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"Multimodal Prevention of Psychosis - Investigating Efficacy of N-Acetylcysteine and Psychotherapy in CHR-Patients" (ESPRIT-B1)

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ClinicalTrials.gov Identifier: NCT03149107
Recruitment Status : Recruiting
First Posted : May 11, 2017
Last Update Posted : March 30, 2018
Sponsor:
Collaborators:
University of Cologne
Central Institute of Mental Health, Mannheim
Ludwig-Maximilians - University of Munich
University Hospital Tuebingen
Heinrich-Heine University, Duesseldorf
Charite University, Berlin, Germany
RWTH Aachen University
Information provided by (Responsible Party):
Rene Hurlemann, University Hospital, Bonn

Brief Summary:
Schizophrenia is a severe mental disorder associated with significant impairments in affective, cognitive and social functioning. Consequently, a special interest in the prevention of schizophrenia and psychotic disorders has emerged. Pharmacological as well as psychological interventions show promising preventive effects. The purpose of this multicentric study is the investigation of possible preventive effects of a treatment combination containing a psychotherapy form and medication (N-Acetylcytein - NAC) in individuals with an enhanced risk for developing schizophrenia. Both treatment forms may reduce the risk in this population due to their specific properties: The psychotherapy can improve social skills, whereas NAC is supposed to develop its protective effects on neuronal level due to its antiinflammatory properties. The investigators will examine the preventive effects by measuring transition rates to psychosis after treatment as well as improvements in social, affective and cognitive functioning.

Condition or disease Intervention/treatment Phase
Prodromal Schizophrenia Drug: N-Acetylcysteine Drug: Placebo Behavioral: IPPI (Integrated Preventive Psychological Intervention) Behavioral: PSM (Psychological stress management) Phase 3

Detailed Description:
Psychotic disorders are among the most expensive brain-related disorders in Europe. This is mainly due to their onset early in life and their long-term disabling courses. Current treatments fail to improve most influential factors such as social-cognitive deficits. Prevention is recognized as one of the key strategies to fight these deteriorating outcomes and is expected to significantly reduce both, the societal costs as well as the immense burden for the patients and for their families. Recent meta-analyses indicate promising preventive effects of both pharmacological and cognitive-behavioural interventions. Yet, reported transition rates are still too high. Clinical evidence suggests that disturbances of social functioning predict conversion to psychosis. Neurobiological evidence implicates glutamatergic dysfunction and redox imbalance in the pathophysiology of schizophrenia. The investigators hypothesize that interventions targeting (i) social functioning and (ii) glutamatergic / oxidative pathways already in at-risk states would significantly reduce transition rates. To test these hypotheses, our study is designed as a randomized, placebo-controlled, 18-month trial (six months of intervention plus 12 months of follow-up), involving 200 subjects at-risk for psychosis. Specifically, the investigators will compare the preventive effects of a cognitive-behavioural and social-cognitive intervention to a pharmacological intervention (IPPI) with Acetylcysteine, a drug with a proglutamatergic, neuroprotective and anti-inflammatory profile in a 2x2 factorial design. The results of our planned study are expected to provide new and well tolerated interventions, thus hopefully helping to achieve the major goal of individualized prevention, and, consequently, lower the individual and societal burden of psychosis.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Multimodal Prevention of First Psychotic Episode - a 2x2-Factorial Randomized Trial Investigating the Efficacy of Acetylcysteine and Integrated Preventive Psychological Intervention in Subjects Clinically at High Risk for Psychosis
Actual Study Start Date : September 1, 2016
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : August 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: IPPI + NAC

IPPI (Integrated Preventive Psychological Intervention): 21 sessions, the first 20 sessions are scheduled weekly, the last session two weeks after session 20. Single blinded (statistician & rater).

N-Acetylcysteine (2000 mg/d, 1000 mg in the morning/evening, oral intake). Will be applied continously over 26 weeks parallel to the psychological intervention. Double-blinded.

Drug: N-Acetylcysteine
N-Acetylcysteine (2000 mg/d, 1000 mg in the morning/evening, oral intake). Will be applied continously over 26 weeks parallel to the psychological intervention (IPPI or PSM).
Other Name: NAC

Behavioral: IPPI (Integrated Preventive Psychological Intervention)
IPPI (Integrated Preventive Psychological Intervention): 21 sessions, the first 20 sessions are scheduled weekly, the last session two weeks after session 20. Single blinded (statistician & rater)

Experimental: PSM + NAC

PSM (Psychological stress management): 11 sessions; the first 10 sessions will be offered biweekly, the last one 2 weeks after session 10. Single blinded (statistician & rater).

N-Acetylcysteine (2000 mg/d, 1000 mg in the morning/evening, oral intake). Will be applied continously over 26 weeks parallel to the psychological intervention. Double-blinded.

Drug: N-Acetylcysteine
N-Acetylcysteine (2000 mg/d, 1000 mg in the morning/evening, oral intake). Will be applied continously over 26 weeks parallel to the psychological intervention (IPPI or PSM).
Other Name: NAC

Behavioral: PSM (Psychological stress management)
PSM (Psychological stress management): 11 sessions; the first 10 sessions will be offered biweekly, the last one 2 weeks after session 10. Single blinded (statistician & rater).

Experimental: IPPI + Placebo

IPPI (Integrated Preventive Psychological Intervention): 21 sessions, the first 20 sessions are scheduled weekly, the last session two weeks after session 20. Single blinded (statistician & rater).

Placebo will be applied continously over 26 weeks (oral intake of capsules) parallel to the psychological intervention (IPPI or PSM).

Drug: Placebo
Will be applied continously over 26 weeks (oral intake of capsules) parallel to the psychological intervention (IPPI or PSM).

Behavioral: IPPI (Integrated Preventive Psychological Intervention)
IPPI (Integrated Preventive Psychological Intervention): 21 sessions, the first 20 sessions are scheduled weekly, the last session two weeks after session 20. Single blinded (statistician & rater)

Active Comparator: PSM + Placebo

PSM (Psychological stress management): 11 sessions; the first 10 sessions will be offered biweekly, the last one 2 weeks after session 10. Single blinded (statistician & rater).

N-Acetylcysteine (2000 mg/d, 1000 mg in the morning/evening, oral intake). Placebo will be applied continously over 26 weeks (oral intake of capsules) parallel to the psychological intervention (IPPI or PSM).

Drug: Placebo
Will be applied continously over 26 weeks (oral intake of capsules) parallel to the psychological intervention (IPPI or PSM).

Behavioral: PSM (Psychological stress management)
PSM (Psychological stress management): 11 sessions; the first 10 sessions will be offered biweekly, the last one 2 weeks after session 10. Single blinded (statistician & rater).




Primary Outcome Measures :
  1. Transition to psychosis [ Time Frame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start) ]
    Transition to psychosis within 18 months, defined (according to EPOS1) as the presence of at least one psychotic symptom for at least one week (assessed by the SIPS).

  2. Psychosocial functioning [ Time Frame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start) ]
    Psychosocial functioning assessed by the SOFAS and the FROGS


Secondary Outcome Measures :
  1. Symptom remission [ Time Frame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start) ]
    1. Remission of symptomatic clinical high risk (CHR) criteria (APS/BLIPS and/or COGIDS); decrease of positive, negative and disorganization symptoms (assessed by the SIPS, BNSS score); conceptual disorganization and cognitive basic symptoms (COGDIS, SPI-A); as well as at-risk symptoms according to UHR (SPI-A);

  2. Depression remission [ Time Frame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start) ]
    Remission of depressive symptoms (measured by CDSS)

  3. Improvement of social cognition [ Time Frame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start) ]
    Improvement of social cognition (measured by SAT-MC I & II, PoFA)

  4. Assessment of safety and tolerability [ Time Frame: I. After intervention phase (26 weeks after trial start) and II. as follow-up (78 weeks after trial start) ]
    Neurologic and general examination (medical history, weight, - adverse events (assessed by UKU SYMPTOM-LIST), Laboratory assessments



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 - 40 years;
  2. Subjects with the ability to follow study instructions and likely to attend and complete all required visits;
  3. Written informed consent of the subject;
  4. Subjects are able to speak, write and understand the German language sufficiently well (at the investigators discretion) to complete all required study procedures;

    Specific inclusion criterion:

  5. Clinical High Risk Criteria : ESPRIT Ultra-high risk criteria (Attenuated Positive Symptoms and/or Brief Llimited Intermittend Psychotic Symptoms and/or a combination of familial risk or schizotypal disorder with a significant loss of functioning; severity assessed by the Structured Interview for Prodromal Syndromes, SIPS 5.0) and/or The Basic Symptom Criterion 'Cognitive Disturbances, COGDIS' (2/9 cognitive-perceptive basic symptoms; assessed by the Schizophrenia Proneness Instrument - Adult Version, SPI-A)

Exclusion Criteria:

  1. Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure;
  2. Simultaneously participation in another clinical trial involving administration of an investigational medicinal product within 30 days prior to clinical trial beginning. The simultaneous participation in a noninterventional clinical trial is permitted in case the subject is nevertheless able and willing to attend and complete all required visits and in case there are no other contraindications;
  3. Subjects with a physical or psychiatric condition which at the investigator's discretion may put the subject at other clinically significant risks than those that are defined as outcome of this study (development of a first psychotic episode, functional deterioration), may confound the trial results, or may interfere with the subject's per protocol participation in this clinical trial;
  4. Acute Suicidality;
  5. Known substance abuse or dependence according to DSM-IV-TR;
  6. Patients with hepatic or renal failure, or with known problems of galactose intolerance, clinically significant lactase deficiency or glucose-galactose malabsorption or histamine-intolerance;
  7. Subjects with known asthma bronchiale;
  8. Subjects with a history of gastrointestinal ulcer;
  9. Intake of antitussives (cough-relieving agents);
  10. Intake of nitroglycerin
  11. Exclusion criteria regarding special restrictions for females: Current pregnancy or pregnancy planned within 9 months after start of medication or nursing women and
  12. Females of childbearing potential, who are not using and not willing to use medically reliable methods of contraception for the entire study duration (such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices) unless they are surgically sterilized / hysterectomized or there are any other criteria considered sufficiently reliable by the investigator in individual cases.

    Indication specific exclusion criteria:

  13. Having had a psychotic episode for > 1 week (according to SIPS 5.0);
  14. Having symptoms relevant for inclusion potentially arising from a known general medical disorder;
  15. Life time antipsychotic medication for more than 30 days (cumulative number of days) at or above minimum dosage of the '1st episode psychosis' range of DGPPN S3 Guidelines (Exception: maximum dosage for aripiprazole 5 mg/d) (Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde, 2006);
  16. Any intake of antipsychotic medication (i.e., independent of duration of intake) within the past 3 months before psychopathological baseline assessments (including self-ratings and screening assessments) at or above minimum dosage of the '1st episode psychosis' range of DGPPN S3 Guidelines (Exception: maximum dosage for aripiprazole 5 mg/d) (Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde, 2006);
  17. Any intake of mood stabilizers (lithium, valproate, carbamazepine, oxcabazepine, lamotrigine) > 30 days (cumulative number of days) during the past three months or any intake during the month before psychopathological baseline assessments;
  18. Intake of antidepressants during the past 30 days before psychopathological baseline assessments;
  19. Intake of benzodiazepines for more than 2 consecutive days during the past 5 days before psychopathological baseline assessments;
  20. Psychotherapeutic intervention during the past 30 days before psychopathological baseline assessments;
  21. Any past psychotherapeutic treatment targeting specifically psychotic symptoms or its prevention.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03149107


Contacts
Contact: René Hurlemann, Prof. Dr. Dr. rene.hurlemann@ukbonn.de
Contact: Johannes Schultz, Ph. D. johannes.schultz@ukbonn.de

Locations
Germany
Zentralinstitut für Gesundheit Mannheim Recruiting
Mannheim, Baden-Württemberg, Germany, 68159
Contact: Dusan Hirjak, PD Dr.         
Universitätsklinik Tübingen Recruiting
Tübingen, Baden-Württemberg, Germany, 72076
Contact: Andreas Fallgatter, Prof. Dr.         
LMU Klinikum München Not yet recruiting
München, Bayern, Germany, 80336
Contact: David Popovic, Dr.         
Uniklinik Aachen Recruiting
Aachen, Nordrhein-Westfalen, Germany, 52074
Contact: Karsten Henkel, Dr.         
Uniklinikum Bonn Recruiting
Bonn, Nordrhein-Westfalen, Germany, 53127
Contact: René Hurlemann, Prof. Dr. Dr.         
LVR Klinik Düsseldorf Recruiting
Düsseldorf, Nordrhein-Westfalen, Germany, 40225
Contact: Thorsten Nolting         
Uniklinik Köln Recruiting
Köln, Nordrhein-Westfalen, Germany, 50937
Contact: Frank Jessen, Prof. Dr.         
Rheinhessen Fachklinik Alzey Recruiting
Alzey, Rheinland-Pfalz, Germany, 55232
Contact: Anke Brockhaus-Dumke, PD Dr.         
Charité Berlin Recruiting
Berlin, Germany, 10117
Contact: Henrik Walter, Prof. Dr. Dr.         
Berlin Vivantes Recruiting
Berlin, Germany, 10967
Contact: Andreas Bechdolf, Prof. Dr.         
Sponsors and Collaborators
University Hospital, Bonn
University of Cologne
Central Institute of Mental Health, Mannheim
Ludwig-Maximilians - University of Munich
University Hospital Tuebingen
Heinrich-Heine University, Duesseldorf
Charite University, Berlin, Germany
RWTH Aachen University

Responsible Party: Rene Hurlemann, Professor Dr. Dr. Rene Hurlemann, University Hospital, Bonn
ClinicalTrials.gov Identifier: NCT03149107     History of Changes
Other Study ID Numbers: University Hospital, Bonn
First Posted: May 11, 2017    Key Record Dates
Last Update Posted: March 30, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Rene Hurlemann, University Hospital, Bonn:
Prodrome, CHR, Schizophrenia, prevention, N-acetylcysteine

Additional relevant MeSH terms:
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Schizophrenia
Schizotypal Personality Disorder
Personality Disorders
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes