Placebo Capsules

The Positive and Negative Syndrome Scale (PANSS) Negative Symptom Score assesses the severity of negative symptoms in schizophrenia, such as emotional withdrawal and reduced motivation. It includes 7 items: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity, and stereotyped thinking. Each item is rated from 1 (absent) to 7 (extreme), for a total score range of 7 to 49. Higher scores indicate more severe symptoms and worse outcomes.

Baseline is defined as last non-missing assessment prior to the first dose of study drug.

The Negative Marder Factor Score is subset of PANSS items used to evaluate negative symptoms based on a five-factor model. It includes 7 items: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of spontaneity, motor retardation, and active social avoidance. Each item is rated from 1 to 7. Higher scores reflect greater severity of negative symptoms and poorer clinical outcomes. PANSS total score is the sum of all 30 items with a minimum score of 30 and a maximum score of 210. Higher scores indicate more severe symptoms. The PANSS Total Score is then the sum of the positive, negative, and general psychopathology symptom scores. Baseline is defined as last non-missing assessment prior to the first dose of study drug.

The CGI-S Score is a clinician-rated scale used to assess the severity of a patient's mental illness at a given time. It ranges from 1 (Normal, not at all ill) to 7 (Among the most extremely ill patients). The score reflects the clinician's overall impression based on observed symptoms, behavior, and functioning. Higher scores indicate greater illness severity and worse clinical status.

Baseline is defined as last non-missing assessment prior to the first dose of study drug.

PANSS Total Score is a clinical tool used to measure the severity of symptoms in individuals with schizophrenia. It includes 30 items divided into three subscales:

Positive Symptoms (e.g., hallucinations, delusions) Negative Symptoms (e.g., social withdrawal, lack of motivation) General Psychopathology (e.g., anxiety, depression) Each item is rated from 1 (absent) to 7 (extreme), resulting in a total score range from 30 to 210.

Higher PANSS Total Scores indicate more severe symptoms and worse clinical outcomes.

Baseline is defined as last non-missing assessment prior to the first dose of study drug.

PANSS Total Score is a clinical tool used to measure the severity of symptoms in individuals with schizophrenia. It includes 30 items divided into three subscales:

Positive Symptoms (e.g., hallucinations, delusions) Negative Symptoms (e.g., social withdrawal, lack of motivation) General Psychopathology (e.g., anxiety, depression) Each item is rated from 1 (absent) to 7 (extreme), resulting in a total score range from 30 to 210.

Higher PANSS Total Scores indicate more severe symptoms and worse clinical outcomes.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

The PANSS Positive Symptom Score assesses the severity of positive symptoms in schizophrenia, such as hallucinations and delusions. It includes 7 items: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. Each item is rated from 1 (absent) to 7 (extreme), for a total score range of 7 to 49. Higher scores indicate more severe symptoms and worse clinical outcomes.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

The Positive and Negative Syndrome Scale (PANSS) Negative Symptom Score assesses the severity of negative symptoms in schizophrenia, such as emotional withdrawal and reduced motivation. It includes 7 items: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity, and stereotyped thinking. Each item is rated from 1 (absent) to 7 (extreme), for a total score range of 7 to 49. Higher scores indicate more severe symptoms and worse outcomes.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

The Negative Marder Factor Score is subset of PANSS items used to evaluate negative symptoms based on a five-factor model. It includes 7 items: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of spontaneity, motor retardation, and active social avoidance. Each item is rated from 1 to 7. Higher scores reflect greater severity of negative symptoms and poorer clinical outcomes.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

The CGI-S Score is a clinician-rated scale used to assess the severity of a patient's mental illness at a given time. It ranges from 1 (Normal, not at all ill) to 7 (Among the most extremely ill patients). The score reflects the clinician's overall impression based on observed symptoms, behavior, and functioning. Higher scores indicate greater illness severity and worse clinical status.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

PANSS Total Score is a clinical tool used to measure the severity of symptoms in individuals with schizophrenia. It includes 30 items divided into three subscales:

Positive Symptoms (e.g., hallucinations, delusions) Negative Symptoms (e.g., social withdrawal, lack of motivation) General Psychopathology (e.g., anxiety, depression) Each item is rated from 1 (absent) to 7 (extreme), resulting in a total score range from 30 to 210.

Higher PANSS Total Scores indicate more severe symptoms and worse clinical outcomes.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Adverse Event (AE):

An AE is any unfavorable and unintended sign, symptom, or disease that occurs in a participant during a clinical trial, regardless of whether it is related to the study treatment. This includes new conditions or worsening of pre-existing ones.

Serious Adverse Event (SAE):

An SAE is an AE that results in death, is life-threatening, requires hospitalization or prolongs existing hospitalization, causes persistent or significant disability/incapacity, or leads to a congenital anomaly/birth defect. Other events may be considered serious if they require medical intervention to prevent one of these outcomes.

Orthostatic vital signs included blood pressure and heart rate. A participant having sustained orthostatic event is defined as the participant experienced at least one orthostatic event for at least 3 consecutive visits.

ULN = upper limit of normal range.; DB = Double-blind period; OL = Open-label period. Hy's law is defined as an elevated alanine aminotransferase level (>3xULN) or an elevated aspartate aminotransferase (>3xULN) in combination with alkaline phosphatase <2xULN and elevated total bilirubin (>2 x ULN). Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

ULN = Upper limit of normal; DB = Double-blind period; OL = Open-label period. Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Anytime post-baseline includes all assessments from the first dose of study drug until end of study visit in double-blind/open-label part, including unscheduled assessments. Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

The C-SSRS is a clinician- or self-administered questionnaire assessing suicidal ideation and behavior. It rates ideation severity from 1 (wish to be dead) to 5 (active suicidal ideation with specific plan and intent). It also records the presence or absence of suicidal behaviors, including actual, interrupted, or aborted attempts, and preparatory acts. The highest level of ideation or most severe behavior reported is used to determine suicide risk; higher ideation scores or any suicidal behavior indicate greater risk. Baseline is the last non-missing assessment before first study drug dose.

Treatment-emergent parkinsonism is defined as Simpson-Angus Scale total score >3 with a baseline score ≤3. Treatment-emergent akathisia is defined as Barnes Akathisia Rating Scale global clinical assessment score >2 with a baseline score ≤2. Treatment-emergent dyskinesia is defined as any Abnormal Involuntary Movement Scale (AIMS) item 1-7 score ≥3 with a baseline score <3 for the item, or score ≥2 on two or more of AIMS items 1-7 with baseline <2 for the items. Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

Study baseline is defined as last non-missing assessment prior to the first dose of study drug. Open-label baseline is defined as last non-missing assessment prior to the first dose of study drug in the open-label part.

AUC₀-12 (Area Under the Concentration-Time Curve from time zero to 12 hours) is the total amount of drug in the blood measured from the time the drug is given (time zero) up to 12 hours after dosing.

Cmax is the highest concentration of a drug measured in the blood after it is given.

Tmax is the amount of time it takes to reach that highest concentration (Cmax) after the drug is given.

Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.

Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Completed = treated

Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.

Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.

Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.

Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.

Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.

Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.

Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.

Participants completed 5-week KarXT treatment in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants completed 5-week matching placebo to KarXT in the double-blind part and signed ICF for the open-label part. Participants continued oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a long-term treatment period of 12 weeks. In the open-label part, participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week (Days 3 to 7) of the open-label part. On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.