| 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 |
|
| 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 safety and tolerability of aripiprazole IM Depot administered every 4 weeks for 52 weeks to patients with schizophrenia |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the efficacy, as measured by the proportion of stable subjects at baseline who remain stable at endpoint and impact on social functioning, of aripiprazole IM depot administered every 4 weeks for 52 weeks to patients with schizophrenia |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Direct Entry Into Study 248 After Studies 246/247
Entry into Phase 2
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
- are Male/female 18-65 years of age, inclusive, at the time of informed consent
- have completed 246/247 or who were withdrawn from the double-blind phase of either study for any reason (*) and did not receive any antipsychotic treatment(s) other than aripiprazole monotherapy after participation in 246/247 *
- in the investigator’s judgment, require chronic treatment with an antipsychotic medication and would benefit from extended treatment with an IM depot formulation
- have =<30 days between the completion/discontinuation date from 246/247 and the enrollment date into 248 *
- have had adequate washout of prohibited concomitant medications *
- have inpatient or outpatient status
- are able to understand the nature of the study and follow protocol requirements, including: prescribed dosage regimens/tablet ingestion/IM depot injection/restrictions on concomitant medications/can read and understand the written word in order to complete patient-reported outcomes measures/can be reliably rated on assessment scales
Entry into Phase 3
Subjects who:
- have outpatient status
- meet ALL of the following criteria on at least one occasion after receiving at least four weeks of treatment with oral aripiprazole at a dose of 10 to 30 mg: Outpatient status; PANSS Total Score =< 80; Lack of specific psychotic symptoms as measured by a score of =<4 on the following PANSS items: Conceptual disorganization/ Suspiciousness/Hallucinatory behavior/Unusual thought content; CGI-S =<4 (moderately ill); CGI-SS =<2 (mildly suicidal) on Part 1 and =<5 (minimally worsened) on Part 2
Entry After Last Visit of 246/247 and Additional Subjects
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
- are male/female 18-65 years of age, inclusive, at time of informed consent
- are currently diagnosised with schizophrenia as defined by DSM-IV-TR criteria and a history of the illness for at least three years prior to screening*
- in the investigator’s judgment, require chronic treatment with antipsychotic medication and would benefit from extended treatment with an IM depot formulation
- showed previous response to antipsychotic treatment (other than clozapine) in the past year, according to the investigator’s opinion
- are currently being treated with oral or depot antipsychotics other than clozapine (*) and who, in the investigator’s judgment, require chronic treatment with an antipsychotic medication and would benefit from treatment with aripiprazole IM depot
- have inpatient or outpatient status prior to entry into Phase 3*
- are able to understand the nature of the study and follow protocol requirements, including: prescribed dosage regimens/tablet ingestion/IM depot injection/restrictions on concomitant medications/can read and understand the written word in order to complete patient-reported outcomes measures/can be reliably rated on assessment scales
Entry into Phase 1:
Subjects who:
- have had adequate washout of prohibited concomitant medications*
- is receiving no more than one benzodiazepine beyond screening*
- has inpatient or outpatient status
- is receiving antipsychotic(s) other than non-generic oral aripiprazole or clozapine and must be cross-titrated to aripiprazole monotherapy (study drug)*
Entry into Phase 2:
Subjects who:
- have had adequate washout of prohibited concomitant medications*
- 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. *
- has inpatient/outpatient status
Entry into Phase 3:
Subjects who:
- 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.
- has outpatient status
- meets ALL of the following criteria on at least one occasion after receiving at least four weeks of treatment with oral aripiprazole at a dose of 10 to 30 mg: Outpatient status; PANSS Total Score =< 80; Lack of specific psychotic symptoms as measured by a score of =< 4 on the following PANSS items: Conceptual disorganization/Suspiciousness/Hallucinatory behavior/Unusual thought content; CGI-S =< 4 (moderately ill); CGI-SS =< 2 (mildly suicidal) on Part 1 and =< 5 (minimally worsened) on Part 2
*see protocol for explanatory details
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| E.4 | Principal exclusion criteria |
Direct Entry After Studies 246/247
Entry into Phase 2
Subjects who:
- are sexually active males/females of childbearing potential, not practicing double-barrier birth control, or who will not remain abstinent during the study and for 180 days (for males) and 150 days (for females) following the last dose of study medication. If employing birth control, two of the precautions (*listed int he protocol) must be used
- are females who have a positive serum pregnancy test prior to receiving study drug
- are receiving any antipsychotic(s) other than oral aripiprazole monotherapy (study drug) after completion/withdrawal from 246/247*
- are currently receiving or likely to require prohibited concomitant therapy during the trial*
- are currently receiving CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers or anticipated use of such agents during the trial*
- have had electroconvulsive therapy since concluding participation in 246/247
Entry into Phase 3
Subjects who:
- receive at least four consecutive weeks of treatment with oral aripiprazole monotherapy int he range of 10-30mg daily and do not achieve stability criteria on at least one occasion between Week 4 and Week 16 of Phase 2
Entry After Last Visit of 246/247 + Additional Subjects
Subjects:
- who are sexually active males/females of child-bearing potential who are not practicing double-barrier birth control or who will not remain abstinent during the study and for 180 days (for males) and 150 days (for females) following the last dose of study medication. If employing birth control, two of the precautions (*listed in protocol) must be used
- who are females who are breast-feeding and/or who have a positive serum pregnancy test result prior to receiving study drug
- with a current DSM-IV-TR diagnosis other than schizophrenia*
- experiencing acute depressive symptoms within the past 30 days, according to the investigator’s opinion, that requires treatment with an antidepressant
- with schizophrenia that are considered resistant/refractory to antipsychotic treatment by history
- with a history of failure to clozapine treatment or response to clozapine treatment only
- with a significant risk of violent behavior or a significant risk of committing suicide based on history or investigator’s judgment
- who currently meet DSM-IV-TR criteria for substance dependence; including alcohol and benzodiazepines, but excluding caffeine and nicotine
- with known hypothyroidism or hyperthyroidism (unless condition has been stabilized with medications for at least the past 90 days)
- who have a history or evidence of a medical condition that would expose them to an undue risk of a significant AE or interfere with assessments of safety or efficacy during the course of the trial*
- with epilepsy or a history of seizures, except for a single childhood febrile seizure, post traumatic, alcohol withdrawal, etc
- with two positive drug screens for cocaine prior to Phase 2*
- with the following laboratory test, vital sign, and ECG results are exclusionary: platelets =< 75,000/mm3; hemoglobin =<9 g/dL; neutrophils, absolute =<1000/mm3; AST > 3x upper limit of normal; ALT > 3x upper limit of normal; Creatinine >= 2 mg/dL; Diastolic blood pressure > 105 mmHg--QTc > 475 msec *
- who are known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other quinolinones
- with a history of hypersensitivity to antipsychotic agents
- who are known to be allergic, intolerant, hypersensitive, or refractory to antipsychotic agents
- with a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia at screening
- likely to require prohibited concomitant therapy during the trial*
- receiving CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers at screening or anticipated use of such agents during the trial*
- 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 than 246/247*
Other Exclusion Criteria
- Prisoners or subjects who are compulsorily detained (*) for treatment of either a psychiatric or physical illness*
- 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
Entry into Phase 2
- Electroconvulsive therapy within 180 days prior to entry into Phase 2
Entry into Phase 3
- Subjects who receive at least four consecutive weeks of treatment with oral aripiprazole monotherapy in the range of 10 to 30 mg daily and do not achieve stability criteria on at least one occasion between Week 4 and Week 16 of Phase 2.
*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 percentage of stable subjects at baseline who remain stable at endpoint, where “stable” is defined as meeting ALL of the following criteria:
1) Outpatient status AND
2) PANSS Total Score =< 80 AND
3) Lack of specific psychotic symptoms on the PANSS as measured by a score of =< 4 on each of the following items (possible scores of 1 to 7 for each item):
· conceptual disorganization
· suspiciousness
· hallucinatory behavior
· unusual thought content AND
4) CGI-S =< 4 (moderately ill) AND
5) CGI-SS =< 2 (mildly suicidal) on Part 1 and =< 5 (minimally worsened) on Part 2
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Multiple timepoints - please refer to protocol |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoint in this study is the proportion of
subjects meeting exacerbation of psychotic symptoms/impending
relapse criteria, defined as meeting ANY or ALL of the following four
criteria at any time during Phase 3:
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 the first dose of open-label aripiprazole IM depot 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
the first dose of open-label aripiprazole IM depot.
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.
Other secondary endpoints evaluated in Phase 3 will include:
• 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),
mnnerisms/posturing (G5), blunted affect (N1),
social withdrawal (N4), and lack of spontaneity (N6)
• Percentage of stable subjects at baseline who remain stable at Week
28 (with "stable" defined as above)
• Time to first exacerbation of psychotic
symptoms/impending relapse during Phase 3 (defined as above)
• 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Multiple timepoints - please refer to protocol. |
|
| 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 | 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 | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | 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 | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 144 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Brazil |
| Bulgaria |
| Chile |
| China |
| Croatia |
| Finland |
| France |
| Hungary |
| India |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Norway |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Taiwan |
| Thailand |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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