Clinical Trials Register

Summary
EudraCT Number:	2020-003745-11
Sponsor's Protocol Code Number:	1346-0014
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-02-08
Trial 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2020-003745-11

A.3

Full title of the trial

An open label, single arm, extension trial to examine long-term safety of BI
425809 once daily in patients with schizophrenia who have completed
previous BI 425809 Phase III trials.(CONNEX-X)

Studio di estensione in aperto e a braccio singolo volto a esaminare la sicurezza a lungo termine di BI 425809 una volta al giorno in pazienti con schizofrenia che hanno completato gli studi precedenti di fase III su BI 425809. (CONNEX-X)

A.3.1

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

A study to test long-term safety of BI 425809 in people with schizophrenia
who took part in a previous CONNEX study

Studio volto a testare la sicurezza a lungo termine di BI 425809 in soggetti con schizofrenia che hanno partecipato a uno studio CONNEX precedente

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

1346-0014

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	BOEHRINGER-INGELHEIM ITALIA S.P.A.
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Boehringer Ingelheim Italia S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH&Co KG
B.5.2	Functional name of contact point	CT Disclosure & Data Transparency
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	+498002430127
B.5.5	Fax number	+498008217119
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.com

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	No
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	-
D.3.2	Product code	[BI 425809]
D.3.4	Pharmaceutical form	Film-coated 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.3.9.2	Current sponsor code	BI 425809
D.3.9.4	EV Substance Code	SUB130377
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	10
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Schizophrenia

schizofrenia

E.1.1.1

Medical condition in easily understood language

Schizophrenia

schizofrenia

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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

The objective of this trial is to collect additional safety data in patients
with cognitive impairment due to schizophrenia, who participated in and
completed the 26-week treatment period with BI 425809 or matching
placebo of one of the phase III clinical trial program for BI 425809 (trial
# 1346-0011, 1346-0012, 1346-0013).

l’obiettivo di questo studio è raccogliere altri dati di sicurezza in pazienti con compromissione cognitiva dovuta a schizofrenia che hanno partecipato e completato 26 settimane di trattamento con BI 425809 o placebo corrispondente in uno degli studi di fase III del programma di sperimentazione clinica di BI 425809 (studio 1346-0011, 1346-0012 o 1346-0013).

E.2.2

Secondary objectives of the trial

Not applicable

Non applicabile

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed and dated written informed consent in accordance with ICH
Harmonized Tripartite Guideline for Good Clinical Practice (ICH-GCP) and
local legislation prior to admission to the trial (Visit 1).
2. Clinically stable outpatients who have been diagnosed with
schizophrenia (as per Diagnostic and Statistical Manual of Mental
Disorders, 5th edition (DSM-5)).
3. Patients, who completed 26 weeks of treatment in the parent trial,
must enter the extension trial within:
• Within 2 weeks the end of treatment visit in 1346-0011, 1346-0013.
• At the end of safety follow up in 1346-0012.
4. Women of childbearning potential (WOCBP) must be ready and able
to use highly effective methods of birth control per Non-Clinical Safety
Studies for the Conduct of Human Clinical Trials and Marketing
Authorization for Pharmaceuticals (ICH M3 (R2)) that result in a low
failure rate of less than 1% per year when used consistently and
correctly. Such methods should be used throughout the trial, and for a
period of at least 35 days after last trial drug intake, and the patient
must agree to periodic pregnancy testing during participation in the trial.
5. Have a study partner, defined as any person capable of understanding
trial related procedures, with a minimum of 8th grade level of
education, who knows the patient well, has been capable of interacting with the patient on regular basis (at least once a week, either private or
professional). Study partner does not need to attend visits with the
patient but must be reachable by phone. Study partner should preferably
be the same person throughout the study, if possible
• Professional study partner (e.g. study nurse, social worker etc.) are
allowed if not involved in administering any of the protocol assessments.

1. Rilascio del consenso informato scritto, firmato e datato, ai sensi della ICH Harmonized Tripartite Guideline for Good Clinical Practice (ICH-GCP) e della legislazione locale prima dell’ammissione allo studio (Visita 1).

2. Pazienti gestiti in regime ambulatoriale clinicamente stabili con diagnosi di schizofrenia (in base al Diagnostic and Statistical Manual of Mental Disorders, quinta edizione [DSM-5]).

3. I pazienti che avranno completato 26 settimane di trattamento nello studio originario dovranno accedere allo studio di estensione:
• Entro 2 settimane dalla visita di fine trattamento (EOT) nello studio 1346-0011 o nello studio 1346-0013
• Alla fine del follow-up di sicurezza nello studio 1346-0012.

4. Le donne in età fertile (WOCBP) dovranno essere disposte e in grado di utilizzare metodi contraccettivi altamente efficaci ai sensi delle linee guida Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (ICH M3 [R2]) che, quando usati con costanza e correttamente, siano associati a un basso tasso di insuccesso (inferiore all’1% all’anno). Un elenco dei metodi contraccettivi che soddisfano tali criteri è fornito nel paragrafo 4.2.2.3. Questi metodi dovranno essere usati per l’intera durata della sperimentazione e per un periodo di almeno 35 giorni dopo l’ultima assunzione del farmaco in studio. La paziente dovrà inoltre acconsentire a sottoporsi a test di gravidanza periodici durante la partecipazione alla ricerca.

5. I pazienti dovranno avere un partner dello studio, da intendersi come qualsiasi persona (privato o professionista) in grado di comprendere le procedure correlate allo studio, che abbia conseguito almeno la licenza media, che conosca bene il paziente e che sia stata in grado di interagire regolarmente con il paziente (almeno una volta a settimana). Il partner dello studio non sarà tenuto a presentarsi alle visite con il paziente, ma dovrà essere raggiungibile per telefono. Se possibile, il partner dello studio dovrà essere preferibilmente la stessa persona per l’intera durata della sperimentazione.

• Sono ammessi partner dello studio professionisti (per es. infermiere/a dello studio, assistente sociale, ecc.) purché non coinvolti nella somministrazione delle valutazioni del protocollo.

E.4

Principal exclusion criteria

or any condition that would prevent the patient from participating in the
extension trial (e.g. stroke, head trauma, developed dementia, severe
uncontrolled movement disorders or other significant condition since
enrolment into the parent phase III trial).
2. Any suicidal behavior and/ or suicidal ideation of type 5 based on the
C-SSRS in parent trial and up to and including Visit 1 of this study.
o Patients with Suicidal Ideation type 4 in the C-SSRS (active suicidal
thought with intent but without specific plan), in the past 3 months prior
to and including Visit 1, can be entered in the study, if assessed and
documented by a licensed mental health professional that there is no
immediate risk of suicide.
3. Patients diagnosed with moderate or severe substance use disorder
(other than caffeine and nicotine), as defined in DSM-5 while the patient
was in parent trial and prior to Visit 1 of this study.
4. Positive urine drug screen = 3 times during the treatment period of
trial 1346-0011, 1346-0012 or 1346-0013 based on central lab test.
5. Patients who are currently or wish to participate in another
investigational drug trial.
6. Any clinically significant finding in the judgment of the investigator
such as :
o Clinically significant finding on he Physical examination and/or ECG
from the last assessment done in the parent trial.
o Vital signs (including blood pressure (BP) and pulse rate (PR)) that
would jeopardize the patient´s safety while participating in the trial or
their capability to participate in the trial.
o Symptomatic/unstable/uncontrolled or clinically relevant concomitant
disease or any other clinical condition that would jeopardize the
patient´s safety while participating in the trial or capability to
participate in the trial.
o Significant or unstable physical condition that may require change in
medication or hospitalization that would impact cognitive function.
7. Any significant central lab findings based on the last available lab
result received during the parent trial such as:
o Severe renal impairment defined as an eGFR < 30mL/min/1.73m²,
o Indication of liver disease, defined by serum levels of either ALT
(SGPT), AST (SGOT), or alkaline phosphatase above 3 times upper limit
or normal or
o Hb drop below 100g/L (10g/dL) OR Hb decrease of 25% or more from
baseline and is below lower limit of normal in parent trial (alert 3 from
last measure Hb in parental trial)
o Patients who meet any of the withdrawal criteria before planned end of
treatment (26 weeks) in parent trial.
8. Patients who have been diagnosed with hemoglobinopathies during
the parent trial.
9. Patients with known ongoing severe or serious infection with SARSCoV-
2.
10. Known history of HIV and/or known on-going Hepatitis B or C
infections. As well as any documented active or suspected malignancy or
history of malignancy within 5 years prior to screening, except
appropriately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix.
11. Women who are pregnant, nursing, or who plan to become pregnant
while in the trial.
12. Patients with an allergy to BI 425809 and/or any of the excipients
(including serious lactose intolerance).
13. Patients who are currently treated or expected to be treated with
any of the following: strong or moderate CYP3A4 inhibitors, strong or
moderate CYP3A4 inducers, CYP3A4 sensitive substrates,. including
grapefruit juice ad St. John's wort (Hypericum perforatum) and
substrates with a narrow therapeutic range (e.g., fentanyl,
cyclosporine).

1. Partecipante con diagnosi diversa dalla schizofrenia in base al DSM-5 o con qualunque condizione che impedirebbe al paziente di partecipare allo studio di estensione
2. Qualsiasi comportamento suicidario e/o ideazione suicidaria di tipo 5 in base alla C-SSRS nello studio originario e fino alla Visita 1 di questo studio compresa.
o I pazienti con ideazione suicidaria di tipo 4 in base alla C-SSRS nei 3 mesi precedenti la Visita 1 compresa potranno accedere allo studio, purché venga valutato e documentato da un professionista della salute mentale abilitato che non sussiste alcun rischio immediato di suicidio.
3. Pazienti con diagnosi di disturbo da uso di sostanze (diverse da caffeina e nicotina) moderato o severo secondo quanto definito nel DSM-5 durante la partecipazione del paziente allo studio originario e prima della Visita 1 di questo studio.
4. Esame tossicologico delle urine positivo = 3 volte durante il periodo di trattamento dello studio 1346-0011, 1346-0012 o 1346-0013 in base al test effettuato dal laboratorio centrale.
5. Pazienti attualmente partecipanti o che desiderano partecipare a un altro studio su un farmaco sperimentale.
6. Qualsiasi evidenza clinicamente significativa secondo il giudizio dello sperimentatore, per esempio:
o Evidenza clinicamente significativa all’esame obiettivo e/o all’ECG nell’ultima valutazione effettuata nello studio originario
o Segni vitali che comprometterebbero la sicurezza del paziente durante la partecipazione allo studio o la sua capacità di prendere parte alla sperimentazione
o Malattia concomitante sintomatica/instabile/non controllata o clinicamente rilevante o qualsiasi altra condizione clinica che comprometterebbe la sicurezza del paziente durante la partecipazione allo studio o la sua capacità di prendere parte alla sperimentazione
o Condizione fisica significativa o instabile che potrebbe richiedere una modifica della terapia farmacologica o un ricovero in ospedale che influirebbe sulla funzione cognitiva.
7. Evidenze significative negli esami effettuati dal laboratorio centrale in base all’ultimo risultato disponibile ricevuto durante lo studio originario, per esempio:
o Compromissione renale severa, intesa come una eGFR < 30 ml/min/1,73m²
o Indicazione di epatopatia, intesa come livelli sierici di alanina aminotransferasi (ALT) (transaminasi glutammico-piruvica sierica [SGPT]), aspartato aminotransferasi (AST) (transaminasi glutammico-ossalacetica sierica [SGOT]) o fosfatasi alcalina > 3 volte il limite superiore della norma
o Calo dell’emoglobina (Hb) al di sotto di 100 g/l (10g/dl) OPPURE riduzione della Hb di almeno il 25% rispetto al basale e Hb più bassa del limite inferiore della norma nello studio originario (allerta 3 nell’ultima misurazione della Hb nello studio originario)
o Pazienti che soddisfano uno qualsiasi dei criteri di interruzione prima della EOT programmata (26 settimane) nello studio originario.
8. Pazienti con diagnosi di emoglobinopatie durante lo studio originario.
9. Pazienti con infezione nota da SARS-CoV-2 severa o grave in corso.
10. Positività pregressa nota all’HIV e/o infezioni note da epatite B o C in corso. Qualsiasi neoplasia maligna attiva o sospetta documentata o anamnesi positiva per neoplasia maligna nei 5 anni precedenti lo screening, eccetto forme adeguatamente trattate di carcinoma cutaneo basocellulare o squamocellulare, o carcinoma in situ della cervice uterina.
11. Donne in gravidanza, in allattamento o che intendono iniziare una gravidanza durante lo studio.
12. Pazienti allergici a BI 425809 e/o a uno qualsiasi degli eccipienti (compresa grave intolleranza al lattosio).
13. Pazienti attualmente trattati o che si prevede di trattare con una qualsiasi delle seguenti sostanze: potenti o moderati inibitori o induttori del CYP3A4, substrati sensibili del CYP3A4, tra cui succo di pompelmo ed erba di San Giovanni e substrati con intervallo terapeutico ristretto .

E.5 End points

E.5.1

Primary end point(s)

1) occurrence of treatment emergent adverse events (TEAEs)

1) l’endpoint primario consiste nella comparsa di eventi avversi emergenti con il trattamento (TEAE) nel corso dell’intero studio di estensione

E.5.1.1

Timepoint(s) of evaluation of this end point

1) 54 weeks

1) 54 settimane

E.5.2

Secondary end point(s)

1) Change from baseline in CGI-S to end of treatment.
2) Change from baseline in hemoglobin to end of treatment.

1) variazione del punteggio nella scala Clinical Global Impressions-Severity (CGI-S) dal basale alla fine del trattamento (EOT)
2) variazione della Hb dal basale alla EOT.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 52 weeks
2) 52 weeks

1) 52 settimane
2) 52 settimane

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

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

In aperto

Open

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

Argentina

Belgium

Brazil

Chile

China

Colombia

Croatia

Czechia

Denmark

Finland

France

Germany

Greece

Hungary

Italy

Japan

Korea, Republic of

Lithuania

Mexico

Netherlands

Norway

Poland

Romania

Russian Federation

Serbia

Slovakia

Spain

Sweden

Taiwan

Ukraine

United Kingdom

United States

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

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.1.1.1

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:

1401

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

477

F.4.2.2

In the whole clinical trial

1401

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)

none

nassuna

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

2022-03-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-17

P. End of Trial
P.	End of Trial Status	Ongoing

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