| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Exacerbation of Schizophrenia |
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001064 |
| E.1.2 | Term | Acute 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 |
For Double-blind (DB) Treatment (Part 1):
To demonstrate the efficacy of RP5063 (brilaroxazine) tablets (at fixed doses of 15 mg or 50 mg administered orally once daily [OD]) compared to placebo in subjects with an acute exacerbation of schizophrenia.
To evaluate the safety and tolerability of RP5063 (brilaroxazine) tablets (at fixed doses of 15 mg or 50 mg OD) compared to placebo in subjects with an acute exacerbation of schizophrenia.
For Open-label (OL) Treatment (Part 2):
To evaluate the safety and tolerability of RP5063 (brilaroxazine) tablets (at flexible doses of 15 mg or 30 mg or 50 mg OD) in an OL treatment part over a period of 52 weeks in stable schizophrenia subjects. |
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| E.2.2 | Secondary objectives of the trial |
DB (Part 1):
To evaluate efficacy of RP5063 tablets (at fixed doses of 15/50 mg administered orally OD) compared to placebo as demonstrated by change in measure from Baseline:
• Clinical Global Impression of Severity (CGI-S) scale for overall disease severity and change
• Remission and factors
• Agitation
• Social and overall functioning
To evaluate safety and tolerability of RP5063 tablets (at fixed doses of 15/50 mg OD) compared to placebo after up to 28 days of treatment.
OL (Part 2):
To evaluate the efficacy of RP5063 tablets (at flexible doses of 15/30/50 mg OD) over a period of 52 weeks in stable schizophrenia subjects as demonstrated by change in measure from the Baseline:
• CGI-S scale for overall disease severity and change
• Remission and factors
• Agitation
• Social and overall functioning
To evaluate the safety and tolerability of RP5063 tablets (at flexible doses of 15/30/50 mg OD) over 52 weeks as demonstrated by change in measure from the Baseline. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
DB Treatment (Study Part 1):
1.Subject is male or female, aged 18 to 65 years for DB treatment part.
2.Subject reads, understands, and signs an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved current ICF prior to performing any of the Screening procedures.
3.Subject has an identified responsible person(s), (a) an informant as standard for the some of PANSS questions and (b) same or another person referred to as the "contact person" who has agreed to provide information, including about the subject's location if needed during day pass/outpatient portion of the study and also completes the CaCGI. The site personnel must consider this identified responsible person (internal staff/external contact) a reliable contact person, and the contact person must have regular contact with the subject (defined at Screening as direct contact no less than 1 time per week), and with the expectation that this frequency of contact would continue (either in person or via other contact method), throughout duration of the study, including the follow-up period).
4.Subject resides in a stable living situation and is anticipated to return there by Investigator opinion. If needed, medical monitor discussion.
5. Subject must be both medically planned and willing to be or already hospitalized (or in case the subject is not in a position to consent, a legally acceptable representative must be willing to have the subject hospitalized) for the first 28 days of treatment and comply (or legally acceptable representative have subject comply) with all protocol, Investigator, and staff instructions for the entire duration of study.
6. Current hospitalization should have started ≤7 days prior to the date of the Screening Visit.
7. Subject must not have had any psychiatric hospitalizations (social/administrative hospitalizations not included) within 1 month prior to Screening other than the current hospitalization.
8. Meet the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) and confirmed by Mini International Neuropsychiatric Interview (MINI) (version 7.0.2).
9. Have an illness duration for schizophrenia of ≥ 1 year and ≤20 years.
10. Have documented history of relapses and/or exacerbation of symptoms when not receiving adequate dose of antipsychotic treatment, excluding the current episode.
11. Confirmed to be experiencing an acute episode of schizophrenia of at least moderate severity as evidenced by ALL of the following:
a) Onset of the current acute episode is ≤2 weeks prior to Screening.
b) Current symptoms represent a marked and substantial worsening compared with the subject's usual symptomatic state prior to the current acute episode, and are associated with diminished functional ability.
c) In need of increased psychiatric attention (hospital) to treat worsening acute episode symptoms.
d) In need of changing medication or dosage to treat newly appearing or worsening positive symptoms.
e) A CGI-S score of ≥4 (moderately ill) at Screening and Baseline.
f) Screening score on the PANSS of ≥4 (using a 1 to 7 scale) on at least 2 of the following 4 PANSS items: ie, delusions, hallucinatory behavior, conceptual disorganization, suspiciousness/persecution at Screening and Baseline Visits. For further information, see inclusion criterion in protocol.
12. A COVID-19 negative result during screening before Day 0 DB Baseline. Day 0 is one-day window between Day -1 and predose Day 1.
13. Women must either be of non–child-bearing potential (defined as either surgically sterilized or at least 1 year post-menopausal) or if with male partner must comply by abstaining from penile-vaginal intercourse or use with double-barrier protection methods against conception (intrauterine device, diaphragm in addition to spermicidal foam and condom on the male partner, or oral/injected hormonal contraceptives) during the study period. Men with female partners of child-bearing potential are eligible to participate if they agree to 1 of the following methods of contraception during the treatment period and for 2 weeks after treatment. Acceptable male contraception is as follows:
• Abstinence from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent.
• Use of a male condom plus partner use of a contraceptive method with a failure rate of < 1% per year when having penile-vaginal intercourse with a woman of child-bearing potential who is not currently pregnant.
OL Treatment (Study Part 2):
The OL treatment will enroll both DB treatment rollover and de novo subjects, and their eligibility criteria are defined in section 8.3.2.1 of the Protocol. |
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| E.4 | Principal exclusion criteria |
DB Treatment (Study Part 1):
1.Has a history of treatment resistance exhibited by any of the following:
a. No or minimal response to at least 2 periods of treatment lasting 28 days or longer, with antipsychotic agents at the maximally tolerated dose.
b. Lifetime history of clozapine use (verified through the clozapine registry for US subjects only).
c. History of electroconvulsive therapy (ECT) for treatment of schizophrenia within the past 5 years.
2.Is treatment-naïve for schizophrenia.
3.Primary current diagnosis other than schizophrenia or a comorbid diagnosis that is primarily responsible for the current symptoms and functional impairment.
4.Has a current diagnosis of a psychotic disorder other than schizophrenia or a behavioral disturbance thought to be due to substance abuse disorder.
5.Meets criteria for moderate-to-severe substance use disorder within past 6 months prior to Screening (excluding those related to caffeine or nicotine). Mild substance abuse should be documented.
6.Has a history of the following: (a) traumatic brain injury causing ongoing cognitive difficulties, Alzheimer's disease, or another form of dementia, or any chronic organic disease of the central nervous system (CNS) (b) intellectual disability of a severity that would impact ability to participate in the study.
7.Subject has a current primary DSM-5 diagnosis other than schizophrenia, including schizoaffective disorder, major depressive disorder, post-traumatic stress disorder, obsessive-compulsive disorder, manic episode, hypomania, panic disorder, delirium, amnestic or other cognitive disorders. Also, subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
8. History of:
a) Seizures (excluding single episode seizures such as child febrile seizure/posttraumatic/alcohol withdrawal).
b) Neuroleptic malignant syndrome.
c) Tardive dyskinesia.
d) Treatment refractory akathisia, or EPS if severe enough to interfere with evaluations.
e) Any other medical condition that would expose the subject to undue risk or interfere with study assessments.
9. Diabetes if not well controlled including stable medication for a month, with fasting glucose >10mmol/L (185 mg/dL) at Screening.
10. Subject has a BMI <15 or >40 kg/m2.
11. A Screening ECG finding of QT interval corrected for heart rate using Fridericia’s method (QTcF) >450 msec for males and >470 msec for females based on the results from the central reader. In addition, subjects should be excluded if they have any other abnormal ECG finding at Screening that, in the Investigator’s judgment, is medically significant in that it would impact the safety of the subject or the interpretation of the study results.
12. A total white blood cell count below the lower limit of normal for the central laboratory (3.5 x 10^9L) or an absolute neutrophil count of less than the lower limit of normal for the central laboratory (1.80 x10^9/L).
13. An antipsychotic within the Screening Period (minimum 3 days prior to Baseline / Day 0 and throughout the study), but antidepressants are allowed if at a stable dose for at least 28 days prior to Screening.
14. Within 28 days prior to Screening: monoamine oxidase (MAO) inhibitors, CNS stimulants, potent CYP3A4/5 enzyme-inducing drugs including but not limited to rifampin and carbamazepine and strong CYP3A4/5 inhibitors like ketoconazole, itraconazole, clarithromycin, etc.
15. Antipsychotic depot medication within one treatment cycle or minimum 30 days whichever is longer, prior to Screening.
16. Use of substances per the urine dipstick (alcohol, amphetamines, barbiturates, benzodiazepines, cocaine, marijuana and opiates) meeting criteria of moderate-to-severe DSM-5 substance use disorder.
17. Currently participating in, or has participated in, another interventional clinical research study within 6 months prior to the Screening Visit of this current study.
18. Female subject who is pregnant or lactating.
19. Currently under involuntary inpatient confinement or is involuntarily incarcerated.
20. Subject is at significant risk of committing suicide (answer “yes” on question 4 or 5 on C-SSRS) or has a history of suicide attempt in the past 2 years.
21. Any other circumstance or concomitant disease or medication which is felt to create a risk for subject wellbeing or study data integrity in the Investigator’s opinion.
OL Treatment (Study Part 2):
The OL treatment will enroll both DB treatment rollover and de novo subjects, and their eligibility criteria are defined in section 8.3.2.2 of the Protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
For Double-blind (DB) Treatment (Part 1):
• Change in Positive and Negative Syndrome Scale (PANSS) total score compared to placebo from Baseline to Day 28.
• Spontaneously reported adverse events (AEs) and serious adverse events (SAEs),
• Changes in physical examination (including body weight and waist circumference),
• Laboratory parameters vital signs (including orthostatic blood pressure [BP]), and 12 lead electrocardiogram (ECG).
For Open-label (OL) Treatment (Part 2):
• Spontaneously reported AEs and SAEs,
• Changes in physical examination (including body weight and waist circumference),
• Laboratory parameters, vital signs (including orthostatic BP), and 12 lead ECG.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
DB:
From Baseline to Day 28.
OL:
During the 52 weeks OL treatment
|
|
| E.5.2 | Secondary end point(s) |
DB (Part 1):
• CGI-S scales: Proportion of subjects with ≥1-point improvement from Baseline to Day 28.
• Proportion of subjects who achieved remission using the modified Andreasen remission criteria at Day 28 using items from the PANSS Positive, Negative, and General subscales; Marder factors; and social cognition factors; PANSS-Excited Component (EC) (Agitation) scale.
• Personal and Social Performance Scale (PSP).
• Columbia Suicide-Severity Rating Scale (C-SSRS) (Suicidality Scale) and other tolerability-related scales: Abnormal Involuntary Movement Scale (AIMS) total score, Barnes Akathisia Rating Scale (BARS), Changes in Sexual Functioning Questionnaire (CSFQ) and Simpson Angus Scale (SAS).
OL (Part 2):
• Proportion of subjects with ≥ 1- point improvement on the CGI-S scale.
• Proportion of subjects who achieved remission using the modified Andreasen remission criteria at Week 52 using items from the PANSS Positive, Negative, and General subscales; Marder factors; and social cognition factors; PANSS-EC (Agitation) scale.
• PSP Scale.
• Change in PANSS total score from the Baseline to Week 52.
• C-SSRS (Suicidality Scale).
• AIMS total score.
• BARS.
• CSFQ.
• SAS. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
DB:
From Baseline to Day 28
OL:
Change from OL treatment Baseline to Week 52
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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 | 8 |
| 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 |
| India |
| United States |
| Bulgaria |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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