| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| 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 evaluate whether OP Depot is superior to haloperidol decanoate in terms of overall effectiveness as measured by the time to all-cause discontinuation for up to 52 weeks in the treatment of symptomatic outpatients with schizophrenia who are at risk for relapse due to nonadherence, and who have previously had an unsatisfactory treatment response.
Time to all-cause discontinuation is defined as the total number of days between the date of first depot dose (Visit 3) and the date of study discontinuation. Superiority of OP Depot treatment group will be assessed using the log-rank test from the Kaplan-Meier survival analysis.
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| E.2.2 | Secondary objectives of the trial |
to evaluate the incidence of all-cause discontinuations of patients on OP Depot compared with haloperidol decanoate, to assess
-improvement in the psychopathology of schizophrenia,
-improvement in depressive symptoms,
-mean change from baseline to Week 8 and to endpoint in the Clinical Global Impression-Severity (CGI-S) score
-improvement in the psychopathology of schizophrenia,
-to evaluate the response rate at Week 8 and endpoint for patients on OP Depot compared with haloperidol decanoate, with response defined as a 30% or greater improvement from the baseline PANSS Total score
-to evaluate the efficacy of OP Depot compared with haloperidol decanoate in time to relapse and incidence of relapse in the subgroup of patients
-to evaluate the incidence of remission of patients treated with OP Depot compared with haloperidol decanoate. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] Male or female patients aged at least 18 and no more than 65 years.
[2] All female patients must test negative for pregnancy and, if of childbearing potential, must be using a medically accepted means of contraception.
[3] Patients must have schizophrenia that meets disease diagnostic criteria as defined in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV; APA 1994) or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR; APA 2000) for a period of at least 2 years (diagnostic codes 295.10, 295.20, 295.30, 295.60, or 295.90); and must be an outpatient (that is, not be in need of acute inpatient stabilization) at the time of study entry and randomization.
[4] Patients must:
• have a PANSS score more than or equal to 60 at Visit 1 and Visit 2; and
• have a history of unsatisfactory clinical response to antipsychotic treatment for schizophrenia (except when treated with olanzapine or haloperidol). For this study, unsatisfactory clinical response is defined as persistent hallucinations, delusions, or thought disorder after at least 6 weeks of contiguous treatment (as supported by patient, medical, or family reports), with a therapeutic dose of at least 1 antipsychotic used for schizophrenia, not including haloperidol or olanzapine; and
• have demonstrated poor functioning in the past year in at least 2 areas of the patient’s life, such as occupational (work/school/vocational), social (interpersonal relations, whether problems within the family or outside the home), or self care.
[5] Each patient must be reliable, have a level of understanding sufficient to perform all tests and examinations required by the protocol, understand the nature of the study, and have given informed consent.
[6] Patients must have experienced at least 2 episodes of clinical worsening of schizophrenia symptoms in the past 12 months such that hospitalization or increased levels of care were required. Increased levels of care can include the addition of or change to any of the following from a lower level of care: day hospital program, outpatient crisis management, short-term psychiatric treatment in an emergency room, or an addition, increase, or switch of medication.
[7] Patients must have experienced AEs to current antipsychotic treatment or have been nonadherent to current antipsychotic therapy (this includes patient nonadherent to haloperidol or oral olanzapine) such that the patient and the treating physician desire a change to the patient’s therapy
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| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[8] Are investigator site personnel or are immediate family of investigator site personnel. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
[9] Are employed by Lilly
[10] Have received treatment within the last 30 days with a drug (not including study drug) that has not received regulatory approval for that indication
[11] Have previously completed or withdrawn from the study after randomization, or have participated in previous OP Depot studies.
[12] Patients who have used olanzapine (any formulation) or haloperidol (any formulation) and have had treatment withdrawn due to clinically significant and/or intolerable adverse effects, or who have exhibited a lack of efficacy/response to treatment to olanzapine or haloperidol
[13] Patients needing a thyroid hormone supplement to treat hypothyroidism must have been on a stable dose of the medication for at least 2 months (56 days) prior to Visit 2.
[14] Patients with DSM-IV – or DSM-IV-TR–defined substance (except nicotine and caffeine) dependence within the past 30 days.
[15] Patients who received treatment with remoxipride within 6 months prior to Visit 2.
[16] Patients who require concomitant treatment with any other medication with primarily central nervous system (CNS) activity,
[17] Patients who are actively suicidal (for example, any suicide attempts within the past month or any current suicidal intent, including plan) in the opinion of the investigator.
[18] Patients with a history of allergic reaction to study drug(s) in any formulation.
[19] Patients with known Human Immunodeficiency Virus positive (HIV+) status.
[20] Female patients who are either pregnant or nursing.
[21] Patients with known, uncorrected, narrow-angle glaucoma.
[22] Patients who have experienced one or more seizures without a clear and resolved etiology.
[23] Patients who have leukopenia or history of leukopenia without a clear and resolved etiology, or known history of agranulocytosis during the patient’s lifetime.
[24] Patients with serious, unstable illnesses such that death is anticipated within 1 year or intensive care unit (ICU) hospitalization for the disease is anticipated within 6 months.
[25] Patients with acute, serious, or unstable medical conditions, including, but not limited to, inadequately controlled diabetes ; severe hypertriglyceridemia; hepatic insufficiency (specifically any degree of jaundice); recent cerebrovascular accident (CVA); uncontrolled seizure disorders; serious acute systemic infection or immunologic disease; unstable cardiovascular disorders (including ischemic heart disease); or renal, gastroenterologic, respiratory, endocrinologic (eg, thyrotoxicosis), neurologic (eg, toxic CNS conditions), or hematologic diseases.
[26] Patients with a history of non-response to previous clozapine therapy within 6 months prior to Visit 1.
[27] Patients with ALT/SGPT values more than or equal to 2 times the upper limit of normal (ULN) of the performing laboratory, or AST/SGOT values more than or equal to 3 times the ULN of the performing laboratory, or total bilirubin values more than or equal to 1.5 times the ULN of the performing laboratory at Visit 1.
[28] Patients not being treated with an antipsychotic drug known to elevate prolactin with a prolactin level more than 200 ng/mL; and patients presently treated with antipsychotic drugs (including risperidone) known to elevate prolactin levels with a prolactin level more than 300 ng/mL at Visit 1.
[29] Patients with a diagnosis of Parkinson’s disease, dementia-related psychosis, or related disorders. If a patient has a past misdiagnosis of Parkinson’s disease, dementia-related psychosis, or related disorders, the investigator will need to contact the Lilly clinical research physician (CRP) prior to enrollment more than 450 milliseconds (msec) (male) or more thatn 470 msec (female), as read by the central vendor cardiologist. If the principle investigator (PI) disagrees with the interpretation, the Lilly CRP must be consulted before the patient is allowed to enter the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Time to all-cause discontinuation for up to 52 weeks in the treatment of symptomatic outpatients with schizophrenia who are at risk for relapse due to nonadherence, and who have previously had an unsatisfactory treatment response.
Time to all-cause discontinuation is defined as the total number of days between the date of first depot dose (Visit 3) and the date of study discontinuation. Superiority of OP Depot treatment group will be assessed using the log-rank test from the Kaplan-Meier survival analysis.
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 | No |
| 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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| 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 | 31 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 31 |
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