A Clinical trial to evaluate the efficacy of vafidemstat in negative symptoms and cognitive impairment associated with schizophrenia. (EVOLUTION study)

Prior treatment

• Suicide attempt or significant risk of suicide within 6-months prior to the Screening visit or the period between Screening and Baseline visit, defined as a “yes” to suicidal ideation questions 4 or 5, or answering “yes” to suicidal behavior on the Columbia-Suicide Severity Rating Scale.
• The participant is in formal structured nonpharmacological psychosocial therapeutic treatment program (e.g. formal cognitive, behavioral therapy, systematic psychotherapy or vocational rehabilitation, including but not limited to cognitive remediation, cognitive-behavioral therapy, intensive symptom/vocational rehabilitation) for a duration of less that (<3) months before Screening. Any ongoing structured nonpharmacological psychosocial therapeutic treatment initiated more than 3 months prior to Screening should be continued with the same frequency and intensity during the entire study.
• A previous or current diagnosis of neuroleptic malignant syndrome.
• Treated with and is resistant to clozapine according to the investigator’s judgement.
• Hospitalization or medication change for any reason 3 months (see inclusion criteria #6) prior to the Screening visit or during the Screening period that makes the participant medically or mentally unsuitable for trial participation.
• Clinically significant infection within the previous 30-days (e.g., persistent, or acute infection such as a urinary tract infection or upper respiratory infection).
• Is treatment resistant. Treatment resistance is defined as inadequate response in the level of psychotic symptoms during more than two (2) documented treatment courses with adequate doses of antipsychotic medications prescribed for adequate periods of time (i.e., at least lasting for 6 weeks) within 2 years prior to the Screening Visit.
• Esketamine and psychedelic treatments (e.g. psilocybin or ketamine) in the past 90 days before the Screening visit.
• Electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) in the past 3 months before the screening visit, and during the trial.
• Any regular intake of medications acting directly on the central nervous system that investigator believes may impact cognition or function.
• Enrollment in another investigational study or intake of investigational drug within the previous 3 months.
• Current DSM-5 diagnosis of panic disorder or agoraphobia. Participants with post-traumatic stress disorder (PTSD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), MDD without psychosis, attention deficit hyperactivity disorder (ADHD) are eligible if symptoms have been stable for at least 90 days prior to the Screening visit, these disorders are not the primary focus of treatment, changes in any treatment for these disorders would not likely be required for the duration of the study, and in the investigator´s opinion these disorders will not interfere with the assessment and/or accuracy of the study endpoints.
• Current diagnosis or a history of substance use disorder according to DSM-5™ criteria within 6 months prior to the Screening Visit. a. Nicotine, caffeine, alcohol and/or cannabis use is not prohibited unless it qualifies as a substance use disorder per DMS-5™.
• Use of illicit drugs for at least one week before Screening and participants unwilling to abstain from use of these substances during the study. Regarding cannabis, patient self-report of abstinence within 24 hours will be used for inclusion decision-making versus the urine drug test results.

Other illness

• Failure to perform screening or baseline procedures.
• Positive results for tuberculosis (the status must be determined as usual clinical practice, that is, by medical history, signs, and symptoms), Human Immunodeficiency Virus (HIV), Hepatitis C or Hepatitis B (Hepatitis B surface antigen [HBsAg]) serology obtained at the Screening Visit
• Any condition that in the opinion of the investigator makes the participant unsuitable for inclusion in the study.
• Diagnosis with any DSM-5 Schizophrenia Spectrum and Other Psychotic Disorders other than schizophrenia.
• DSM-5 diagnosis of neurodevelopmental disorders including, but not limited to, intellectual disability, autism spectrum disorder as well as bipolar disorder and related disorders or major depressive disorder (MDD) with psychosis.
• Current DSM-5 diagnosis of anorexia nervosa, bulimia nervosa, binge-eating disorder, oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, paranoid personality disorder, borderline personality disorder or obsessive-compulsive disorder

Lab values

• Clinically significant, advanced, or unstable disease that is likely to result in rapid deterioration of the participant’s condition or affect their safety during the study, including but not limited to: a. Seizure disorders, excluding febrile seizures of childhood b. Respiratory insufficiency, the status must be determined as usual clinical practice c. Hepatic impairment (serum values of total bilirubin value, alanine aminotransferase [ALT], aspartate aminotransferase [AST] and/or gamma-glutamyl transferase [GGT] 1.5 times the upper limit of normal [ULN]). Any elevations greater than 1.5 times the ULN will be reviewed by the Medical Monitors on a case-by-case basis, and these participants will only be allowed with Sponsor approval. d. Renal insufficiency (serum creatinine >2mg/dl) e. Heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within 6 months before Screening visit) f. Hypertension treatment with more than 2 drugs g. Atrioventricular block (type II/Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcF-interval (males >450 msec and females >470 msec) h. Uncontrolled diabetes (Hb1Ac >7.5) i. Hematological disorders j. Platelets <130,000/mm3 and/or neutrophils <1,800/mm3 k. Malignant tumors within the last 5 years other than basal cell or Stage 1 squamous cell carcinoma of the skin l. Moderate-to-severe traumatic brain injury
• Uncontrolled hypo- or hyperthyroidism at Screening Visit, based on laboratory parameters.
• Chronic drug intake of: a) Anticoagulants (only 81 mg/day acetylsalicylic acid is permitted) b) Corticosteroids or immunosuppressant (only inhaled or topical suspension are allowed) c) Myelosuppressive treatments such as chemotherapy and radiation d) Medications known to be UGT inhibitors or inducers should be used with caution (*) - (*) UGT Inhibitors (e.g.: adenine, propofol, flunitrazepam, ertugliflozin, ketoconazole, valproic acid, flurbiprofen, silibinin, sodium aurothiomalate, gemfibrozil, deferasirox, probenecid, amitriptyline, indomethacin, ubrogepant) - UGT inducers (e.g.: carbamazepine, phenytoin, phenobarbital, rifampicin, testosterone propionate, lamotrigine, primidone, ethinylestradiol, desogestrel, orthosiphon stamineus) These lists are not intended to be exhaustive. Drug-Drug Interactions (DDI) interactions should be reviewed on the label. e) Hypnotics as Z-drugs – i.e.: zaleplon, zolpidem, zopiclone – are allowed in occasional short-term prescription. Participants should not have this medication within 24 hours before any study visit. f) The concomitant use of short and medium half-life oral benzodiazepines in stable dose for at least 3 months before the Screening visit is allowed for the treatment of psychiatric comorbidities (as per inclusion/exclusion criteria) when these medications are prescribed as per their labelled indications. The dose should remain stable throughout the study. g) The concomitant use of MAO inhibitors and antidepressants in stable dose for at least 3 months before the Screening visit is allowed for the treatment of psychiatric comorbidities (as per inclusion/exclusion criteria) when these medications are prescribed as per their labelled indications XX. XXXXXX h) The concomitant use of typical antipsychotics is forbidden. The concomitant use of atypical antipsychotics (except clozapine, which is forbidden), in stable dose for at least 3 months before Screening visit is allowed for the treatment of psychiatric comorbidities (as per inclusion/exclusion criteria) when these medications are prescribed as per their labelled indications. The dose should remain stable throughout the study. i) The concomitant use of mood stabilizers in stable dose for at least 3 months before Screening visit is allowed for the treatment of psychiatric comorbidities (as per inclusion/exclusion criteria) when these medications are prescribed as per their labelled indications. j) The concomitant use of nootropics; for instance, racetams, amphetamines, methylphenidate, levodopa, atomoxetine, preparations containing Gingko biloba, is forbidden throughout the study and two weeks before the Screening visit. k) The concomitant use of centrally active anti-hypertensive drugs, such as clonidine, a-methyldopa and guanfacine hydrochloride, as well as guanethidine, is forbidden throughout the study and two weeks before the Screening visit. l) The concomitant use of medications which may have an impact on blood cells count changes should be used with caution (e.g.: heparin, quinine, quinidine, penicillin, sulphonamides, NSAIDs, anticonvulsants, antirheumatics, oral antidiabetics, gold salts, diuretics rifampicin, ranitidine). This list is not intended to be exhaustive. Drug-Drug Interactions (DDI) interactions should be reviewed in the label of the concomitant medications. m) The concomitant use of platelet aggregation inhibitors should be used with caution (e.g.: COX-2 inhibitors, ADP receptor inhibitors, thromboxane inhibitors). This list is not intended to be exhaustive. Drug-Drug Interactions (DDI) interactions should be reviewed in the label of the concomitant medications.

Other

• Use of alcohol or cannabinoids within 24 hours of a study visit.
• Member or immediate family of the study personnel or subordinate to any of the study personnel.
• Undergoing gender reassignment and, particularly, gender affirming hormone treatments.

• Male or female participant 18-55 years of age.
• Otherwise, healthy, and medically stable based on medical history.
• Clinical and neurological examinations and laboratory tests, as well as 12-lead ECG performed during screening that confirms the participant is healthy and medically stable.
• Able to read and write fluently and must have adequate hearing and visual acuity to complete the required testing outlined in this protocol.
• Negative Covid-19 test (PCR, antigen test or serology) at Screening (only applicable if Covid-19 precautions are still in force by the time of the Screening Visit).
• The participant has a study partner/caregiver (e.g. family member, social worker, caseworker, residential facility staff, or nurse) who, in the investigator's judgement, has frequent and sufficient contact (i.e. spends at least 4 hours/week with the participant) and can accompany the participant during study visits, as well as provide accurate information about the participant's cognitive and functional abilities. A separate informed consent must be provided by the study partner/caregiver.
• Stable living environment for > 6 months before the Screening visit, as confirmed by study partner/caregiver.
• Fertile male and female participants must use highly efficient contraception, from the Screening visit until 30 days after last dose of the IMP, defined as: A method with less than 1% failure rate (e.g., permanent sterilization, hormone implants, hormone injections, some intrauterine devices, or vasectomized partner) OR The use of two methods of contraception (e.g., one barrier method [condom, diaphragm, or cervical/vault caps] with spermicide and one hormonal contraceptive [e.g., combined oral contraceptives, patch, vaginal ring, injectable and implants]).
• Female participants of childbearing potential must have a negative urine pregnancy test at screening and baseline.
• Signed informed consent by the participant and the participants´ study partner/caregiver. Investigator needs to judge and determine whether the participant is capable of understanding and complying with study requirements.
• A current diagnosis of schizophrenia, according to DSM-5™ as confirmed by the Mini International Neuropsychiatric Interview (MINI) Version 7.0.2 at Screening
• Documented DSM-5™ diagnostic criteria for schizophrenia greater than one (1) year
• Persistent, predominant negative symptoms (PNS) of schizophrenia, and minimal positive symptoms, defined as: o PANSS Factor Score for Negative Symptoms (PANSS-FSNS) of >24 at Screening and Baseline with ≤ 4 points total difference between these visits, AND o Minimal positive symptomatology as defined by a PANSS - positive symptoms ≤ 20 and individual scoring ≤ 4 for any of the 7 items of the positive scale at Screening and Baseline.
• Stable in terms of positive and negative symptoms of schizophrenia over the last 3 months according to their referring/treating psychiatrist and based upon medical records documentation.
• Outpatient and day treatment (i.e., those not requiring 24-hour inpatient care) participants with stable symptomatology >=3 months prior to the Screening visit (e.g., no acute hospitalizations for schizophrenia, no emergency room admission due to symptoms of schizophrenia, no increase in level of psychiatric care due to worsening schizophrenia symptoms, no changes in atypical antipsychotic medications)
• Stable in their regimen of background therapy other than for psychiatric indications for at least 3 months, as per the Summary of Product Characteristics (SmPC) for concomitant medications at the Screening visit, and they should maintain treatment throughout the study and do not initiate any prohibited medications during the trial. Participants should agree to inform their study physician of any medication changes throughout the trial.
• Body mass index (BMI) between 18.5-35 kg/m2, at screening. Participants with a BMI between 35-40 kg/m2 will be reviewed by the Medical Monitors on a case-by-case basis (e.g., cardiovascular risk factors, laboratory results) to ensure participant safety, and only permitted with Sponsor approval
• Considered by the investigator to be reliable and willing and able to adhere to the prohibitions, restrictions and requirements specified in this protocol.