E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
This study will assess the effects of poly-unsaturated fatty acids on working memory (measured using an n-back test) in healthy volunteers, in subjects who are at high risk for developing a psychotic disorder and in patients with first-episode schizophrenia. |
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E.1.1.1 | Medical condition in easily understood language |
This study will assess the effects of fatty acids on working memory in healthy volunteers, in subjects at high risk for developing psychosis and in patients with first-episode schizophrenia |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Psychological processes [F02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10039628 |
E.1.2 | Term | Schizophrenia and other psychotic disorders |
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 |
To study the effects of dietary supplementation with poly-unsaturated fatty acids(PUFAs) and of amphetamine-induced dopamine-release on dopamine-dependent, working-memory related brain networks. To develop a [11C]-(+)-PHNO positron-emission tomography (PET) paradigm for the 3T Siemens mMRBiograph system for studying amphetamine-induced dopamine release in a single scanning session. To develop an in-vitro model of altered dopamine function in schizophrenia by transorming fibroblasts derived from study participants viy skin punch biopsy into dopaminergic neuron-like cells. To study the impact of phospholipase-2 (PLA2) stimulation by melittin and PUFAs on the dopamine transporter in HEK 293 cells and later in fibroblast-derived neuron-like cells; initiation of molecular dynamics (MD) simulations on the impact of dopamine transporter conformations. |
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E.2.2 | Secondary objectives of the trial |
To relate the magnitude of amphetamine-induced dopamine-release measured with [11C]-(+)-PHNO PET on specific functional brain networks (for example default-mode network) using functional magnetic resonance imaging (fMRI) and connectivity analyses. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All subjects • age 18-65 • good general health • absence of relevant abnormalities in laboratory screening, ECG or vital signs • no regular use of drugs of abuse or alcohol based on history and urine drug screen. Healthy subjects • Absence of psychiatric disorders according to M.I.N.I. ARMS subjects • CAARMS above ARMS threshold Patients with schizophrenia • diagnosis of SCZ or other non-affective psychotic disorder according to DSM-5 • minimum Positive and Negative Syndrome Scale (PANSS) total score of 55 (> 3 on at least two or >4 on one psychosis item • ability to give informed consent |
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E.4 | Principal exclusion criteria |
All subjects • severe or unstable medical or neurologic disorders or clinically significant abnormality on screening laboratory studies • clinically relevant abnormalities in the electro-cardiogram (ECG) • history of myocardial infarction or angina pectoris, arterial hypertension or paroxysmal hypertensive states • established diagnosis of advanced arteriosclerosis or hyperthyroidism • current substance use disorder (except nicotine) • lifetime use of stimulants exceeding 5 or more exposures • pregnancy or breast feeding • known hypersensitivity to sympathomimetics • history of severe head trauma • positive urine drug screen • presence of MRI exclusion criteria • if participation in this study would exceed annual radiation dose limits (30mSv) • known allergy to any ingredients of the PUFA or placebo capsules • Patients with schizophrenia • previous oral antipsychotic treatment for more than 2 weeks, or antipsychotics within two weeks prior to PET scan; previous treatment with antipsychotic depot preparation. • ARMS subjects • psychotic disorder according to DSM-5 (CAARMS above psychosis threshold) |
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E.5 End points |
E.5.1 | Primary end point(s) |
1) To measure an increased amphetamine-induced reduction in binding of the dopamine D2/3 agonist radioligand [11C]-(+)-PHNO in patients with schizophrenia and part of the at risk mental state (ARMS) collective as compared to healthy control subjects. 2) To measure a significant amphetamine-induced reduction in working memory performance assessed using an n-back paradigm in subjects with presumed high baseline dopamine activity (patients with schizophrenia and part of the ARMS collective). 3) To measure a normalization of amphetamine-induced reductions in [11C]-(+)-PHNO binding in ARMS subjects with increased baseline response after PUFA intakeas compared to placebo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) and 2) at baseline (i.e. before PUFA or placebo intake) 3) after intake of PUFA (EPAX 6000) capsules for 8-12 weeks and after intake of placebo for 8-12 weeks |
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E.5.2 | Secondary end point(s) |
1) To measure alterations in dopamine-related brain networks (at rest and while performing an n-back test) in patients with schizophrenia or ARMS as compared to healthy control subjects using functional magnetic resonance imaging 2) To relate amphetamine-induced changes in these networks to amphetamine-induced dopamine release as measured by reductions in [11C]-(+)-PHNO binding 3) To image changes in the response of dopamine-related brain networks to amphetamine after PUFA (EPAX 6000) supplementation in healthy and ARMS subjects
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) and 2) at baseline (i.e. before PUFA or placebo intake) 3) after intake of PUFA (EPAX 6000) capsules for 8-12 weeks and after intake of placebo for 8-12 weeks |
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
To study the role of dopamine in psychosis and cognitive function; to study a possible impact of PUFA supplementation on dopamine-related cognitive networks |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
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 | Yes |
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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |