| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
| To assess the relative bioavailability of LY03004 compared to EU Risperdal® Consta® at 50 mg following multiple intramuscular injections at steady-state; |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of LY03004 following multiple dose administration in two different periods |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Only subjects presenting the following criteria will be enrolled in the present study:
[1] Male or female patients aged 18 to 65 years old, inclusive;
[2] Patients must have a DSM-IV-TR diagnosis of schizophrenia based on the Mini-International Neuropsychiatric Interview (MINI). The duration of the
illness must be at least 2 years prior to screening;
[3] Patients must have an identified support person (e.g. family member, case worker, social worker) considered reliable by the investigator to help ensure compliance with study treatment and visits and to alert staff of any issues of
concern;
[4] Patients must have a stable place of residence for the 3 months prior to screening;
[5] Patients must not have been either hospitalized for worsening of schizophrenic symptoms or judged by the investigator as having significant
exacerbation of schizophrenic symptoms during the 3 months prior to screening;
[6] Patients must be on a stable dose of oral antipsychotic medication(s) or on Risperidone depot 50 mg for at least 4 weeks prior to screening, AND
clinically stable based on clinical assessments and having a Positive and Negative Syndrome Scale (PANSS) total score of ≤70 as well as a subtotal
score of HATE (hostility, anxiety, tension and excitement) <16 within the PANSS interview at screening and baseline visits;
[7] Patients with a Body Mass Index in range of 18.0 to 38.0, inclusive;
[8] Patients with an Informed Consent Form signed by the patient;
[9] Female patients must have a negative serum pregnancy test at screening;
[10] Female patients must be either postmenopausal [postmenopausal women defined as one of the following: more than 6 months amenorrhea in patients ≥55 years, OR more than 18 months amenorrhea in patients <55 years, OR baseline serum FSH >35 IU/l in patients <55 years and less than 18
months amenorrhea, OR surgical menopause for more than 4 weeks] or woman of childbearing potential [A woman of childbearing potential is
defined as a premenopausal female capable of becoming pregnant. This includes women on oral, injectable, or mechanical contraception; women
who are single; women whose husbands have been vasectomized or whose husbands have received or are utilizing mechanical contraceptive
devices];
[11] Women of childbearing potential must be practicing or agree to practice an effective method of birth control if they are sexually active before study entry, during the study and two months after the end of the study by using an acceptable method of contraception. Acceptable methods of birth control must be used for at least 30 days prior to the use of study drug. Acceptable methods of birth control are oral, injected, vaginal or patch contraceptive and IUD (intrauterine device);
[12] Sexually active male subjects must use condoms as contraception method for at least 30 days prior to the use of study drug, during the participation in the trial, and until 2 months after the end of the study. |
|
| E.4 | Principal exclusion criteria |
[1] Patients with a primary and active DSM-IV-TR diagnosis other than schizophrenia;
[2] Patients who received paliperidone palmitate within 10 months prior to screening. Oral risperidone tolerability test should be performed in those
patients without documented evidence of tolerability to risperidone;
[3] Patients who are non-responders to risperidone or paliperidone;
[4] Patients who pose a significant risk of a suicide attempt based on history or the investigator’s judgment, or are at imminent risk of suicide or violent behavior based on the investigator’s clinical assessment;
[5] Patients with a history of neuroleptic malignant syndrome or tardive dyskinesia, or a history of severe akathisia or extra-pyramidal reactions
such as dystonia with previous use of risperidone or other neuroleptic treatments;
[6] Patients with uncontrolled diabetes mellitus, or a HbA1c level ≥7%, or with diabetes mellitus requiring use of insulin. Patients with newly diagnosed Type 2 diabetes during the screening period are excluded;
[7] Patients with a history of or who are currently diagnosed as having epilepsy or convulsion disorders;
[8] Patients who have had electroconvulsive therapy within the past 2 months prior to screening;
[9] Patients who used medication known to be a potent or moderate inhibitor of CYP 2D6 or a potent inducer of CYP 3A4 within 2 weeks or 5 PK half-lives, whichever is longer, prior to screening;
[10] Patients with a history of an allergic reaction to risperidone or to the excipients of LY03004, or show an allergic reaction to oral risperidone
tolerability test;
[11] Patients who have met DSM-IV-TR criteria for substance abuse or dependence with the exception of caffeine or nicotine in the past 6 months
prior to screening, or test positive for a drug of abuse or alcohol at screening or baseline (except positive findings that can be accounted for by
documented prescription use prescribed by a treating physician as a part of the treatment for the patient’s psychiatric illness);
[12] Patients with a history of, or current clinically relevant cardiac arrhythmia, cardiovascular disease, thyrotoxicosis, parkinsonism, or hemorrhagic
diathesis;
[13] Patients who have a history of malignancy within the past five years except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer;
[14] Patients who have received a MAO inhibitor within 30 days prior to screening;
[15] Female patients who are pregnant, or tested positive for pregnancy at screening, or are breastfeeding, or are of childbearing potential without
adequate use of contraception;
[16] Patients who have any uncontrolled, unstable clinically relevant medical condition (e.g. hepatic, renal, cardiovascular, endocrine, respiratory,
hematologic, immunologic or cerebrovascular disease), or other medical condition, which in the judgment of the investigator would interfere with the
subject's ability to participate in the study;
[17] Patients with a QTcF interval greater than 450 msec for males and 470 msec for females, or other clinically significant ECG findings in the opinion
of the investigator;
[18] Patients who have any one of the following three conditions: (i) clinically significant liver dysfunction, (ii) HBsAg positive, (iii) a serum alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) levels of > 2x upper limit of normal (ULN) range (if the ALT or AST levels are between 2x
– 3x ULN in the first screening test and the elevation may be caused by non-specific reasons in the judgment of investigators, a second test can be
performed after one week. If the repeated ALT or AST levels are still 2x ULN, the subject must not be included in the study). However, patients who
are hepatitis C positive may be enrolled, if this condition has been previously considered stable without treatment and liver function is normal;
[19] Patients who have received an investigational drug as part of a clinical trial within 30 days prior to screening or current participation in another clinical trial;
[20] Patients who show any clinical observation, or clinical laboratory abnormality including HIV positive, or abnormal ECG findings at screening
or baseline visit, which in the opinion of the investigator may endanger the subject or interfere with the endpoints of study. If the results of clinical
laboratory or ECG testing are outside normal reference ranges, the subject may be enrolled but only if these findings are determined to be not clinically significant by the investigator. This determination must be recorded in the subject’s source document.
[21] Patients who lost their ability to give their consent. If the investigator doubts the ability of the patient to consent to the participation in this study at any time, the ability to do so must be checked by an independent medical expert.
[22] Female Patients who have a positive pregnancy test (urine) in the course of the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Css-max, Ctrough and AUCss-tau of risperidone |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After completion of the clinical part of the trial and database closure. |
|
| E.5.2 | Secondary end point(s) |
Css-max, Ctrough and AUCss-tau of 9-OH-risperidone and active moiety
Additional endpoints are:
Css-min, % Fluctuation, Tss-max of risperidone, 9-OH-risperidone and active moiety |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After completion of the clinical part of the trial and database closure. |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | Yes |
| 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 | Yes |
| 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 | Yes |
| 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 | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 | 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
|
LVLS. The final examination is planned to be performed up to 14 days
after day 85 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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