| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| brain disorder that causes altered state of affect a person's ability to think, feel, and behave clearly. |
|
| 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 | 10039626 |
| E.1.2 | Term | Schizophrenia |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| 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 the efficacy of adjunctive KarXT compared with placebo in the treatment of subjects with inadequately controlled symptoms of schizophrenia |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of adjunctive KarXT compared with placebo on the Personal and Social Performance Scale (PSP).
• To evaluate the efficacy of adjunctive KarXT compared with placebo 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)
• To evaluate the safety and tolerability of adjunctive KarXT compared with placebo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is aged 18 to 59 years at the time of randomization (Visit 3)
2. Subject is capable of providing signed Informed Consent Form (ICF) before any study assessments will be performed.
3. 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
4. Subject is currently being treated with stable dosing of monotherapy risperidone, paliperidone, aripiprazole, or their LAIs, 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)
5. The subject has had at least one previous inadequate response to above antipsychotics that was dosed appropriately (within the label) for at least 6 weeks
6. 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
7. To be eligible for randomization, subjects need to have detectable levels of background antipsychotic medication (measured at Visit 1)
8. PANSS total score ≥ 70 at Screening (Visit 1) and randomization (Day 1, Visit 3)
9. CGI-S scale with a score ≥ 4 (moderate) at Screening (Visit 1) and randomization
10. 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)
11. Subjects with ≤ 20-point decrease in PANSS total score between Visit 1 and Visit 3
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. Body Mass Index (BMI) must be within 18 to 40 kg/m2 (inclusive of both values)
14. Subject resides in a stable living situation, in the opinion of the Investigator
15. 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 needs to be physically present at the Baseline visit, but 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.
16. Women of childbearing potential (WOCP), or men whose sexual partners are WOCP, 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 WOCP 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. Any primary DSM-5 disorder other than schizophrenia within 12 months before Screening (confirmed using MINI version 7.0.2 at Screening)
2. 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
3. Subject has a history of treatment-resistant schizophrenia defined as:
a. 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
4. History of symptom instability
a. > 3 psychiatric hospitalizations over the last 12 months or 2 over the last 6 months
5. Current APD is other than aripiprazole, risperidone, paliperidone, or their LAI versions, ziprasidone, lurasidone, or cariprazine
6. Subjects who are diagnosed with schizophreniform disorder or are experiencing their first treated episode of schizophrenia
7. 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
8. Subjects with human immunodeficiency virus (HIV), 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
10. History of irritable bowel syndrome (with or without constipation) or any serious constipation requiring treatment within the last 6 months
11. 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
12. Clinically significant abnormal finding on the physical examination, medical history, ECG (QTc of > 450 msec in males and > 470 msec in females), or clinical laboratory results at Screening
13. Urine toxicology screen is positive for phencyclidine, amphetamines, opiates, cocaine, or alcohol (clinically significant alcohol use in the opinion of the Investigator)
14. Subject is currently taking, or plans to take while in the study, any prohibited concomitant medication as outlined in APPENDIX 4
15. Pregnant, lactating, or less than 3 months postpartum
16. 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
17. Positive test for coronavirus (COVID-19) within 2 weeks before or at Screening
18. 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
19. Unable to taper and discontinue a concomitant medication that would preclude participation in the double-blind adjunctive treatment (e.g., cannot stop anticholinergic)
20. Subjects with prior exposure to KarXT
21. Subjects who experienced any adverse effects due to xanomeline or trospium
22. Participation in another clinical study in which the subject was enrolled within 3 months before Screening
23. Risk of violent or destructive behavior as per Investigator’s judgment that would interfere with subject’s participation
24. Current involuntary hospitalization or incarceration or on parole/probation
25. 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 (PSA) >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
To see full list of Exclusion criteria please refer to the protocol section 5.2 of the Protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from Baseline in PANSS Total at Week 6 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Change from Baseline in PSP at Week 6
• Change from Baseline in CGI-S at Week 6
• Change from Baseline in PANSS M-Pos Symptom Factor score at Week 6
• Change from Baseline in PANSS M-Neg symptom factor score at Week 6
• Categorical response defined as the proportion of subjects achieving a ≥ 30% improvement in PANSS total score at Week 6
• POM at Week 6 |
|
| 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 | Yes |
| 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 | 18 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| India |
| Serbia |
| United Kingdom |
| United States |
| Bulgaria |
| Poland |
| Romania |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 22 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 18 |
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