- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04001517
Cognitive Effects of Oral p38 Alpha Kinase Inhibitor Neflamapimod in Dementia With Lewy Bodies (AscenD-LB)
June 10, 2023 updated by: EIP Pharma Inc
A Double-Blind, Placebo-Controlled 16-Week Study of the Cognitive Effects of Oral p38 Alpha Kinase Inhibitor Neflamapimod in Dementia With Lewy Bodies (DLB)
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, proof-of-principle study of neflamapimod versus matching placebo (randomized 1:1) administered with food for 16 weeks in subjects with DLB.
The primary objective is to evaluate the effect of neflamapimod on cognitive function as assessed in a study-specific Cogstate Neuropsychological Test Battery (NTB).
Secondary endpoints include the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI-10), Timed Up and Go Test, and electroencephalogram (EEG) as a potential biomarker for DLB.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Study Type
Interventional
Enrollment (Actual)
91
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Amsterdam, Netherlands
- Brain Research Center
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Den Bosch, Netherlands
- Brain Research Center
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California
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La Jolla, California, United States, 92037
- University of California San Diego (UCSD)
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Santa Monica, California, United States, 90404
- Pacific Neuroscience Institute
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Colorado
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Aurora, Colorado, United States, 80045
- University of Colorado
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Florida
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Miami, Florida, United States, 33144
- Elite Clinical Research
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Kansas
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Kansas City, Kansas, United States, 66103
- University of Kansas Medical Center
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Massachusetts
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Charlestown, Massachusetts, United States, 02129
- Massachusetts General Hospital
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Michigan
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Ann Arbor, Michigan, United States, 48105
- University of Michigan
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Minnesota
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Rochester, Minnesota, United States, 55905
- Mayo Clinic
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Nevada
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Las Vegas, Nevada, United States, 89106
- Cleveland Clinic - Lou Ruvo Center for Brain Health
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New York
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New York, New York, United States, 10032
- New York Presbyterian Hospital - Columbia University Medical Center
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Rochester, New York, United States, 14618
- University of Rochester
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North Carolina
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Chapel Hill, North Carolina, United States, 27599
- University of North Carolina
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Ohio
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Cleveland, Ohio, United States, 44195
- Cleveland Clinic
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Columbus, Ohio, United States, 43210
- The Ohio State University
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Oregon
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Portland, Oregon, United States, 97239
- Oregon Health & Science University
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Portland, Oregon, United States, 97210
- Summit Research Network
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19107
- Thomas Jefferson University
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Virginia
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Charlottesville, Virginia, United States, 22908
- University of Virginia
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Richmond, Virginia, United States, 23294
- National Clinical Research, Inc.
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Washington
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Bellevue, Washington, United States, 98007
- Northwest Clinical Research Center
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Seattle, Washington, United States, 98104
- University of Washington
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Spokane, Washington, United States, 99202
- Inland Northwest Research
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
55 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Description
Inclusion Criteria:
- Men and women aged ≥55 years.
- Subject or subject's legally authorized representative is willing and able to provide written informed consent.
- Probable DLB and identified cognitive deficits, according to current consensus criteria (McKeith et al, 2017), specifically one core clinical feature and a positive DaTscan. If a negative DaTscan, but the subject has historical PSG-verified RBD, the subject would also qualify.
- MMSE score of 15-28, inclusive, during Screening.
- Currently receiving cholinesterase inhibitor therapy, having received such therapy for greater than 3 months and on a stable dose for at least 6 weeks at the time of randomization. Except for reducing the dose for tolerability reasons, the dose of cholinesterase inhibitor may not be modified during the study.
- Normal or corrected eye sight and auditory abilities, sufficient to perform all aspects of the cognitive and functional assessments.
- No history of learning difficulties that may interfere with their ability to complete the cognitive tests.
- Must have reliable informant or caregiver.
Exclusion Criteria:
- Diagnosis of any other ongoing central nervous system (CNS) condition other than DLB, including, but not limited to, post-stroke dementia, vascular dementia, Alzheimer's disease (AD), or Parkinson's disease (PD).
- Suicidality, defined as active suicidal thoughts within 6 months before Screening or at Baseline, defined as answering yes to items 4 or 5 on the C-SSRS, or history of suicide attempt in previous 2 years, or, in the Investigator's opinion, at serious risk of suicide.
- Ongoing major and active psychiatric disorder and/or other concurrent medical condition that, in the opinion of the Investigator, might compromise safety and/or compliance with study requirements.
- Diagnosis of alcohol or drug abuse within the previous 2 years.
- Poorly controlled clinically significant medical illness, such as hypertension (blood pressure >180 mmHg systolic or 100 mmHg diastolic); myocardial infarction within 6 months; uncompensated congestive heart failure or other significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that would interfere with assessment of drug safety.
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 × the upper limit of normal (ULN), total bilirubin >1.5 × ULN, and/or International Normalized Ratio (INR) >1.5.
- Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.
- Participated in a study of an investigational drug less than 3 months or 5 half-lives of an investigational drug, whichever is longer, before enrollment in this study.
- History of previous neurosurgery to the brain.
- If male with female partner(s) of child-bearing potential, unwilling or unable to adhere to contraception requirements specified in the protocol.
- If female who has not has not reached menopause >1 year previously or has not had a hysterectomy or bilateral oophorectomy/salpingo-oophorectomy, has a positive pregnancy test result during Screening and/or is unwilling or unable to adhere to the contraception requirements specified in the protocol.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Neflamapimod
40 mg capsules administered orally, BID or TID with food for 16 weeks; subjects will follow the BID regimen if weighing <80 kg or the TID regimen if weighing ≥80 kg
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Double-Blind, Placebo-Controlled
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Placebo Comparator: Placebo
40 mg matching placebo capsules administered orally, BID or TID with food for 16 weeks; subjects will follow the BID regimen if weighing <80 kg or the TID regimen if weighing ≥80 kg
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Double-Blind, Placebo-Controlled
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Composite Z-score of a Study-specific Neuropsychological Test Battery (NTB) Including Tests From Cogstate Battery, Letter Fluency Test and Category Fluency Test
Time Frame: As the analysis was by Mixed Model for Repeated Measures, all time points at which NTB was assessed utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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Change from Baseline to Week 4, Week 8, and Week 16 in the composite z-score of a study-specific Neuropsychological Test Battery (NTB) that included the following six tests: Cogstate Detection test (DET), Cogstate Identification test (IDN), Cogstate One Card Learning test (OCL), Cogstate One Back test (ONB), Letter Fluency Test, and Category Fluency Test (CFT).
Each score on the individual tests was converted to a z-score, and then a total z-score for the composite was calculated, in which each test is weighted equally.
As the analysis is based on z-scores, there is no minimum or maximum value.
A z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher.
A positive change in z-score indicate an improvement in cognition, i.e., a better outcome; and a negative change in z-score indicates a worsening in cognition, i.e., a worse outcome.
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As the analysis was by Mixed Model for Repeated Measures, all time points at which NTB was assessed utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB)
Time Frame: As the analysis was by Mixed Model for Repeated Measures, both time points at which CDR-SB was assessed (week 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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Change in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score from Baseline to Week 8 and Week 16 based on semi-quantitative scoring of six domains (i.e., "box": 1) memory, 2) orientation, 3) judgement & reasoning, 4) home & hobbies, 5) community affairs, and 6) personal care.
The CDR score ranges from 0 (no impairment), 0.5 (questionable impairment), 1 (mild impairment), 2 (moderate impairment), and 3 (severe impairment).
The domain (box) scores are then added for a Sum of Boxes score.
With six domains, the CDR-SB score then ranges from 0 to 18; with higher scores indicated worse outcomes.
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As the analysis was by Mixed Model for Repeated Measures, both time points at which CDR-SB was assessed (week 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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Mini-Mental State Examination (MMSE)
Time Frame: As the analysis was by Mixed Model for Repeated Measures, both time points at which MMSE was assessed (week 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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The Mini-Mental State Examination (MMSE) is a general measure of cognition that assesses orientation, memory, concentration, language, and praxis.
Scores range from 0 to 30 with lower scores indicating greater cognitive impairment, i.e. a worse outcome).
The MMSE was assessed at Week 8 and Week 16 during the study.
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As the analysis was by Mixed Model for Repeated Measures, both time points at which MMSE was assessed (week 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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Neuropsychiatric Inventory (NPI-10) - Mean Change in Hallucinations Domain Score
Time Frame: As the analysis was by Mixed Model for Repeated Measures, all time points at which NPI-10 was assessed (weeks 4, 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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The NPI-10 consists evaluates ten domains: delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, and aberrant motor activity.
If caregiver reports symptoms within a domain then the caregiver rates the frequency of the symptoms on a 4-point scale, and severity on a 3-point scale.
Total score for each domain is the frequency score multiplied by the severity score; i.e. the domain score (e.g. for hallucinations) for any one domain ranges from 0-12, with higher scores indicating worsening.
A secondary objective of this study was to evaluate the effect of neflamapimod in four specific domains, specifically depression (dysphoria), anxiety, hallucinations, and agitation/aggression, in neflamapimod-treated subjects compared to placebo-recipients.
Of these four, the only domain in which more than one-quarter of the patients reported symptoms is hallucinations, and the result of this analysis is reported.
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As the analysis was by Mixed Model for Repeated Measures, all time points at which NPI-10 was assessed (weeks 4, 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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International Shopping List Test (ISLT) - Immediate Recall
Time Frame: As the analysis was by Mixed Model for Repeated Measures, both time points at which ISLT was assessed (Weeks 4, 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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The International Shopping List Test (ISLT) was developed specifically to assess verbal list learning and memory in people from different language and cultural backgrounds.
12 words, consisting to items typically in a grocery shopping list in the specific culture are provided verbally, and subject asked to recall ask many words as possible.
The immediate recall score consists of the number of words that the subject correctly repeats during three consecutive trials immediately following provision of words.
The range is then from 0 to 36 (12 words maximum in each of 3 trials), with higher scores (i.e., the more words recalled) reflecting better outcomes.
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As the analysis was by Mixed Model for Repeated Measures, both time points at which ISLT was assessed (Weeks 4, 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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Timed Up and Go Test (TUG)
Time Frame: As the analysis was by Mixed Model for Repeated Measures, both time points at which the TUG was assessed (week 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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The Timed Up and Go test assesses function mobility, and was included in the study to evaluate the effects of neflamapimod on motor function.
The TUG measures the time in seconds that a person takes to rise from a chair, walk three meters, turn around 180 degrees, walk back to the chair, and sit down while turning 180 degrees.
The TUG was evaluated at Baseline, and Weeks 8 and 16 of the study.
There is no minimum or maximum value for this test, though in Parkinson's disease patients values above 11.5 seconds was associated with an increased risk of falls and each one second increase in the time required to complete the TUG is associated with a 5.4% increase in the risk of falls (Arch Phys Med Rehabil.
2013;94: 1300-1305).
That is, an increase in the time required to complete the TUG is a worse outcome.
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As the analysis was by Mixed Model for Repeated Measures, both time points at which the TUG was assessed (week 8 and 16) was utilized in the analysis. The difference reported is the mean difference over the entire course of the study.
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Quantitative Electroencephalogram (qEEG)m - Dominant Peak Frequency Over Parietal Lobe
Time Frame: 16 weeks
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Change in quantitative electroencephalogram (qEEG) parameters with the subject awake in accordance with the 10-20 International System of Electrode placement was to be evaluated as a potential biomarker for DLB.
However, due to COVID19 related restrictions, baseline and week 16 EEG recordings were obtained only in limited number of subjects.
As slowing of the dominant frequency band by qEEG over posterior aspects of the brain has been recognized to be prominent in DLB, the change in the dominant frequency band over the parietal lobe in Hz from baseline to week 16 is reported.
This is a continuous variable with no minimum or maximum.
A decrease in the frequency (i.e., slowing) reflects worsening of disease, while a positive treatment effect would be an increase in the frequency.
With the limited number of subjects formal statistical analysis was not conducted.
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16 weeks
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Study Director: John Alam, MD, EIP Pharma
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
September 30, 2019
Primary Completion (Actual)
June 30, 2020
Study Completion (Actual)
June 30, 2020
Study Registration Dates
First Submitted
June 7, 2019
First Submitted That Met QC Criteria
June 26, 2019
First Posted (Actual)
June 28, 2019
Study Record Updates
Last Update Posted (Actual)
June 29, 2023
Last Update Submitted That Met QC Criteria
June 10, 2023
Last Verified
June 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- EIP19-NFD-501
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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