Clinical Trials Register

Summary
EudraCT Number:	2017-001357-14
Sponsor's Protocol Code Number:	KUM_PSY_2017_1
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-07-27
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

Germany - BfArM

A.2

EudraCT number

2017-001357-14

A.3

Full title of the trial

Randomized, doubleblind, 4-arms, monocentric, interventinal Study for enhancing the efficacy of tDCS across from single intervention or Placebo by nicotinergic stimulation in schizophrenia.

Randomisierte, doppelblinde, 4-armige, monozentrische Interventionsstudie zum Nachweis der Überlegenheit der kombinierten Stimulation mittels Vareniclin und tDCS gegenüber den Einzelinterventionen oder Placebo (NicStim)

A.3.1

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

Randomized, doubleblind, 4-arms, monocentric, interventinal Study for enhancing the efficacy of tDCS across from single intervention or Placebo by nicotinergic stimulation in schizophrenia.

Verbesserung der klinischen Effekte der tDCS durch nikotinerger Stimulation bei Patienten mit einer Schizophrenie

A.4.1

Sponsor's protocol code number

KUM_PSY_2017_1

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	Klinikum der Universität München - AöR verteten durch den Vorstand des Bereiches Humanmedizin
B.1.3.4	Country	Germany
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	Deutsche Forschungsgemeinschaft (DFG) Förderkennzeichen HA 6091/5-1
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Technische Universität München Fakultät für Medizin Münchner Studienzentrum
B.5.2	Functional name of contact point	Dr. med. Christiane Blankenstein
B.5.3	Address:
B.5.3.1	Street Address	Ismaningerstr. 22
B.5.3.2	Town/ city	München
B.5.3.3	Post code	81675
B.5.3.4	Country	Germany
B.5.4	Telephone number	00498941406321
B.5.5	Fax number	00498941406322
B.5.6	E-mail	christiane.blankenstein@mri.tum.de

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	Champix
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Champix
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	VARENICLINE
D.3.9.1	CAS number	249296-44-4
D.3.9.4	EV Substance Code	SUB25195
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	1
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	Yes
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	Capsule, hard
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

Schizophrenie

E.1.1.1

Medical condition in easily understood language

Schizophrenia

Schizophrenie

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10040707
E.1.2	Term	Simple type schizophrenia, chronic state
E.1.2	System Organ Class	100000004873

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 evaluate whether the improvement of cognitive functioning in schizophrenia via the combination of varenicline and trancranial direct current stimulation is superior to the stimulation with varenicline or tDCS alone.

Evaluation, ob bei Patienten mit einer Schizophrenie die Kombination aus transkranieller Gleichstromstimulation (tDCS) und nikotinerger Stimulation durch Vareniclin (Partialagonist an α4β2 Nikotinrezeptoren) effektiver in der Verbesserung kognitiver Funktionen als die tDCS oder Vareniclin alleine ist.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male and female (with contraception) patients with schizophrenia (ICD-10 Criteria), age 18 to 65 being diagnosed according to the “Statistical
Classification of Diseases and Related Health Problems (ICD-10)“. Diagnosis will be confirmed via the MINI interview.
- Antipsychotic monotherapy or a maximum combination of two antipsychotics with a maximum dosage of 1000 mg CPZ equivalents (using the
minimum effective dose method)
- Being no longer in the acute phase of illness defined as (PANSS Total ≤ 75, CGI ≤ 4). No relevant depressive symptoms (CDSS < 8)
- Female patients of childbearing potential: use of a proper method of contraception (according to the CTFG guideline) and negative pregnancy test
before study inclusion

- Männlich und weibliche einwilligungsfähige Teilnehmer im Alter von 18-65 Jahren die, die diagnostischen Kriterien einer Schizophrenie nach
dem “Statistical Classification of Diseases and Related Health Problems (ICD-10)“ erfüllen. Die Diagnose erfolgt über ein „Mini-International
Neuropsychiatric Interview - PLUS“, (Sheehan, Lecrubier et al. 1998), welches im Rahmen des Patientenscreenings durchgeführt wird.
- Kontinuierliche antipsychotische Behandlung in Monotherapie nach aktuellen Leitlinien oder bei klinischer Notwendigkeit eine
Kombinationsbehandlung mit maximal 2 Antipsychotika (dann maximal 1000 mg CPZ Äquivalente)
- Zum Zeitpunkt des Studieneinschlusses eine mittlere Schwere der Psychopathologie (PANSS Gesamtscore ≤ 75) aufweisen. Keine relevanten
depressiven Symptome (CDSS < 8).
- Männliche Teilnehmer und weibliche Teilnehmer, die nicht gebärfähig sind oder eine adäquate medizinisch Empfängnisverhütung (nach CTFG Leitlinie, siehe Haupttext für detaillierte Aufstellung) anwenden
- Bei weiblichen Teilnehmern: negativer Schwangerschaftstest (Urin-Schwangerschaftstest), sichere Verhütungsmethode nach der CTFG Leitlinie
Recommendations related to contraception and pregnancy testing in clinical trials (CTFG 2014):

E.4

Principal exclusion criteria

- Lacking capacity to give informed consent or involuntary treatment
- Pregnancy or lactation
- Current suicidality as well as the risk to injure others
- Treatment resistance or Treatment with Clozapin
- Never treated schizophrenia or documented non-compliance
- Lacking german language skills
- Start of antidepressants or mood stabilizers during the 1-week intervention phase. Previous treatment can be continued in unaltered dosages.
- Alcohol- or substance abuse during the last 6 months before inclusion into study except for Coffein and Nicotin (smoker), no narcotic drugs may be taken during the 1-week intervention phase
- Detection of active substance abuse by positive D-Urin or CDT test before start of the intervention
- Epileptic seizures in the anamnesis
- Epileptic potentials in EEG
- Proof of active substances by positve results in D-urine or CDT.
- Moderate kidney insufficiency (creatinine-clearance: 30–50 ml/min) or severe kidney insufficiency (< 30 ml/min)
- Known intolerance to the study medication (Vareniclin) or to tDCS
- Clinically relevant interaction between clinically necessary per-medication and investigational medicinal product (to be tested by medic software
- Known intolerance to the study medications or to tDCS

-Bei weiblichen Teilnehmern bestehende Schwangerschaft.
-Gegenwärtige Suizidalität sowie Fremdgefährdung.
-Schwere neurologische und internistische Komorbiditäten
-Behandlungsresistente Schizophrenie.
-Bekannte oder vermutete non-compliance hinsichtlich der Medikamenteneinnahme.
-Eindosierung von Stimmungsstabilisatoren, Benzodiazepine oder Antidepressiva während der 1-wöchigen Interventionsphase. Eine vorher bestehende Therapie kann in unveränderter Dosis fortgesetzt werden.
-Alkohol- oder Substanzabhängigkeit innerhalb der letzten sechs Monate vor Studieneinschluss (überprüft durch Mini-International Neuropsychiatric Interview). Koffein und Nikotin ist hiervon ausgenommen. Während der einwöchigen Interventionsphase dürfen bis auf Koffein und Nikotin (Raucher)keinerlei Suchtstoffe eingenommen werden.
- Nachweis von aktivem Substanzkonsum durch positive Befund im D-Urin oder im CDT vor Beginn der Intervention.
- Epileptische Anfälle in der Anamnese.
- Epilepsietypische Potentiale im EEG.
- Kreatinin nicht im Normbereich
- Bekannte Unverträglichkeit zu dem Studienmedikament (Vareniclin) oder zu der tDCS
- Klinisch relevante Interaktion zwischen der klinisch notwendigen Vormedikation und der Prüfmedikation (zu prüfen mittels der mediq Software)
- Fehlende Einwilligungsfähigkeit oder Unterbringung gegen den Willen des Patienten.
- Unzureichende Kenntnis der deutschen Sprache.
- Zustand der Behandlungsresistenz oder noch nie behandelte Schizophrenie.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint will be change in working memory according to the n-back task.

Verbesserung des Arbeitsgedächtnisses im n-back nach einer Woche.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 0 (V1), Day 5 (V2), Day 33 (V3), Day 61 (V4)

Am Tag 0 (V1), Tag 5 (V2), Tag 33 (V3), Tag 61 (V4)

E.5.2

Secondary end point(s)

Secondary endpoints will include several other measures of cognition (processing speed, verbal memory, and cognitive flexibility), psychopathology (Positive and Negative Syndrome Scale), depressive symptoms (Calgary Depression Scale for Schizophrenia), functioning (Global Assessment of Functioning) and disease severity (Clinical Global Impression). Physiological measures will (1) include EEG to investigate changes regional (below the stimulation electrodes) and remote electrical activity before after intervention9 and (2) motor-cortex excitability measures to investigate the impact of varenicline (steady state) on cortical excitability and plasticity.

Verbesserung anderer neurokognitiver Funktionen nach einer, vier und acht Wochen (Verbales Gedächtnis, Arbeitsgeschwindigkeit), Veränderung in der Psychopathologie nach PANSS und CDSS, Veränderung im CGI und GAF, Auftreten von einzelnen Nebenwirkungen, Veränderung der kortikalen Erregbarkeit und Konnektivität

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 0 (V1), Day 5 (V2), Day 33 (V3), Day 61 (V4)
PANSS and GAF

Day 0 (V1), Day 33 (V3)
CDSS and CGI

Am Tag 0 (V1), Tag 5 (V2), Tag 33 (V3), Tag 61 (V4)
PANSS und GAF

Am Tag 0 (V1), Tag 33 (V3)
CDSS und CGI

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

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

E.6.11

Pharmacogenomic

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)

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

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

tDCS neuro / conn Gleichstromtherapie/ Vergleich mit oder ohne Strom

tDCS Device neuro / conn / DC Therapy/Comparison with or without electricity

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.8.5

The trial involves multiple Member States

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

LVLS 39 months after start of recruitment.

Nach Beginn der Rekrutierung ist "LVLS" 39 Monate später.

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.1.3.1

Number of subjects for this age range:

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.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 end of the study patients regardless of wether the study participation ends prematurely or according to protocol, the patients continue the antipsychotic therapy which they had taken prior to inclusion into the study. Also switching to a different medication is possible.

Nach Ende der Studie können Patienten unabhängig davon, ob die Studie protokollgemäß oder vorzeitig / nicht- protokollgemäß beendet wurde, mit demjenigen Antipsychotikum weiter behandelt werden, das sie eingenommen hatten. Auch eine Umstellung auf ein anderes Medikament ist möglich.

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

2017-09-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-16

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2021-10-21

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