Evaluation of KarXT Efficacy and Safety in Treating Psychosis Associated with Alzheimer's Disease: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-504416-16-00
Protocol: KAR-032
Sponsor: Karuna Therapeutics Inc.

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Diseases & Conditions

Dementia Alzheimer's type

Objectives

The primary objective of this study is to evaluate the **efficacy** of KarXT compared with placebo in the treatment of **psychosis** associated with Alzheimer's disease (AD). This is measured by the Neuropsychiatric Inventory-Clinician (NPI-C) focusing on hallucinations and delusions (H+D) score. The clinical relevance of this objective lies in addressing the significant challenge of managing psychosis in AD, which can severely impact patient quality of life and caregiver burden.

Secondary objectives include:

Evaluating the efficacy of KarXT compared with placebo in the treatment of agitation in subjects with psychosis associated with AD, as measured by the Cohen-Mansfield Agitation Inventory (CMAI).
Assessing the efficacy of KarXT compared with placebo using various measures: Global severity of illness with the Clinical Global Impressions-Severity (CGI-S) scale, NPI-C Core score for hallucinations, delusions, agitation, and aggression domains, NPI-C Agitation score, NPI-C Core Score for Caregiver Distress scale, and responder rate defined as a ≥40% improvement in NPI-C H+D score.

These secondary objectives aim to provide a comprehensive evaluation of KarXT's impact on multiple dimensions of psychosis and related symptoms in AD, which is crucial for understanding its potential therapeutic benefits.

Participants

The clinical trial involves a total of **625 participants** diagnosed with **psychosis associated with Alzheimer's disease**. The study population includes both male and female subjects, aged between 55 and 90 years. Participants are required to have a **Mini-Mental State Examination (MMSE)** score ranging from 8 to 22, indicating mild to moderate cognitive impairment. The trial population was selected based on specific criteria, including the ability to understand the trial's nature and provide informed consent, or have a legally acceptable representative do so. Participants must have a stable living situation, residing in the same home or assisted-living facility for at least six weeks prior to screening. They should be capable of self-locomotion, with or without an assistive device, and have a study partner who can assist with compliance and attend all visits. Lifestyle considerations include maintaining a stable dose of any cholinesterase inhibitors or memantine for six weeks before screening and throughout the study. Participants must have a **Body Mass Index (BMI)** between 18 and 40 kg/m². The trial includes individuals with a history of psychotic symptoms for at least two months prior to screening, and they must meet specific criteria on the **Neuropsychiatric Inventory-Clinician (NPI-C)** for hallucinations and delusions. The study ensures that female participants are not pregnant or breastfeeding and that effective contraception is used if applicable. The trial population is considered vulnerable, given the nature of the disease and the age group involved.

Plans and Procedures

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, parallel group study designed to evaluate the safety and efficacy of KarXT for the treatment of **psychosis associated with Alzheimer's disease**. The trial aims to assess the efficacy of KarXT compared to placebo by measuring changes in the Neuropsychiatric Inventory-Clinician (NPI-C) Hallucinations and Delusions (H+D) score. The study is expected to commence recruitment on March 31, 2024, and conclude by May 31, 2026.

Participants will be involved in the study for a duration that includes several key visits. The initial visit, known as the screening visit, will determine eligibility based on criteria such as age (55 to 90 years), **Mini-Mental State Examination (MMSE)** score (8 to 22), and stable use of cholinesterase inhibitors or memantine. Eligible participants will then be randomized to receive either KarXT or a placebo. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and compliance with the study protocol. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted.

The expected length of participant involvement is contingent upon the study's timeline and adherence to protocol requirements. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent. The primary endpoint of the trial is the change in NPI-C: H+D score, while secondary endpoints include changes in the Cohen-Mansfield Agitation Inventory (CMAI) total score, Clinical Global Impression-Severity (CGI-S) scale, and NPI-C Core scores for hallucinations, delusions, agitation, and aggression.

Treatment

The clinical trial involves the evaluation of **KarXT**, an investigational medication developed by Karuna Therapeutics Inc., for the treatment of psychosis associated with Alzheimer's Disease. **KarXT** is a chemical compound, and its pharmaceutical form is not specified in the provided data. The medication is administered in a double-blind, placebo-controlled manner, ensuring that neither the participants nor the investigators know who receives the active treatment or the placebo. The specific dosage, route, and frequency of administration for **KarXT** are not detailed in the available information.

In addition to the experimental treatment, a **placebo** is used as a comparator in this study. The placebo is designed to mimic the appearance and administration of **KarXT** but does not contain any active pharmaceutical ingredients. This approach allows for the assessment of **KarXT**'s efficacy and safety by comparing outcomes between the treatment and placebo groups. The study is structured as a parallel group trial, meaning participants are randomly assigned to either the **KarXT** group or the placebo group, and they remain in their assigned group throughout the study duration.

Participant compliance with the dosing schedule is monitored, although specific methods for compliance monitoring are not provided in the data. The trial's main objective is to evaluate the efficacy of **KarXT** compared to placebo in treating psychosis in subjects with Alzheimer's Disease, as measured by the Neuropsychiatric Inventory-Clinician (NPI-C) Hallucinations and Delusions score. The study is conducted under rigorous conditions to ensure the reliability and validity of the results.

Efficacy

The efficacy of KarXT in the treatment of **psychosis associated with Alzheimer's disease** will be assessed using the Neuropsychiatric Inventory-Clinician (NPI-C): Hallucinations and Delusions (H+D) score. The primary endpoint is the change in the NPI-C: H+D score, which will be measured to evaluate the treatment's effectiveness compared to placebo. Secondary endpoints include changes in the Cohen-Mansfield Agitation Inventory (CMAI) total score, the Clinical Global Impression-Severity (CGI-S) scale, and various NPI-C core scores, including hallucinations, delusions, agitation, and aggression domains. Additionally, the responder rate, defined as a 40% or greater improvement in the NPI-C: H+D score, will be assessed.

The efficacy parameters will be collected and analyzed at specified timepoints throughout the study. The NPI-C and CGI-S scales are validated tools that will be used to measure symptom severity and changes over time. The study is designed as a Phase 3, randomized, double-blind, placebo-controlled, parallel group trial, ensuring rigorous assessment of the treatment's efficacy. The trial will include male and female subjects aged 55 to 90 years with mild to severe Alzheimer's disease, and the study duration is planned to extend until May 31, 2026.

Inclusion and Exclusion Criteria

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Inclusion Criteria

1.Is a male or female aged 55 to 90 years, inclusive, at Screening (Visit 1)
2.Can understand the nature of the trial and protocol requirements and provide informed consent (IC) before any study assessments are performed. If the subject is deemed not competent to provide IC, the following requirements for consent must be met: a.The subject’s legally acceptable representative must provide IC b.The subject must provide informed assent
3.Meets clinical criteria for 1 of the following disorders: - Possible AD or Probable AD (refer to Appendix 1 National Institute on Aging – Alzheimer’s Association Guidelines for All cause Dementia and Alzheimer’s Disease)
4.Has a magnetic resonance imaging (MRI) or computed tomography (CT) scan of the brain (completed within the past 5 years) taken during or subsequent to the onset of dementia to rule out other central nervous system (CNS) disease that could account for the dementia syndrome, e.g., major stroke, neoplasm, subdural hematoma. If not available, a non-contrast brain MRI or non-contrast head CT must be done during Screening
5.Living at the same home or residential assisted-living facility for a minimum of 6 weeks before Screening (Visit 1)
6.Capable of self-locomotion (alone or with the aid of an assistive device) and have an identified study partner who should have daily contact (approximately 10 hours a week or more) and is willing to: a.Attend all visits and report on subject’s status b.Oversee subject compliance with medication and study procedures c.Participate in the study assessments and provide IC to participate in the study
7.History of psychotic symptoms (meeting International Psychogeriatric Association criteria) (Cummings 2020) for at least 2 months prior to Screening (Visit 1) (subjects may or may not have symptoms of agitation)
8.CGI-S scale with a score ≥ 4 (moderate) at Screening (Visit 1) and at Visit 2. CGI-S requires the assessor to consider aspects of the psychosis (hallucinations and delusions) prior to providing a global assessment of severity
9.AD subjects are required to have NPI-C: H+D score of ≥ 6 AND meet at least 1 of the following criteria at Screening (Visit 1) and Visit 2: a.Moderate to severe delusions, defined as NPI-C: Delusions domain score of ≥ 2 on 2 of the 8 items OR b.Moderate to severe hallucinations, defined as NPI-C: Hallucinations domain score of ≥ 2 on 2 of the 7 items
MMSE score of 8 to 22, inclusive, at Screening (Visit 1)
11.If the subject is taking a cholinesterase inhibitor and/or memantine, they must have been on a stable dose for 6 weeks prior to Screening (Visit 1) and willing to maintain a stable dose for the duration of the study
12.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
13.BMI must be within 18 to 40 kg/m2 inclusive
14.Female subjects must not be pregnant or breastfeeding. 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 IMP. Sperm donation is not allowed for 30 days after the final dose of the IMP. 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)

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Exclusion Criteria

1.Psychotic symptoms that are primarily attributable to a condition other than the AD causing the dementia, e.g., schizophrenia, schizoaffective disorder, delusional disorder, or mood disorder with psychotic features
2.History of major depressive episode with psychotic features during the 12 months prior to Screening (Visit 1)
3.History of bipolar disorder, schizophrenia, or schizoaffective disorder
4.Significant or severe medical conditions including pulmonary, hepatic*, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, cardiovascular, or oncologic disease or any other condition that, in the opinion of the Investigator, could jeopardize the safety of the subject, ability to complete or comply with the study procedures or validity of the study results *Note: participants with any grade of hepatic impairment (mild [Child-Pugh Class A], moderate [Child-Pugh Class B], and severe [Child-Pugh Class C]) will be excluded
5.Significant and severe renal impairment based on a screening cutoff for estimated glomerular filtration rate of ≤ 50 mL/min/1.73 m2
6.History of ischemic stroke within 12 months prior to Screening (Visit 1) or any evidence of hemorrhagic stroke
7.History of cerebral amyloid angiopathy, epilepsy, CNS neoplasm, unstable thyroid function, or unexplained syncope
8.Any of the following: a.New York Heart Association Class II or greater congestive heart failure b.Grade 2 or greater angina pectoris c. History of Sustained ventricular tachycardia d. History of Ventricular fibrillation e. History of Torsade de pointes f. History of Implantable cardiac defibrillator
9.Myocardial infarction within the 6 months prior to Screening (Visit 1)
10.Personal or family history of symptoms of long QT syndrome as evaluated by the Investigator
11.Human immunodeficiency virus (HIV), cirrhosis, biliary duct abnormalities, active biliary disease (e.g., symptomatic gallstones), hepatobiliary carcinoma, and/or active hepatic viral infections as indicated by medical history or LFT results
12.History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma as evaluated by the Investigator
13.Male subjects are excluded from the study if any of the following criteria apply: a.History of bladder stones b.History of recurrent urinary tract infections c.Serum prostate specific antigen > 10 ng/mL at Screening (Visit 1) d.An IPSS score of 5 (almost always) on items 1, 3, 5, or 6 e.A sum of scores on IPSS items 1, 3, 5, and 6 of ≥ 9
14.History of irritable bowel syndrome (with or without constipation) or serious constipation requiring treatment within the last 6 months
15.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 3, 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
16.Clinically significant abnormal finding on the physical examination, ECG, or clinical laboratory results at Screening (Visit 1)
17.Urine toxicology screen is positive for substances other than cannabis or benzodiazepines (both cannabis and short- or medium-acting benzodiazepines are allowed in limited quantities during the study) unless approval has been given by the Medical Monitor
18.Recent history of receiving monoamine oxidase inhibitors, anticonvulsants (e.g., lamotrigine, divalproex), mood stabilizers (e.g., lithium), tricyclic antidepressants (e.g., imipramine, desipramine), or any other psychoactive medications except for as needed anxiolytics (e.g., lorazepam) a.Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors taken at a stable dose for at least 8 weeks prior to Screening (Visit 1) may be permitted b.Mirtazapine or trazodone may be used as a hypnotic if started at least 8 weeks prior to Screening (Visit 1) c. If needed, an extension (up to 2 weeks) of the Screening Period may be allowed with approval of the Sponsor/Medical Monitor
19.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
Known positive test for coronavirus disease 2019 (COVID-19) within 2 weeks before or at Screening (Visit 1); antigen or polymerase chain reaction local testing can be done at the discretion of the Investigator
21.Unable to taper and discontinue a concomitant medication that would preclude participation in this study (e.g., cannot stop potent anticholinergic or antihistamine medication)
22.Prior exposure to KarXT
23.History of hypersensitivity to KarXT excipients or trospium chloride
24.Experienced any significant AEs due to trospium, including a known hypersensitivity to trospium
25.Participation in another clinical study in which the subject received an experimental or investigational drug within 3 months before Screening (Visit 1) or has participated in more than 2 clinical studies in the 12 months prior to Screening