Clinical trial NCT03305809: A Study of LY3154207 in Participants With Dementia Due to Lewy Body Dementia (LBD) Associated With Idiopathic Parkinson's Disease (PD) or Dementia With Lewy Bodies (DLB)
Official title: Effect of LY3154207 on Cognition in Mild-to-Moderate Dementia Due to Lewy Body Dementia (LBD) Associated With Idiopathic Parkinson's Disease (PD) or Dementia With Lewy Bodies (DLB)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lewy Body Dementia
Keywords: Parkinson Disease Dementia
Parkinson Disease
Dopamine
Cognition
Lewy Body Dementia
Dementia with Lewy Bodies
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2017-10-10
Enrollment: 344
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A randomized placebo-controlled trial to evaluate the safety and efficacy of three doses of study drug LY3154207 treated for 12 weeks in participants with mild-to-moderate dementia associated with LBD (PDD or DLB).


Eligibility criteria: Inclusion Criteria:

* Have dementia as defined by a decline in cognitive function, which in the opinion of the investigator has resulted in functional impairment.
* Meet diagnostic criteria for PD per MDS criteria or DLB per 4th Consensus Report of the DLB Consortium.
* Have a score on the MoCA of 10 - 23.
* Are Modified Hoehn and Yahr Stages 0 - 4.
* Have a blood pressure (BP) or pulse rate at screening and randomization, as determined by three sequential BP/pulse rate measurements in a seated position:

  * Participants \<60 years old:

    1. A mean systolic BP less than or equal to 140 millimeters of mercury (mmHg), a mean diastolic BP less than or equal to 90 mmHg and a mean pulse rate less than or equal 90 beats/minute in a seated position.
    2. Each of the 3 systolic BP measurement must be less than 180 mmHg
  * Participants ≥60 years old:

    1. A mean systolic BP less than or equal to 150 mmHg, a mean diastolic BP less than or equal to 90 mmHg and a mean pulse rate less than or equal to 90 beats/min in a seated position.
    2. Each of the 3 systolic BP measurement must be less than 180 mmHg
* If on anti-parkinsonian agents, participants must be on stable dosage for at least 3 weeks prior to screening, and should remain on stable doses during the course of the study.
* If on medications affecting cognition (rivastigmine, galantamine, donepezil, memantine), participants must be on stable dosage for at least 3 weeks prior to screening and should remain at a stable dosage during the course of the study.
* If on antidepressant medications, participants must be on stable dosage for at least 3 weeks prior to screening and should remain at a stable dosage during the course of the study.
* If on clozapine, quetiapine, and pimavanserin to address drug induced or disease related psychosis, participants must be on stable dosage for 3 weeks prior to screening and should remain at a stable dosage during the course of the study.
* If on antihypertensive medications, participants must be on stable dosage for at least 3 weeks prior to screening.
* Men should use appropriate contraception.
* All participants must have a reliable caregiver who is in frequent contact with the participant (defined as at least 10 hours per week) and will accompany the participant to screening, baseline, day 7, day 42, day 84 and follow-up.

Exclusion Criteria:

* Are women of childbearing potential.
* Have significant central nervous system or psychiatric disease, other than PD or DLB, that in the investigator's opinion may affect cognition or the ability to complete the study.
* Have a history in the last 6 months of transient ischemic attacks or ischemic stroke.
* Have a history of intra cerebral hemorrhage due to hypertension.
* Have a history of hypertensive encephalopathy.
* Have atypical or secondary parkinsonism due to drugs (e.g., antipsychotics) or disease (such as progressive supranuclear palsy, essential tremor, multiple system atrophy (e.g. striatonigral degeneration, olivopontocerebellar atrophy), or postencephalitic parkinsonism).
* Have a current implantable intracranial stimulator or history of intracranial ablation surgery (e.g., subthalamic, globus pallidus-internal segment \[GPi\]).
* Have a history of substance abuse within the past 1 year (drug categories defined by the Diagnostic and Statistical Manual of Mental Disorder, 5th Edition \[DSM-5\], and/or substance dependence within the past 1 year, not including caffeine and nicotine.
* Have a serious or unstable medical illness, other than idiopathic LBD (PDD or DLB), including cardiovascular, hepatic, respiratory, hematologic, endocrinologic, neurologic, or renal disease, or clinically significant laboratory or electrocardiogram (ECG) abnormality as determined by the investigator.

  * Have a history in the last 6 months of exertional angina, unstable angina, myocardial infarction, and acute coronary syndrome.
  * Have a history of heart failure of either New York Heart Association Class III or IV.
  * A history of additional risk factors for Torsades de Pointes (TdP; \[e.g., chronic hypokalemia, family history of Long QT Syndrome\]).
* Participants with acute liver disease (e.g. acute viral hepatitis, alcoholic hepatitis); participants with a known chronic liver disease (e.g. hepatitis B, C, alcoholic liver disease, cirrhosis); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal to or higher than 2X upper limit of normal (ULN); total bilirubin (TBL) equal to or higher than 1.5X ULN; (except for participants with Gilbert's syndrome); or alkaline phosphatase (ALP) equal to or higher than 2X ULN.
* Participants have answered 'yes' to either Question 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) or Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the "Suicidal Ideation" portion of the Columbia Suicide Severity Rating Scale (C-SSRS)- Children's version, or answer "yes" to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt).
* Have used antipsychotic medications, with the exception of clozapine, quetiapine, pimavanserin in the 6 months prior to screening and at any time during the course of the study.
* Have used anticholinergics trihexyphenidyl and benztropine in the 4 weeks prior to screening and at any time during the course of the study.
* Have motor conditions for which the antiparkinsonian treatment is expected to change during the course of the study, as well as unpredictable motor fluctuations that in the investigator's opinion would interfere with administering assessments.
* Are taking any medications or food, herbal or dietary supplements that are inhibitors (e.g., ketoconazole, grapefruit juice), or strong/moderate inducers of cytochrome P450 3A4 (CYP3A4) (e.g., rifampicin) or are unable or unwilling to discontinue usage of them 4 weeks prior to first dose of study drug.

Primary outcomes:
measure: Change From Baseline in the Continuity of Attention (CoA) Composite Score of the Cognitive Drug Research Computerized Cognition Battery (CDR-CCB)
timeFrame: Baseline, Week 12
Secondary outcomes:
measure: Change From Baseline on the Alzheimer's Disease Cooperative Study-Clinician Global Impression of Change (ADCS-CGIC) Score
timeFrame: Baseline, Week 12
measure: Change From Baseline on the CDR-CCB Power of Attention (PoA) Composite Score
timeFrame: Baseline, Week 12
measure: Change From Baseline in the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13)
timeFrame: Baseline, Week 12
measure: Change From Screening in the Montreal Cognitive Assessment (MoCA) Score
timeFrame: Screening (Baseline), Week 12
measure: Change From Baseline in the Neuropsychiatric Inventory (NPI) Total Score and Individual Item Scores
timeFrame: Baseline, Week 12
measure: Change From Baseline in the Epworth Sleepiness Scale (ESS) Score
timeFrame: Baseline, Week 12
measure: Change From Baseline in the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total Score (Sum of Parts I-III)
timeFrame: Baseline, Week 12
measure: Change From Baseline in the Penn Parkinson's Daily Activities Questionnaire-15 (PDAQ-15) Total Score
timeFrame: Baseline, Week 12
measure: Change From Baseline in Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency Test Score
timeFrame: Baseline, Week 12
measure: Change in MDS-UPDRS Parts II (Motor Experiences of Daily Living) and III (Motor Exam) From Baseline to Week 12
timeFrame: Baseline, Week 12
measure: Number of Participants Who Met the Potentially Clinically Significant Vital Signs Criteria at 3 Consecutive Time Points at Visit 3
timeFrame: Visit 3 (Day 1 stopping rules)
measure: Change From Baseline in Clinic Blood Pressure (BP) to 8 Hours Post Dose
timeFrame: Baseline, 8 Hours Post Dose
measure: Change From Baseline in Pulse Rate to 8 Hours Post Dose
timeFrame: Baseline, 8 Hours Post Dose
measure: Change From Baseline In-clinic BP to Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in Pulse Rate to Week 12
timeFrame: Baseline, Week 12
measure: Change in Home Blood Pressure Measurement (HBPM), for SBP, DBP From Baseline to Week 12
timeFrame: Baseline, Week 12
measure: Change in HBPM for Pulse Rate From Baseline to Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in the Physician Withdrawal Checklist (PWC)-20 Total Score From Week 12 to In-Clinic Follow-up Visit
timeFrame: Week 12, Follow-up (2 Weeks after Week 12)
measure: Pharmacokinetics (PK): Steady-State Trough Plasma Concentrations of LY3154207
timeFrame: Day 1: 1-3 hours post-dose; Day 7, Day 14 and Day 42: post-dose; Day 84: pre-dose
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic of Scottsdale
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Health Sciences
state: Arizona
city: Fountain Valley
country: United States
facility: Parkinson'S & Movement Disorder Institute
state: California
city: Irvine
country: United States
facility: University of CA, Irvine
state: California
city: Long Beach
country: United States
facility: Collaborative Neuroscience Network - CNS
state: California
city: Los Angeles
country: United States
facility: University of Southern California School of Medicine
state: California
city: Oxnard
country: United States
facility: Pacific Neuroscience Medical Group
state: California
city: Palo Alto
country: United States
facility: Stanford Neuroscience Health Center
state: California
city: Pasadena
country: United States
facility: SC3 Research Group Inc Pasadena
state: California
city: Reseda
country: United States
facility: SC3 Research Group Inc Reseda
state: California
city: Sacramento
country: United States
facility: University of California, Davis - Health Systems
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Denver
country: United States
facility: Denver Neurological Research
state: Colorado
city: Englewood
country: United States
facility: Rocky Mountain Movement Disorders Center
state: Colorado
city: Stamford
country: United States
facility: New England Institute for Clinical Research
state: Connecticut
city: Vernon
country: United States
facility: Hartford Healthcare Chase Movement Disorders Center
state: Connecticut
city: Newark
country: United States
facility: Christiana Care Health Service
state: Delaware
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Atlantis
country: United States
facility: JEM Research Institute
state: Florida
city: Aventura
country: United States
facility: Visionary Investigators Network
state: Florida
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders
state: Florida
city: Gainesville
country: United States
facility: Norman Fixel Institute for Neurological Diseases (FIND)
state: Florida
city: Maitland
country: United States
facility: ClinCloud, LLC
state: Florida
city: Miami
country: United States
facility: Visionary Investigators Network
state: Florida
city: Miami
country: United States
facility: Suncoast Research Group, LLC
state: Florida
city: Miami
country: United States
facility: VIN - Victor Faradji
state: Florida
city: Naples
country: United States
facility: Collier Neurologic Specialists
state: Florida
city: Ocala
country: United States
facility: Renstar Medical Research
state: Florida
city: Orlando
country: United States
facility: Compass Research
state: Florida
city: Ormond Beach
country: United States
facility: Neurology Associates of Ormond Beach
state: Florida
city: Pembroke Pines
country: United States
facility: Visionary Investigators Network -VIN-Margarita Almeida
state: Florida
city: Tampa
country: United States
facility: Axiom Research
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Atlanta Center of Medical Research
state: Georgia
city: Winfield
country: United States
facility: Central DuPage Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Indianapolis
country: United States
facility: Josephson Wallack Munshower Neurology
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas School of Medicine
state: Kansas
city: Scarborough
country: United States
facility: Maine Neurology
state: Maine
city: Methuen
country: United States
facility: New England Neurological Associates, PC
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Farmington Hills
country: United States
facility: QUEST Research Institute
state: Michigan
city: Chesterfield
country: United States
facility: Clinical Research Professionals
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Las Vegas
country: United States
facility: Cleveland Clinic of Las Vegas
state: Nevada
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Springfield
country: United States
facility: The Cognitive and Research Center of NJ
state: New Jersey
city: Toms River
country: United States
facility: Bio Behavioral Health
state: New Jersey
city: Amherst
country: United States
facility: Dent Neurological Institute
state: New York
city: Buffalo
country: United States
facility: Alzheimer's Disease and Memory Disorders Center
state: New York
city: Glens Falls
country: United States
facility: Adirondack Medical Research
state: New York
city: New Hyde Park
country: United States
facility: Parker Jewish Insititue for Heatlh Care and Rehabilition
state: New York
city: New York
country: United States
facility: NYU Langone
state: New York
city: Charlotte
country: United States
facility: Carolinas Healthcare System
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Hershey
country: United States
facility: Penn State Univ. Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pennsylvania Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Willow Grove
country: United States
facility: Abington Neurological Associates
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: Texas Neurology, PA
state: Texas
city: Dallas
country: United States
facility: Neurology Consultants of Dallas, PA
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: Houston Methodist Research Ins
state: Texas
city: Virginia Beach
country: United States
facility: Sentara Neurology Specialists
state: Virginia
city: Bellevue
country: United States
facility: Northwest Clinical Research Center
state: Washington
city: Kirkland
country: United States
facility: Evergreen Professional Plaza
state: Washington
city: Madison
country: United States
facility: University of Wisconsin-Madison Hospital and Health Clinic
state: Wisconsin
city: Toronto
country: Canada
facility: Toronto Memory Program
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
city: Bayamón
country: Puerto Rico
facility: Santa Cruz Behavioral PSC
city: Las Piedras
country: Puerto Rico
facility: Cortex, PSC
city: San Juan
country: Puerto Rico
facility: Instituto de Neurologia Dra. Ivonne Fraga
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico
Study officials:
affiliation: Eli Lilly and Company
name: Call 1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
role: STUDY_DIRECTOR
References:
citation: Wilbraham D, Biglan KM, Svensson KA, Tsai M, Kielbasa W. Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator (D1PAM), in Healthy Subjects. Clin Pharmacol Drug Dev. 2021 Apr;10(4):393-403. doi: 10.1002/cpdd.874. Epub 2020 Oct 7.