| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Maintenance treatment of schizophrenia in patients currently treated with oral antipsychotics |
|
| E.1.1.1 | Medical condition in easily understood language |
| Maintenance treatment of schizophrenia in patients currently treated with oral antipsychotics |
|
| 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 | 20.0 |
| 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 |
| The primary objective of this study is to evaluate the efficacy of TV-46000 during maintenance treatment in adult patients with schizophrenia. |
|
| E.2.2 | Secondary objectives of the trial |
- to evaluate the efficacy of TV-46000 during maintenance treatment in a
total population (adults and adolescents) and in adolescent patients with
schizophrenia.
- to evaluate the specific efficacy parameters of TV-46000 in the total population beyond the measures of the primary objective
- to evaluate the safety and tolerability of TV-46000 in the total population
- to evaluate the pharmacokinetics of oral risperidone and TV-46000
after administration of multiple doses in adults, adolescents, and the total population
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Screening
a. The patient has a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for >1 year (diagnosis must be reconfirmed by SCID-5) and has had ≥ 1 episode of relapse in the last 24 months.
b. The patient has been responsive to an antipsychotic treatment (other than clozapine) in the past year based on investigator judgement (and discussions with family members, caregivers or healthcare professionals as applicable).
c. The patient has provided written informed consent and is competent to do so.
d. The patient, in the investigator's judgment, requires chronic treatment with an antipsychotic medication.
e. The patient, in the investigator's judgment, can benefit from participation in this study.
f. The patient is able to understand the nature of the study and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, sc depot injection, and discontinuation of prohibited concomitant medications; can read and understand the written word in order to complete patient-reported outcomes measures; and can be
reliably rated on assessment scales.
g. The patient has a PANSS total score lower than 100 at screening.
h. The patient has a stable place of residence for the previous 3 months before screening, and changes in residence are not anticipated over the course of study participation.
i. The patient has no significant life events (such as pending loss of housing, family status change, long travel abroad, surgery, etc) that could affect study outcomes expected throughout the period of study participation.
j. The patient is a male or female of any ethnic origin, 18 through 65 years of age at screening.
k. The patient has a body mass index between 18.0 and 38.0 kg/m2, inclusive at screening.
l. The patient is in adequate health as determined by medical and psychiatric history, medical examination, electrocardiogram (ECG), serum chemistry, hematology, urinalysis, and serology.
m. Women of childbearing potential (see Appendix E of protocol) must agree not to try to become pregnant, and, unless they have exclusively same-sex partners, must agree to use a highly effective method of contraception, and agree to continue use of this method beginning 1 month before the first administration of study drugs and for the duration
of the study and for 120 days after the last injection of study drug.
Highly effective methods of contraception include:
- Combined estrogen and progestogen hormonal contraception (oral, intravaginal, transdermal) associated with inhibition of ovulation; these should be initiated at least 1 month before the first dose of IMP.
- Progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation; these should be initiated at least 1 month before the first dose of IMP.
- Intrauterine device and intrauterine hormone-releasing system; these need to be in place at least 2 months before screening.
- Bilateral tubal occlusion
- Vasectomized partner provided that he is the sole sexual partner and has received medical assessment of the surgical process
- Sexual abstinence is only considered a highly effective method if defined as refraining from heterosexual intercourse in the defined period. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
n. The patient, if male, is surgically sterile, or, if capable of producing offspring, has exclusively same-sex partners or is currently using an approved method of birth control and agrees to the continued use of this method for the duration of the study (and for 120 days after the last dose of study drug). Male patients with sex partners who are women of
childbearing potential (see Appendix E) must use condoms even if surgically sterile. In addition, male patients may not donate sperm for the duration of the study and for 120 days after taking the study drug.
o. The patient must be willing and able to comply with study restrictions and willing to return to the investigational center for the required visits throughout the duration of the study period, including follow-up procedures and assessments as specified in this protocol.
Randomization:
p. The patient has not experienced mentalor physical deterioration, which prevents participation in the study per investigator judgement.
q. The patient has demonstrated good compliance in following protocol requirements during Stage 1.
- If the investigator or the sponsor determines that the patient was not in compliance with the study protocol, the case will be evaluated on a case-by-case basis, and the investigator and the sponsor will determine whether the patient will be randomized in the double-blind period (Stage 2). (Please refer to protocol for further randomisation inclusion criteria). |
|
| E.4 | Principal exclusion criteria |
a. The patient has a current clinically significant DSM-5 diagnosis other than schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar disorder, delirium, dementia, amnestic or other cognitive disorders, or borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
b. The patient is currently on clozapine or has received electroconvulsive therapy in the last 12 months.
c. The patient has a history of epilepsy or seizures, neuroleptic malignant syndrome, clinically significant tardive dyskinesia, or other medical condition that would expose the patient to undue risk.
d. The patient has a positive serology for human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B surface antigen, and/or hepatitis C.
e. The patient currently has or has a history of known hypersensitivity to risperidone or any of the excipients of TV-46000 or the oral formulation of risperidone used in the stabilization phase.
f. The patient has a substance use disorder, including alcohol and benzodiazepines but excluding nicotine and caffeine.
g. The patient has a significant risk of violent behavior based on the patient's medical history or investigator's judgement.
h. The patient has a significant risk of committing suicide based on the patient's medical history or investigator's judgement and/or the C-SSRS (lifetime). Patients with a C-SSRS (current) positive response to suicidal ideation items 3, 4, or 5 are not eligible.
i. The patient has previously participated in a Teva-sponsored clinical study with TV-46000.
j. The patient has a clinically significant deviation from normal in the physical examination.
k. The patient has clinically significant findings in biochemistry, hematology, ECG, or urinalysis results.
- If the patient has a prolonged QTcF interval (defined as a QTcF interval of >450 msec for males and >470 msec for females) at screening and baseline, calculated as the mean of the triplicate ECG measurements,
eligibility will be decided on a case-by-case basis following discussion between the investigator and the sponsor.
l. The patient has any clinically significant uncontrolled medical condition (treated or untreated). The investigator may discuss with the medical monitor as needed.
m. The patient is a pregnant or lactating female.
n. The patient has any disorder that may interfere with drug absorption, distribution, metabolism, or excretion (including gastrointestinal surgery).
o. The patient has any other disease or condition that, in the opinion of the investigator, would make participation not in the best interest of the patient or that could prevent, limit, or confound the protocol-specified assessments.
p. The patient has used an investigational drug within 3 months prior to screening or has participated in a non-drug clinical trial within 30 days prior to screening.
q. The patient is using or consuming the medications prohibited in this protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is time to impending relapse. Relapse is
defined as 1 or more of the following items:
- Clinical Global Impression–Improvement (CGI-I) of ≥5 (greater than or
equal to minimally worse, ie, minimally
worse, much worse or very much worse), AND
- an increase of any of the following individual Positive and Negative
Syndrome Scale (PANSS) items: conceptual disorganization,
hallucinatory behavior, suspiciousness, and unusual thought content, to
a score of >4 with an absolute increase of ≥2 on that specific item since
randomization, OR
- an increase in any of the following 4 individual PANSS items:
conceptual disorganization, hallucinatory behavior, suspiciousness, and
unusual thought content, to a score of >4 and an absolute increase of ≥4
on the combined score of these 4 PANSS items (conceptual
disorganization, hallucinatory behavior, suspiciousness, and unusual
thought content) since randomization
- hospitalization due to worsening of psychotic symptoms (including
partial hospitalization programs), excluding hospitalization for
psychosocial reasons
- Clinical Global Impression-Severity of Suicidality (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
- violent behavior resulting in clinically significant self-injury, injury to
another person, or property damage |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Endpoint is time to relapse |
|
| E.5.2 | Secondary end point(s) |
- time to impending relapse (as defined under the primary objective) in the total population (adults and adolescents)
- impending relapse rate at week 24
- percentage of patients who maintain stability at endpoint (Section 9.5.2.3 of study protocol)
- percentage of patients achieving remission at endpoint (Section 9.5.2.4 of study protocol)
- observed rate of impending relapse at endpoint
- Drug Attitudes Inventory 10-item version (adult patients only)
- Schizophrenia Quality of Life Scale (SQLS) (adult patients only)
- time to impending relapse in adolescent patients with schizophrenia
The safety variables include adverse events, extrapyramidal symptoms
(EPS), risk of suicide events, depression symptoms, injection pain and
other injection site reactions (local tolerability), vital signs, laboratory
tests, physical examination, electrocardiogram (ECG) measurements,
body weight, rescue medication use, time to all-cause discontinuation,
all-cause discontinuation rates and discontinuation rates due to adverse
events (tolerability), and the following rating scales:
- Abnormal Involuntary Movement Scale (AIMS)
- Simpson-Angus Scale
- Barnes Akathisia Rating Scale
- Columbia Suicide Severity Rating Scale (C-SSRS)
- Calgary Depression Scale for Schizophrenia (CDSS)
- CGI-SS
- The pharmacokinetic endpoints are the plasma concentrations of
risperidone, 9-OH-risperidone, and total active moiety (sum of
risperidone and 9-OH-risperidone). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| week 24 and time to relapse |
|
| 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 7 |
| 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 | 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 |
|
| 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
|
| End of study is defined as the date when the last patient in Stage 2 has completed all efficacy and safety assessments at the final visit per protocol. |
|
| 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 | 27 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 30 |
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