E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 17.0 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the potential efficacy of 40 mg/day of oral F17464 in comparison to placebo over 6 weeks in patients with acute exacerbation of schizophrenia
|
|
E.2.2 | Secondary objectives of the trial |
•To assess safety of the tested product •To describe pharmacokinetics of F17464 in this patient population •To assess the genotype-efficacy relationship
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Demographic and other characteristics 1.Male or female, 18-64 years of age inclusive; 2.For female patient of child-bearing potential: •Must have been using an effective method of contraception (defined as surgical or hormonal birth control, or intra-uterine device only), assessed by the investigator, for at least 2 months before the enrolment in the study (Visit 1), and must accept to go on using it during the whole duration of the study and up to 1 month after the study end visit, in order to avoid pregnancy while being exposed to the study treatment. A pregnancy test will be carried out at enrolment visit (Visit 1), at inclusion visit (Visit 2) and at the End Of Treatment visit of concerned patient; •Agreement of her male partner(s) to use a condom during each sexual intercourse during the study period and to continue until 1 month after the study end visit; 3.For male patient: •Agreement to use an effective contraceptive method himself and his female partner(s) during each sexual intercourse during the study period and to continue until 3 months after the study end visit. Diagnostic criteria Schizophrenia history: Before Visit 1 4.Patient with a current primary diagnosis of schizophrenia undergoing an acute exacerbation with prominent “active phase“ symptoms, as described by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition – Text Revision (DSM IV-TR) using the MINI 6.0 (Mini-International Neuropsychiatric Interview) for schizophrenia and psychotic disorders related to DSM IV-TR; 5.For a minimum of 1 year and maximum 5 years, well-documented diagnosis with the first hospitalization for acute exacerbation of schizophrenia; 6.Since the diagnosis of schizophrenia, the average number of hospitalisations should be no higher than 2 per year (the minimum duration of hospitalization should be more than 4 days); 7.During the year before Visit 1, maximum 3 acute psychotic episodes that required hospitalization or change of antipsychotic medication or other therapeutic intervention; 8.Adequate clinical response to well-conducted treatment courses during previous acute episodes. A well conducted treatment course is defined as an antipsychotic treatment with the usual doses for at least 4 weeks; Current acute episode: 9.Structured Clinical Interview for the Positive And Negative Syndrome Scale (SCI-PANSS) with a PANSS total score ≥ 70 to < 120 (at Visit 1 and 2); 10.Rating of at least 4 (moderate) on at least 2 of the following 4 PANSS positive symptoms: delusions, hallucinatory behaviour, conceptual disorganization, suspiciousness/persecution; 11.Clinical Global Impression of Severity (CGI-S) score ≥ 4 (moderate or severe). 12.Antipsychotic initiated for this acute episode and/or ongoing chronic antipsychotic treatment, with a maximum of 2 antipsychotics in total needed to be changed (due to inefficacy or safety reasons) ; 13.Hospitalization and/ or treatment for the current psychotic episode for less than 2 weeks prior to Visit 1; 14.No significant improvement of PANSS total score between enrolment (Visit 1) and inclusion (Visit 2) corresponding to a score improvement < 20% on positive symptoms subscale;
Examination 15.Normal physical examination results, vital signs and clinical laboratory test results or other results judged not clinically significant by the investigator; 16.Body mass index (BMI) ≥ 18 and ≤ 35kg/m2 inclusive.
Ethical/legal considerations 17.Patient able to read and understand the information leaflet and to give his/her written informed consent before the initiation of any study-specific procedures; 18.Patient able to accept all the constraints of the study in the investigator’s opinion, in particular with regard to the duration of the hospitalization in the clinical centre and compliance to treatment after discharge; 19.Patient able to report all intercurrent events that might occur during the study. |
|
E.4 | Principal exclusion criteria |
Related to the pathology 1.Patients in their first acute episode of psychosis; 2.Current schizophrenic episode with predominant negative symptoms; 3.Patient « known to be refractory » defined as lack of significant improvement (no significant relief of symptoms, and no period of good function) despite adequate courses with at least 3 different antipsychotics medication cycles of an adequate duration (at least 4 weeks) and at adequate dosage during the previous 5 years; 4.Schizoaffective disorder, schizophreniform disorder and other psychotic disorders; 5.Bipolar I and II disorder; 6.Pervasive developmental disorder, mental retardation, delirium, dementia, memory impairment and other cognitive disorders that would compromise a reliable assessment according to the investigator’s opinion; 7.Known or suspected borderline or antisocial personality disorder or other DSM IV axis II disorder of sufficient severity to interfere with participation in this study; 8.History of tardive dyskinesia or chronic extra-pyramidal symptoms (EPS), serotonin syndrome or neuroleptic malignant syndrome; 9.Major depressive disorder which requires a pharmacological treatment; 10.At imminent risk of injuring him/herself or others or causing significant damage to property, as judged by the investigator; 11.Suicidal risk based on the Columbia-Suicide Severity Rating Scale (C-SSRS): •Any suicidal behavior in the past year, •Suicidal ideation of type 4 or 5 in the past month. Related to treatments 12.Structured psychotherapy (e.g. cognitive behavioural therapy) started within 6 weeks before Visit 1; 13.Electroconvulsive therapy within 3 months before Visit 1; 14.Previous lack of response to electroconvulsive therapy; 15.Treatment ongoing with a depot neuroleptic (even if less than 1 cycle in duration before Visit 1); 16.Patient having previous treatment course with clozapine within 4 months prior to Visit 1; 17.Requirement of concomitant treatment with any of the prohibited medications, supplements, herbal products or products listed in “Prohibited concomitant treatments for associated drug -drug interactions”, including any psychotropic drug or any drug with psychotropic activity or with a potentially psychotropic component; 18.History of intolerance or hypersensitivity to other drugs of the same chemical class as F17464 or to rescue medications or any history of severe drug allergy or hypersensitivity;
Related to medical conditions 19.History or presence of any significant or uncontrolled medical finding such as cancer or neurological, cardiac, hepatic, metabolic, renal, haematological, muscular, endocrine, respiratory, gastrointestinal, dermatological, venereal disorders or diseases, or of any other significant medical condition that may impact the safety, the interpretation of the results, that might affect the absorption, distribution, biotransformation or excretion of the investigational product and/or the participation of the patient in the study according to the opinion of the investigator; 20.History of seizure disorder, stroke, significant head injury, severe chronic movement disorder or psychiatric symptoms possibly secondary to any other organic medical condition; 21.Known human immunodeficiency virus (HIV) or hepatitis B or C infection; 22.Liver enzyme tests (AST, ALT) > 2x upper limit of normal or any abnormal level judged as clinically significant by the investigator; 23.ECG out of normal ranges (45 < or = HR < or = 90 bpm, 120 < or = PR < or = 200 ms, QRS < or = 110 ms, QTcF < or = 450 ms for males and < or = 470 for female patients) and judged as clinically significant by the investigator; 24.For women, pregnancy or in post-partum period or a nursing mother.
Related to habits 25.Substance or alcohol abuse within the prior 6 months or dependence (other than benzodiazepines, nicotine or caffeine) assessed using the MINI 6.0 for schizophrenia and psychotic disorders related to DSM IV-TR; 26.Positive result from the Urine Drug Screen (UDS).
Others 27.The patient is a family member or work associate of one member of the investigational site personnel; 28.Is in a position likely to represent a conflict of interest 29.Has participated in a previous F17464 study; 30.Has participated in another clinical trial within the last 6 months, has received treatment with known remnant effects or undergone investigation liable to interfere with the present clinical trial; 31.Is participating in another clinical trial; 32.Patient having forfeited his/her freedom by an administrative or legal obligation or being under guardianship; 33.Is mentally unable to understand the nature, objectives and possible consequences of the trial; or refusing to subject himself/ herself to its constraints. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy parameter PANSS total score.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy parameters CGI-S and CGI-I PANSS subscores.
Tolerability and Safety - Adverse Events (observed and / or spontaneously reported) - Physical examinations, including body weight, BMI and waist circumference - Standard 12-lead ECG - Blood pressure and heart rate - CDSS (Calgary Depression Scale for Schizophrenia - EPS scales : BARS, AIMS, SAS - Suicidal risk scale: C-SSRS (Columbia-Suicide Severity Rating Scale) - Blood and urine laboratory tests - Fasting glucose - Hemoglobin A1c - Haematology - Biochemistry - Serum-hCG pregnancy test - Urinary pregnancy test
Pharmacodynamics : Prolactin (PRL) (blinded for Sponsor and investigator)
Pharmacokinetics : Plasma concentrations of F17464: 11 blood samples will be collected for each patient.
Genotyping : Genotype regard D3 receptors will be determined on blood sample
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy CGI-I : Visit 3,4,5,6,7,8,9 CGI-S : Visit 1,2,6,9,10.
Tolerability and safety Depending on examination.
Pharmacodynamics Visit 2,4,5,6,9,10.
Pharmacokinetics Visit 4,5,6,7,8,9.
Genotyping Visit 2. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 | No |
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 |
|
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
|
|
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 | 19 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 19 |