| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cognitive impairment associated with schizophrenia |
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| E.1.1.1 | Medical condition in easily understood language |
| Disorder that affects the ability to think, concentrate, formulate ideas, reason and remember and is associated with schizophrenia |
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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 | 18.1 |
| 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 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009846 |
| E.1.2 | Term | Cognitive impairment |
| E.1.2 | System Organ Class | 100000004852 |
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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 |
| The primary objectives of this study are to assess the safety and the efficacy of 2 doses of once daily EVP-6124 tablets (1 and 2 mg) as an adjunctive pro-cognitive treatment, versus placebo, when added to chronic, stable, atypical antipsychotic therapy in subjects with schizophrenia. Safety will be determined by clinical and laboratory safety assessments. Efficacy will be determined by cognitive function as measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS™) Consensus Cognitive Battery (MCCB™) Neurocognitive Composite Score, and by clinical function as measured by the interview-based Schizophrenia Cognition Rating Scale (SCoRS). |
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| E.2.2 | Secondary objectives of the trial |
| The key secondary objective is to assess the clinical efficacy of EVP-6124, versus placebo, as measured by Negative Symptom Factor (Marder Factor) of the Positive and Negative Syndrome Scale (PANSS) for the dose or doses that met both co-primary objectives. Additional secondary objectives are to assess the clinical efficacy of 2 doses of once daily EVP-6124 versus placebo, as measured by the Negative Subscale of the PANSS, MCCB Overall Composite Score, SCoRS Global Rating,Clinical Global Impression-Severity (CGI-S), Clinical Global Impression - Change scale (CGI-C), and quality of life, using the EuroQol-5D™ (EQ-5D). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Signed informed consent, indicating that the subject understands the purpose of and procedures required for the study, before the initiation of any study specific procedures. Subjects who are unable to provide informed consent will not be included in the study
2.Signed acknowledgment of responsibilities by an identified informant before the initiation of any activities required by the study for the designated informant
3.Male or female subjects of any race; between 18 to 50 years of age, inclusive
4.Resides in a stable living situation, according to the investigator’s judgment, and must have an identified informant who should be consistent throughout the study. If possible, the informant should accompany the subject or be available for in person ratings at the screening, baseline (Day 1) and final study visits. In person informant ratings on all relevant study visits are preferred whenever possible. However, if the informant is not available for in person ratings, telephone interview is acceptable. The informant must be available for a telephone interview throughout the study at all visits. As long as both the informant visit and subject visit are within the study visit windows, it is not necessary that they occur on the same day. The informant must interact with the subject at least 2 times a week.
5.Diagnosis of Schizophrenia of at least 3 years duration established by utilizing the SCID-I, direct clinical assessments, family, informants, and confirmation of diagnosis from clinical sources (medical records, confirmation of diagnosis by treating clinician through telephone contact, written confirmation from treating clinic, or other sources of diagnostic confirmation may also be acceptable after discussion with the medical monitor).
6.(Schizophrenia) illness in a nonacute (eg, chronic) phase as determined by their primary treating clinician
7.Treated with an atypical antipsychotic drug (in any approved dosage form) other than clozapine at a stable dose for at least 8 weeks before screening and be clinically stable; the subject must remain clinically stable (in the opinion of the principal investigator) through randomization. The use of up to 2 atypical antipsychotic drugs is permitted, as long as in the opinion of the investigator, the second medication is not required to control treatment-resistant or intractable psychotic symptoms. No subject will be washed off antipsychotic therapy to become eligible for this study.
8.Schizophrenia clinical symptom burden severity defined by the following: a Brief Psychiatric Rating Scale (BPRS) Conceptual Disorganization item score ≤ 4; and, a BPRS Hallucinatory Behavior item score ≤ 5, or an Unusual Thought Content item score ≤ 5. Either Hallucinatory Behavior or Unusual Thought Content, but not both, may have a score of 6 (but not > 6).
9.A minimal level of EPS; SAS total score ≤ 6
10.A minimal level of depression; CDSS total score ≤ 10
11.General health status acceptable for participation in a 26-week clinical study
12.Fertile, sexually active subjects (men and women) must use an effective method of contraception during the study. Female subjects and the female partner of male subjects must be surgically sterile (hysterectomy or bilateral tubal ligation), postmenopausal for at least 1 year, or willing to practice adequate methods of contraception if of childbearing potential (defined as consistent use of combined effective methods of contraception [including at least 1 barrier method])
13.Women of childbearing potential must have a negative pregnancy test at screening and pre-dose on Day 1
14.Fluency (oral and written) in the language in which the standardized tests will be administered
15.The ability to refrain from using any tobacco or other nicotine-containing products for at least 30 minutes before any cognitive testing |
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| E.4 | Principal exclusion criteria |
1.Violation of any inclusion criteria
2.Failure to perform screening or baseline examinations
3.Hospitalization within 12 weeks before screening or during the screening period, or change of antipsychotic medication or dose within 8 weeks before screening or during the screening period (Section 8.1)
4.Psychiatric hospitalization or incarcerations due to breakthrough symptoms or acute exacerbations for a period of 3 months before screening. Subjects with a recent “social” hospitalization or incarceration may be entered into screening after consultation with the medical monitor
5.Participation in another therapeutic (medication administration) clinical study within the past 2 months
6.Likelihood, in the opinion of the investigator, that either the subject or informant will be unable to complete a 26-week study
7.Serum electrolytes (sodium, potassium, and magnesium) clinically significantly abnormal
8.Insufficiently controlled diabetes mellitus in the judgment of the investigator
9.Renal insufficiency with serum creatinine > 1.8 mg/dL
10.Malignant tumor within the last 5 years with the exception of squamous and basal cell carcinoma or cervical carcinoma in situ
11.Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study
12.Unstable medical condition that is clinically significant in the judgment of the investigator
13.Body mass index (BMI) of > 38 kg/m2
14.History of myocardial infarction or unstable angina within the last 3 months before screening
15.Cardiovascular disease history; including uncontrolled hypotension or hypertension, that is clinically significant in the judgment of the investigator
16.Clinically significant abnormality on screening or baseline (pre-dose Day 1) ECG, including but not necessarily limited to a confirmed QTc value ≥ 450 msec for males or ≥ 470 msec for females
17.Alanine transaminase (ALT) or aspartate transaminase (AST) > 2.5 times the upper limit of normal (ULN)
18.Treatment with prohibited antipsychotic drug, and/or treatment with more than 2 permitted antipsychotic drugs. Treatment with a first generation antipsychotic drug (typical antipsychotic) is prohibited unless it is administered at a low dose after discussion with the medical monitor.
19.Current treatment with any anticholinergic agent
20.Subjects with other DSM-IV-TR Axis I or Axis II disorders are ineligible if the comorbid condition is clinically unstable or has been the focus of treatment in the past 3 months
21.DSM-IV criteria for alcohol abuse within the past 3 months or substance abuse (other than nicotine) within the last 6 months before screening
22.Significant suicide risk as defined by 1) suicidal ideation as endorsed on items 4 and 5 of the C-SSRS within the past 2 years) suicidal behaviors detected by the C SSRS during the past 2 years; or 3) psychiatric interview and examination
23.Subjects planning to initiate a new course of cognitive remediation or psychotherapy during the study period including cognitive and cognitive-behavioral therapies. Subjects who have been receiving individual or group therapy with no significant change in frequency or focus for at least 3 months prior to screening are eligible for enrollment
24.Stroke within 6 months before screening
25.History of brain tumor, subdural hematoma, or other clinically significant neurological condition within the past 12 months before screening
26.Head trauma with loss of consciousness within 12 months before screening
27.Active acute or chronic CNS infection
28.History of a chronic seizure disorder
29.Untreated clinically significant hypothyroidism or hyperthyroidism
30.History of mental deficiency
31.MAO inhibitor antidepressants or tricyclic medications used in antidepressant doses are excluded. Other antidepressant medications are allowed if the subject has been treated with a stable dose for at least 3 months before screening.
32.Immunosuppressants (administered at a dose that is considered to be immunosuppressant, in the judgment of the investigator)
33.Mood stabilizers (eg, lithium) unless the subject has been treated at a stable dose for ≥ 8 weeks prior to screening
34.Use of benzodiazepine medication is allowed if the subject has not had a change in medication or dose for at least 3 months. For subjects prescribed benzodiazepines, short-acting benzodiazepines are to be used whenever possible. Use of longer-acting benzodiazepines may be acceptable if prior authorization is obtained from the medical monitor. The use of more than one sedative-hypnotic medication is not allowed.
35.Chronic intake of clinically significant (in the judgment of the investigator) doses of opioid containing analgesics or any current methadone treatment
36.Use of CNS stimulants (eg, Adderall, Ritalin)
37.Nicotine therapy, varenicline (Chantix), or similar therapeutic agent within the last 6 months before screening
38.Prohibited antipsychotic medications (Section 8.2)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Cognition will be assessed by MCCB and functional status by SCoRS interviewer total score. The co-primary endpoints are the change from baseline in MCCB Neurocognitive Composite Score and change from baseline in the SCoRS, for EVP-6124 compared to placebo at Day 182. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of each primary endpoint will be performed on the ITT population. Changes from baseline in each assessment at Days 28, 56, 84, 182, and over all visits will be analyzed using a mixed-effects model repeated measures (MMRM) analysis that includes country, visit, treatment, and treatment-by-visit interaction as fixed effects, baseline as a covariate, and subject as a random effect. Each dose level of EVP-6124 will be compared to placebo. |
|
| E.5.2 | Secondary end point(s) |
| The key secondary endpoint is the change from baseline to Day 182, as measured by the Negative Symptom Factor (Marder Factor) of the PANSS for the dose or doses that met both co-primary objectives. Additional secondary endpoints: the Negative Subscale of the PANSS, MCCB Overall Composite Score, SCoRS Global Rating, CGI-C and CGI-S. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Changes from baseline in the Modified MCCB (excluding the MSCEIT), negative subscale of the PANSS, and EQ-5D will be analyzed using the same methods as the primary endpoints.
Other secondary endpoints comprise the CGI-C at Days 28, 56, 84, 112, 140, and 182 in the ITT and PP populations.
The PANSS and EQ-5D will be performed at Days -14, -4, 1 (pre-dose), and 28, 56, 84, 112, 140, and 182.
The CGI-S will be performed at Days 1 (pre-dose, baseline), and 28, 56, 84, 112, 140, and 182.
The CGI-C will be performed at Days 28, 56, 84, 112, 140, and 182. |
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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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 |
| Argentina |
| Australia |
| Canada |
| Colombia |
| Mexico |
| Poland |
| Romania |
| Russian Federation |
| Ukraine |
| United Kingdom |
| United States |
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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
|
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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