How were the trials designed?

Each trial consisted of a 5-week double-blind treatment period, during which patients with schizophrenia who were currently experiencing symptoms of psychosis (e.g., hearing voices, feeling as though others are out to get them) stayed at the hospital in an inpatient unit. All patients were between 18 to 65 years of age and had a prior diagnosis of schizophrenia with moderate to severe symptoms.

Each patient received either placebo or COBENFY for the entire 5-week period, and neither the patient nor their care providers were aware of the treatment assigned during the trial. Each patient received a starting dose of one 50 mg/20 mg capsule (contains 50 mg of xanomeline and 20 mg of trospium chloride) orally twice daily for at least two days. The dosage was increased to one 100 mg/20 mg capsule (100 mg xanomeline and 20 mg trospium chloride) orally twice daily for at least five days, and, if tolerated, the dosage was increased to one 125 mg/30 mg capsule (125 mg xanomeline and 30 mg trospium chloride) orally twice daily.

Each week patients were asked about their symptoms of schizophrenia and any side effects. At certain visits blood was drawn and a measure of heart function was taken to check for any changes in health. At the end of five weeks of treatment, the patient’s symptoms of schizophrenia were measured and compared to the symptoms reported before starting the trial. Patients receiving placebo were compared to patients receiving COBENFY to determine if COBENFY improves symptoms of schizophrenia.

Who participated in the trials?

Table 1. Trial 1 Baseline Demographics, Efficacy Population

_{Source: Adapted from FDA Review of Clinical Data
Abbreviation: SD standard deviation}

Table 2. Trial 2 Baseline Demographics, Efficacy Population

_{Source: Adapted from FDA Review of Clinical Data
Abbreviation: SD standard deviation}

What are the benefits of this drug (results of trials used to assess efficacy)? 

In the two trials assessing efficacy of COBENFY, where the primary efficacy endpoint was the change from baseline in the PANSS total score at Week 5, COBENFY resulted in larger reductions than placebo in symptoms of schizophrenia over five weeks of treatment.

Table 3 summarizes efficacy results for the evaluated patients in the clinical trials. The primary efficacy endpoint was the change from baseline in the PANSS total score at the end of the treatment course (Week 5).

Table 3. Change From Baseline in PANSS Total Score at Week 5, Trial 1 and Trial 2, Efficacy Population

_{Source: COBENFY Prescribing Information
Abbreviation: CI, confidence interval; LS, least squares; N, number of participants in the efficacy population; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation; SE, standard error}

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups? 

Table 4 and Table 5 summarize efficacy results by subgroup based on the mean change from baseline in the PANSS total score. Of note, the comparisons were not powered to determine differences between demographic groups for changes in the PANSS Total Score.

Table 4. PANSS Total Score by Subgroup, Trial 1, Efficacy Population

_{Source: Adapted from FDA Review of Clinical Data
Abbreviation: CI, confidence interval; LS, least squares; N, number of participants in the efficacy population; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation; SE, standard error}

Table 5. PANSS Total Score by Subgroup, Trial 2, Efficacy Population 

_{Source: Adapted from FDA Review of Clinical Data
Abbreviation: CI, confidence interval; LS, least squares; N, number of participants in the efficacy population; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation; SE, standard error}

What are the possible side effects (results of trials used to assess safety)? 

The most common side effects seen in the clinical studies were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and heartburn (also known as GERD). Other side effects observed in more patients receiving COBENFY as compared to placebo include dry mouth, sleepiness, blurry vision, drooling, dizziness upon standing, cough, and involuntary muscle movements or spasms. 

Table 6 summarizes the adverse reactions that occurred in greater than 1% of patients and at a greater rate than placebo in Trials 1 and 2 combined.

Table 6. Safety Results, Trial 1 and Trial 2, Safety Population

_{Source: COBENFY Prescribing Information
^a Dyspepsia includes dyspepsia and esophageal discomfort
^b Hypertension includes hypertension, blood pressure increased, labile hypertension, and orthostatic hypertension
^c Abdominal Pain includes abdominal discomfort, abdominal pain upper, abdominal pain, abdominal pain lower, and abdominal tenderness
^d Tachycardia includes tachycardia, heart rate increased, and sinus tachycardia
^e Cough includes cough and productive cough
^f EPS (non-akathisia) includes dyskinesia, drooling, dystonia, extrapyramidal disorder, muscle contraction involuntary, and muscle spasms}

Were there any differences in side effects of the clinical trials among sex, race, and age groups? 

Table 7 summarizes the occurrence of adverse reactions by subgroup in the safety population for Trial 1 and Trial 2. 

Table 7. Adverse Reactions by Subgroup, Safety Population

<sub>Source: Adapted from FDA Review of Company data 
* “Grades” refer to a five-grade system to indicate the severity of side effects, where grades 1 and 2 are mild/moderate, 3 and 4 are life-threatening/urgent intervention needed, and grade 5 is death. 
Abbreviation: N, number of participants in the safety population; n, number with given characteristic; NA, not applicable; Ns, total number in each category</sub>