Clinical Trials Register

Summary
EudraCT Number:	2020-003745-11
Sponsor's Protocol Code Number:	1346-0014
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-06-18
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

France - ANSM

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)

Etude d’extension, en ouvert, avec un bras de traitement afin d’évaluer la sécurité à long terme du BI 425809 administré une fois par jour chez des patients atteints de schizophrénie qui ont terminé l’étude antérieure de phase III avec le 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

Etude pour tester la sécurité à long terme du BI 425809 chez des personnes atteintes de schizophrénie qui ont participé à une étude antérieure CONNEX.

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
B.1.3.4	Country	France
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
B.4.2	Country	France
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.3.2	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.3.8	INN - Proposed INN	None yet
D.3.9.2	Current sponsor code	BI 425809
D.3.9.3	Other descriptive name	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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Schizophrenia

Schizophrénie

E.1.1.1

Medical condition in easily understood language

Schizophrenia

Schizophrénie

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’objectif principal de cet essai est de recueillir des données de sécurité supplémentaires chez les patients atteints d'insuffisance cognitive due à la schizophrénie et qui ont participé et terminé la période de traitement de 26 semaines avec BI 425809 ou un placebo correspondant de l'un des programmes d'essais cliniques de phase III pour BI 425809 (études cliniques1346-0011 , 1346-0012, 1346-0013).

E.2.2

Secondary objectives of the trial

Not applicable

Non applicable

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. Consentement éclairé daté et signé en accord avec les ICH-GCP et la législation française avant l’admission dans l’étude (visite 1).
2. Patients en ambulatoire et cliniquement stables, atteints de schizophrénie (selon le DSM-5).
3. Les patients ayant terminé la période de 26 semaines de traitement dans l’étude clinique principale doivent entrer dans l’étude d’extension :
• Dans les 2 semaines suivant la visite EOT des études 1346-0011 et 1346-0013 (N/A pour la France).
• A la fin de la période de sécurité de l’étude 1346-0012 (applicable pour la France).
4.Les femmes en âge de procréer capables et disposées à utiliser des méthodes de contraception hautement efficaces selon ICH M3 (R2) qui
présentent un taux d’échec faible inférieur à 1 % si utilisées de façon consistante et correcte. Une liste des méthodes de contraception répondant à
ces critères est fournie dans la section 4.2.2.3 du protocole. De telles méthodes doivent être utilisées tout au long de l’essai, et pour une période d’au
moins 35 jours après la dernière prise de traitement, et la patiente doit accepter des tests de grossesse périodiques pendant la participation à l’étude.
5. Avoir une personne référente, définie comme toute personne qui est capable de comprendre les procédures liées aux essais, qui a un minimum
niveau d’éducation équivalent à la 4ème, qui connaît bien le patient et qui est capable d'interagir régulièrement avec le patient (au moins une fois par
semaine, soit de l’ordre privé ou professionnel). La personne référente n'a pas besoin d'assister aux visites avec le patient, mais elle doit être joignable
par téléphone. De préférence et dans la mesure du possible, la personne référente doit être la même personne tout au long de l'étude.
• Les personnes référentes professionnelles (p. ex. infirmière, travailleur social, etc.) sont autorisées si elles ne participent à aucune évaluation du protocole.

E.4

Principal exclusion criteria

1. Participant who developed DSM5 diagnosis other than Schizophrenia 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 the 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 SARS-CoV-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 and St. John’s wort (Hypericum perforatum) and substrates with a narrow therapeutic range (e.g., fentanyl, cyclosporine).

1. Selon le DSM-5, patients ayant un diagnostic autre que la schizophrénie ou ayant une autre maladie qui les empêcheraient de participer à l’étude
d’extension (ex : accident vasculaire cérébral, traumatisme crânien, démence, troubles du mouvement graves non contrôlés ou d’autres maladies
depuis leur participation à l’étude principale (étude clinique 1346-0012)).
2. Tout comportement suicidaire et/ou toute idée suicidaire de type 5 selon l’échelle C-SSRS dans l’étude clinique principale et jusqu’à la visite 1 de
cette étude d’extension.
o Les patients ayant des idées suicidaires de type 4 selon l’échelle C-SSRS (c-à-d pensée active avec intention mais sans un plan de passage à l’acte
spécifique) au cours des 3 derniers mois et ce incluant la visite 1 peuvent participer si un professionnel de la santé mentale certifié, évalue et
documente qu'il n'y a pas de risque immédiat de suicide.
3.Patients ayant des antécédents de trouble modéré ou grave liés à la consommation de substances (autre que la caféine et la nicotine), tels que
définis dans le DSM-5 pendant leur participation à l’étude principale et avant la visite 1 de l’étude d’extension.
4. Dépistage urinaire positif aux drogues ≥ 3 fois pendant la période de traitement de l'étude principale, selon les résultats du laboratoire centralisé.
5. Patients qui sont actuellement ou souhaitent participer à un autre essai clinique avec un traitement.
6. Toute anomalie cliniquement significative selon le jugement de l’investigateur, telle que :
o Anomalie cliniquement significative de l'examen physique et/ou de l’ECG lors de la dernière évaluation effectuée dans l’étude principale ;
o Signes vitaux (y compris pression artérielle et fréquence cardiaque) qui compromettraient la sécurité des patients lors de leur participation à l'essai
ou leur capacité à y participer ;
o Maladie concomitante symptomatique/instable/non contrôlée ou cliniquement pertinente ou toute autre maladie clinique qui compromettrait la s
sécurité des patients lors de leur participation à l'essai ou leur capacité à y participer.
o Condition physique importante ou instable qui peut nécessiter un changement de traitement ou une hospitalisation qui aurait un impact sur la
fonction cognitive.
7. Toute anomalie significative des résultats du laboratoire centralisé basé sur le dernier résultat reçu au cours de l’étude principale, tel que :
o Insuffisance rénale grave définie par une valeur du taux d’eGFR < 30 mL/min/1.73 m² .
o Maladie hépatique, définie par des niveaux sériques de l’ALAT (SGPT), de l’ASAT (SGOT) ou de la phosphatase alcaline à plus de 3 fois la limite
supérieure de la valeur normale .
o Taux d’Hb inférieur à 100 g/L (10 g/dL) OU baisse du taux d’Hb à hauteur de 25 % ou plus par rapport à la valeur initiale et inférieure à la limite
normale dans l’étude principale (alerte 3 depuis la dernière mesure du taux d’Hb dans l’étude principale) ;
o Patients qui répondent à l'un des critères d’arrêt avant la visite EOT planifiée (26 semaines) dans l’étude principale.
8. Patients ayant des antécédents d’hémoglobinopathie diagnostiquée pendant l’étude principale.
9. Patients ayant une infection grave ou connue par le SRAS-CoV-2.
10. Infection connue au VIH et/ou infection active connue à l’hépatite B ou C. Toute tumeur active ou suspectée documentée ou antécédant tumoral
dans les 5 ans précédant la sélection, à l’exception du carcinome basocellulaire de la peau, traité de façon appropriée, du carcinome cellulaire
squameux cutané, et du carcinome in situ du col utérin.
11. Femmes enceintes, allaitantes, ou qui prévoient une grossesse pendant l'essai.
12. Patients allergiques au BI 425809 et/ou à l'un des excipients (y compris intolérance grave au lactose).
13. Patients qui sont actuellement traités ou qui devraient être traités avec l'un des traitements suivants : inhibiteurs forts ou modérés du CYP3A4,
inducteurs forts ou modérés du CYP3A4, substrats sensibles au CYP3A4, y compris le jus de pamplemousse et le millepertuis (Hypericum perforatum)
et substrats à gamme thérapeutique étroite (p. ex. fentanyl, cyclosporine).

E.5 End points

E.5.1

Primary end point(s)

1) occurrence of treatment emergent adverse events (TEAEs)

1) apparition d'événements indésirables associés au traitement (TEAE : Treatment Emergent Adverse Event)

E.5.1.1

Timepoint(s) of evaluation of this end point

1) 54 weeks

1) 54 semaines

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) Changement par rapport à la valeur initiale des évaluations Clinical Global Impressions – Severity (CGI-S) à la fin du traitement (EOT)
2) Changement de la valeur de référence du taux d’hémoglobine (Hb) à la visite EOT.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 52 weeks
2) 52 weeks

1) 52 semaines
2) 52 semaines

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

Yes

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

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

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

Brazil

Chile

China

Colombia

Japan

Korea, Republic of

Mexico

Russian Federation

Serbia

Taiwan

Ukraine

United States

Belgium

Croatia

Denmark

Finland

France

Germany

Greece

Hungary

Italy

Lithuania

Netherlands

Norway

Poland

Romania

Slovakia

Spain

Sweden

United Kingdom

Czechia

Argentina

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

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	ESMS Global Ltd
G.4.3.4	Network Country	United Kingdom

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-08-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2024-03-02

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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