| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 14.1 |
| 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 |
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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 is to evaluate the efficacy of aripiprazole IM depot
compared with oral aripiprazole, as measured by the proportion of subjects
experiencing exacerbation of psychotic symptoms/impending relapse by the end of 26 weeks of treatment from the date of randomization in Phase 3, in schizophrenic patients who have maintained stability on oral aripiprazole for at least 8 weeks in Phase 2 of the study before initiating
treatment with aripiprazole IM depot. |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of aripiprazole IM depot as maintenance therapy in patients with Schizophrenia. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Screening
1. Subjects who are able to provide written informed consent and/or consent obtained from a legally acceptable representative (as required by IRB/IEC), prior to the initiation of any protocol-required procedures.
2. Male and female subjects 18 to 60 years of age, inclusive, at time of informed consent.
3. Subjects with a current diagnosis of schizophrenia as defined by DSM-IV-TR criteria and a history of the illness for at least 3 years prior to screening*
4. Subjects who, in the investigator’s judgement, require chronic treatment with antipsychotic medication(s).
5. Subjects who showed previous response to antipsychotic treatment (other than clozapine) in the past year, according to the investigator’s opinion.
6. Subjects who are currently being treated with oral or depot antipsychotics other than clozapine (a recent lapse in antipsychotic treatment [defined as >3 consecutive days without medication] will be considered as current treatment for the purpose of determining eligibility for this trial) and who, in the investigator’s judgement, require chronic treatment with an antipsychotic medication and would benefit from treatment with aripiprazole IM depot.
7. Subjects with a history of relapse and/or exacerbation of symptoms when they are not receiving antipsychotic treatment.
8. Inpatient or outpatient status prior to entry into Phase 2 (oral stabilization)
9. Subjects able to understand the nature of the study and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, IM depot injection, discontinuation of prohibited concomitant medications, who can read and understand the written word in order to complete patient-reported outcomes measures, and who can be reliably rated on assessment scales.
Inclusion Criteria Assessed Prior to Entry into Phase 1
10. Adequate washout of prohibited concomitant medications, including 3 days prior to entry into Phase 1 for mood stabilizers and antidepressants (14 days for fluoxetine or Symbyax®).
11. Subject is receiving no more than one benzodiazepine beyond screening.*
12. Inpatient or outpatient status.
13. Subject is receiving antipsychotics other than aripiprazole or clozapine and must be cross-titrated to aripiprazole monotherapy over 4 to 6 weeks using an initial dose of 5 mg to achieve a recommended target aripiprazole monotherapy starting dose in Phase 2 of 10 or 15 mg.*
Inclusion Criteria Assessed Prior to Entry into Phase 2
14. Adequate washout of prohibited concomitant medications, including 14 days prior to entry into Phase 2 for mood stabilizers and antidepressants (42 days for fluoxetine or Symbyax) and one cycle plus 14 days prior to entry into Phase 2 for approved long-acting antipsychotics (eg, 2-week cycle plus an additional 14 days for risperidone long-acting injection) or 60 days for investigational long-acting antipsychotics.
15. Subject is receiving oral aripiprazole as monotherapy (generic aripiprazole must be cross-titrated in Phase 1) for treatment of schizophrenia at a starting dose of 10 or 15 mg daily.*
16. Inpatient or outpatient status.
Inclusion Criteria Assessed Prior to Entry into Phase 3
17. Subject is receiving oral aripiprazole as monotherapy (generic aripiprazole must be cross-titrated in Phase 1) for treatment of schizophrenia at a dose ranging from 10 to 30 mg daily.
18. Outpatient status.
19. Subject’s condition is stable as evidenced by meeting ALL of the following criteria for 8 consecutive weeks (4 consecutive bi-weekly visits), including the last visit prior to entering Phase 3:
a) Outpatient status
b) PANSS Total score =< 80
c) Lack of specific psychotic symptoms as measured by a score of =< 4 on the following PANSS items:
• Conceptual disorganization
• Suspiciousness
• Hallucinatory behaviour
• Unusual thought content
d) CGI-S =< 4 (moderately ill)
e) CGI-SS =< 2 (mildly suicidal) on Part 1 and =< 5 (minimally worsened) on Part 2 *
20. Stability criteria are met on or before Week 28 of Phase 2.
*See Protocol for explanatory details
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| E.4 | Principal exclusion criteria |
Sex and Reproductive Status
1. Sexually active males not practicing double-barrier birth control or who will not remain abstinent during the study and for 180 days following the last dose of study medication, or sexually active females of childbearing potential not practicing double-barrier birth control or who will not remain abstinent during the study and for 150 days following the last dose of study medication. If employing birth control, two precautions to be used *
2. Females breast-feeding and/or who have a positive serum pregnancy test result prior to receiving study drug.
Target Disease
3. Subjects with a current DSM-IV-TR diagnosis other than schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar disorder, delirium, dementia, amnestic or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
4. Subjects experiencing acute depressive symptoms within the past 30 days, according to the investigator’s opinion, that requires treatment with an antidepressant.
5. Subjects with schizophrenia that are considered resistant/refractory to antipsychotic treatment by history.
6. Subjects with history of failure to clozapine treatment or response to clozapine treatment only.
Medical History and Concurrent Disease
7. Subjects with a significant risk of violent behavior or a significant risk of committing suicide based on history or investigator’s judgment
8. Subjects who currently meet DSM-IV-TR criteria for substance dependence; including alcohol and benzodiazepines, but excluding caffeine and nicotine.
9. Subjects with known hypothyroidism or hyperthyroidism (unless condition has been stabilized with medications for at least the past 90 days).
10. Subjects who have history or evidence of a medical condition that would expose them to an undue risk of a significant adverse event or interfere with assessments of safety or efficacy during the course of the trial.*
11. Subjects with epilepsy or history of seizures, except for a single childhood febrile seizure, post traumatic, alcohol withdrawal, etc.
Physical and Laboratory Test Findings
12. Subjects with two positive drug screens for cocaine prior to Phase 2. Two positive drug screens for other drugs of abuse must be discussed with the Medical Monitor prior to entry into Phase 2 unless the subject satisfies criteria for dependence, in which case the subject should be excluded from the study.
13. The following laboratory test, vital sign, and ECG results are exclusionary:
a) Platelets =<75,000/mm3
b) Hemoglobin =<9 g/dL
c) Neutrophils, absolute =<1000/mm3
d) AST > 3x upper limit of normal
e) ALT > 3x upper limit of normal
f) Creatinine >=2 mg/dL
g) Diastolic blood pressure > 105 mmHg
h) QTc > 475 msec*
Allergies and Adverse Drug Reactions
14. Subjects known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other quinolinones.
15. Subjects with history of hypersensitivity to antipsychotic agents.
16. Subjects who are known to be allergic, intolerant, hypersensitive, or refractory to antipsychotic agents.
17. Subjects with history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia at screening.
Prohibited Therapies and/or Medications
18. Subjects likely to require prohibited concomitant therapy during the trial.
19. Subjects receiving CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers at screening or anticipated use of such agents during the trial.*
20. Subjects who received any investigational agent in a clinical trial within 30 days prior to screening or who were randomized into a clinical trial with aripiprazole IM depot at any time.*
Other Exclusion Criteria
21. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious disease) illness must not be enrolled into this trial.
22. Subjects who have been hospitalized, including hospitalization for psychosocial reasons, for more than 30 days total in the last 90 days prior to entry into Phase 1 for subjects entering Phase 1, or prior to Phase 2 for subjects entering Phase 2 directly after screening.
Exclusion Criteria Assessed Prior to Entry into Phase 2
23. Electroconvulsive therapy within 180 days prior to entry into Phase 2.
Exclusion Criteria Assessed Prior to Entry into Phase 3
24. Subjects who have more than one excursion from stability criteria after achieving a response to oral aripiprazole at a point in the trial where they would not be able to maintain stability for a minimum of 8 weeks without exceeding 28 weeks total in Phase 2.
25. Subjects who have not achieved stability criteria on oral aripiprazole for 8 consecutive weeks (4 consecutive bi-weekly visits) by Week 28 of Phase 2 or who have consecutive excursions at Weeks 20 and 22.
*See Protocol for explanatory details
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is the proportion of subjects
experiencing
exacerbation of psychotic symptoms/impending relapse by the end of 26
weeks from the
date of randomization in Phase 3, in schizophrenic patients who have
maintained stability on oral aripiprazole for at least 8 weeks in Phase 2 of the study. Exacerbation of psychotic symptoms or impending relapse is defined as meeting any or all of the following four criteria:
1) CGI-Improvement of >= 5 (minimally worse) AND
• an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score > 4 with an absolute increase of >= 2 on that specific item since randomization OR
• an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) to a score > 4 and an absolute increase of >= 4 on the combined four PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content) since randomization.
OR
2) Hospitalization due to worsening of psychotic symptoms (including partial hospitalization programs), but excluding hospitalization for psychosocial reasons.
OR
3) CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much worse) or 7 (very much worse) on Part 2.
OR
4) Violent behavior resulting in clinically significant self-injury, injury to another person, or property damage. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints for Phase 3 are as follows:
• Time to exacerbation of psychotic symptoms/impending relapse (ie,
defined
as meeting criteria; see protocol) from the date of randomization in
Phase 3
• Percentage of responders (ie, defined as meeting stability criteria; see
protocol) at endpoint in Phase 3
• Percentage of subjects achieving remission, where remission is defined
as a score of ≤ 3 on each of the following specific PANSS items,
maintained for a period of 6 months: delusions (P1), unusual thought
content (G9),
hallucinatory behavior (P3), conceptual disorganization (P2),
mannerisms/posturing (G5), blunted affect (N1), social withdrawal
(N4), lack of spontaneity (N6)
Other efficacy endpoints evaluated for Phase 3 will include:
• Mean change from baseline to endpoint in PANSS Total Score
• Mean change from baseline to endpoint in CGI-S
• Mean change from baseline to endpoint in PANSS positive and negative
subscales
• Mean CGI-I score at endpoint
• Time to discontinuation due to all causes |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Austria |
| Belgium |
| Bulgaria |
| Chile |
| Croatia |
| Estonia |
| France |
| Korea, Republic of |
| Poland |
| South Africa |
| Thailand |
| United States |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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