E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Schizophrenia ICD-10 code F20 or schizophreniform disorder ICD-10 code F23.1 |
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E.1.1.1 | Medical condition in easily understood language |
Schizophrenia or schizophreniform 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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039647 |
E.1.2 | Term | Schizophreniform 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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039621 |
E.1.2 | Term | Schizoaffective 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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039626 |
E.1.2 | Term | Schizophrenia |
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 test applicability of amisulpride as the first step in a treatment algorithm.
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E.2.2 | Secondary objectives of the trial |
To test guideline recommendation that non-responders to an antipsychotic (AP) drug benefit from a switch to an AP with a different receptor binding profile.
To provide the acceptability and outcome data on the application of clozapine in non-responding patients within the first 10 weeks of their treatment initiation.
To test if an IT-enabled psycho-social intervention can improve treatment adherence and global functional outcome in symptomatically remitted first-episode schizophrenia patients.
To test whether glutamatergic markers predict response to 1. and 2. line treatments.
To test if a combination of pharmacogenetic, proteomics- and metabolomic markers can provide clinical valuable predictive value.
To define the nature and prevalence of ’organic’ pathology in patients presenting with a first episode schizophreniform psychosis.
To determine the extent to which MRI measures at first presentation predict the therapeutic response to subsequent AP treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Diagnosis of schizophrenia, schizophreniform or schizoaffective disorder as defined by DSM-IV on the basis of
the Mini International Neuropsychiatric Interview Plus (M.I.N.I. Plus; Sheehan et al. 1998).
•Age 18-40 years
•Written informed consent. |
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E.4 | Principal exclusion criteria |
•A time interval between the onset of positive symptoms (hallucinations and/or delusions) and study entry
exceeding two years.
•Prior use of antipsychotic medication longer than an episode of two weeks in the previous year and/or 6 weeks
lifetime.
•Intolerance to one of the drugs in this study.
•Patients who are coercively treated at a psychiatric ward (based on a judicial ruling)
•Patients who are represented by a legal ward or under legal custody
•The presence of one or more of the contraindications against any of the study drugs as mentioned in the IB texts
•Pregnancy or lactation |
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E.5 End points |
E.5.1 | Primary end point(s) |
I) Finding evidence for pharmacotherapy guidelines in first episode schizophrenia
The primary outcome is the number of participants in remission at the end of phase I (4 weeks open treatment with amisulpride), phase II (double-blind treatment with amisulpride or olanzapine, comparison between arms) and phase III (open treatment with clozapine). Symptomatic remission will be defined according to the criteria of Andreasen et al. (2005): 8 specific symptoms (PANSS items P1, P2, P3, N1, N4, N6, G5 and G9) of schizophrenia as measured by the Positive and Negative Syndrome Scale (Kay et al. 1987) are at the most only mildly present (maximum rating of “3”) so that they do not interfere with daily life functioning. The PANSS itself is a validated measure (Kay et al. 1987) and it is the most widely used scale to assess the symptoms of schizophrenia.
II) Finding interventions to improve medication adherence
The primary outcome will be (i) drug adherence rates defined categorically (adherent vs non-adherent) as a function of standardized self report and Sellwood rating scales; and (ii) global functioning (SOFAS score) at 1 year. Based in self report, the most widespread definitions of non-adherence are (a) stopping medication for at least one week during follow up (b) taking the prescribed drug less than 90% of the time.
III) Finding biological predictors of treatment response
The primary outcome for biological predictors will be drug response defined categorically (good vs bad responders) as a function of biological profile (eg: presence or absence of genetic variants, proteomic profile, metabolomic profile, immunologic profile). The primary outcomes of the MRS scans are the difference between responders and non-responders in regional glutamate levels a) al baseline and b) between baseline and after one month of treatment with amisulpride.
IV) Testing the utility of MRI screening
Primary outcome is the percentage of first episode patients that show radiological abnormalities suggestive of neurological disorders.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
I) week 4, week 6, week 20
II) week 6, week 10, week 22, non-responders: week 34 and 74
III) MRS scan not applicable; blood draw week 0, week 4, week 10 , week 20
IV) MRI scan at baseline
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E.5.2 | Secondary end point(s) |
I) Finding evidence for pharmacotherapy guidelines in first episode schizophrenia
The secondary outcome measure is all-cause treatment discontinuation. Number and reason for premature discontinuations (treatment discontinuation) of amisulpride and the olanzapine group will e compared.
Other measures which are included are the severity and improvement subscores of the Clinical Global Impression Scale (CGI; Guy 1976) which will assess the overall severity and improvement of the participants. Levels of depression will be assessed with the Calgary Depression Scale for Schizophrenia (CDSS, Addington). The Global Assessment of Functioning scale (GAF; Jones et al. 1995) will be used to assess social functioning. Extrapyramidal symptoms will be recorded by the St. Hans rating scale (Gerlach et al. 1993). We will assess weight gain, abdominal circumference and further advere events with open interviews. The safety and tolerability of the study drugs will be monitored by the frequency and severity of side-effects.
II) Finding interventions to improve medication adherence
Two process measures will also be used at baseline and 3 months, to test whether any improvements in adherence seen in the psychosocial intervention group can be attributed to the interventions: psycho-education assessed by Knowledge About Psychosis Scale (adapted from KASI scale and MI assessed by Drug Attitude Inventory (DAI-30). Secondary analyses include a comparison of all-cause treatment discontinuation between treatment groups.
III) Finding biological predictors of treatment response
1. The ability of biological markers to predict response to antipsychotic in schizophrenia considered as a continuous variable (percentage of diminution of the PANSS total and sub-scores)
2. The ability of biological markers to predict antipsychotic treatment tolerability.
IV) Testing the utility of MRI screening
The secondary outcome is the ability of MRI to predict response to antipsychotic treatment in schizophrenia.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
refer to timetable (protocol pages 36 and 37) |
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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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
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) | 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 | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Czech Republic |
Denmark |
France |
Israel |
Italy |
Poland |
Romania |
Spain |
United Kingdom |
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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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The end of the trial is 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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |