| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with schizophrenia who are experiencing an acute exacerbation of psychosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Schizophrenia is mental disorder that exhibits problems with positive symptoms (e.g. hallucinations), negative symptoms (e.g. lack of motivation) and cognitive deficits (e.g. information processing). |
|
| 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 | HLGT |
| E.1.2 | Classification code | 10039628 |
| E.1.2 | Term | Schizophrenia and other psychotic disorders |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| 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 long-term safety and tolerability of oral emraclidine in adult participants with schizophrenia |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Rollover Participants
1. Completed 6 weeks of post-randomization treatment in Trial CVL-231-2001 or CVL-231-2002 and who, in the opinion of the investigator, could potentially benefit from treatment with emraclidine for schizophrenia.
2. Outpatient status at last day of treatment period (Day 45) of the preceding double-blind trial (CVL-231-2001 or CVL-231-2002) defined as follows:
• Ability to be discharged from the hospital on Day 45 of Trial CVL-231-2001 or CVL-231-2002
• Hospitalization for psychosocial reasons (eg, homelessness or need for shelter that is unrelated to the participant’s underlying psychiatric condition) will be considered outpatient status
• Participants remaining in hospital at Day 45 of Trial CVL-231-2001 or CVL-231-2002 (for other than psychosocial reasons) will be permitted to enroll in Trial CVL-231-2003 at Day 45 of the double-blind trial if they are planned to be discharged from the hospital before the Week 1 visit of Trial CVL-231-2003
• Participants not discharged by the Week 1 visit of Trial CVL-231-2003 must be withdrawn
3. Agree to comply with the following contraception requirements during the trial and for 7 days after the last dose of IMP:
• Sexually active men must agree to use a condom during treatment and until the end of relevant systemic exposure in women of childbearing potential (ie, 7 days after the last dose of IMP)
• Sexually active women of childbearing potential must use acceptable (at minimum) contraception as defined in Section 10.4.1.1 of the Protocol
In addition, male participants should not donate sperm for a minimum of 7 days following the last dose of IMP.
4. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in Section 10.1.3. of the Protocol
5. Ability, in the opinion of the investigator, to understand the nature of the trial, participate in trial visits, and comply with protocol requirements, including the prescribed dosage regimens, scheduled visits, laboratory tests, outcomes measures, and other trial procedures.
De Novo Participants
6. Male and female participants, ages 18 to 65 years, inclusive, at the time of signing the ICF.
7. Primary diagnosis of schizophrenia per DSM-5, as confirmed by the MINI for Psychotic Disorders version 7.0.2.
8. Participants who have been stable on antipsychotic medication for at least one 3-month period in the year prior to screening (received the same medication or group of medications for at least 3 consecutive months in the prior year and demonstrated stability of symptoms on the antipsychotic medication).
9. Outpatient status at the time of signing the ICF. Hospitalization for psychosocial reasons (eg, homelessness or need for shelter that is unrelated to the participant’s underlying psychiatric condition) will be considered outpatient status. Participants may be hospitalized for not more than 14 days during the conversion to emraclidine with the approval of the medical monitor but must be discharged from the hospital before the Week 1 visit.
10. Scores as follows (normal to mild symptoms) at the time of signing the ICF and Baseline (Day 1):
• All individual items of the SAS <2
• All individual items (Items 1-7) of the AIMS <2
• Clinical global assessment item of the BARS <3
11. Willing to discontinue all prohibited medications to meet protocol-required washouts prior to and during the trial period.
12. Resides in a stable living environment as demonstrated by the ability to provide contact information for themselves and/or family/friend/caregiver.
13. Agree to comply with the following contraception requirements during the trial and for 7 days after the last dose of IMP:
• Sexually active men must agree to use a condom during treatment and until the end of relevant systemic exposure in women of childbearing potential (ie, 7 days after the last dose of IMP).
• Sexually active women of childbearing potential must use acceptable (at minimum) contraception as defined in Section 10.4.1.1 of the Protocol
In addition, male participants should not donate sperm for a minimum of 7 days following the last dose of IMP.
14. Body mass index of 18.0 to 40.0 kg/m2 and a total body weight ≥50 kg (110 lbs).
15. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in Section 10.1.3. of the Protocol
16. Ability, in the opinion of the investigator, to understand the nature of the trial, participate in trial visits, and comply with protocol requirements, including the prescribed dosage regimens, scheduled visits, laboratory tests, outcomes measures, and other trial procedures. |
|
| E.4 | Principal exclusion criteria |
Rollover Participants
1.Participants who had a clinically significant medical, surgical, psychiatric, or laboratory/ECG abnormality during conduct of the previous double-blind trial that could compromise either participant safety or the results of the trial
2.“Yes” responses for suicidal ideation item 4 and 5 or any of the suicidal behavior items on the C-SSRS at any time point during the prior double-blind trial
3.Likely to require prohibited concomitant therapy during the trial
4.Positive pregnancy test result prior to receiving IMP
5.Orthostatic hypotension or Systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg at the Week 6 Visit (Day 45) of preceding double-blind trial
6.Considering or scheduled to undergo any surgical procedure during the trial
De Novo Participants
7.Current DSM-5 diagnosis other than schizophrenia
8. Schizophrenia considered resistant/refractory to antipsychotic treatment by history or history of response to clozapine treatment only or failure to respond to clozapine treatment for schizophrenia
9.History of tardive dyskinesia or extrapyramidal symptoms that required medication within 6 months prior to signing the ICF
10.Current or past history of significant pulmonary, gastrointestinal, renal, hepatic, metabolic, genitourinary, endocrine, malignancy, hematological, immunological, neurological, or psychiatric disease that could compromise either participant safety or the results of the trial
11.Current or past history of significant cardiovascular disease
12.Active central nervous system infection, demyelinating disease, degenerative neurological disease, intellectual disability, brain tumor, prior hospitalization for severe head trauma, seizures, or any central nervous system disease deemed to be progressive during the course of the trial that may confound the interpretation of the trial results
13.Diagnosis of moderate to severe substance or alcohol-use disorder as per DSM-5 criteria within 12 months prior to signing the ICF
14.“Yes” responses for suicidal ideation item 4 and 5 or any of the suicidal behavior items on the C-SSRS (within the past 6 months)
15.Any condition or surgery that could possibly affect drug absorption
16.This criterion has been removed effective protocol version 3.0
17.Use of prohibited medications prior to randomization within the required wash-out period or likely to require prohibited concomitant therapy during the trial
18.Transcranial magnetic stimulation or electroconvulsive therapy within 90 days of signing the ICF
19.Positive result for HIV antibody, HBV surface antigen, or HCV antibody with detectable viral RNA levels at Screening
20.Positive drug screen or a positive test for alcohol
21. AST or ALT ≥2 × ULN or total bilirubin >1.5 × ULN at the Screening Visit, confirmed by a single repeat measurement
22.Positive pregnancy test result prior to receiving IMP
23.12-lead ECG demonstrating any of the following at the Screening Visit and at Baseline:
• QTcF interval >450 ms
• QRS interval >120 ms (unless right bundle branch block)
• PR interval >200 ms
• LVH with ST depressions and/or T wave inversions in leads with relatively tall R waves
• Type 2 second-degree or third-degree atrioventricular block
• Heart rate <45 bpm or >100 bpm
• Abnormal ECG changes
• Abnormal heart rhythm
24.Orthostatic hypotension or Systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg at the Screening Visit and/or at Baseline
25.Any other abnormal safety findings unless, based on the investigator’s judgment, the findings are not medically significant and would not impact the safety of the participant or the interpretation of the trial results. The medical monitor should be contacted to discuss individual cases, as needed
26.Considering or scheduled to undergo any surgical procedure during the trial
27.Any other condition that would preclude IMP administration or trial participation
28.Known allergy or hypersensitivity to emraclidine, closely related compounds, or any of its specified ingredients
29.Received IMP in a prior clinical trial of emraclidine, with the exception of Trial CVL-231-1005
30.History of participation in any clinical trial involving an IMP as defined by the following:
• Current enrollment in another interventional trial, with the exception of a trial with a long-term follow-up period where dosing occurred more than 12 months prior to signing the ICF for this trial
• Enrollment in more than 2 interventional trials within 12 months prior to signing the ICF
31.Anyone who should not participate in the trial in the opinion of the sponsor, investigator, or medical monitor, eg, participants who would be considered a risk for violent or destructive behavior
32.Employee of the investigator, clinic, or sponsor with direct involvement in the proposed trial or other trials under the direction of the investigator or clinic, as well as family members of the employee or investigator |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Treatment-emergent adverse events
• Clinically significant changes in vital sign measurements, body weight, physical and neurological examination results, ECG assessments, clinical laboratory assessments, and metabolic parameters
• Clinically significant findings in suicidality assessed using the C-SSRS
• Extrapyramidal symptoms evaluated using the change from Baseline in SAS, AIMS, and BARS assessments |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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 | 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 | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| United States |
| Bulgaria |
| Hungary |
|
| 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 the trial is defined as the date of the last visit (including follow-up safety contact) of the last participant in the trial globally |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 9 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 9 |
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