Efficacy of Lu AF35700 in Patients With Early-in-disease or Late-in-disease Treatment-resistant Schizophrenia

In the study, patients will receive risperidone (4-6 mg/day), or, if recently failed on risperidone, olanzapine (15-20mg/day). Later during the study, patients will be randomized to either receive Lu AF35700 (10 mg/day), or continue their treatment from the prospective confirmation (PC) period.

The study consists of a Screening Period (up to 3 weeks), a single-blind PC Period (6 weeks), a Double-blind Treatment (DBT) Period (8 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Patients who did not fulfil the randomization criteria for the DBT Period, were withdrawn from the study after the PC period.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 the 2 treatmetn arms (1:1) with either Lu AF35700 10 mg or to continue the treatment allocated in the PC period (olanzapine or risperidone) at the dose set at the last visit of the PC period. This means that approximately half of the confirmed treatment-resistant patients were randomised back to the failed treatment in the PC period.

Data was not collected seperately for the DBT olanzapine and DBT risperidone participants, and there was no intent to compare Lu AF35700 to each drug seperately.

• Lu AF35700 (Drug): 10 mg/day, encapsulated tablets, orally
• Risperidone (Drug): 4-6 mg/day, encapsulated tablets, orally
• Olanzapine (Drug): 15-20 mg/day, encapsulated tablets, orally

Primary outcomes

• Change From Randomization to Week 8 in Positive and Negative Syndrome Scale (PANSS) Total Score [From Randomization to Week 8]: PANSS total score administered by the investigator. It included 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 negative score indicates an improvement compared to Randomization.

Secondary outcomes

• Change From Randomization to Week 8 in Global Clinical Impression - Severity of Illness (CGI-S) Score [From Randomization to Week 8]: 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
• Change From Randomization to Week 8 in 16-item Negative Symptom Assessment (NSA-16 Total) Score [From Randomization to Week 8]: The NSA-16 is a clinician-rated scale designed to assess the presence, severity, and range of negative symptoms associated with schizophrenia. The NSA-16 consists of 16 items arranged in 5 subdomains: communication dysfunction (items 1 to 4), emotional/affective dysfunction (items 5 to 7), dysfunction in sociality (items 8 to 10), motivational/hedonic dysfunction (items 11 to 14), and reduced psychomotor activity (items 15 and 16), and a Global Negative Symptom Rating. NSA-16 items are rated on a 6-point scale from 1 (behaviour is normal) to 6 (behaviour severely reduced), and a score of 9 if the item is not-rateable. The Global Negative Symptom Rating is rated from 1 (no evidence of symptoms) to 7 (extremely severe symptoms). The 16 items are summed to yield a total score ranging from 16 to 96 and the global rating ranges from 1 to 7.
• Change From Randomization to Week 8 in PANSS Marder Negative Factor Score [From Randomization to Week 8]: The PANSS Negative Factor score is a subset of the PANSS assessing negative symptoms of schizophrenia. The factor consist of the seven items: blunted affect, emotional withdrawal, poor rapport, passive social withdrawal, lack of spontaneity, motor retardation, and active social avoidance which are each rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Negative Factor score (7 items) range from 7 to 49 with a higher score indicating greater severity of symptoms.
• Response [at Week 8]: Response is defined as a ≥20% reduction in PANSS total score from Randomization

Sex: All, ages: 18 Years to any

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 (MINI-Schz).
* The patient is receiving treatment with a psychiatrist in either an inpatient or outpatient facility.
* The patient has been treated with adequate dose(s) of antipsychotic drug treatment for at least 2 weeks prior to the Screening Visit.
* The patient has failed to show an adequate response in the level of psychotic symptoms during at least one documented treatment trial with an adequate dose of an antipsychotic drug prescribed for an adequate time (at least lasting for 6 weeks) within 2 years prior to the Screening Visit. The failure to respond to the current antipsychotic drug treatment trial may be considered a retrospective failed treatment, if the patient has been treated for 6 weeks with adequate dose(s) of antipsychotic drug(s).
* The patient has a PANSS total score of ≥80 (on 1-7 scale) and a score of ≥4 (≥ "Moderate" on 1-7 scale) on at least 2 of the following PANSS items at the Screening and at Baseline 1 \[Week 0\] Visits: P2 - Conceptual disorganization, P3 - Hallucinatory behavior, P6 - Suspiciousness/persecution, G9 - Unusual thought content; AND the patient has a CGI-S score of ≥4 (≥ "Moderately ill") at the Screening and at Baseline 1 (Week 0) Visits.

Exclusion Criteria:

* The patient has any current primary psychiatric disorder other than schizophrenia, as assessed using the MINI-Schz.
* The patient suffers from mental retardation, organic mental disorders, or mental disorders due to a general medical condition (DSM-5™ criteria).
* The patient is experiencing an acute exacerbation of his/her psychotic symptoms.
* The patient has been treated with, AND is resistant to, clozapine according to the investigator's judgement.

Participant flow

Outcome results

• Change From Randomization to Week 8 in Positive and Negative Syndrome Scale (PANSS) Total Score (Primary), Mean, units on a scale: Double-blind Treatment (DBT) Period, Lu AF35700 10 mg -4.71 +/- 2.22; DBT, Continued Treatment From PC Period -10.19 +/- 2.16 (p 0.0809)
• Change From Randomization to Week 8 in Global Clinical Impression - Severity of Illness (CGI-S) Score (Secondary), Mean, units on a scale: DBT, Lu AF35700 10 mg -0.18 +/- 0.12; DBT, Continued Treatment -0.37 +/- 0.11
• Change From Randomization to Week 8 in 16-item Negative Symptom Assessment (NSA-16 Total) Score (Secondary), Mean, units on a scale: DBT, Lu AF35700 10 mg -2.99 +/- 1.64; DBT, Continued Treatment -3.14 +/- 1.58
• Change From Randomization to Week 8 in PANSS Marder Negative Factor Score (Secondary), Mean, units on a scale: DBT, Lu AF35700 10 mg -1.51 +/- 0.77; DBT, Continued Treatment -1.74 +/- 0.75
• Response (Secondary), Count of participants, Participants: DBT, Lu AF35700 10 mg 6; DBT, Continued Treatment 13

Adverse events

Time frame: 20 weeks

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The study was terminated early and hence the statistical analysis was conducted on a smaller sample size than originally planned.

• Study Protocol (PDF, 2018-09-07)
• Statistical Analysis Plan (PDF, 2019-03-13)

• Email contact via H.Lundbeck A/S, Study director, LundbeckClinicalTrials@Lundbeck.com