABCB1, P-glykoprotein) and pharmacokinetics (CYM enzymes). |
| Biologische Mechanismen, welche basierend auf genetischen Varianten in serotonergen, glutamatergen und dopaminergen Neurotransmittersystemen und anderen wichtigen Proteinen hinsichtlich der Pharmakodynamik (ABCB1, P-Glykoprotein) und der Pharmakokinetik (CYM-Enzyme) Unterschiede in der individuellen Wirkung von Ketamin verursachen. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pilot Study I
An initial pilot study will be performed in order to optimize procedures associated with ketamine application, PET, and ketamine metabolite assessment. This study will be performed in a small (n=12), explorative sample group of healthy controls, at a lower ketamine dosage, and without arterial blood sampling in order to be able to focus on optimization of operations during drug application and PET. In addition to establishment of PET related operating procedures, the study will assess to which extent (R,S)-ketamine (Ketamin Hydrochloride), given at the dose in which it is implemented as an antidepressant, binds to the SERT in the brain.
12 healthy subjects will be assessed twice with [11C]DASB positron emission tomography (PET), once without study medication and once after Ketamine Hydrochloride infusion.
Pilot Study II
A pilot study will be performed in 10 healthy controls in order to assess differences in serotonin transporter (SERT) binding between Esketamine Hydrochloride and Ketamine Hydrochloride.
Subjects will be assessed with [11C]DASB PET, once during Esketamine Hydrochloride and once during Ketamine Hydrochloride infusion. The sequence of the applied condition will be randomised.
Pilot Study III:
Results from the pilot study I showed discrete binding of the serotonin transporter (SERT) by ketamine hydrochloride at the antidepressant dose of 0.5 mg/kg body weight as well as a positive regional correlation between ketamine plasma levels and ketamine occupancy of the SERT. As SERT occupancy values were low, they were potentially obscured by [11C]DASB PET test-retest variability. An additional pilot study (pilot study III) will be performed utilizing a higher dose of ketamine hydrochloride in order to assess with increased certainty, if ketamine binds the SERT. Furthermore, the time-point of application and time-frame of PET measurement have been modified, as ketamine shows a rapid initial elimination phase.
This pilot study will be performed in 12 healthy male controls. Subjects will be assessed twice with [11C]DASB PET. The first PET will serve as a baseline. Ketamine hydrochloride is applied during the second PET, and PET measurement will be extended to 140 minutes utilizing a bolus plus infusion method of radioligand administration. Two MRIs will be performed using structural, resting state, and magnetic resonance spectroscopy (MRS) sequences, once as a baseline, and once after ketamine administration. MRI scanning is performed in order to explore the relevance of SERT blockade on the changes to the glutamatergic and GABAergic systems as well as to resting state (RS) fMRI activity and functional connectivity (FC) that are induced by ketamine.
Sub-study:
Due to limited access to positron emission tomography (PET) a sub-study will be performed that is designed in analogy to the pilot study III, with the exception that two magnetic resonance imaging (MRI) measurements, but no PET measurements will be performed. We aim to explore the effects of ketamine administration on changes to the glutamatergic and GABAergic systems using magnetic resonance spectroscopy (MRS), as well as to resting state (RS) functional MRI and functional connectivity (FC). We will investigate if changes to these MRI measures are present after ketamine infusion, with measurement starting approximately two hours after ketamine infusion. For this purpose, 30 healthy controls (HC) will be investigated twice with MRI, once before, and once after treatment with 0.80 mg/kg bodyweight (R, S)-ketamine (Ketamin-hameln (Ketaminhydrochlorid) 50mg/ml Ampullen; Hameln Pharma Plus GmbH) i.v. over 50 minutes.With the exception of the lack of PET, all study procedures will be in analogy to those performed during the pilot study III.
|
Pilotstudie I
Die Pilotstudie I soll in einem kleineren Kollektiv (n=12) von gesunden KontrollprobandInnen, nicht randomisiert, und nicht verblindet erfolgen, um Abläufe der Positronen-Emissions-Tomographie (PET) und der Ketamininfusion zu optimieren. Weiters wird die Okkupanz von (R,S)-Ketamin (Ketamine Hydrochloride) am Serotonintransporter (SERT) bestimmt.
12 gesunde ProbandInnen werde zweimal mittels [11C]DASB PET erfasst, einmal ohne Studiemedikation und einmal nach Infusion von (R,S)-Ketamin (Ketamine Hydrochloride)
Pilotstudie II
10 gesunde KontrollprobandInnen werden in eine Pilotstudie eingeschlossen um mögliche Unterschiede in der SERT Binding von Esketamine Hydrochloride und Ketamine Hydrochloride zu erfassen.
Probanden werden jeweils einmal unter Esketamine Hydrochloride und einmal unter Ketamine Hydrochloride Infusion mit [11C]DASB Positronen-Emissions Tomographie gemessen. Die Reihenfolge der Konditionen wird randomisiert.
Pilot Study III:
Im Rahmen der Pilot Studie I wurden niedrige Okkupanzwerte sowie ein positives Verhältnis zwischen Ketaminspiegel und Ketaminokkupanz nach Gabe von der antidepressiven Dosis (0.5mg/kg Körpergewicht) Ketaminhydrochlorid gezeigt. Weiters zeigt Ketamin eine rasche Eliminationskinetik. Um diese Punkte im Studienprotokoll zu berücksichtigen, soll die Dosis an verabreichtem Ketaminhydrochlorid erhöht werden, die Dauer der PET Messung soll auf 140 Minuten erhöht werden, und der Radioligand soll in einem Bolus plus Infusions Modell verabreicht werden.
12 gesunde männliche Kontrollprobanden werde zwei mal mittels [11C]DASB PET untersucht. Die erste PET Messung erfolgt ohne Gabe des Studienmedikamentes, Ketaminhydrchlorid soll während der zweiten PET verabreicht werden. Weiters werden zwei MRT Scans durchgeführt, einmal vor Gabe des Studienmedikamentes, und ein zweites mal nach Gabe von Ketaminhydrochloride. Neben einer strukturellen Messung sollen auch Magnetresonanzspektroskopie (MRS) und Ruhemessungen durchgeführt werden, um den Einfluss von Ketamin auf die Glutamat und GABA Systeme sowie auf die neuronale Aktivität (fMRT) und funktioneller Konnektivität (FC) während der Ruhemessung erfassen zu können.
Sub-studie:
Eine sub-studie, welche im wesentlichen aus den selben Studienmaßnahme wie die Pilotstudie III besteht wird durchgeführt um 1) Mangel an PET Termine zu umgehen und 2) den Einfluss von Ketamin auf die Struktur, die Funktion, und den Metabolismus des Gehirns zu untersuchen. |
|
| E.3 | Principal inclusion criteria |
-Men and women aged 18-55
-Participants free from internal medicine or neurologic diseases
-Negative pregnancy test at the screening visit and before PET visits (only women)
-Participants must be willing and able to give informed consent
-Severe unipolar depression tested with a structured clinical interview for DSM-IV (SCID) and HAM-D (only patients) |
|
| E.4 | Principal exclusion criteria |
-Severe medical or neurologic disorder
-Psychiatric disorder (only in healthy controls)
-DSM-IV Axis-1 comorbidity other than anxiety symptoms (only patients)
-Clinically relevant alterations in blood draw (hematology, blood chemistry) or standard physical examination
-Addiction to alcohol or another substance (current or past)
-Intake of psychopharmaceutical medication in the last 6 months
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Serotonin transporter occupancy: assessed with [11C]DASB binding potential |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Main Study: Serotonin transporter occupancy: during PET measurement, which begins immediately (10 minutes) after Esketamine Hydrochloride infusion
Pilot study I: Serotonin transporter occupancy: during PET measurement, which begins immediately (5 minutes) after Ketamine Hydrochloride infusion
Pilot study II: Serotonin transporter occupancy: during PET measurement, during which Esketamine Hydrochloride or Ketamine hydrochloride infusion takes place.
Pilot study III: Serotonin transporter occupancy: during PET (PET1, PET2) measurement, Ketamine Hydrochloride infusion takes place during PET2 measurement
|
|
| E.5.2 | Secondary end point(s) |
-Antidepressant Response: assessed with Hamilton Depression Rating Scale, HAM-D. (Response: Point reduction by at least 50%, Remission: < 7 Points)
Not assessed in pilot studies
-Antidepressant Response: assessed with Clinical Global Impressions Scale, CGI
Not assessed in pilot studies
Pilot study III and sub-study:
-Levels of GABA, Glutamate, and their metabolites (assessed with MRS), resting state fMRI (RS fMRI) activity and functional connectivity (RS FC)
-Brief psychiatric rating scale (BPRS) and Positive and Negative Syndrome Scale (PANSS).
-Plasma levels of ketamine and its metabolites
- Blood samples (24 ml EDTA): ABCBC1 and glycoprotein-p SNPs (DNA will be isolated from whole blood using the QiaAmp DNA blood maxi kit (Qiagen, Hilden, Germany). Genotyping will be performed using the iPLEX assay on the MassARRAY MALDI-TOF mass spectrometer): all participants from PILOT STUDY I-III and SUB-STUDY
-Sleep Quality Index (PSQI) [13] and sexual behavior using in-house questionnaires (only sub-study)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
HAM-D: 2 hours after Esketamine Hydrochloride infusion, 24 hours after Esketamine Hydrochloride infusion.
Not assessed in pilot studies
CGI: 2 hours after Esketamine Hydrochloride infusion, 24 hours after Esketamine Hydrochloride infusion.
Not assessed in pilot studies
Pilot study III and sub-study:
-MRS, RS fMRI, RS FC: Before PET2 and after ketamine. Sub-study: MRI performed before and after ketamine.
-BPRS, PANSS: PET1 and PET 2 after ketamine. Sub-study: MRI1s and MRI2s after ketamine.
-Plasma levels of ketamine and its metabolites: before, during, and after ketamine at PET2 . Sub-study: before, during, and after ketamine at MRI2s.
-Sleep Quality Index (PSQI) [13] and sexual behavior questionnaires (only sub-study): MRI1s and MRI2s after ketamine. |
|
| 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 | Yes |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| randomization, placebo-control, double-blind only HC main study; cross-over only in pilot study II |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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