| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Psychosis Associated with Alzheimer's Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Delusions or hallucinations associated with mild to severe Alzheimer's disease |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012271 |
| E.1.2 | Term | Dementia Alzheimer's type |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037234 |
| E.1.2 | Term | Psychosis |
| E.1.2 | System Organ Class | 100000004873 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate relapse prevention in subjects with psychosis associated with AD treated with KarXT compared to placebo |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the time from randomization to discontinuation for any reason in subjects with psychosis associated with AD treated with KarXT compared to placebo
- To evaluate the safety and tolerability of KarXT compared to placebo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is a male or female aged 55 to 90 years, inclusive, at Screening (Visit 1A)
2. Can understand the nature of the study and protocol requirements and provide a signed informed consent (IC) form before any study assessments are performed. If local regulations do not allow electronic IC forms, then paper IC forms are permitted. 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 (LAR) or caregiver/study partner, if local regulations allow, must provide IC (paper or electronic)
b. The subject must provide informed assent (paper or electronic)
3. Meets clinical criteria for the following disorders:
a. Possible or probable AD
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. (Note: If waiting for MRI or CT results, an extension [up to two weeks] of the Screening Period may be allowed with approval of the Sponsor/Medical Monitor)
5. Living at the same home or residential assisted-living facility for a minimum of six weeks before Screening (Visit 1A)
6. Capable of self-locomotion (alone or with the aid of an assistive device) and have an identified or proxy caregiver (spends approximately 10 hours/week with the subject) that 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 (paper or electronic) to participate in the study
7. History of psychotic symptoms (meeting International Psychogeriatric Association [IPA] criteria [1]) for at least 2 months prior to Screening (Visit 1A). (Subjects may or may not have symptoms of agitation)
8. Clinical Global Impressions-Severity (CGI-S) scale with a score ≥4 (moderate) at Screening (Visit 1A) and Baseline (Visit 2). CGI-S requires the assessor to consider aspects of the psychosis prior to providing a global assessment of severity. These aspects include hallucinations and delusions.
9. AD dementia subjects are required to meet at least one of the following criteria at Screening (Visit 1A)and Baseline (Visit 2):
a. Moderate to severe delusions, defined as NPI-C: Delusions domain score of ≥2 on two of the eight items
OR
b. Moderate to severe hallucinations, defined as NPI-C: Hallucinations domain score of ≥ 2 on two of the seven items.
10. MMSE score of 8 to 22, inclusive, at Screening (Visit 1A)
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 1A) and be 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
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 or matching placebo. Sperm donation is not allowed for 30 days after the final dose of the IMP or matching placebo. 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). |
|
| E.4 | Principal exclusion criteria |
1. Psychotic symptoms that are primarily attributable to a conditionother than the AD causing 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 1A)
3. History of diagnosis 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
5. Significant or severe renal impairment based on a screening cutoff for Estimated Glomerular Filtration Rate (eGFR) of <60 mL/min/1.73 m2
6. History of ischemic stroke within 12 months prior to Screening (Visit 1A) or any evidence of hemorrhagic stroke
7. History of cerebral amyloid angiopathy (CAA), epilepsy, central nervous system (CNS) neoplasm, unstable thyroid function or unexplained syncope
8. Any of the following:
a. New York Heart Association (NYHA) Class 2 congestive heart failure
b. Grade 2 or greater angina pectoris
c. Sustained ventricular tachycardia
d. Ventricular fibrillation
e. Torsade de pointes
f. Implantable cardiac defibrillator
9. Myocardial infarction within the 6 months prior to Screening (Visit 1A)
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, 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. For males only any one of the following:
a. History of bladder stones
b. History of recurrent urinary tract infections
c. Serum prostate specific antigen (PSA) > 10 ng/mL at Screening (Visit 1A)
d. An International Prostate Symptom Score (IPSS) 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 1A)
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), 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 1A) may be permitted
b. Mirtazapine or trazodone may be used as a hypnotic if started at least 8 weeks prior to Screening (Visit 1A)
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
20. Positive test for coronavirus (COVID-19) within 2 weeks before or at Screening (Visit 1A); antigen or PCR 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 the study (e.g. cannot stop potent anticholinergic medication)
22. Prior exposure to KarXT
23. Experienced any significant AEs due to trospium incl. a known hypersensitivity to trospium
24. Participation in another clinical study in which the subject received an experimental or investigational drug within 3 months before Screening (Visit 1A) or has participated in more than 2 clinical studies in the past year |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time from randomization (end of Week 12; Visit 10) to relapse during the 26-week Double-Blind Randomized Withdrawal Treatment Period |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Time from randomization (end of Week 12; Visit 10) to discontinuation for any reason during the 26-week Double-Blind Randomized Withdrawal Treatment Period |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Croatia |
| Czechia |
| France |
| Germany |
| Italy |
| Serbia |
| Slovakia |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The study will complete when the last active subject fulfills all the requirements for the study
and has completed the last scheduled assessment (SFU, Week 40/Visit 20, or 2 weeks after study
discontinuation for subjects who withdraw early). For those subjects enrolling into the OLE
safety study, Week 38/Visit 19 will serve as the last visit of the KAR-031study and the first visit
of the OLE study (KAR-033). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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