Clinical trial NCT02281773: A Study to Investigate the Efficacy, Safety and Tolerability of Four Different Doses of BI 409306 Compared to Placebo Given for 12 Weeks in Patients With Schizophrenia on Stable Antipsychotic Treatment.
Official title: A Phase II Randomised, Double-blinded, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Four Orally Administrated Doses of BI 409306 During a 12-week Treatment Period in Patients With Schizophrenia on Stable Antipsychotic Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Schizophrenia
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2014-11-04
Enrollment: 518
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of the study is to investigate the efficacy, safety and tolerability of four different doses of BI 409306 once daily compared to placebo given for 12 weeks in patients with schizophrenia on stable antipsychotic treatment.


Eligibility criteria: Inclusion criteria:

1. Patients with established diagnoses of schizophrenia (per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)) with the following clinical features:

   a) Clinically stable and are in the residual (non-acute) phase of their illness for at least 8 weeks b) Current antipsychotic and concomitant psychotropic medications must meet the criteria below: b)-1 Maintained on current atypical (second generation) antipsychotic medications (in any approved dosage form) other than Clozapine and on current dose for at least 8 weeks prior to randomisation, and/or b)-2 Maintained on current typical (first generation) antipsychotic medications and on current dose for at least 6 months, optionally combined with anticholinergics if treated with a stable dose for at least 6 months prior to randomisation, and/or b)-3 Maintained on current concomitant psychotropic medications other than anticholinergics, antiepileptics and lithium, and on current dose for at least 8 weeks prior to randomisation. Antiepileptics and lithium are allowed if initiated at least 6 months prior to randomisation.

   b)-4 Anticholinergics, antiepileptics and lithium have been washed out for at least 6 months prior to randomisation if the treatments that patients were using before entering the clinical trial are discontinued.

   c) Have no more than a "moderate" severity rating on hallucinations and delusions (Positive and Negative Syndrome Scale (PANSS)-positive syndrome Hallucinatory Behavior item score \< =4 and Delusions item score \< = 4) d) Have no more than a "moderate" severity rating on positive formal thought disorder (PANSS-positive syndrome Conceptual Disorganization item score \< = 4) e) Have a minimal level of extrapyramidal symptoms (Simpson-Angus Scale total score \< 6) and depressive symptoms (PANSS-general psychopathology syndrome Depression item score \< = 4)
2. Male or female patients age 18 to 55 years
3. Patients must exhibit reliability, physiologic capability, and an educational level sufficient to comply with all protocol procedures,in the investigator's opinion.
4. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and the local legislation. If the patient needs a legal representative, then this legal representative must give written informed consent as well.
5. Patients must have an identified informant who will be consistent throughout the study. The informant must interact with the subject at least 2 times a week.

Note: Informant ratings are needed for SCoRS global ratings at Randomisation Visit (Visit 2) and (early) End of Treatment Visit. In person informant ratings on the study visits are preferred whenever possible. However, if the informant is not available for in person ratings, telephone interview is acceptable. The informant must be available for a telephone interview at Visit 2 and (e)EOT Visit.

Exclusion criteria:

1. Patient treated with more than two antipsychotic medications (including more than two dosage forms)
2. Patient's cognitive impairment severity compromises the validity of the cognitive outcome measures, in the clinical judgment of the investigator
3. Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior)
4. Any suicidal ideation of type 4 or 5 in the Columbia Suicidal Severity Rating Scale (C-SSRS) in the past 3 months (i.e. active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent)
5. In the judgment of the investigator, any clinically significant finding of the medical examination (including BP, PR and ECG) or laboratory value deviating from normal or any evidence of a clinically significant concomitant disease or any other clinical condition that would jeopardize a patient's safety while participating in the clinical trial
6. History or diagnosis of symptomatic and unstable/uncontrolled gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, hematological or hormonal disorders
7. For female patients:

   Pre-menopausal women (last menstruation \< =1 year prior to informed consent) who:
   * are nursing or pregnant or
   * are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the trial until 28 days after the last treatment administration, and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, vasectomized partner, transdermal patch, intra uterine devices/systems (IUDs/IUSs), combined estrogen-progestin oral contraceptives as well as implantable or injectable hormonal contraceptives. Complete sexual abstinence (if acceptable by local health authorities) is allowed when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Double barrier methods are permissible (if acceptable by local health authorities, note that this is not an acceptable method in EU countries).

   For male patients:

   Men who are able to father a child, unwilling to be abstinent or use adequate contraception for the duration of study participation and for at least 28 days after treatment has ended.
8. Known history of HIV infection
9. Diseases of the central nervous system (including but not limited to any kind of seizures, stroke or any psychiatric disorders other than schizophrenia)
10. Any subject who on the Mini-international neuropsychiatric Interview (M.I.N.I.) has a categorical diagnosis of another current major psychiatric disorder.
11. History of malignancy within the last 5 years, except for basal cell carcinoma
12. Planned elective surgery requiring general anaesthesia, or hospitalisation for more than 1 day during the study period
13. Significant history of drug dependence or abuse (including alcohol, as defined in DSM-5-substance use disorder or in the opinion of the investigator) within the last two years prior to informed consent, or a positive urine drug screen for cocaine, opioid, PCP, amphetamine, heroin, or marijuana at screening
14. Patient needs to take long-acting hypnotics and anxiolytics (i.e. Diazepam)
15. Patients taking medications that are known to be strong or moderate CYP3A4 inhibitors
16. Participation in another trial with an investigational drug or procedure within 30 days or 6 half-lives (whichever is longer) or participation in another trial with any cognitive-enhancing therapy or procedure within 90 days prior to screening
17. Previous participation in any BI 409306 study
18. Not fluent in the language of the batteries/questionnaires which will be used in the country

Primary outcomes:
measure: Change From Baseline in the Composite Score of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) After 12 Weeks of Treatment
timeFrame: Baseline and Week 12
measure: Occurrence of Serious Adverse Events (SAEs) (Including the Abnormalities of Physical Examination, Vital Signs, Electrocardiogram (ECG) Test and Laboratory Tests)
timeFrame: Up to 20 weeks
measure: Occurrence of Protocol-specified Adverse Events of Special Interest (AESI)
timeFrame: Up to 20 weeks
measure: Dramatic Worsening of Disease State as Assessed by Positive and Negative Syndrome Scale (PANSS)
timeFrame: Baseline, Week 6 and Week 12
measure: Suicidality as Assessed by Columbia Suicidal Severity Rating Scale (C-SSRS)
timeFrame: Up to 12 weeks
Secondary outcomes:
measure: Change From Baseline in Everyday Functional Capacity as Measured by Schizophrenia Cognition Rating Scale (SCoRS) Global Ratings After 12 Weeks of Treatment
timeFrame: Baseline and Week 12
measure: Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Scale Score After 12 Weeks of Treatment
timeFrame: Baseline and Week 12
measure: Patient Global Impressions-Improvement (PGI-I) Scale Score Measured After 12 Weeks of Treatment
timeFrame: Up to 12 weeks
measure: Change From Baseline in PANSS Negative Symptom Factor Score After 12 Weeks of Treatment (for Subset of Patients Diagnosed With Negative Symptom)
timeFrame: Baseline and Week 12
measure: Change in Psychopathology Symptoms as Assessed by Positive and Negative Syndrome Scale (PANSS)
timeFrame: Baseline, Week 6 and Week 12
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: K and S Professional Research Services, LLC
state: Arkansas
city: Cerritos
country: United States
facility: Comprehensive Clinical Development, Inc.
state: California
city: Garden Grove
country: United States
facility: Collaborative Neuroscience Network
state: California
city: Los Angeles
country: United States
facility: Pacific Institute of Medical Research
state: California
city: National City
country: United States
facility: SRSD, Inc. dba Synergy San Diego
state: California
city: Orange
country: United States
facility: NRC Research Institute
state: California
city: San Diego
country: United States
facility: Artemis Institute for Clinical Research, LLC
state: California
city: Torrance
country: United States
facility: Collaborative Neuroscience Network
state: California
city: Washington, D.C.
country: United States
facility: Comprehensive Clinical Development
state: District of Columbia
city: Lauderhill
country: United States
facility: Innovative Clinical Research
state: Florida
city: Maitland
country: United States
facility: Florida Clinical Research Center
state: Florida
city: North Miami
country: United States
facility: Behavioral Clinical Research, Inc.
state: Florida
city: Atlanta
country: United States
facility: Atlanta Center
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Uptown Research Institute
state: Illinois
city: Lake Charles
country: United States
facility: Lake Charles Clinical Trials LLC
state: Louisiana
city: Saint Louis
country: United States
facility: Mid-America Clinical Research, LLC
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis Clinical Trials
state: Missouri
city: Cedarhurst
country: United States
facility: Neurobehavioral Research, Inc.
state: New York
city: Rochester
country: United States
facility: Finger Lakes Research
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Staten Island
country: United States
facility: Richmond Behavioral Associates
state: New York
city: Austin
country: United States
facility: Community Clinical Research, Inc.
state: Texas
city: DeSoto
country: United States
facility: InSite Clinical Research
state: Texas
city: Penticton
country: Canada
facility: Dr. Alexander McIntyre Inc.
state: British Columbia
city: Burlington
country: Canada
facility: Depression, Mood Disorders and Schizophrenia Treatment Centr
state: Ontario
city: Düsseldorf
country: Germany
facility: LVR-Klinikum Düsseldorf
city: Heidelberg
country: Germany
facility: Uniklinikum Heidelberg
city: Köln
country: Germany
facility: Universitätsklinikum Köln (AöR)
city: Aichi, Toyoake
country: Japan
facility: Fujita Health University Hospital
city: Hokkaido, Sapporo
country: Japan
facility: Hokkaido University Hospital
city: Hyogo, Kobe
country: Japan
facility: Kobe University Hospital
city: Nara, Kashihara
country: Japan
facility: Nara Medical University Hospital
city: Osaka, Moriguchi-city
country: Japan
facility: Kansai Med. Univ. Med. Ctr., Osaka, Neuropsychiatry
city: Saga, Kanzaki-gun
country: Japan
facility: Hizen Psychiatric Center, Saga, PSY
city: Tokushima, Anan
country: Japan
facility: Iwaki Clinic, Tokushima, Psychosomatic Medicine
city: Tokyo, Kodaira
country: Japan
facility: National Center Neurology and Psychiatry
city: Tokyo, Setagaya
country: Japan
facility: Showa University Karasuyama Hospital
city: Tokyo, Shinagawa
country: Japan
facility: Showa University East Hospital
city: Changhua
country: Taiwan
facility: Chang-Hua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kai-Syuan Psychiatric Hospital
city: Tainan
country: Taiwan
facility: NCKUH
city: Taipei
country: Taiwan
facility: Taipei City Hospital
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Dorner-Ciossek C, Kroker KS, Rosenbrock H. Role of PDE9 in Cognition. Adv Neurobiol. 2017;17:231-254. doi: 10.1007/978-3-319-58811-7_9.
citation: Georgiades A, Davis VG, Atkins AS, Khan A, Walker TW, Loebel A, Haig G, Hilt DC, Dunayevich E, Umbricht D, Sand M, Keefe RSE. Psychometric characteristics of the MATRICS Consensus Cognitive Battery in a large pooled cohort of stable schizophrenia patients. Schizophr Res. 2017 Dec;190:172-179. doi: 10.1016/j.schres.2017.03.040. Epub 2017 Apr 20.