Acute Effects of Partial GABA(A)-Receptor Modulation by GT-002 on Psychophysiological Measures: The TOTEMS Phase II Clinical Trial Targeting Cognitive Impairment Associated with Schizophrenia

Prior treatment

• General exclusion criteria (for all participants): 1. Prior serious adverse reaction, hypersensitivity, or intolerance to benzodiazepines, GT-002, placebo, or their excipients.
• General exclusion criteria (for all participants): 12. Participation in a clinical study involving study medical treatment administration within three months prior to screening or in more than 2 clinical studies within 1 year prior to the screening visit.
• General exclusion criteria (for all participants): 13. Positive results from urine drug tests.
• Additional exclusion criteria for healthy controls: 1. Lifetime substance dependence (ICD-10: F1x.2) (exception: nicotine dependence, F17.x) or any use of illicit drugs within the 12 months prior to inclusion.
• Additional exclusion criteria for healthy controls: 2. Any prescribed medications and over-the-counter medications (exceptions specified in the protocol) within 3 weeks prior to the first study drug administration.
• Additional exclusion criteria for patients: 1. Current substance dependence (ICD-10 F1x.2) (exception: nicotine dependence, F17.x) or any use of illicit drugs within the three months prior to inclusion.
• Additional exclusion criteria for patients: 3. Electroconvulsive therapy (ECT) in the last three months.
• General exclusion criteria (for all participants): 2. Ongoing treatment with benzodiazepines (see also concomitant treatment/medication).
• General exclusion criteria (for all participants): 6. Unwillingness or inability to use contraception methods during the study period and until the end of the relevant systemic exposure period, defined as 5 days after the last study drug administration. This applies only to women of childbearing potential.

Other illness

• General exclusion criteria (for all participants): 3. Severe (co-morbid) physical condition (as judged by the TOTEMS investigators), including but not limited to kidney disease, liver disease, chronic obstructive pulmonary disease (COPD), sleep apnea, hypotension, heart failure, and suicidal behavior.
• General exclusion criteria (for all participants): 7. Hearing impairment compromising the planned EEG assessments.

Lab values

• General exclusion criteria (for all participants): 11. Clinically relevant findings in laboratory samples at screening (as judged by the TOTEMS investigators).

Other

• General exclusion criteria (for all participants): 10. Clinically relevant abnormalities on 12-lead ECG at the screening visit (as judged by the TOTEMS investigators).
• General exclusion criteria (for all participants): 14. Unwillingness to refrain from donating blood or blood products during the study
• Additional exclusion criteria for patients: 2. Current coercive measure, or any coercive measure within the last three months, as per Danish legislation ('Lov om Tvang i Psykiatrien').
• General exclusion criteria (for all participants): 4. Pregnancy (assessed by urine pregnancy test).
• General exclusion criteria (for all participants): 5. Lactation
• General exclusion criteria (for all participants): 8. Physical or language impairments that negatively impact the accuracy of cognitive assessment data or verified mental retardation (IQ ≤ 70).
• General exclusion criteria (for all participants): 9. Clinically relevant findings on physical examination at the screening visit (as judged by the TOTEMS investigators).

• General inclusion criteria (for all participants): 1. Legally competent (in Danish: 'myndige og habile i retslig forstand').
• General inclusion criteria (for all participants): 2. Males or non-pregnant, non-lactating females aged between 18 and 45 years.
• Additional inclusion criteria for healthy controls: 1. No current or previous diagnosed mental disorder.
• Additional inclusion criteria for healthy controls: 2. No first-degree relative with known major psychiatric disorder (ICD-10: F1x; F2x; F3x), defined as having received medical treatment for and/or hospitalizations related to these diagnoses.
• Additional inclusion criteria for patients: 1. Fulfilling the diagnostic criteria for schizophrenia, persistent delusional disorder, acute and transient psychotic disorders, induced delusional disorders, schizoaffective disorders, other non-organic psychotic disorders or unspecified non-organic psychosis (ICD-10: F20.x; F22.x; F23.x; F24.x; F25.x; F28; F29), prioritizing patients with a shorter antipsychotic history.
• Additional inclusion criteria for patients: 2. Treated with a maximum of one regular antipsychotic medication and a maximum of one antipsychotic medication pro re nata (PRN). Any change in regular antipsychotic treatment (initiation, dose increase, dose reduction of more than 50%, or discontinuation) must have occurred at least three months prior to screening. Patients treated with dopamine receptor partial agonists, irrespective of formulation, will be prioritized.
• Additional inclusion criteria for patients: 3. Clinically stable for a minimum of the last three months, i.e., without hospitalizations for schizophrenia or recently intensified psychiatric care (as judged by the TOTEMS investigators).