A Study to Assess Efficacy and Safety of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia (ARISE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Karuna Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

Trial duration

22 Mar 2023 → 19 Mar 2025

Decision date (initial)

2024-06-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Karuna Therapeutics

External identifiers

EU CT number

2024-510770-25-00

EudraCT number

2022-001665-12

ClinicalTrials.gov

NCT05145413

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic

To evaluate the efficacy of adjunctive KarXT compared with placebo in the treatment of subjects with inadequately controlled symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale (PANSS) Total Score

Secondary objectives 3

1. To evaluate the efficacy of adjunctive KarXT compared with placebo on the Personal and Social Performance Scale (PSP)
2. 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)
3. To evaluate the safety and tolerability of adjunctive KarXT compared with placebo

Conditions and MedDRA coding

Schizophrenia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Subject is aged 18 to 65 years (inclusive) 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. Subject must be fluent in the language of the ICF to consent.
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 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)
5. The subject has an inadequate response to above antipsychotics that was dosed appropriately (within the label), as defined per inclusion criteria 8 and 9
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 (Day1, Visit 3)
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. 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 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
16. 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 25

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: 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 > 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 formulations, 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. 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)
8. 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
9. History or high risk of urinary retention, gastric retention, or narrow- angle glaucoma as evaluated by the Investigator
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 (QTcF 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 SARS-CoV-2 (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. Subjects who received investigational product as part of a clinical trial within 3 months of 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, unless approved by the Medical Monitor
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 >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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from Baseline in PANSS total score at Week 6

Secondary endpoints 6

1. Change from Baseline in PSP at Week 6
2. Change from Baseline in CGI-S at Week 6
3. Change from Baseline in PANSS M-Pos Symptom Factor score at Week 6
4. Change from Baseline in PANSS M-Neg symptom factor score at Week 6
5. Categorical response defined as the proportion of subjects achieving a ≥ 30% improvement in PANSS total score at Week 6
6. POM at Week 6

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Karuna Therapeutics Inc.

Sponsor organisation

Karuna Therapeutics Inc.

Address

99 High Street Floor 26

City

Boston

Postcode

02110-2320

Country

United States

Scientific contact point

Organisation

Karuna Therapeutics Inc.

Contact name

GSM-CT

Public contact point

Organisation

Karuna Therapeutics Inc.

Contact name

GSM-CT

Third parties 9

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 53 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications