| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Persons at risk of being prodromally symptomatic of psychosis (PAR) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Persons who are at high risk of developing psychosis in the near future |
|
| 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 |
Drawing on the first evaluations of SPS, ethical, acceptance and compliance considerations, the study addresses the following principal research questions (PRQ):
(1) Are clinical management and aripiprazole combined (CM+ARI) more effective in PAR than CM and placebo combined (CM+PL)?
(2) Is CBT more effective in PAR than CM+PL?
(3) Is CBT not less effective in PAR than CM+ARI?
If PRQ 1-3 will be answered positively, there will be substantial empirical evidence for SPS. Moreover, the results will suggest that AN and CBT are comparable effective. Thus PAR will benefit from a choice of prevention strategies. Thereby acceptance, tolerance and compliance with SPS efforts in PAR, in their families and in the general population is likely to improve.
The major motivation for the study is to answer PRQ 1, 2 and 3 regarding the primary aim of SPS, the “delay or prevention of progression to psychosis”.
|
|
| E.2.2 | Secondary objectives of the trial |
Moreover PRQ 1, 2 and 3 will be explored with regard to secondary aims of SPS, “improvement of symptoms, of social functioning and neuropsychological functioning or of quality of life”. In addition, safety, tolerability and compliance will be compared (secondary outcomes). The latter data become highly clinical relevant only when PRQ 1, 2 and 3 will be answered positively with regard to “transition to psychosis” and are therefore of minor motivation for the research group.
Additional: Influences of neurotrophic factors and oxidative stress during the prodromal phase of schizophrenia |
|
| 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 |
Title of the sub-study:
Structural Brain Changes During the Prodromal Phase of Schizophrenia (Köln) Date 25.08.2008; Version 1.1
Objectives: 1. What are the morphometrically identifiable neural correlates of PAR as compared to normal healthy control persons? (cross-sectional design)
2. What are the neural correlates of the progression of PAR? (longitudinal design)
2a. What are the morphometrically identifiable neural correlates of the transition from PAR to schizophrenia? (to be studied only in cases of transition within one year of observation)
2b. What are the morphometrically identifiable neural correlates of the progression during PAR? (to be studied only in cases of ongoing prodromal states during one year of observation)
3. What are the differential morphometrically identifiable neural correlates of PAR at the time of inclusion that have predictive value for the success of (pharmaco- and psycho-) therapy?
Oscillatory brain activity and auditory information processing in prodromal patients
(Köln) Date 05.05.2008; Version 1.0
Objective:
The Aim of the Add-on study is
to investigate whether reduced ERP amplitudes, reduced phase reset
(ERPR), or reduced amplitude changes (ERAC) after auditory stimulation
in patients at risk (prodromal syndrome) predictive of transition to
psychosis.
Genotypes and stress hormones as predictors of response to treatment and course of illness in persons at risk for psychotic disorders
(Bonn) Date 05.02.2009; Version 2.1
Objectives:
1. Do candidate genes for psychosis (as known from other studies) or do levels of initial cortisol predict psychosis or response to treatment in PAR subjects?
2. Are Cortisol levels changed by the interventions (additional outcome parameter) ?
3. Are Cortisol levels cross-sectionally related to neurobiological (neuropsychology, MRI) and psychopathological measures putatively related to experienced stress ?
The extended assessment will allow to address in addition the following questions:
4. There is an increased cortisol awakening response in PAR compared to healthy controls.
5. Dysfunctional coping strategies are related to the cortisol awakening response.
6. In comparison to healthy controls, persons at risk for psychosis (PAR) show a stronger correlation between daily stress and the occurrence and intensity of general symptoms (e. g. anxiety and depression) and psychotic symptoms.
7. Early traumatic experience is associated with specific psychotic symptoms.
Cortical excitability in prodromal patients measured by dTMS
(Göttingen) Date 25.08.2008; Version 1.1
Objective:
The Aim of the Add-on study is to decide, if reduced cortical inhibition or enhanced cortical facilitation could be a neurobiological marker for UHR subjects who will develop schizophrenia.
|
|
| E.3 | Principal inclusion criteria |
• Age between 18-49 years
• belong to one or more of the following groups:
(1) Attenuated positive symptoms (APS): Presence of at least one of the following symptoms (SOPS-score 3-5): Unusual thought content/delusional ideas, suspiciousness/persecutory ideas, grandiosity, perceptual abnormalities /hallucinations, disorganized communication
(2) Brief limited intermittent psychotic symptoms (BLIPS): Presence of at least one of the following symptoms 7 days resolving spontaneously (SOPS Score=6): Hallucinations, delusions, formal thought disorder
(3) Predictive basic symptoms: Presence of at least two of the nine following symptoms (SPI-A 3 ) during the last three months and a presence for more than one year: inability to divide attention, thought interferences, thought pressure, thought blockages, disturbance of receptive speech, disturbance of expressive speech, disturbance in abstract thinking, unstable ideas of reference, captivation of attention by details of the visual field.
(4) Family risk plus reduced functioning: A first-degree relative with a history of any DSM-IV psychotic disorder or DSM-IV schizotypal personality disorder of the index person and a change in mental state or functioning leading to a reduction of 30% or more on the Global Assessment of Functioning (GAF-M) Scale for at least one month within the last year compared to the highest level of previous functioning.
• Verbal IQ>70,
• Written informed consent.
|
|
| E.4 | Principal exclusion criteria |
- Present or past diagnosis of a schizophrenic, schizophreniform, schizoaffective, delusional or bipolar disorder according to DSM IV;
- present or past diagnosis of a brief psychotic disorder according to DSM IV with a duration equal to or of more than one week;
- diagnosis of delirium, dementia, amnestic or other cognitive disorder, mental retardation, autism spectrum disorders;
- psychiatric disorders due to a somatic factor or related to psychotropic substances according to DSM IV;
- present alcohol- or drug dependence according to DSM IV;
- diseases of the central nervous system (inflammatory, traumatic, epilepsy etc.);
- EEG abnormalities;
- current or past antipsychotic treatment without a washout phase of at least 4 weeks;
- current or intended pregnancy, lactation or missing reliable method of contraception;
- current suicidality or dangerous behavior;
- Contraindication accordant SMPC: Known intolerance of the active pharmaceutical ingredient or another ingredient of verum or placebo;
- use of drugs with anticipated interactions (in accordance to SMPC);
- known cardiovascular disease (Myocardial infarct or ischemic heart disease, cardiac insufficiency), cerebrovascular disease, conditions that predispose for hypotonia (dehydration, hypovolemia, treatment with antihypertensive drugs) or hypertonia, known heredity for galactose intolerance, lactase deficit or glucose-galactose-malabsorption;
- participance in other clinical trials, which could intervene with the present trial;
- persons, who are depending on the investigator or the sponsor;
- recent hospitalisation due to legal or regulatory devices;
- persons which have been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint:
a. Transition to psychosis: The primary endpoint is given by the dichotomous outcome measure “transition to psychosis”, which is summarized through an event rate within a time interval. The event ”transition to psychosis” will by operationalized in accordance with McGorry et al. (2002), Morrison et al. (2004) and Ruhrmann et al. (2005) by one or more of 5 SOPS positive items rated with score=6 longer than 7 days, to be further specified as DSM IV 292.11-12, 295.1-4, 295.7, 295.9, 296.04, 296.24, 296.34, 297.1, 298.8. |
|
| E.5.2 | Secondary end point(s) |
b. Time to transition: is summarized by a time-dependent cumulative event rate of transition to psychosis.
c. Symptoms:
Prodromal symptoms (UHR): Severity of prodromal symptoms as described by the UHR criteria will be interview-measured by the SOPS. (Miller et al., 2003a). The SOPS is a 19-item scale designed to measure changes in symptomatology over time. It contains positive, negative, disorganization and general symptoms sub-scores.
Basic symptoms (BS): The severity of BS will be assessed by a short version and the complete interviewer-administered SPI-A (Schultze-Lutter et al., 2004; 2006). The SPI-A is a 34-items scale with 6 subscales designed to quantify basic symptoms and to complement SOPS.
Schizophrenia symptoms will be interviewer-measured by the Positive and Negative Syndrome Scale (PANSS; Kay, 1987), which gives a total score as well as positive, negative and general psychopathology sub-scores.
Depression: Symptoms of depression will be self-rated by the Beck Depression Inventory (BDI, Beck et al., 1961) and interviewer rated by the MADRS (Montgomery Asperg Depression Rating Scale), which contain one total score each.
Anxiety: Anxiety will be self-rated by the State Trait Anxiety Inventory (STAI, Spielberger et al., 1970), which gives a state and a trait anxiety scale.
Psychiatric diagnosis: Structured clinical interview for DSM-IV, SCID I and II (Wittchen et al., 1997), for the structured investigation of actual and past mental illnesses according to DSM-IV.
d. Social adjustment: The SOFAS (Social and Occupational Functioning Assessment Scale) total score will be used for interviewer-rated social functioning (one total score). In addition the SAS II (Schooler et al., 1987), which gives 4 subscales and one general adjustment global score, will be assessed.
e. Neuropsychological functioning: The neuropsychological battery comprises Rey Auditory Verbal Learning Test, Digit symbol substitution, Trail Making Test, Oseretzki Test, Digit Span, Letter Number Span, Verbal Fluency, MWT-B. A single global measure, derived by averaged z-transformed test scores will be used.
f. Quality of Life (QoL): QoL will be examined using the core module, covering 7 areas of QoL, of the self-rating measure ”Modular System for Quality of Life” (MSLQ; Pukrop et al., 2003).
g. Neurotrophic factors and oxidative stress: The concentration of the neurotrophic factors (BDNF, GDNF, NT 3) and pro-neurotrophines (proBDNF), the genotype of BDNF as well as the concentration of antioxidative enzymes and the activity of the enzymes of oxidative stress cascade (catalase, glutathione peroxidise, superoxide dismutase, etc) in high-risk patients will be determined. The concentration of nerve growth factors and activity as well as concentration of enzymes of oxidative stress will be measured with Enzyme Linked Immunosorbent Assay (ELISA) and Activity-Assays respectively. Genotype of BDNF will be determined by Polymerase Chain Reaction (PCR).
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| 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 | No |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Cognitive behaviour therapy (CBT) |
|
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| 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
|
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
