Evaluation of the Efficacy and Safety of Adjunctive Trospium Chloride and Xanomeline Tartrate in Patients with Inadequately Controlled Schizophrenia Symptoms
- Trial ID
- 2024-510770-25-00
- Protocol
- KAR-012
- Sponsor
- Karuna Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of adjunctive KarXT compared with placebo in the treatment of subjects with inadequately controlled symptoms of **schizophrenia**. This is measured by the Positive and Negative Syndrome Scale (PANSS) Total Score. The clinical relevance of this objective lies in its potential to improve therapeutic outcomes for patients with schizophrenia who do not respond adequately to existing treatments.
Secondary objectives include:
- Evaluating the efficacy of adjunctive KarXT compared with placebo on the Personal and Social Performance Scale (PSP).
- Assessing the efficacy on Clinical Global Impression Severity (CGI-S), PANSS Marder Positive symptom factor (PANSS M-Pos), PANSS Marder Negative symptom factor (PANSS M-Neg), PANSS responder rate, and Preference of Medication (POM).
- Evaluating the safety and tolerability of adjunctive KarXT compared with placebo.
Participants
The clinical trial involves a total of **285 participants** diagnosed with **schizophrenia**, aged between **18 to 65 years**. The study population includes both male and female subjects, with a focus on individuals who have inadequately controlled symptoms of schizophrenia. Participants were selected based on specific criteria, including a stable living situation and the ability to comply with study requirements. The trial includes individuals who are currently on stable doses of certain antipsychotic medications and have not required psychiatric hospitalization or acute crisis intervention within eight weeks prior to screening. Participants are required to have a **BMI** within the range of 18 to 40 kg/m² and must be capable of providing informed consent. The study also considers lifestyle factors such as the presence of a reliable informant or caregiver to assist with study activities. The trial population is characterized by a vulnerable group, as indicated by the inclusion of individuals with a primary diagnosis of schizophrenia confirmed by comprehensive psychiatric evaluation.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the safety and efficacy of adjunctive KarXT in subjects with inadequately controlled symptoms of **schizophrenia**. The primary objective is to assess the efficacy of KarXT compared to placebo, as measured by the Positive and Negative Syndrome Scale (PANSS) Total Score. The trial is expected to conclude by April 2025, with recruitment having commenced in December 2022. Participants will be involved in the study for a duration of six weeks, during which they will undergo a series of structured visits.
The sequence of study visits includes an initial screening visit, where eligibility is determined based on criteria such as age, PANSS scores, and current treatment stability. Following successful screening, participants will be randomized at Visit 3, marking the start of the treatment phase. Throughout the trial, participants will attend regular follow-up visits to monitor their response to the treatment and any adverse effects. The end-of-study visit will occur at Week 6, where the primary endpoint, the change from baseline in PANSS total score, will be evaluated.
Participants are expected to adhere to the study protocol, including attending all scheduled visits and complying with medication regimens. Conditions that may lead to early termination from the study include significant non-compliance, withdrawal of consent, or any adverse event that, in the opinion of the investigator, warrants discontinuation. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of **KarXT**, an experimental medication formulated as a **capsule**. The active substances in KarXT are **trospium chloride** and **xanomeline tartrate**, both of which are of chemical origin. The medication is produced by Karuna Therapeutics Inc. and is administered orally. The dosing regimen varies, with a maximum daily dose ranging from 140 mg to 310 mg, depending on the specific treatment period, which can last from 1 to 5 weeks. The total maximum dose over the treatment period ranges from 980 mg to 6720 mg. Participant compliance with the dosing schedule is monitored throughout the trial.
In addition to the experimental treatment, a **KarXT Matching Placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the experimental medication in appearance and administration route, ensuring blinding is maintained. The placebo does not contain any active substances and is administered orally in a similar capsule form. The use of the placebo allows for the evaluation of the efficacy and safety of KarXT in subjects with inadequately controlled symptoms of schizophrenia, as measured by the Positive and Negative Syndrome Scale (PANSS) Total Score.
Efficacy
The efficacy of the investigational product, KarXT, in the treatment of subjects with inadequately controlled symptoms of **schizophrenia** will be assessed using the Positive and Negative Syndrome Scale (PANSS) Total Score. The primary endpoint is the change from baseline in the PANSS total score at Week 6. Secondary endpoints include changes from baseline in the Personal and Social Performance (PSP) scale, Clinical Global Impression-Severity (CGI-S) scale, PANSS Marder Positive Symptom Factor score, and PANSS Marder Negative Symptom Factor score, all measured at Week 6. Additionally, a categorical response will be evaluated, defined as the proportion of subjects achieving a ≥ 30% improvement in PANSS total score at Week 6.
Efficacy parameters will be collected and analyzed at specified timepoints, with baseline measurements taken prior to the initiation of treatment and subsequent assessments conducted at Week 6. The PANSS, PSP, and CGI-S scales are validated tools commonly used in clinical trials to assess symptom severity and functional outcomes in schizophrenia. The study will employ a randomized, double-blind, placebo-controlled design to ensure the reliability and validity of the efficacy assessments. Data collection will be conducted in accordance with the study protocol, and statistical analyses will be performed to determine the significance of the observed changes in efficacy endpoints.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject is aged 18 to 65 years (inclusive) at the time of randomization (Visit 3)
- Subject is capable of providing signed Informed Consent Form (ICF) before any study assessments will be performed. Subject must be fluent in the language of the ICF to consent.
- Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric evaluation based on the Diagnostic Statistical Manual 5 (DSM-5) criteria and confirmed by Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2
- Subject is currently being treated with stable dosing of monotherapy risperidone, paliperidone, aripiprazole, or their LAI formulations, ziprasidone, lurasidone, or cariprazine and has been taking this treatment with the same dosing regimen for at least 8 weeks at the time of Day 1 (Visit 3) (supported by documentation)
- The subject has an inadequate response to above antipsychotics that was dosed appropriately (within the label), as defined per inclusion criteria 8 and 9
- The subject has not required psychiatric hospitalization, incarceration in prison, acute crisis intervention, or other increase in the level of care due to symptom exacerbation within 8 weeks of Screening and is psychiatrically stable in the opinion of the Investigator
- To be eligible for randomization, subjects need to have detectable levels of background antipsychotic medication (measured at Visit 1)
- PANSS total score ≥ 70 at Screening (Visit 1) and randomization (Day 1, Visit 3)
- CGI-S scale with a score ≥ 4 (moderate) at Screening (Visit 1) and randomization (Day1, Visit 3)
- PANSS Marder Positive symptom factor ≥ 4 on 2 (or more) items (PANSS items, delusions, hallucinations, grandiosity, suspiciousness and persecution, stereotyped thinking, somatic concern, unusual thought content or lack of judgment and insight), at Screening (Visit 1) and randomization (Day 1, Visit 3)
- Subjects with ≤ 20-point decrease in PANSS total score between Visit 1 and Visit 3
- Subject is willing and able to visit the clinic in an outpatient setting for the study duration, follow instructions, and comply with the protocol requirements
- BMI must be within 18 to 40 kg/m2 (inclusive of both values)
- Subject resides in a stable living situation, in the opinion of the Investigator
- Subject has identified a reliable informant/ caregiver willing and able to assist with study activities as needed throughout the subject's participation in the study. The informant does not have to be someone responsible for the subject’s physical or psychiatric well-being. The informant needs to be physically present at the Baseline visit, but and can complete the remaining study visits assessments via phone (as needed and as per local regulations). In Bulgaria, the informant needs to be physically present at the Baseline visit and should be physically present at all study visits where the Investigator determines that his/her input would be beneficial
- Women of childbearing potential (WOCBP), or men whose sexual partners are WOCBP, must be able and willing to use at least 1 highly effective method of contraception during the study and for at least 1 menstrual cycle (e.g., 30 days) after the last dose of study drug. Sperm donation is not allowed for 30 days after the final dose of the study drug. A female subject is considered to be a WOCBP after menarche and until she is in a postmenopausal state for 12 months or otherwise permanently sterile (for which acceptable methods include hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). For the definition and list of highly effective methods of contraception, see APPENDIX 2.
Exclusion Criteria
- Any primary DSM-5 disorder other than schizophrenia within 12 months before Screening (confirmed using MINI version 7.0.2 at Screening)
- The subject has a history of moderate to severe substance use disorder (other than nicotine) within the past 12 months a. A Screening subject with mild substance use disorder within the 12 months before Screening must be discussed with the Medical Monitor before being allowed into the study b. Subjects who test positive for cannabis at Screening may be permitted to enroll in consultation with the Medical Monitor if the subject's pattern of use is not indicative of a moderate to severe substance use disorder
- Subject has a history of treatment-resistant schizophrenia defined as: Failure to minimally respond to 2 adequate courses of APD pharmacotherapy Note: Failure to minimally respond is defined as persistence of at symptoms of moderate severity in 2 or more psychotic symptom domains or persistence of severe symptoms in 1 or more psychotic symptom domains despite adequate dose and duration (6 weeks or longer) of APD treatment
- History of symptom instability > 3 psychiatric hospitalizations over the last 12 months or 2 over the last 6 months
- Current APD is other than aripiprazole, risperidone, paliperidone, or their LAI formulations, ziprasidone, lurasidone, or cariprazine
- Subjects who are diagnosed with schizophreniform disorder or are experiencing their first treated episode of schizophrenia
- Significant or severe medical conditions including pulmonary, cardiovascular, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the Investigator, could jeopardize the safety of the subject or the validity of the study results. Subjects with any of the following laboratory values at Screening (Visit 1) are excluded: a. eGFR < 60 mL/min b. Alanine transaminase or aspartate transaminase (AST) > 1.5 x upper limit of normal (ULN) c. Total bilirubin > 1.5 x ULN (Subjects with Gilbert’s syndrome can be included as long as direct bilirubin is ≤ 1.5 x ULN)
- Subjects with human immunodeficiency virus, cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections as indicated by medical history, serologies or LFT results
- History or high risk of urinary retention, gastric retention, or narrow- angle glaucoma as evaluated by the Investigator
- History of irritable bowel syndrome (with or without constipation) or any serious constipation requiring treatment within the last 6 months
- Risk of suicidal behavior during the study as determined by the Investigator's clinical assessment and/ or C-SSRS as confirmed by the following: a. Answers "Yes" on items 4 or 5 (C-SSRS – ideation) with the most recent episode occurring within the 2 months before Screening or, b. Answers "Yes" to any of the 5 items (C-SSRS behavior) with an episode occurring within the 12 months before Screening
- Clinically significant abnormal finding on the physical examination, medical history, ECG (QTcF of > 450 msec in males and > 470 msec in females), or clinical laboratory results at Screening
- Urine toxicology screen is positive for phencyclidine, amphetamines, opiates, cocaine, or alcohol (clinically significant alcohol use in the opinion of the Investigator)
- Subject is currently taking, or plans to take while in the study, any prohibited concomitant medication as outlined in APPENDIX 4
- Pregnant, lactating, or less than 3 months postpartum
- If, in the opinion of the Investigator and/or Sponsor/Medical Monitor, subject is unsuitable for enrollment in the study or subject has any finding that, in the view of the Investigator and/or Sponsor/ Medical Monitor, may compromise the safety of the subject or affect his/her ability to adhere to the protocol visit schedule or fulfill visit requirements
- Positive test for SARS-CoV-2 (COVID-19) within 2 weeks before or at Screening
- Subjects with extreme concerns relating to global pandemics, such as COVID-19 that would obscure ratings or be expected to disrupt adherence to trial procedures
- Unable to taper and discontinue a concomitant medication that would preclude participation in the double-blind adjunctive treatment (e.g., cannot stop anticholinergic)
- Subjects with prior exposure to KarXT
- Subjects who experienced any adverse effects due to xanomeline or trospium
- Subjects who received investigational product as part of a clinical trial within 3 months of Screening
- Risk of violent or destructive behavior as per Investigator's judgment that would interfere with subject's participation
- Current involuntary hospitalization or incarceration or on parole/probation, unless approved by the Medical Monitor
- For all male subjects only, any one of the following: a. History of bladder stones b. History of recurrent urinary tract infections c. Serum prostate specific antigen >10 ng/mL d. An IPSS of 5 (almost always) on either item 1, 3, 5, or 6 e. A sum of scores on IPSS items 1, 3, 5, and 6 of ≥9
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 20 Dec 2022 | 65 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KarXT Matching Placebo | Placebo | N/A | — | — | — | N/A |
KarXT | Test | CAPSULE | ORAL | 190 | 5 | PRD11105607 |
KarXT | Test | CAPSULE | ORAL | 240 | 4 | PRD11105608 |
KarXT | Test | CAPSULE | ORAL | 140 | 1 | PRD11105606 |
KarXT | Test | CAPSULE | ORAL | 310 | 3 | PRD11105609 |