Clinical Trials Register

Summary
EudraCT Number:	2010-020185-19
Sponsor's Protocol Code Number:	KP7 242114
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-07-28
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Austria - BASG

A.2

EudraCT number

2010-020185-19

A.3

Full title of the trial

Optimization of Treatment and Management of Schizophrenia in Europe

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Optimization of Treatment and Management of Schizophrenia in Europe

A.3.2

Name or abbreviated title of the trial where available

the optimise trial

A.4.1

Sponsor's protocol code number

KP7 242114

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01248195

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Medical Center Utrecht
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	European Union
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Utrecht
B.5.2	Functional name of contact point	University Medical Center Utrecht
B.5.3	Address:
B.5.3.1	Street Address	Heidelberglaan 100
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3584CX
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031887556025
B.5.5	Fax number	0031887555443
B.5.6	E-mail	i.sommer@umcutrecht.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Zyprexa
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly Nederland B.V., Grootslag,
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	olanzapine
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OLANZAPINE
D.3.9.1	CAS number	132539-06-1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Amisulpride
D.2.1.1.2	Name of the Marketing Authorisation holder	Winthrop Pharmaceuticals UK Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	solian
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AMISULPRIDE
D.3.9.1	CAS number	71675859
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Leponex
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma GmbH, Wien
D.2.1.2	Country which granted the Marketing Authorisation	Austria
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	clozapine
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLOZAPINE
D.3.9.1	CAS number	5786-21-0
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	100 to 1800
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	anti-psychotic medication
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Leponex
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharma GmbH, Wien
D.2.1.2	Country which granted the Marketing Authorisation	Austria
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	clozapine
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLOZAPINE
D.3.9.1	CAS number	5786-21-0
D.3.9.4	EV Substance Code	SUB06787MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	25 to 1800
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	anti-psychotic medication

D.8 Information on Placebo

E. General Information on the Trial

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

E.1.1.1

Medical condition in easily understood language

Schizophrenia or schizophreniform disorder

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

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

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

E.1.3

Condition being studied is a rare disease

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.

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.

E.2.3

Trial contains a sub-study

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.

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

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.

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

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.

E.5.2.1

Timepoint(s) of evaluation of this end point

refer to timetable (protocol pages 36 and 37)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

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

The end of the trial is 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

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

300

F.4.2.2

In the whole clinical trial

350

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients in symptomatic remission after the trial will be randomized to receive either psychosocial treatment intended to increase medication adherence or to treatment as usual. Non-responders at the end of the double blind part of the study will be switched to clozapine using general prescription.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-08-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-06-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-11-01

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