Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-1)

MCCB comprises 10 tests, which assess 7 cognitive domains, including speed of processing, attention vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. The larger the MCCB overall composite T-score, the better patient cognition. A mean T-score of 50 and a standard deviation of 10 reflects the general population. The estimated treatment effect included the effect of any concomitant therapies for all randomized patients on on-treatment periods. On-treatment is defined as the period of first drug administration/first resumed dose after interruption until last drug administration + REP (residual effect period). The change from baseline was analyzed with a MMRM (mixed-effects model for repeated measures) with the fixed effects: treatment at each visit, stratification factor using the screening MCCB overall composite T-score, and baseline MCCB overall composite T-score at each visit. Visit was the repeated measure.

Time frame: MMRM included measurements at baseline, Week 12, and Week 26. Change from baseline values at Week 26 is reported.

Population: Randomized set: all patients randomized into the trial, regardless of whether a patient was treated with trial medication. Patients on an off-treatment period due to temporary treatment discontinuation or early permanent treatment discontinuation were excluded from the analysis according to the strategy to handle intercurrent events defined in the statistical analysis plan. One patient was randomized in error and discontinued from the trial before the start of trial medication.

The Tower of London (ToL) evaluates executive functioning, reasoning, problem-solving, and goal-directed behavior. It measures the number of correct responses in solving an exercise that consists on moving colored balls to match a target configuration. The higher the ToL T-score, the better patient's cognitive function. A mean T-score of 50 and a standard deviation of 10 reflects the T-score in a general population. The estimated treatment effect included the effect of any concomitant therapies for all randomized patients on-treatment. On-treatment is defined as the period of 1st drug administration/1st resumed dose after interruption until last drug administration + REP. The change from baseline comparing the groups was analyzed using analysis of covariance (ANCOVA) model including treatment, stratification factor of screening MCCB overall composite T-score, and baseline number of correct responses on Tower of London T-score.

Time frame: At baseline and at Week 26.

Population: Randomized set: all patients randomized into the trial, regardless of whether a patient was treated with trial medication. Patients on an off-treatment period due to temporary treatment discontinuation or early permanent treatment discontinuation were excluded from the analysis of this endpoint according to the strategy to handle intercurrent events defined in the statistical analysis plan. One patient was randomized in error and discontinued from the trial before the start of trial medication.

The Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) score evaluates how cognitive difficulties impact the daily life of individuals with schizophrenia. It is composed of 28 items on a 5-category Likert scale (1=not at all/not at all hard, 5=very much/very hard), and the total score was derived by calculating the average score of the first 26 items, where higher scores mean a worse patient experience. The estimated treatment effect included the effect of any concomitant therapies for all randomized patients on-treatment. On-treatment is defined as the period of 1st drug administration/1st resumed dose after interruption until last drug administration + REP. The change from baseline was analyzed with MMRM with the fixed effects: treatment at each visit, stratification factor using the screening MCCB overall composite T-score, and baseline MCCB overall composite T-score at each visit. Visit was treated as the repeated measure.

Time frame: MMRM included measurements at Visit 1a (Week -2/Week -1), Week 15, and Week 24. Change from Visit 1a values at Week 24 is reported.

Population: Randomized set: all patients randomized into the trial, regardless of whether a patient was treated with trial medication. Patients on an off-treatment period due to temporary treatment discontinuation or early permanent treatment discontinuation were excluded from the analysis of this endpoint according to the strategy to handle intercurrent events defined in the statistical analysis plan. One patient was randomized in error and discontinued from the trial before the start of trial medication.

The SCoRS is an interview based- assessment tool to evaluate the cognitive function of individuals with schizophrenia that incorporates the input of the patient, the caregiver and the interviewer. It is composed of 20 items on a 7-point Likert scale, ranging from 20 to 140 points, where a higher score indicates a greater cognitive impairment. The estimated treatment effect included the effect of any concomitant therapies and partner change in SCoR assessment for all randomized patients on-treatment. On-treatment is defined as the period of 1st drug administration/1st resumed dose after interruption until last drug administration + REP. The change from baseline was analyzed with mixed-effects model for repeated measures (MMRM) with the fixed effects: treatment at each visit, stratification factor using the screening MCCB overall composite T-score, and baseline MCCB overall composite T-score at each visit. Visit was treated as the repeated measure.

Time frame: MMRM included measurements at baseline, Week 12, and Week 26. Change from baseline values at Week 26 is reported.

Population: Randomized set: all patients randomized into the trial, regardless of whether a patient was treated with trial medication. Patients on an off-treatment period due to temporary treatment discontinuation or early permanent treatment discontinuation were excluded from the analysis of this endpoint according to the strategy to handle intercurrent events defined in the statistical analysis plan. One patient was randomized in error and discontinued from the trial before the start of trial medication.

The VRFCAT is a computerized assessment measuring the functional capacity of an individual to perform everyday tasks. It generates a composite score based on the amount of time taken to complete the tasks. The lower the VRFCAT T-score, the better patient's functional capacity. A mean T-score of 50 and a standard deviation of 10 reflects the T-score in a general population. The estimated treatment effect included the effect of any concomitant therapies for all randomized patients on-treatment. On-treatment is defined as the period of 1st drug administration/1st resumed dose after interruption until last drug administration + REP. The change from baseline was analyzed with MMRM with the fixed effects: treatment at each visit, stratification factor using the screening MCCB overall composite T-score, and baseline MCCB overall composite T-score at each visit. Visit was treated as the repeated measure.

Time frame: MMRM included measurements at baseline, Week 12, and Week 26. Change from baseline values at Week 26 is reported.

Population: Randomized set: all patients randomized into the trial, regardless of whether a patient was treated with trial medication. Patients on an off-treatment period due to temporary treatment discontinuation or early permanent treatment discontinuation were excluded from the analysis of this endpoint according to the strategy to handle intercurrent events defined in the statistical analysis plan. One patient was randomized in error and discontinued from the trial before the start of trial medication.

The central retinal thickness for both eyes was measured by high-definition optical coherence tomography (spectral domain OCT), which evaluates the retinal and sub-retinal structures of both eyes.

Time frame: At baseline and at Week 24.

Population: Ocular sub-study set: all treated patients who consented to participate in the ocular sub-study. Only patients with measurements were included in the analysis.

The Humphrey Visual Field 24-2 SITA Standard is a diagnostic test to measure visual fields, or perimetry. The Humphrey visual field test measures the entire area of peripheral vision that can be seen while the eye is focused on a central point. During this test, lights of varying intensities appear in different parts of the visual field while the patient's eye is focused on a central spot. The perception of these lights is charted and then compared to results of a healthy eye at the same age of the patient to determine if any damage has occurred. The tests ranks from 0 to 100%, where 0 means no vision and 100 means perfect vision.

Time frame: At baseline and at Week 24.

Population: Ocular sub-study set: all treated patients who consented to participate in the ocular sub-study. Only patients with measurements were included in the analysis.