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ADAGIO-2: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of KarXT for the Treatment of Agitation Associated with Alzheimer’s Disease

Overview

Alzheimer’s disease is more than memory loss.

Agitation is one of the most common and disruptive symptoms of Alzheimer’s disease.

If you or someone you know is experiencing agitation associated with Alzheimer’s disease, the ADAGIO-2 Study may interest you. Researchers are testing an oral investigational medicine to see if it can help.

Participants may qualify if they:
• Are 55 to 90 years of age.
• Have Alzheimer’s disease.
• Have been experiencing physical and/or verbal agitation (eg, hitting, kicking, shouting, swearing, pacing, wandering, throwing things, resistance to care) for at least 2 weeks.

Participants must have a caregiver who is willing to attend study visits and help with certain study activities. The study doctor will also check other eligibility requirements.

Participants are eligible if they are in care homes, assisted living facilities, memory care facilities, or living at home.

Participation in the study lasts about 5 months with regular visits and phone calls with the study team for health checks and tests. All eligible participants will receive study-related drugs and tests at no cost. The study participants’ caregiver or study partner may be reimbursed for time and travel.

Being in the study is voluntary, and participants can leave the study at any time.

To learn more, talk to your doctor or contact the study site.

Interested in taking part in the study? 

Please fill in this form. 

Planned end date

14 Jun 2028 15:32

Conditions

Alzheimer's

Inclusion Criteria

  • Is a male or female aged 55 to 90 years, inclusive, at Screening (Visit 1).
  • Participants or their legally acceptable representative must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent form (ICF) in accordance with regulatory, local, and institutional guidelines. This ICF must be obtained before performing any protocol-related procedures that are not part of normal patient care. If the participant is deemed not competent to provide IC, the following requirements for consent must be met:
    • The participant’s legally acceptable representative (LAR) must provide IC.
    • The participant must provide informed assent.
  • Diagnosis of probable Alzheimer disease, defined by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria.
  • Mini-Mental State Examination (MMSE) score of 5 to 22, inclusive, at Screening (Visit1).
  • 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 2 weeks] of the Screening Period may be allowed with approval of the Sponsor/Medical Monitor).
  • Stable living environment for at least 6 weeks prior to Screening (Visit 1). Participants are eligible if they are in nursing homes, assisted living facilities, memory care facilities, or living at home.
  • Capable of self-locomotion (alone or with the aid of an assistive device; wheelchairs and other mobility aids are acceptable).
  • Have one identified caregiver who should have sufficient contact (approximately 10 hours a week or more) and is willing to:
    • Attend all visits and report on participant’s status
    • Oversee participant compliance with medication and study procedures
    • Participate in the study assessments and provide IC to participate in the study
    • The caregiver role in non-institutionalized settings may or may not be the same individual who fulfils the role of caretaker. In institutionalized settings (e.g., nursing homes or memory care facilities), a caregiver may be a staff member of the institutionalized setting or another individual (e.g., family member, family friend, hired professional caregiver) who fulfils the above criteria.
  • History of agitation with onset at least two weeks prior to Screening (Visit 1).
  • AD participants are required to have NPI Agitation/Aggression score ≥ 4 at Screening (Visit 1) and Baseline (Visit 2).
  • CGI-S ≥ 4, as related to agitation, at Screening (Visit 1) and Baseline (Visit 2).
  • At least 1 of the following 3 criteria must be established from the CMAI at Screening (Visit 1) and Baseline (Visit 2; CMAI Factor 1 Positivity):
    • 1 or more aggressive behaviours occurring several times per week
    • 2 or more aggressive behaviours occurring once or twice per week
    • 3 or more aggressive behaviours occurring less than once per week.

  • If the participant 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 be willing to maintain a stable dose for the duration of the study.
  • Participant is willing and able to visit the clinic in an outpatient setting for the study duration, follow instructions, and comply with the protocol requirements.
  • BMI must be within 18 to 40 kg/m2 inclusive.
  • Individuals of childbearing potential (IOCBP), or male participants whose sexual partners are IOCBP, 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. A female participant is considered to be an IOCBP 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, refer to the appendix for contraception guidelines. Sperm donation is not allowed for 30 days after the final dose of the IMP.

Exclusion Criteria

  • Agitation symptoms that are primarily attributable to a condition other than the AD causing the dementia
  • History of major depressive episode with psychotic features during the 12 months prior to Screening (Visit 1).
  • History of bipolar disorder, schizophrenia, or schizoaffective disorder.
  • Significant or severe medical conditions including pulmonary, hepatic*, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, cardiovascular, or oncologic disease or any other condition or ongoing treatment that, in the opinion of the Investigator, could jeopardize the safety of the participant, ability to complete or comply with the study procedures or validity of the study results.
    *Note: participants with any grade of hepatic impairment will be excluded from the study.
  • History of ischemic stroke within 12 months prior to Screening (Visit 1) or any evidence of haemorrhagic stroke.
  • History of cerebral amyloid angiopathy, epilepsy, CNS neoplasm, unstable thyroid function, or unexplained syncope.
    • History of any of the following:
        o New York Heart Association Class II or greater congestive heart failure
        o Grade 2 or greater angina pectoris
        o Sustained ventricular tachycardia
        o Ventricular fibrillation
        o Torsade de pointes
        o Implantable cardiac defibrillator.
  • Myocardial infarction within the 6 months prior to Screening (Visit 1).
  • Personal or family history of symptoms of long QT syndrome as evaluated by the Investigator.
  • Human immunodeficiency virus (HIV), cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections as indicated by medical history or LFT results.
  • History of (or at high risk for) urinary retention, gastric retention, or narrow-angle glaucoma as evaluated by the Investigator.
  • Male participants are excluded from the study if any of the following criteria apply:
      o History of bladder stones
      o History of recurrent urinary tract infections
      o Serum prostate-specific antigen > 10 ng/mL at Screening (Visit 1).
  •  An IPSS score of 5 (almost always) on items 1, 3, 5, or 6
      o A sum of scores on IPSS items 1, 3, 5, and 6 of ≥ 9.
  • History of irritable bowel syndrome (with or without constipation) or serious constipation requiring treatment within the last 6 months.
  • Risk of suicidal behavior during the study as determined by the Investigator’s clinical assessment and/or C-SSRS as confirmed by the following:
      o Answers “Yes” on items 3, 4, or 5 (C-SSRS – ideation) with the most recent episode occurring within the 2 months before screening or,
      o Answers “Yes” to any of the 5 items (C-SSRS behavior) with an episode occurring within the 12 months before Screening.
  • Clinically significant abnormal finding on the physical examination, ECG, or clinical laboratory results at Screening (Visit 1).
  • 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 first 6 weeks of the study) unless approval has been given by the Medical Monitor.
  • 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).
  • 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.
  • Mirtazapine or trazodone may be used as a hypnotic if started at least 8 weeks prior to Screening (Visit 1).
  • If, in the opinion of the Investigator and/or Sponsor/Medical Monitor, participant is unsuitable for enrolment in the study or participant has any finding that, in the view of the Investigator and/or Sponsor/Medical Monitor, may compromise the safety of the participant or affect his/her ability to adhere to the protocol visit schedule or fulfill visit requirements.
  • Known acute infection or symptomatic illness within 2 weeks before Screening (Visit 1); local testing can be done at the discretion of the Investigator. Rescreening can be permitted after the infection/illness is resolved and consultation with the medical monitor.
  • Unable to taper and discontinue a concomitant medication that would preclude participation in this study.
  • Prior exposure to KarXT.
  • History of hypersensitivity to KarXT excipients or trospium chloride.
  • Experienced any significant AEs due to trospium, including a known hypersensitivity to trospium.
  • Participation in another clinical study in which the participant 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.
  • Individuals who are breastfeeding.
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