Clinical Trials Register

Summary
EudraCT Number:	2014-000520-14
Sponsor's Protocol Code Number:	NL46653
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-16
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

Netherlands - Competent Authority

A.2

EudraCT number

2014-000520-14

A.3

Full title of the trial

Prednisolone addition for atients with recent onset psychotic disorder: the role of immune-modulating strategies in the treatment of psychosis.

Prednisolon additie voor patiënten met recent ontstane psychotische stoornis: de rol van immuun-modulerende strategieën in de behandeling van psychose.

A.3.1

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

Prednsiolone use next to standard treatment for patients with recent onset psychotic disorder: what is the effect of medication that affects the immune system?

Prednisolon gebruik naast de standaard behandeling voor patiënten met recent ontstane psychotische stoornis: wat is het effect van medicatie die het afweersysteem beinvloedt?

A.3.2

Name or abbreviated title of the trial where available

Prednisolone addition for patients with recent onset psychotic disorder.

Prednisolon additie voor patiënten met recent ontstane psychotische stoornis.

A.4.1

Sponsor's protocol code number

NL46653

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	Stanley Medical Research Institute
B.4.2	Country	United States
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	i.winter@umcutrecht.nl
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	3584 CX
B.5.3.4	Country	Netherlands
B.5.6	E-mail	i.winter@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	Prednisolone Mylan
D.2.1.1.2	Name of the Marketing Authorisation holder	Mylan
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Prednisolone Mylan
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	Prednisolone
D.3.9.1	CAS number	50-24-8
D.3.9.3	Other descriptive name	PREDNISOLONE
D.3.9.4	EV Substance Code	SUB10018MIG
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.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Schizophrenia, schizophreniphorm disorder, schizoaffective disorder, psychosis NOS.

Schizofrenie, schizofreniforme stoornis, schizoaffectieve stoornis, psychose NAO.

E.1.1.1

Medical condition in easily understood language

Schizophrenia, psychosis-related disorder

Schizofrenie, psychose-gerelateerde stoornis

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

E.2 Objective of the trial

E.2.1

Main objective of the trial

Different lines of evidence now suggest that low grade inflammation in the central lines of the central nervous system is involved in the pathogenesis of schizophrenia. Such inflammation could cause increased gray matter loss and consequently contribute to more severe negative and cognitive symptoms. We propose to investigate the effect of administering prednisolone (a broad-acting, potent immune suppressive agent) versus placebo, on psychotic symptoms, in addition to standard antipsychotic medication in patients with early stage schizophrenia or related disorders. This may revent neuronal damage caused by low-grade inflammatory rocesses in the brain. It is expected that symptom severity will be improved with prednisolone use.

Verschillende onderzoekslijnen suggereren dat lage ontstekingsgraad in het centraal zenuwstelsel betrokken is bij de pathogenese van schizofrenie. Een dergeijke ontsteking zou het verlies van grijze cellen kunnen vergroten en via deze weg bijdragen aan ernstigere negatieve en cognitieve symptomen. Middels deze studie willen we onderzoeken wat het effect is van prednisolon (een breed-werkende, potente immuunsuppressor) versus placebo op psychotische symptomen, naast de standaardbehandeling bij patiënten in een vroege fase van schizofrenie of een gerelateerde stoornis. Deze behandeling zou neuronale schade, veroorzaakt dor een lage ontstekingsgraad in de hersenen, kunnen voorkomen. We verwachten dat de ernst van de symptomen zal afnemen bij prednisolon gebruik.

E.2.2

Secondary objectives of the trial

Secondary objectives concern the comarison of the 2 groups with regards to changes in:
- Positive and Negative Symptom Scale (PANSS) subscales
- Cognitive performance (Brief Assesssment of Cognition in Schizophrenia; BACS)
- General functioning (Global Assessment of Functioning)
- Depressive symptoms (Calgary Depression Scale for Schizophrenia)
- Safety data will be evaluate by comparing incidences (number and % of subjects with at least one occurrence) of key SAEs and SUSARs (e.g. hospitalisations)

Secundaire objectieven vergelijken de 2 groepen met betrekking tot veranderingen op:
- Positve and Negative Symptom Scale (PANSS) subschalen
- Cognitief functioneren (Brief Assesssment of Cognition in Schizophrenia; BACS)
- Algemeen functioneren (Global Assessment of Functioning)
- Depressieve symptomen (Calgary Depression Scale for Schizophrenia)
- Veiligheidsdata worden geëvalueerd door de incidentie te vergelijken (aantal en percentage van deelnemers waarbij events voorkomen) wat betreft belangrijke SAEs en SUSARs (bijvoorbeeld: hospitalisatie)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. DSM-IV-R diagnosis of 295.x (schizophrenia, schizophreniform or schizoaffective disorder) or 298.9 (psychosis NOS).
2. Start of first psychosis no longer than 7 years ago.
3. Age 18 - 70years.
4. Patients use a stable dosis of antipsychotic medication for at least 3 weeks.
5. Written informed consent is obtained.
6. Female patients of childbearing potential need to utilize a proper method of contraception in case of sexual intercourse during the study.

1. DSM-IV-R diagnose 295.x (schizofrenie, schizofreniforme or schizoaffectieve stoornis) of 298.9 (psychotische stoornis NAO)
2. Eerste psychose niet langer dan 7 jaar geleden vastgesteld.
3. Leeftijd 18 -70 jaar.
4. Patienten gebruiken antipsychotica
5. Geschreven informed consent is verkregen.
6. Vrouwen op vruchtbare leeftijd dienen een acceptabel anticeptiemiddel te gebruiken in geval van geslachtsgemeenschap tijdens de studie.

E.4

Principal exclusion criteria

1. Presence of any of the contra-indications of prednisolone as reported in the SPC.
2. Presence of diabetes mellitus or random (non-fasting) glucose levels exceeding 11 mmol/L at screening, severe heart failure, severe osteoporosis or systemic fungal infections.
3. Body Mass Index (BMI) of >30.
4. Current or chronic use of systemic glucocorticosteroids (temporary use is permitted, if stopped 1 month before start of treatment trial).
5. Chronic use of non-steroidal anti-inflammatory drugs (2 months or more of continuous use)
6. Pregnancy or breast-feeding.
7. Concurrent use of enzyminducing medication such as carbamazepine, riphampicine, primidone, barbiturates and phenytoine
8. Concurrent use of HAART medication (both HIV protease inhibitors and (non)-nucleoside reverse transcriptase inhibitors), especially efavirenz, ritonavir and lopinavir
9. Current use of telaprevir and boceprevir in treatment of Hepatitis C.

1. Aanwezigheid van één of meer contraindicaties zoals aangegeven in de bijsluiter.
2. Aanwezigheid van diabetes mellitus of random (niet-nuchter) glucosewaarden boven 11mmol/L tijdens screeningvisite, ernstige hartaandoening, ernstige osteoporose of systemische schimmelinfecties.
3. Body Mass Index (BMI) van >30.
4. Huidig of chronisch gebruik van glucocorticosteroiden (tijdelijk gebruik is toegestaan, indien 1 maand voor start van de trial gestopt).
5. Chronisch gebruik van non-steroidal anti-inflammatory drugs (NSAID; dagelijkse gebruik voor 2 maanden of langer).
6. Zwangerschap of borstvoeding.
7. Gelijktijdig gebruik van leverenzyminducerende medicatie zoals carbamazepine, rifampicine, primidon, barbituraten en fenytoine.
8. Gelijktijdig gebruik van HAART medicatie (zowel HIV protease inhibitors als (non)-nucleoside reverse transcriptase inhibitors), in het bijzonder efavirenz, ritonavir en lopinavir.
9. Huidig gebruik van telaprevir en boceprevir in de behandeling van Hepatitis C.

E.5 End points

E.5.1

Primary end point(s)

Change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end point (6 weeks assessment).

Verandering in totale score op de Positive and Negative Symptom Scale (PANSS) vanaf baseline tot eindpunt (6 weken).

E.5.1.1

Timepoint(s) of evaluation of this end point

6 weeks after start of treatment.

6 weken na start van de behandeling.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

6 weeks after start of treatment.

6 weken na start van de behandeling.

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

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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)

E.8.2.2

Placebo

Yes

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

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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 last visit of the last subject.

De laatste visite van de laatste deelnemer.

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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

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

F.4.2.2

In the whole clinical trial

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)

After the 6-week prednisolone/placebo treatment, there is no option to continue to use prednisolone within the study. The unblinding will be performed after database closure; in case we find at that moment that prednisolone has been very effective for individual patients, we can discuss the situation with the patients' treating physician at that time. Most likely, additional diagnostical procedures will have to take place, such as liquor punction.

Na de 6 weken behandeling met prednisolon/placebo is er geen mogelijkheid om door te gaan met prednisolon binnen studieverband. Deblindering vindt plaats na het sluiten van de database. Wanneer we op dat moment zien dat een individuele patient bijzonder goed heeft gerageerd op prednisolon, zullen contact opnemen met de -op dat moment- behandelend arts. Hoogstwaarschijnlijk zullen er op dat moment, additionele diagnostische procedures moeten plaatsvinden, zoals bijvoorbeeld een liquor punctie.

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

2014-07-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-05-16

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