Evaluation of GT-002 and Oxazepam on Cognitive Impairment in Schizophrenia: A Phase II Randomized Controlled Trial

The primary objective of the TOTEMS Phase II clinical trial is to evaluate the **acute effects** of partial **GABA(A)-receptor modulation** by GT-002 on psychophysiological measures in patients with schizophrenia spectrum disorders. This includes assessments using event-related EEG and EMG, as well as resting-state EEG. These psychophysiological parameters serve as proxy measures of hypofrontality, a key mechanism underlying cognitive impairment in schizophrenia. Understanding these effects is clinically relevant as it may provide insights into potential therapeutic strategies for addressing cognitive deficits associated with schizophrenia.

The clinical trial involves a study population comprising both **male** and **female** participants, aged between 18 and 45 years. The trial includes individuals diagnosed with schizophrenia spectrum disorders, such as schizophrenia, persistent delusional disorder, and schizoaffective disorders, as well as healthy controls. Participants are required to be legally competent and, for females, non-pregnant and non-lactating. The trial population was selected based on specific diagnostic criteria, with patients needing to have a history of antipsychotic monotherapy treatment for at least three months and be clinically stable. Healthy controls must have no current or previous diagnosed mental disorder and no first-degree relatives with major psychiatric disorders. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, and the trial does not involve a vulnerable population.

The clinical trial is designed to evaluate the **acute effects** of partial GABA(A)-receptor modulation by GT-002 on psychophysiological measures in patients with schizophrenia spectrum disorders. This is a Phase II, randomized, double-blind, controlled trial involving both schizophrenia spectrum patients and healthy controls. The trial will assess the impact of GT-002, oxazepam, and placebo on various psychophysiological parameters, including event-related EEG and EMG, as well as resting-state EEG. The primary endpoint is the change in Pre-pulse Inhibition of the Startle Reflex (PPI) in schizophrenia spectrum patients following exposure to GT-002, placebo, or oxazepam. Secondary endpoints include changes in EEG paradigms, safety and tolerability, and cognitive changes.

The trial is expected to commence recruitment on February 1, 2025, and conclude by January 31, 2028. Participants will be involved in the study for a maximum treatment period of one month. The study visits will include an initial screening visit to confirm eligibility based on inclusion criteria such as age, legal competence, and specific diagnostic criteria for schizophrenia spectrum disorders. Follow-up visits will be scheduled to monitor the effects of the interventions and collect data on the primary and secondary endpoints. The end-of-study visit will assess the overall outcomes and any adverse events experienced by the participants.

Participants will be randomly assigned to receive either GT-002, oxazepam, or a placebo, with the interventions administered orally in the form of soft capsules or tablets. The trial will employ a double-blind design to ensure that neither the participants nor the investigators are aware of the treatment allocations, thereby minimizing bias. The expected length of participant involvement is contingent upon adherence to the study protocol, and any deviation or adverse event that compromises participant safety may lead to early termination from the study. The trial aims to provide insights into the potential therapeutic effects of GT-002 on cognitive impairment associated with schizophrenia, contributing to the understanding of hypofrontality as a key mechanism in this condition.

The clinical trial involves the administration of **GT-002**, an experimental medication formulated as a soft capsule. The active substance, GT-002, is of chemical origin and is administered orally. The maximum daily dose is 2 mg, with a total maximum dose of 3 mg over the treatment period. The trial aims to assess the acute effects of partial GABA(A)-receptor modulation by GT-002 on psychophysiological measures in patients with schizophrenia spectrum disorders.

**Oxazepam "Alternova"** is used as a comparator treatment in the study. It is provided in tablet form, with each tablet containing 15 mg of the active substance, oxazepam. The tablets are encapsulated to resemble the placebo tablets used in the trial. The maximum daily and total dose is 15 mg, administered orally. Oxazepam is a chemically derived substance and serves as a standard-of-care therapy in the trial.

The study also includes a **placebo** for GT-002, which is a soft gelatine capsule identical in appearance to the 1 mg GT-002 capsule but contains no active drug substance. This placebo is used to maintain blinding and assess the efficacy of GT-002 against a non-active control.

Additionally, a **placebo** for oxazepam is utilized, consisting of a tablet encapsulated to resemble the oxazepam tablet but containing no active drug substance. This placebo is employed to ensure the integrity of the trial's blinding process and to evaluate the effects of oxazepam against a non-active control.

Efficacy in the TOTEMS Phase II clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of partial GABA(A)-receptor modulation by GT-002 on psychophysiological measures in patients with schizophrenia spectrum disorders. The primary endpoint focuses on the **Change in Pre-pulse Inhibition of the Startle Reflex (PPI)** in schizophrenia spectrum patients following exposure to GT-002, placebo, or oxazepam. The primary analysis will specifically assess the difference between 2 mg GT-002 and placebo.

Secondary endpoints include changes in the Mismatch Negativity (MMN) paradigm, Selective Attention (SA) paradigm, 40-Hz Auditory Steady-State Response (40-Hz ASSR) paradigm, and frequency bands at resting state in schizophrenia spectrum patients. These will be measured following exposure to GT-002, oxazepam, or placebo. Additionally, safety and tolerability will be evaluated in both antipsychotic-treated schizophrenia spectrum patients and healthy controls through reported adverse events (AEs) and visual analogue mood scales (VAMS). Changes in EEG paradigms due to the differential acute effects between GT-002, oxazepam, and placebo in healthy controls will also be assessed, along with changes in cognition due to GT-002 compared to oxazepam and placebo in both patient groups. The impact of antipsychotic medication type and its duration, sex, age, diagnosis, and duration of illness on the acute effect of GT-002 on the EEG paradigms in schizophrenia spectrum patients will be analyzed.