KarXT for Psychosis associated with Alzheimer's disease|Alzheimer's disease dementia

Inclusion criteria

• {"criterion_text":"- 1.Is a male or female aged 55 to 90 years, inclusive, at Screening (Visit 1)\n- 10. MMSE score of 8 to 22, inclusive, at Screening (Visit 1)\n- 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\n- 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\n- 13.BMI must be within 18 to 40 kg/m2 inclusive\n- 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)\n- 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\n- 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)\n- 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\n- 5.Living at the same home or residential assisted-living facility for a minimum of 6 weeks before Screening (Visit 1)\n- 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\n- 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)\n- 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\n- 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"}

Exclusion criteria

• {"criterion_text":"- 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\n- 10.Personal or family history of symptoms of long QT syndrome as evaluated by the Investigator\n- 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\n- 12.History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma as evaluated by the Investigator\n- 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\n- 14.History of irritable bowel syndrome (with or without constipation) or serious constipation requiring treatment within the last 6 months\n- 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\n- 16.Clinically significant abnormal finding on the physical examination, ECG, or clinical laboratory results at Screening (Visit 1)\n- 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\n- 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\n- 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\n- 2.History of major depressive episode with psychotic features during the 12 months prior to Screening (Visit 1)\n- 20. 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\n- 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)\n- 22.Prior exposure to KarXT\n- 23.History of hypersensitivity to KarXT excipients or trospium chloride\n- 24.Experienced any significant AEs due to trospium, including a known hypersensitivity to trospium\n- 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\n- 3.History of bipolar disorder, schizophrenia, or schizoaffective disorder\n- 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\n- 5.Significant and severe renal impairment based on a screening cutoff for estimated glomerular filtration rate of ≤ 50 mL/min/1.73 m2\n- 6.History of ischemic stroke within 12 months prior to Screening (Visit 1) or any evidence of hemorrhagic stroke\n- 7.History of cerebral amyloid angiopathy, epilepsy, CNS neoplasm, unstable thyroid function, or unexplained syncope\n- 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\n- 9.Myocardial infarction within the 6 months prior to Screening (Visit 1)"}

Primary endpoints

• {"endpoint_text":"- Change in NPI-C: H+D score","definition_or_measurement_approach":"Measured by the Neuropsychiatric Inventory-Clinician (NPI-C): Hallucinations and Delusions (H+D) score"}

Secondary endpoints

• {"endpoint_text":"- •Change in the CGI-S scale: CGI-S requires the assessor to consider aspects of the psychosis (hallucinations and delusions) prior to providing a global assessment of severity","definition_or_measurement_approach":"Clinical Global Impression – Severity (CGI-S) scale; assessor considers psychosis aspects (hallucinations and delusions) when providing global severity assessment"}
• {"endpoint_text":"- •Change in the: - NPI-C Core score: hallucinations, delusions, agitation, and aggression domains - NPI-C: Agitation score - NPI-C Core score: Caregiver Distress scale (Hallucinations, Delusions, Agitation, and Aggression domains)","definition_or_measurement_approach":"Changes in NPI-C core domains (hallucinations, delusions, agitation, aggression), NPI-C agitation domain score, and NPI-C Caregiver Distress scale; measured using NPI-C instrument"}
• {"endpoint_text":"- •Responder rate defined as NPI-C: H+D score ≥ 40% improvement","definition_or_measurement_approach":"Responder defined as ≥40% improvement in NPI-C: H+D (Hallucinations and Delusions) score"}

Methods

• Printed posters at clinic sites (document: K2_KAR-032_Poster_PL_Polish_Public) targeted to patients/caregivers (Poland)
• Patient-Caregiver brochures and brochures targeted to Alzheimer’s patients and caregivers (K2_KAR-032_Patient-Caregiver-Brochure_PL_Polish_Public and ADP versions) for distribution at sites and to potential participants (Poland)
• Study information postcards and flipchart materials for site staff to use during outreach and information sessions (K2_KAR-032_Study-Info-Postcard_PL_Polish_Public; K2_KAR-032_FlipChart_PL_Polish_Public) (Poland)
• Patient letters and Physician letters to inform potential participants and referring clinicians (K2_KAR-032_Patient-Letter_PL_Polish_Public; K2_KAR-032_Physician-Letter_PL_Polish_Public) (Poland)
• Patient-caregiver targeted website and online materials (K2_KAR-032_Patient-Caregiver-Website_PL_Polish_Public; Website cookies/tracking policy documents) (Poland)
• Inclusion-Exclusion cards and study branding materials for site-based recruitment (K2_KAR-032_Inclusion-Exclusion-Card_PL_Polish_Public; K2_KAR-032_Patient-Caregiver-Website and branded materials) (Poland)

Hungary

Earliest CTIS Part Ii Submission Date

25-01-2024

Latest Decision Or Authorization Date

29-07-2024

Processing Time Days

186

Number Of Sites

3

Number Of Participants

30

Greece

Earliest CTIS Part Ii Submission Date

14-02-2024

Latest Decision Or Authorization Date

01-08-2024

Processing Time Days

169

Number Of Sites

5

Number Of Participants

67

Belgium

Earliest CTIS Part Ii Submission Date

05-02-2024

Latest Decision Or Authorization Date

24-07-2024

Processing Time Days

170

Number Of Sites

3

Number Of Participants

22

Poland

Earliest CTIS Part Ii Submission Date

01-02-2024

Latest Decision Or Authorization Date

11-05-2026

Processing Time Days

830

Number Of Sites

2

Number Of Participants

67

Primary sponsor

Full Name

Karuna Therapeutics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

PPD Development LP

Responsibilities

Clinical supplies and multiple operational/site services (various operational codes and responsibilities listed)

Name

PPD Global Ltd.

Responsibilities

Operational and regional support (duties codes present in submission)

Name

Veristat LLC

Responsibilities

Statistical services (code 10)

Name

Signant Health Global LLC

Responsibilities

eCOA administration and rater qualification; scales management

Name

Suvoda LLC

Responsibilities

eClinical services (code 3)

Third parties

• {"country":"United Kingdom","full_name":"The Doctors Laboratory Limited","duties_or_roles":"Hepatitis D and Hepatitis E testing","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"Biomarker Analysis, Clinical chemistry, Clinical haematology, Clinical microbiology","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"PPD Global Central Labs","duties_or_roles":"Central Lab for Clinical chemistry, Haematology, microbiology, Histopathology, Serology and endocronology, Primary/surrogate endpoint test and Sample management","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Travel Reimbursement, Patient transport management, reimbursement, stipend management","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Clinical Supplies and multiple operational roles (codes listed in submission)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Quanterix Corp.","duties_or_roles":"Serology/ endocrinology, Biomarker Lab","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"eClinical services (code 3)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Olink Proteomics Inc.","duties_or_roles":"Biomarker analysis","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Cardiac safety management, EKG shipment","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Elligo Health Research Inc.","duties_or_roles":"Patient recruitment materials development, clinical study branding","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"Electronic data capture / clinical trial platform services","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Greece","full_name":"PPD Global Ltd.","duties_or_roles":"Operational roles (codes 1,12,2 listed in submission)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"Central Lab for Clinical Chemistry, Haematology, Microbiology, Histopathology, Serology and endocrinology, Primary/surrogate endpoint test and Sample management","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Veristat LLC","duties_or_roles":"Statistical services (code 10)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"eCOAs and rater qualification, scales management","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Celerion Inc.","duties_or_roles":"PK analysis","organisation_type":"Pharmaceutical company"}