Evaluation of Vafidemstat on Negative Symptoms and Cognitive Impairment in Adult Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled Phase IIb Trial
- Trial ID
- 2023-507372-42-00
- Protocol
- CL09-ORY-2001
- Sponsor
- Oryzon Genomics S.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the effect of **vafidemstat** on negative symptoms of schizophrenia in adult patients. Negative symptoms, such as reduced emotional expression and social withdrawal, significantly impact the quality of life and functional outcomes in individuals with schizophrenia. Addressing these symptoms is crucial for improving patient prognosis and overall well-being.
Secondary objectives include:
- Assessing the effect of vafidemstat on cognitive impairment associated with schizophrenia (CIAS) in adult patients.
- Evaluating the effect of vafidemstat on positive symptoms of schizophrenia in adult patients.
- Assessing the effect of vafidemstat on the Positive and Negative Syndrome Scale (PANSS) Total Score in adult patients.
- Evaluating the effect of vafidemstat on functional impairment in adult schizophrenia patients.
- Evaluating the safety of vafidemstat in adult schizophrenia patients.
- Assessing the effect of vafidemstat on the use of health care services in adult schizophrenia patients.
- Evaluating the effect of vafidemstat on the use of stable background antipsychotic medication in adult schizophrenia patients.
Participants
The clinical trial focuses on evaluating the effect of vafidemstat on the **negative symptoms** of **schizophrenia** in adult patients. The study population comprises both male and female participants aged 18 to 55 years, who are otherwise healthy and medically stable based on comprehensive medical assessments. Participants are required to have a stable living environment and a study partner or caregiver who can provide accurate information about their cognitive and functional abilities. The trial does not include a vulnerable population. Participants must have a body mass index (BMI) between 18.5 and 35 kg/m², with those having a BMI between 35 and 40 kg/m² being reviewed on a case-by-case basis for safety. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize the stability of schizophrenia symptoms and the absence of significant positive symptoms, as well as the requirement for participants to maintain a stable regimen of background therapy. Lifestyle considerations such as the use of highly efficient contraception and the ability to adhere to study requirements are also integral to participant selection.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** Phase IIb study to evaluate the efficacy of **vafidemstat** in treating negative symptoms and cognitive impairment associated with **schizophrenia**. The trial will span a duration of 24 weeks, with an estimated end date of December 31, 2026. Participants will be randomly assigned to receive either vafidemstat or a placebo, both administered in capsule form via **oral use**. The primary objective is to assess the change in the PANSS Factor Score for Negative Symptoms (PANSS-FSNS) from baseline to week 24 between the active treatment and placebo arms. Secondary endpoints include evaluating changes in cognitive function using the Brief Assessment in Cognition in Schizophrenia (BACS) and other clinical measures over the same period.
The study will involve several key visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, health status, and a confirmed diagnosis of schizophrenia according to DSM-5™ criteria. Participants must also have a study partner or caregiver who can provide additional information and support. Following the screening, participants will undergo baseline assessments before commencing the treatment phase. Regular follow-up visits will be conducted to monitor efficacy and safety, with assessments including physical examinations, laboratory tests, and evaluations of psychiatric symptoms. The end-of-study visit will occur at week 24, where final assessments will be made to determine the overall impact of the treatment.
Participant involvement is expected to last approximately 28 weeks, including the screening period. Conditions that may lead to early termination from the study include the occurrence of serious treatment-emergent adverse events (TEAEs), non-compliance with study protocols, or withdrawal of consent. The study is structured to ensure participant safety and the integrity of the data collected, with all procedures adhering to ethical guidelines and regulatory requirements.
Treatment
The clinical trial involves the administration of **vafidemstat**, an experimental medication developed by Oryzon Genomics S.A. Vafidemstat is provided in the form of **capsules** for **oral use**. The active substance, vafidemstat, is of chemical origin. The trial is designed to evaluate the efficacy of vafidemstat in treating negative symptoms and cognitive impairment associated with schizophrenia. The maximum treatment period for vafidemstat is 180 days. The dosage and frequency of administration are determined according to the study protocol, ensuring adherence to the specified dosing schedule. Participant compliance is monitored throughout the trial to ensure accurate assessment of the medication's effects.
In addition to the experimental treatment, the study includes a **placebo** control group. The placebo capsules are Swedish orange-colored, size 3, and are visually identical to the vafidemstat capsules but contain no active drug substance. The use of placebo is integral to maintaining the double-blind nature of the trial, allowing for unbiased evaluation of vafidemstat's efficacy. The placebo is administered following the same schedule as the experimental medication, ensuring consistency in the treatment regimen across all study participants.
Efficacy
The efficacy of **vafidemstat** in treating negative symptoms and cognitive impairment associated with schizophrenia will be assessed in a double-blind, randomized, placebo-controlled, adaptive 24-week Phase IIb trial. The primary endpoint for evaluating efficacy is the change in the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS) from baseline to week 24, comparing the active treatment arm with the placebo arm. Secondary endpoints include the change from baseline to week 24 on the Brief Assessment in Cognition in Schizophrenia (BACS), as well as changes over time on the PANSS-FSNS and BACS. Additional secondary endpoints involve evaluating differences from baseline to week 24 and changes over time on the PANSS Positive Symptoms Subscale (PANSS-PSS), PANSS Total Score, Clinical Global Impression – Severity (CGI-S) for Schizophrenia, and the Personal and Social Performance Scale (PSP).
Assessments will be conducted at every study visit from baseline to week 24, including the number of visits to healthcare services and changes in stable background therapy. The efficacy parameters will be measured using validated scales such as PANSS and BACS, ensuring reliable and consistent data collection. The trial will also monitor safety endpoints throughout the study, from baseline to week 28, including the number, frequency, and severity of Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs, as well as the use of concomitant medications and frequency of physical examination parameters and vital signs.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female participant 18-55 years of age.
- 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.
- 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.
Exclusion Criteria
- Failure to perform screening or baseline procedures.
- 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.
- Diagnosis with any DSM-5 Schizophrenia Spectrum and Other Psychotic Disorders other than schizophrenia.
- Undergoing gender reassignment and, particularly, gender affirming hormone treatments.
- 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
- 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.
- Use of alcohol or cannabinoids within 24 hours of a study visit.
- 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, 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
- 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
- Uncontrolled hypo- or hyperthyroidism at Screening Visit, based on laboratory parameters.
- Clinically significant infection within the previous 30-days (e.g., persistent, or acute infection such as a urinary tract infection or upper respiratory infection).
- 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.
- 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.
- Member or immediate family of the study personnel or subordinate to any of the study personnel.
- Enrollment in another investigational study or intake of investigational drug within the previous 3 months.
- Any condition that in the opinion of the investigator makes the participant unsuitable for inclusion in the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Recruiting | 16 Nov 2021 | 65 |
 Poland | Not Yet Recruiting | 16 Nov 2021 | 30 |
 Romania | Recruiting | 16 Nov 2021 | 40 |
 Slovakia | Not Yet Recruiting | 16 Nov 2021 | 20 |
 Spain | Recruiting | 16 Nov 2021 | 84 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo capsules will be supplied as Swedish orange colored size 3 capsules that look identical to the
vafidemstat capsules but contain no drug substance. | Placebo | N/A | — | — | — | N/A |