| 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 compare inpatient psychiatric hospitalization rates (proportion of subjects with > or = 1 inpatient psychiatric hospitalization[s]) between the retrospective period Months 4-6 (Weeks -12 to -24) while on oral standard-of-care (SOC) antipsychotic treatment(s) and the prospective period Phase B Months 4-6 (Weeks 12 to 24) after the switch to aripiprazole IM depot. |
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| E.2.2 | Secondary objectives of the trial |
| To further evaluate long-term safety and tolerability of aripiprazole IM depot. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)
Subjects who are able to provide written informed consent. If the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requires consent by a legally acceptable representative (LAR) in addition to the subject, all required consents must be obtained prior to the initiation of any protocol-required procedure.
2)
Male and female subjects 18 to 65 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 1 year (12 months) prior to screening from a reliable source (eg, subject, family member, friend, caregiver, healthcare provider, or medical records).
4)
Subjects who in the investigator’s judgment would benefit from extended treatment with a long-acting injectable formulation.
5)
Subjects who will be able to produce at least 7 months retrospective data by records or a reliable source, pertaining to all hospitalizations and interventions (psychiatric and nonpsychiatric).
6)
Subjects who have at least 1 inpatient psychiatric hospitalization in the 2 years (24 months) prior to screening, but have been managed as outpatients for the 4 weeks prior to signing the ICF and for the full duration of the screening period.
7)
Subjects must have been on oral antipsychotic treatment for the full 7 months prior to the screening phase.
8)
Subjects who showed response to antipsychotic treatment (other than clozapine), according to the investigator’s opinion.
9)
In the investigator’s opinion, subjects who are able to understand the nature of the trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, aripiprazole IM depot injection, and discontinuation of prohibited concomitant medications; who can read and understand the written word in order to complete subject-reported outcomes measures; and who can be reliably rated on assessment scales. |
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| E.4 | Principal exclusion criteria |
1)
Prisoners or subjects who are compulsorily detained (involuntarily incarcerated), or have been incarcerated in the past 7 months for any reason must not be enrolled into this trial.
2)
Subjects who may require potent CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers during the trial.
3)
Any subject who requires or may need any other antipsychotic medications during the course of the trial, other than allowed rescue medication.
4)
Subjects who are known to be allergic, intolerant, or unresponsive to prior treatment with aripiprazole or other quinolinones.
5)
Subjects with a history of hypersensitivity to antipsychotic agents.
6)
Subjects deemed intolerant of receiving injectable treatment.
7)
Subjects who have received electroconvulsive therapy within the last 7 months prior to screening.
8)
Subjects with a history of neuroleptic malignant syndrome or clinically significant tardive dyskinesia as assessed by the investigator.
9)
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.
10)
Subjects requiring hospitalization for any psychiatric reason during the 4 weeks prior to signing the ICF or during the screening period.
11)
Subjects without at least 1 inpatient psychiatric hospitalization in the last 2 years (24 months) prior to screening.
12)
Subjects who have met DSM-IV-TR criteria for any significant substance use disorder within 3 months prior to screening.
13)
Subjects who are considered treatment-resistant to antipsychotic medication other than clozapine.
14)
Treatment with long-acting injectable antipsychotics (eg, haloperidol decanoate, fluphenazine decanoate, risperidone long-acting injection [Risperdal® Consta®], paliperidone palmitate extended-release injectable suspension [Invega® Sustenna®], olanzapine for extended-release injectable suspension [Zyprexa® Relprevv®]), in which the last dose was within 7 months prior to screening.
15)
Subjects who have not been treated with oral antipsychotics for 7 months prior to screening.
16)
Subjects who have a significant risk of committing suicide based on history, routine psychiatric status examination, investigator’s judgment, or who have an answer of “yes” on questions 4 or 5 (current or over the last 30 days) on the baseline version of the Columbia Suicide Severity Rating Scale (C-SSRS).
17)
Subjects who have a 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, including but not limited to hepatic, renal, respiratory, cardiovascular, endocrine, neurologic, hematologic, or immunologic disease as determined by the clinical judgment of the investigator.
18)
Sexually active males who will not commit to utilizing 2 of the approved birth control methods or who will not remain abstinent during the trial and for 180 days following the last dose of trial medication, or sexually active females of childbearing potential who will not commit to utilizing 2 of the approved birth control methods or who will not remain abstinent during the trial and for 150 days following the last dose of trial medication. Abstinence will be permitted if it is confirmed and documented at every trial visit. If employing birth control, 2 of the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pill, birth control depot injections, implant, condom or sponge with spermicide. Note: Women of child bearing potential (WOCBP) is defined as all women unless they have had an oophorectomy and/or hysterectomy or have been menopausal for 12 consecutive months.
19)
The following laboratory test, vital sign, and electrocardiogram (ECG) results are exclusionary:
a) Platelets < or = 75,000/mm3
b) Hemoglobin < or = 9 g/dL
c) Neutrophils, absolute < or = 1000/mm3
d) Aspartate aminotransferase (AST) > 3x upper limit of normal
e) Alanine aminotransferase (ALT) > 3x upper limit of normal
f) Creatinine > or = 2 mg/dL
g) Diastolic blood pressure > 105 mm Hg
h) QTc > 475 msec on either the QTcB (Bazett) or QTcF (Fridericia) corrections on 2 out of 3 time points of ECGs performed (based on the report by the central service).
20)
Subjects who have previously enrolled in an aripiprazole IM depot clinical study.
21)
Subjects who have participated in any clinical trial with an investigational agent within the past 30 days. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy: The primary endpoint of this trial is the comparison of inpatient psychiatric hospitalization rates (proportion of subjects with ≥ 1 inpatient psychiatric hospitalization[s]) between the retrospective period Months 4-6 (Weeks -12 to -24) while on oral SOC antipsychotic treatment and the prospective period Phase B Months 4-6 (Weeks 12 to 24) after switch to aripiprazole IM depot. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The analysis will be performed using a McNemar test on those who have hospitalization data during months 4-6 prior to the 4-week outpatient treatment period before study entry and during months 4-6 after switch to aripiprazole IM depot.
Please see protocol for more details. |
|
| E.5.2 | Secondary end point(s) |
The last 3 months of the retrospective and prospective (Phase B) treatment periods will be compared in the analysis of the following endpoints:
- Number of inpatient psychiatric hospitalizations per subject.
- Cumulative duration of inpatient psychiatric hospitalizations.
- Mean duration of inpatient psychiatric hospitalizations.
- Number and mean duration of all other (non-inpatient) psychiatric treatment visits including, but not limited to, partial hospitalizations, intensive outpatient programs, assertive community treatment programs, emergency room visits, hospitalizations for psychosocial reasons, etc.
- Number of inpatient nonpsychiatric hospitalizations per subject.
- Cumulative duration of inpatient nonpsychiatric hospitalizations.
- Mean duration of inpatient nonpsychiatric hospitalizations.
- Number and mean duration of all other (outpatient or non-inpatient) nonpsychiatric treatment visits including, but not limited to, emergency room visits.
In addition, the following endpoints will be assessed in Phase B:
- Mean change from baseline (Day 0) to Week 24 in PANSS total score.
- Mean change from baseline (Day 0) to Week 24 in PANSS positive and negative subscale scores.
- Mean change from baseline (Day 0) to Week 24 in CGI-S score.
- Mean CGI-I score at Week 24.
- Discontinuation rate due to all causes.
- Time to discontinuation due to all causes.
- Proportion of responders (ie, defined as > or = 30% decrease from baseline in PANSS total score or a score of 1 [very much improved] or 2 [much improved] on the CGI-I scale).
- Mean change from baseline (Day 0) to Week 24 in QLS score.
- Mean change from baseline (Day 0) to Week 24 in SWN-S score.
- Mean change from baseline (Day 0) to Week 24 in DAI total score.
- Mean change from baseline (Day 0) to Week 24 in IWQoL-Lite total score.
- Mean change from baseline (Day 0) to Week 24 in IAQ total score.
Safety Endpoints:
Adverse events will be examined by frequency, severity, seriousness, and discontinuation (all cause and due to AEs). The Columbia Suicide Severity Rating Scale (C-SSRS) will be completed at baseline and all subsequent visits to assess the risk of suicide events and to classify reported suicide events. Injection site pain will be assessed by mean visual analogue scale (VAS) scores as reported by the subject after each injection in Phase B.
The investigator rating of localized pain, redness, swelling, and induration at the injection site will also be tabulated.
The incidence of clinically significant changes will be calculated for vital signs and routine laboratory tests. Mean change from baseline and incidence of clinically significant changes will be calculated for ECG parameters, prolactin concentrations, lipid/metabolic profile (fasting glucose, fasting total cholesterol, fasting high density lipoprotein (HDL), fasting low density lipoprotein (LDL), fasting triglycerides) and body weight. A central ECG service will be utilized to review all ECGs in order to standardize interpretations for the safety analysis. Extrapyramidal symptoms will be evaluated by calculating mean change from baseline in the Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BARS). By-subject listings of physical examination findings will be reviewed as a further assessment of safety. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For a complete schedule of assessments please see the following tables in the protocol:
- Table 3.6.1 (Screening and phase A)
- Table 3.6.2 (Phase B)
- Table 3.6.3 (Phase C) |
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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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 95 |
| 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 |
| Belgium |
| Bulgaria |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| United Kingdom |
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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
|
| The End of Trial Date is defined as the last Date of Contact or the Date of Final Contact Attempt from the Post-treatment Follow-up eCRF page for the last subject completing or withdrawing from the trial. |
|
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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