Study With Lu AF11167 for the Treatment of Negative Symptoms in Patients With Schizophrenia

Study Overview
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Brief Summary
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A study to evaluate the efficacy of 2 fixed-flexible doses of Lu AF11167 on negative symptoms in patients with schizophrenia

Official Title
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Interventional, Randomized, Double-blind, Parallel-group, Placebo-controlled, Fixed-flexible-dose Study of Lu AF11167 for the Treatment of Persistent Prominent Negative Symptoms in Patients With Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Lu AF11167 (1-2 mg/day)
* Drug: Lu AF11167 (3-4 mg/day)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria The patient has schizophrenia, diagnosed according to DSM-5® as confirmed by the Mini-International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders Studies (MINI-Schz). The patient has been known to the site or investigator and treated by the site or investigator for at least the last 6 months prior to Screening Visit 1. The patient has suffered from persistent prominent negative symptoms for the last 6 months prior to the Screening Visit 1, in the opinion of the investigator and recorded in medical records. The patient has been treated for schizophrenia with stable doses of an oral antipsychotic within the approved dose range and without any dose increase during the last 6 months prior to Screening Visit 1 (dose reductions are acceptable). Combination therapy of two antipsychotics is only allowed with the written approval of the Medical Monitor in cases where the second antipsychotic is a low-potency first generation antipsychotic drug (e.g., chlorpromazine, promazine or chlorprothixene at low doses) or quetiapine at a dose of ≤150 mg, given in the evening for sleep problems and where both can be discontinued during the washout phase without endangering the patient's safety. Both antipsychotics will be withdrawn during the washout phase and need to be discontinued before Screening Visit 2. Combination therapy of more than 2 antipsychotic medications is not allowed during the previous 6 months prior to Screening Visit 1. The patient has had no psychiatric admissions/hospitalization due to a clinical deterioration during the last 6 months prior to Screening Visit 1, this excludes ambulatory visits to ask for advice from the psychiatry team.Patients hospitalized during the last 6 months for social reasons only or patients who are currently hospitalized for social reasons can be included with the Medical Monitor's approval. The patient is in a clinically stable phase of schizophrenia and has not more than moderate severity on relevant positive symptoms, that is a score of ≤4 (moderate) out of score of 7 on each of the following PANSS items: Delusions (P1), Hallucinatory behaviour (P3), Suspiciousness / persecution (P6), Uncooperativeness (G8), Unusual thought content (G9) at Screening Visit 1, Washout Visit(s), Screening Visit 2, and Baseline Visit and a score ≤5 on Conceptual disorganization (P2). The patient currently has no clinically significant acute extrapyramidal side effects (acute EPS) or tardive dyskinesia (TD) based upon the protocol-specified clinical examination. The patient has prominent negative symptoms as demonstrated by a PANSS Marder Negative Symptom Factor Score (NSFS) ≥20 at Screening Visit 1, Washout Visit(s) and Screening Visit 2. NSFS is the sum of scores of the following PANSS items: Blunted affect (N1), Emotional withdrawal (N2), Poor rapport (N3), Passive/apathetic social withdrawal (N4), Lack of spontaneity & flow of conversation (N6), Motor retardation (G7) and Active social avoidance (G16). The patient has a Clinical Global Impression-Schizophrenia Severity of Illness (CGI-SCH-S) overall severity score ≤4 at Screening Visit 1. The patient does not currently have a diagnosis of Major Depressive Disorder or have depressive symptoms rated with a total score ≥5 on the Calgary Depression Scale for Schizophrenia (CDSS). The patient has no history of violent behaviour for the last 12 months prior to Screening Visit 1. The patient has a caregiver or an identified responsible person (for example, partner, family member, social worker, case worker, or nurse) considered reliable by the investigator in providing support to the patient to ensure compliance with study treatment, outpatient visits, and protocol procedures. Exclusion criteria The patient has had an acute exacerbation requiring hospitalization within the last 6 months prior to Screening Visit 1. The patient has had an acute exacerbation requiring change in antipsychotic medication (with reference to drug or dose) within the last 6 months prior to Screening Visit 1. The patient has a current diagnosis or a history of substance use disorder according to DSM-5® criteria within 6 months prior to Screening Visit 1 with the exception of tobacco, or mild cannabis or mild alcohol use disorder (occasional - but not weekly recreational cannabis use is acceptable). Patients with a positive drug screen test for opiates, methadone, cocaine, amphetamines [including ecstasy], barbiturates, verified by repeated testing, are excluded from the study. The patient is at significant risk of harming himself/herself or others in the investigator's opinion. The patient has tested positive for hepatitis A virus antibody (anti-HAV IgM), hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV). If the anti-HCV test result is positive, but acute/chronic infection is excluded with a negative HCV RNA test patient can be included in the study. The patient has tested positive for human immunodeficiency virus (HIV). The patient has a present condition that might compromise liver function (for example, alcohol abuse, hepatitis, hepatic insufficiency, cholestasis, haemachromatosis, deficit in alpha 1 antitrypsine, Wilson's Disease, autoimmune diseases, cirrhosis). The patient has any other disorder for which the treatment takes priority over treatment of schizophrenia or is likely to interfere with the study treatment or impair treatment compliance. Other in- and exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lu AF11167 low dose<br> | Drug: Lu AF11167 (1-2 mg/day)<br>* Fixed-flexible oral dose, tablets. Once daily. 12 weeks.<br>|
| Experimental: Lu AF11167 high dose<br> | Drug: Lu AF11167 (3-4 mg/day)<br>* Fixed-flexible oral dose, tablets. Once daily. 12 weeks.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo oral dose, tablets. Once daily. 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Negative Symptom Scale (BNSS) total score | The BNSS is a brief clinician rating scale, intended to measure negative symptoms. It consists of 13 items organized into 6 subscales: anhedonia, distress, asociality, avolition, blunted affect and alogia. The items score the impairment. Items 1 to 4 are rated from 0 (Normal) to 6 (Extremely severe) and items 5 to 13 are rated from 0 (No impairment) to 6 (Severe deficit). The BNSS total score is calculated by summing the 13 individual items; subscale scores are calculated by summing the individual items within each subscale. Users of the BNSS should have training in psychiatric interview techniques and have clinical experience working with patients with schizophrenia and related psychotic disorders. The BNSS total scores ranges from 0 to 78. | from baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Personal and Social Performance (PSP) score | The PSP is a clinician-rated scale designed and validated to measure a patient's current level of social functioning. The PSP consists of 4 items: socially useful activities (including work and study), personal and social relationships, self-care, and disturbing and aggressive behaviours. The 4 items are assessed on a 6-point scale, from absent to very severe. Based on these assessments and their combination, individual scores are converted into a global score ranging from 1 to 100. | from baseline to Week 12 | 
| Change in Positive and Negative Syndrome Scale (PANSS) total score | The PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms. The PANSS includes 3 sub-scales and 30 items | from baseline to Week 12 | 
| Change in PANSS Marder Negative Symptom Factor score: negative symptoms | The PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms. The PANSS includes 3 sub-scales and 30 items | from baseline to Week 12 | 
| Change in PANSS Negative subscale score | The PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms. The PANSS includes 3 sub-scales and 30 items | from baseline to Week 12 | 
| Change in Clinical Global Impression - Schizophrenia (CGI-SCH-S) negative symptoms score | The CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia. For both the global illness severity and degree of change, the CGI-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder. The CGI-SCH-S severity of illness category symptoms and overall severity are rated on a 7-point scale ranging from 1 (normal - not ill) to 7 (Among the most severely ill). For the first four ratings (positive, negative, depressive, and cognitive symptoms), the assessment should focus on the severity of symptoms only. Additionally, for 'overall severity' rating, both severity of symptoms and interference with functioning should be considered. | from baseline to Week 12 | 
| Clinical Global Impression - Schizophrenia (CGI-SCH-DC) negative symptoms score | The CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia. For both the global illness severity and degree of change, the CGI-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder. In the CGI-SCH-DC degree of change category symptoms and overall severity are rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived. | at Week 12 | 
| CGI-SCH-DC negative symptoms response | The CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia. For both the global illness severity and degree of change, the CGI-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder. In the CGI-SCH-DC degree of change category symptoms and overall severity are rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived. Response defined as CGI-SCH-DC negative symptoms = 1 or 2 | at Week 12 | 
| BNSS response | The BNSS is a brief clinician rating scale, intended to measure negative symptoms. It consists of 13 items organized into 6 subscales: anhedonia, distress, asociality, avolition, blunted affect and alogia. The items score the impairment. Items 1 to 4 are rated from 0 (Normal) to 6 (Extremely severe) and items 5 to 13 are rated from 0 (No impairment) to 6 (Severe deficit). The BNSS total score is calculated by summing the 13 individual items; subscale scores are calculated by summing the individual items within each subscale. Users of the BNSS should have training in psychiatric interview techniques and have clinical experience working with patients with schizophrenia and related psychotic disorders. The BNSS total scores ranges from 0 to 78. Response criteria defined as 20,30 or 40% decrease in BNSS total score. | at Week 12 | 
| Change in PANSS -Positive subscale score | The PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms. The PANSS includes 3 sub-scales and 30 items | from baseline to Week 12 | 
| Change in Clinical Global Impression - Schizophrenia (CGI-SCH-S) severity of illness overall severity score | The CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia. For both the global illness severity and degree of change, the CGI-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder. The CGI-SCH-S severity of illness category symptoms and overall severity are rated on a 7-point scale ranging from 1 (normal - not ill) to 7 (Among the most severely ill). For the first four ratings (positive, negative, depressive, and cognitive symptoms), the assessment should focus on the severity of symptoms only. Additionally, for 'overall severity' rating, both severity of symptoms and interference with functioning should be considered. | from baseline to Week 12 | 
| Clinical Global Impression - Schizophrenia (CGI-SCH-DC) degree of change in overall severity score | The CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia. For both the global illness severity and degree of change, the CGI-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder. In the CGI-SCH-DC degree of change category symptoms and overall severity are rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived. | at Week 12 | 
| Change in Calgary Depression Scale for Schizophrenia (CDSS) total score | The CDSS is a 9-item clinician rated scale specifically developed for the assessment of depression in patients with schizophrenia. The items on the CDSS are all typical depressive symptoms and do not appear to overlap with the negative symptoms of schizophrenia. All items are rated on a 4-point scale from 0 (absent) to 3 (severe) | from baseline to Week 12 |