E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039626 |
E.1.2 | Term | Schizophrenia |
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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 |
The primary objective of this study is to test the hypothesis that at least 1 dose level of LY2140023, given orally to patients with schizophrenia at 80 mg BID or 40 mg BID (twice daily), will demonstrate significantly greater efficacy than placebo at Visit 9, as measured by the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score, in one or more of the following populations: • the overall schizophrenia population; and • a subgroup of patients determined by a combination of SNPs from the genes HTR2A and DRD2 (the genetic subgroup, as defined in Section 10.4.3). |
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E.2.2 | Secondary objectives of the trial |
The following key secondary objectives will be tested for possible inclusion in the label: • That LY2140023, at 80 mg BID or 40 mg BID doses, demonstrates significantly greater improvement than placebo at Visit 9 in the overall schizophrenia population, as assessed by the change from baseline in the Personal and Social Performance (PSP) score. • That LY2140023, at 80 mg BID or 40 mg BID doses, demonstrates significantly greater improvement than placebo at Visit 9 in the genetic subgroup, as assessed by the change from baseline in the PSP score.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
[1] Patients are male or female, 18 to 65 years of age (inclusive) at study entry, with a diagnosis of schizophrenia as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR; APA 2000) (Disorganized, 295.10; Catatonic, 295.20; Paranoid 295.30; or Undifferentiated, 295.90) and confirmed by the Structured Clinical Interview for DSM-IV-TR (SCID). [2] Female patients of childbearing potential must test negative for pregnancy at Visit 1 and agree to use a single, effective, medically acceptable method of birth control, specifically: an oral contraceptive combined pill; an implantable contraceptive; an injectable contraceptive; a contraceptive patch (for women <198 pounds or 90 Kg); or an intrauterine device/system. The double-barrier method, as defined by two physical barriers such as a condom, diaphragm, or cervical occlusive cap, coupled with an additional barrier such as spermicidal foam, gel, film, cream or suppository, is also an acceptable method of birth control. Patients having undergone a hysterectomy or bilateral oophorectomy or other form of female sterilization, or patients having been medically confirmed to be post-menopausal, would not require any method of contraception. [3] At Visits 1 and 2, patients must meet a Clinical Global Impression- Severity (CGI-S) rating ≥4 (moderately ill) and must be patients in whom a modification of antipsychotic medication, or the initiation of antipsychotic medication, is acutely indicated, in the opinion of the investigator. [4] Patients must be willing to participate in a minimum of 3 weeks of inpatient hospitalization, and this must be appropriate for the patient in the clinical judgment of the investigator. [5] Patients must have been suffering from schizophrenia for at least 1 year prior to Visit 1, as determined from onset of illness. [6] At Visit 1, patients who are not antipsychotic treatment-naive must have a lifetime history of at least one hospitalization for the treatment of schizophrenia, not including hospitalization required for this study. Patients who are antipsychotic treatment-naive may enter the study, even without a history of hospitalization. [7] At Visit 1, patients who are not antipsychotic treatment-naïve must have a history of at least one episode of illness exacerbation requiring an intensification of treatment intervention or care in the last 2 years, not including the present episode of illness. Patients who are antipsychotic treatment-naive may enter the study, even without a past history of illness exacerbation and intensification of treatment in the last 2 years. [8] At Visit 1, patients also must have experienced an exacerbation of their illness within the 2 weeks prior to Visit 1, leading to an intensification of psychiatric care in the opinion of the investigator. Examples of intensification of care include, but are not limited to: inpatient hospitalization, day/partial hospitalization, outpatient crisis management, or psychiatric treatment in an emergency room. If exacerbation occurs in patients who are presently hospitalized, the patient must not have been hospitalized longer than 60 days prior to Visit 1. [9] Patients must be considered reliable and have a level of understanding sufficient to perform all tests and examinations required by the protocol, and be willing to perform all study procedures. [10] Patients must be able to understand the nature of the study and have given their own informed consent. |
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E.4 | Principal exclusion criteria |
[13] Have any other current Axis I psychiatric diagnoses (as defined in DSM-IV-TR) in addition to schizophrenia. [16] Patients for whom treatment with risperidone, LY2140023, or placebo, as specified in this protocol, is relatively or absolutely clinically contraindicated. [17] Patients who have received treatment with clozapine at doses greater than 200 mg daily within 12 months prior to Visit 1, or who have received any clozapine at all during the month before Visit 1. [21] Patients who require concomitant treatment with any other medication with primary central nervous system activity, other than those allowed as specified in Section 9.8 and Attachment HBBM.3, or with any other medication specifically excluded in Protocol Attachment HBBM.3. [22] Patients currently receiving treatment (within 1 dosing interval, minimum of 4 weeks, prior to Visit 1) with a depot formulation of an antipsychotic medication. [23] Patients have answered ‘yes’ to either Question 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) or Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the "Suicidal Ideation" portion of the C–SSRS, or answer "yes" to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the "Suicidal Behavior" portion of the C–SSRS; and the ideation or behavior occurred within the past month. [26] Female patients who are pregnant, nursing, or who intend to become pregnant within 30 days of completing the study. [27] Have known, uncorrected, narrow-angle glaucoma. [28] Have a history of one or more seizures, except for those who experienced a single simple febrile seizure between ages 6 months and 5 years (a single simple febrile seizure is defined as lacking focality and lasting less than 15 minutes, not associated with a central nervous system (CNS) infection or severe metabolic disturbance). [29] Patients are excluded if they have a first-degree relative (that is, biological father, mother, brother, sister, or child) with history of idiopathic epilepsy. [30] Within 1 year of study enrollment, patients have a history of CNS infection, uncontrolled migraine, transient ischemic attack (TIA), or head trauma with loss of consciousness or a post-concussive syndrome. [31] Patients are excluded if they have a lifetime history of any of the following: o head trauma, stroke, or CNS infection with persistent neurological deficit (focal or diffuse); o brain surgery; o an EEG with paroxysmal (epileptiform) activity, for example, one that demonstrates 3 or more focal sharp or spike waves, any sharp and slow wave complex, or any epileptiform discharge that is rhythmic, sustained, or generalized; or as locally defined; or o brain structural lesion, including developmental abnormalities, as determined by examination or previous neuroimaging studies that are consistent with a diagnosable neurological disease or syndrome. [32] Patients who have had electroconvulsive therapy (ECT) within 3 months of Visit 1 or who will have ECT at any time during the study. [33] Patients with untreated hyper- or hypothyroidism. An abnormal TSH (outside the limits of the central laboratory reference range) will automatically result in a Free T3 and a Free T4 by the central laboratory. Patients with mildly abnormal thyroid test results may be included if their hyper- or hypothyroidism is adequately treated based on the investigator’s clinical assessment and interpretation of these results. [34] Have leukopenia (WBC <3500/mm3, or <3.5 GI/L, or <3.5 103/uL) or a history of leukopenia without a clear and resolved etiology, or known history of agranulocytosis (absolute neutrophil count <500/mm3, or <0.5 GI/L, or <0.5 103/uL) during the patient’s lifetime. [35] Patients with known medical history of Human Immunodeficiency Virus positive (HIV+) status. [36] Test positive for (1) Hepatitis C virus antibody or (2) Hepatitis B surface antigen (HBsAg) with or without positive Hepatitis B core total antibody. Patients with positive Hepatitis B core antibody test and negative HBsAg may be included in the study if ALT/SGPT and AST/SGOT levels are less than 2 times the upper limit of normal (ULN) and total bilirubin does not exceed the ULN of the central laboratory. [40] Patients with a corrected QT interval (Bazett’s; QTcB) >450 msec (male) or >470 msec (female) at Visit 1 (based on the central vendor’s ECG overread). [42] Patients with moderate to severe renal impairment as defined by creatinine clearance (CrCl) <60 ml/min (measured by the Cockcroft- Gault equation) at Visit 1. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Positive and Negative Syndrome Scale (PANSS) total score |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | No |
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 |
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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
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last visit of the last subject. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 20 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 20 |
E.8.9.2 | In all countries concerned by the trial days | 0 |