Effect of Lu AF35700 in Patients With Treatment-resistant Schizophrenia

Study Overview
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Brief Summary
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To evaluate the efficacy of 10 and 20 mg/day of Lu AF35700 on schizophrenia symptoms in patients with treatment-resistant schizophrenia (TRS)

Detailed Description
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The study consists of a Screening Period (3 weeks), a single-blind Prospective Confirmation (PC) Period (6 weeks), a Double-blind Treatment (DBT) Period (10 weeks), and a Safety Follow-up Period (6 weeks). Patients who did not fulfil the randomization criteria for the DBT Period, were withdrawn from the study after the PC period. Patients who fulfilled the randomization criteria for the DBT Period, continued into the DBT Period and were randomized into one of 3 treatment arms (1:1:1) with either Lu AF35700 10 mg/day, Lu AF35700 20 mg/day or to continue the treatment allocated in PC Period (olanzapine or risperidone) at the dose set at last visit of PC Period. This mean that approximately one third of the confirmed treatment-resistant patients were randomised back to the failed treatment used in the PC Period. Data was not collected separately for the DBT Olanzapine and DBT Risperidone participants, and there was no intent to compare Lu AF35700 to each drug separately.

Official Title
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Interventional, Randomised, Double-blind, Active-controlled, Fixed-dose Study of Lu AF35700 in Patients With Treatment-resistant Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Risperidone
* Drug: Olanzapine
* Drug: Lu AF35700
* Drug: Lu AF35700


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has schizophrenia, diagnosed according to DSM-5(TM) (Diagnostic and Statistical Manual of Mental Disorders) and confirmed by the Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders The patient is either an inpatient at a psychiatric setting or outpatient consulting a psychiatrist. Patients should be treated with adequate dose(s) and agent(s) of antipsychotic treatment for at least 2 weeks prior to Screening The patient has failed to show an adequate response in the level of psychotic symptoms despite at least one documented treatment trial with an adequate dose of an antipsychotic agent prescribed for an adequate time (at least lasting for 6 weeks) during 2 years prior to Screening. The failure to respond to the current antipsychotic treatment trial may be considered a retrospective failed treatment, if the patient was treated for 6 weeks with adequate dose(s) and agent(s) The patient has a PANSS total score of ≥80 and a score of ≥4 on at least 2 of the following PANSS items (at Screening and at the first visit of Period A) The patient has a CGI-S score of ≥4 at Screening and at the first visit of Period A Exclusion Criteria: The patient has any current primary psychiatric disorder other than schizophrenia as assessed by the Mini International Neuropsychiatric Interview (MINI) The patient is experiencing an acute exacerbation of his/her psychotic symptoms The patient has not responded to treatment with clozapine Other protocol defined inclusion and exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 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: Prospective Confirmation (PC) Period<br>Single (patient)-blinded treatment period with risperidone or olanzapine for 6 weeks | Drug: Risperidone<br>* 4-6 mg/day, encapsulated tablets, orally<br>Drug: Olanzapine<br>* 15-20 mg/day, encapsulated tablets, orally<br>|
| Experimental: Double-blind Treatment (DBT) Period, Lu AF35700 10 mg<br>Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks | Drug: Lu AF35700<br>* 10 mg/day, encapsulated tablets, orally<br>|
| Experimental: DBT Period, Lu AF35700 20 mg<br>Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks | Drug: Lu AF35700<br>* 20 mg/day, encapsulated tablets, orally<br>|
| Experimental: DBT Period, Continued treatment from PC Period<br>Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period | Drug: Risperidone<br>* 4-6 mg/day, encapsulated tablets, orally<br>Drug: Olanzapine<br>* 15-20 mg/day, encapsulated tablets, orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Randomization to Week 10 in Positive and Negative Syndrome Scale (PANSS) Total Score | PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. | From Randomization to Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Randomization to Week 10 in PSP Total Personal and Social Performance (PSP) Total Score | PSP is a clinician-rated scale designed and validated to measure a patient's current level of social functioning. It consists of 4 items: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behaviours. Each items were assessed on a 6-point scale, from 1 (absent) to 6 (very severe). PSP score was calculated as sum of all the items on the scale and ranged from 4 to 100. A higher score represents more severe functional impairment. | From Randomization to Week 10 | 
| Change From Randomization to Week 10 in Global Clinical Impression - Severity of Illness (CGI-S) Score | CGI-S provides the clinician's impression of the patient's current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients). Higher scores indicate worsening. | From Randomization to Week 10 | 
| Response at Week 10, Defined as ≥20% Reduction in PANSS Total Score, PANSS (Positive and Negative Syndrome Scale) Total Score ≤70, CGI-S (Clinical Global Impression Scale - Severity of Illness) Score <4 | PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement. The Clinical Global Impression scale - severity of illness (CGI-S) is administered by the investigator. The patient is rated on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients). A reduction in scale indicates improvement. | From Randomization to Week 10 | 
| Response at Week 10, Defined as ≥20% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization | PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement. | From Randomization to Week 10 | 
| Response at Week 10, Defined as ≥30% Reduction in PANSS Total Score From Randomization | Positive and Negative Syndrome Scale (PANSS) total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement. | From Randomization to Week 10 | 
| Response at Week 10, Defined as ≥40% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization | PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement. | From Randomization to Week 10 | 
| Response at Week 10, Defined as ≥50% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization | PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement. | From Randomization to Week 10 |