A Study of E2027 in Participants With Dementia With Lewy Bodies (DLB) or Parkinson's Disease Dementia (PDD) With or Without Amyloid Copathology

An Open-Label Study To Evaluate the Pharmacodynamic Effects, Efficacy, Safety, and Tolerability of E2027 in Subjects With Dementia With Lewy Bodies or Parkinson's Disease Dementia With or Without Amyloid Copathology

The purpose of study is to demonstrate the pharmacodynamic (PD) effects of E2027 on cerebrospinal fluid (CSF) cyclic guanosine monophosphate (cGMP) in participants with DLB and PDD with and without amyloid copathology after 9 weeks of treatment.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease; Lewy Body Disease
• Intervention / Treatment: Drug: E2027

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Toronto, Canada, M3B 2S7
    • Toronto Memory Program
• United States
  • Arizona
    • Sun City, Arizona, United States, 85351
      • Banner Sun Health Research Institute
  • Florida
    • Atlantis, Florida, United States, 33462
      • JEM Research Institute
    • Miami, Florida, United States, 33155
      • Elias Research Associates (Allied Biomedical Research Institute)
    • Pompano Beach, Florida, United States, 33064
      • NAPA Research
    • Tampa, Florida, United States, 33613
      • University of South Florida, Department of Psychiatry and Behavioral Neurosciences
    • Wellington, Florida, United States, 33414
      • Alzheimer's Research and Treatment Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky, Dept of Neurology, Sanders Brown Center on Aging
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Advanced Memory Research Institute of NJPC
  • New York
    • Albany, New York, United States, 12208
      • Neurological Associates of Albany, PC
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Ohio
    • Dayton, Ohio, United States, 45459
      • Neurology Diagnostics, Inc.
    • Lakewood, Ohio, United States, 44107
      • Cleveland Clinic, Lou Ruvo Center for Brain Health at Lakewood Hospital
  • Oregon
    • Portland, Oregon, United States, 97210
      • Summit Research Network (Oregon) Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 46 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, age 50 to 85 years, inclusive at time of consent
2. Meet criteria for probable DLB (as defined by the 4th report of the DLB Consortium) or meet criteria for probable PDD (as defined by the task force of the Movement Disorder Society).
3. Mini-mental state examination (MMSE) greater than (>) 14 and less than (<) 26 at Screening Visit
4. For DLB participants, have experienced visual hallucinations since onset of their DLB
5. If receiving acetylcholinesterase inhibitors (AChEIs), must have been on a stable dose for at least 12 weeks before Screening Visit, with no plans for dose adjustment during the study. Treatment naive participants can be entered into the study but there should be no plans to initiate treatment with AChEIs from Screening to the end of the study.
6. If receiving memantine, must have been on a stable dose for at least 12 weeks before Screening Visit, with no plans for dose adjustment during the study. Treatment naive participants can be entered into the study but there should be no plans to initiate treatment with memantine from Screening to the end of the study.
7. If receiving Parkinson's disease medications, must have been on a stable dose for at least 4 weeks before Screening Visit, with no plans for dose adjustment during the study.
8. Must have an identified caregiver or informant who is willing and able to provide follow up information on the participant throughout the course of the study.
9. Provide written informed consent.

Exclusion Criteria:

1. Any neurological condition that may be contributing to cognitive impairment above and beyond those caused by the participant's DLB or PDD, including any comorbidities detected by clinical assessment or magnetic resonance imaging (MRI) (identification of amyloid copathology is not exclusionary)
2. History of transient ischemic attacks or stroke within 12 months of Screening
3. Modified Hachinski Ischemic Scale >4
4. Parkinsonian (extrapyramidal) features with Hoehn and Yahr Scale (HYS) stage 4 or higher
5. Any major psychiatric diagnosis, including schizophrenia, bipolar disorder and current major depressive disorder as per Diagnostic and Statistical Manual of Mental Disorders Fifth Edition
6. Geriatric Depression Scale (GDS) score >8
7. Severe visual or hearing impairment that may interfere with the participant study assessments including cognitive testing
8. Any contraindications to lumbar puncture
9. History of deep brain stimulation or other neurosurgical procedure for Parkinson's disease
10. Has thyroid stimulating hormone (TSH) above normal range
11. Abnormally low serum vitamin B12 levels (< the lower limit of normal [LLN]) for the testing laboratory
12. Contraindications to MRI scanning
13. Evidence of other clinically significant lesions that suggest a dementia diagnosis other than DLB or PDD on brain MRI at Screening
14. Other significant pathological findings on brain MRI at Screening
15. Hypersensitivity to E2027 or any of the excipients
16. A prolonged corrected QT interval calculated using Fridericia's formula (QTcF) as demonstrated by triplicate ECG at the Screening or Baseline Visit (that is, mean value >450 millisecond [msec])
17. Had symptomatic orthostatic hypotension or symptomatic orthostatic tachycardia which resulted in hospitalization or urgent medical review in hospital in the past 12 months before Screening
18. Any other clinically significant abnormalities in vital signs, ECG and laboratory values that in the opinion of the investigator, require further investigation or treatment or that may interfere with study procedures or safety
19. Malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma of the skin, or localized prostate cancer in male participants). Participants who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before Screening need not be excluded.
20. Has a "yes" answer to C-SSRS suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at the Baseline Visit, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening
21. Known or suspected history of drug or alcohol dependency or abuse within 2 years before Screening, current use of recreational drugs or a positive urine drug test at Screening.
22. Any other medical conditions (example, cardiac, respiratory, gastrointestinal, renal disease) which are not stably and adequately controlled, or which in the opinion of the investigator may affect the participant's safety or interfere with the study assessments
23. Taking any of the prohibited medications or not meeting the requirements regarding stable doses of permitted medications
24. Participation in a clinical study involving any investigational drug/device for DLB or PDD within 6 months before Screening or any other investigational drug/device in the 8 weeks or 5 half-lives (whichever is longer) of the study medication before Screening unless it can be documented that the participant was in a placebo treatment arm
25. Planned surgery which requires general, spinal or epidural anesthesia that will take place during the study.
26. Males who have not had a successful vasectomy (confirmed azoospermia) if their female partners are of childbearing potential and are not willing to use a highly effective contraceptive method throughout the study period and for 98 days after study drug discontinuation. No sperm donation is allowed during the study period and for 98 days after study drug discontinuation.
27. Females who are breastfeeding or pregnant at Screening or Baseline

28. Females of childbearing potential who:

    • Within 28 days before study entry, did not use a highly effective method of contraception
    • Do not agree to use a highly effective method of contraception throughout the entire study period and for 28 days after study drug discontinuation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DLB Without Amyloid Copathology; Participants with DLB (without amyloid copathology) will receive E2027 50 milligram (mg) capsules, orally, once daily up to 12 weeks.	Drug: E2027; Oral hypromellose capsules.
Experimental: DLB With Amyloid Copathology; Participants with DLB (with amyloid copathology) will receive E2027 50 mg capsules, orally, once daily up to 12 weeks.	Drug: E2027; Oral hypromellose capsules.
Experimental: PDD Without Amyloid Copathology; Participants with PDD (without amyloid copathology) will receive E2027 50 mg capsules, orally, once daily up to 12 weeks.	Drug: E2027; Oral hypromellose capsules.
Experimental: PDD With Amyloid Copathology; Participants with PDD (with amyloid copathology) will receive E2027 50 mg capsules, orally, once daily up to 12 weeks.	Drug: E2027; Oral hypromellose capsules.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Cerebrospinal Fluid (CSF) Cyclic Guanosine Monophosphate (cGMP) at Week 9	cGMP was measured in CSF samples using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantitative at 0.500 nanogram per milliliter (ng/ml). Evaluation of cGMP following dosing of E2027 was based on relative percent change from baseline.	Baseline, Week 9

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia Suicide Severity Rating Scale (C-SSRS)	The C-SSRS (mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories); is an interview-based instrument to systematically assess suicidal ideation and suicidal behavior. C-SSRS assess whether participant experience any of the following: completed suicide; suicide attempt (response of "yes" on "actual attempt"); preparatory acts toward imminent suicidal behavior ("yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior"). Here, number of participants with positive response ("yes") to suicidal behavior or/and Ideation, any non-suicidal self-injurious behavior was reported.	From first dose of study drug up to Week 16
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Severe TEAEs, Serious TEAEs, Adverse Events (AEs) Resulting in Study Discontinuation	A TEAE was defined as an AE that emerged during treatment, having been absent at pretreatment or reemerged during treatment, having been present at pretreatment but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE is continuous. Severe TEAE was defined as inability to work or to perform normal daily activity. A Serious TEAE was any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria. An AE was defined as any untoward medical occurrence in a participant administered an investigational product. AE resulting in study discontinuation was defined as AE due to which the study medication was stopped.	From first dose of study drug up to Week 16
Number of Participants With Treatment Emergent Orthostatic Hypotension	Orthostatic hypotension was defined based on the following criteria per protocol: Drop in standing systolic blood pressure (SBP) greater than or equal to (>=) 20 millimeter of mercury (mmHg) compared to supine or drop in standing diastolic blood pressure (DBP) >=10 mmHg compared to supine. Treatment-emergent orthostatic hypotension was defined as: if at baseline participant did not have SBP drop >=20 mmHg and no DBP drop >=10 mmHg, but developed one or more of these two events during post baseline visits.	Week 3, Week 6, Week 9, Week 12 and Week 16
Number of Participants With Post Baseline Treatment Emergent Orthostatic Tachycardia	Orthostatic tachycardia was defined by the following criteria per protocol: Standing heart rate (HR) increased by greater than (>) 30 beats/min compared to supine and absolute standing HR was >100 beats/min. A participant was counted as treatment-emergent if orthostatic tachycardia emerged during the treatment, having been absent at baseline (pretreatment).	From first dose of study drug up to Week 16
Number of Participants With Markedly Abnormal Laboratory Values	A laboratory value was determined to be a markedly abnormal value if the postbaseline grade increased from baseline and the post-baseline grade was greater than or equal to 2. Markedly abnormal laboratory values were based on Common Terminology Criteria for Adverse events (CTCAE) Version 5.0.	From first dose of study drug up to Week 16
Number of Participants With Post-Baseline Abnormal Electrocardiogram (ECG) Findings	Abnormal ECG findings were defined as follows: corrected QT interval calculated using Fridericia's formula (QTcF) prolonged by >60 millisecond (ms) from baseline and absolute QTcF >450 ms; QTcF prolonged to >500 ms; Change from baseline of PR interval >=25 percent (%) to an absolute PR value of >220 ms; Change from baseline of QRS interval >=25% to an absolute QRS value of >120 ms.	From first dose of study drug up to Week 16
Change From Baseline in Total Score of Unified Parkinson's Disease Rating Scale Part III: Motor Examination (UPDRS-III)	The UPDRS scale evaluates extrapyramidal features in motor function in Parkinson's disease. It contains 33 items in 18 categories: (1) speech, (2) facial expression, (3) rigidity, (4) finger tapping, (5) hand movements, (6) supinational and pronation movements of hands, (7) toe tapping, (8) leg agility, (9) arising from chair, (10) gait, (11) freezing of gait, (12) postural stability, (13) posture, (14) body bradykinesia, (15) postural tremor of hands, (16) kinetic tremor of hands, (17) rest tremor amplitude and (18) constancy of rest tremor. Each item is scored 0 to 4, giving a total score range 0 to 132. Higher scores indicating more severe symptoms.	Baseline, Week 12 and Week 16

Collaborators and Investigators

• Sponsor: Eisai Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2021
• Primary Completion (Actual): December 8, 2021
• Study Completion (Actual): January 27, 2022

Study Registration Dates

• First Submitted: February 19, 2021
• First Submitted That Met QC Criteria: February 19, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Actual): September 26, 2022
• Last Update Submitted That Met QC Criteria: August 30, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Parkinson's Disease Dementia; E2027; Amyloid Copathology; Dementia With Lewy Bodies
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Dementia; Lewy Body Disease
• Other Study ID Numbers: E2027-A001-203

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No