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Trial record 1 of 1 for:    neflamapimod | Dementia with Lewy Bodies
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Cognitive Effects of Oral p38 Alpha Kinase Inhibitor Neflamapimod in Dementia With Lewy Bodies (AscenD-LB)

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ClinicalTrials.gov Identifier: NCT04001517
Recruitment Status : Completed
First Posted : June 28, 2019
Results First Posted : November 2, 2021
Last Update Posted : November 2, 2021
Sponsor:
Collaborator:
Worldwide Clinical Trials
Information provided by (Responsible Party):
EIP Pharma Inc

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Dementia With Lewy Bodies (DLB) Drug: Neflamapimod Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 91 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : September 30, 2019
Actual Primary Completion Date : June 30, 2020
Actual Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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
Drug: Neflamapimod
Double-Blind, Placebo-Controlled

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
Drug: Neflamapimod
Double-Blind, Placebo-Controlled




Primary Outcome Measures :
  1. 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. ]
    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.


Secondary Outcome Measures :
  1. 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. ]
    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.

  2. 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. ]
    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.

  3. 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. ]
    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.

  4. 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. ]
    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.

  5. 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. ]
    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.

  6. Quantitative Electroencephalogram (qEEG)m - Dominant Peak Frequency Over Parietal Lobe [ Time Frame: 16 weeks ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   55 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women aged ≥55 years.
  2. Subject or subject's legally authorized representative is willing and able to provide written informed consent.
  3. 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.
  4. MMSE score of 15-28, inclusive, during Screening.
  5. 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.
  6. Normal or corrected eye sight and auditory abilities, sufficient to perform all aspects of the cognitive and functional assessments.
  7. No history of learning difficulties that may interfere with their ability to complete the cognitive tests.
  8. Must have reliable informant or caregiver.

Exclusion Criteria:

  1. 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).
  2. 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.
  3. 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.
  4. Diagnosis of alcohol or drug abuse within the previous 2 years.
  5. 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.
  6. 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.
  7. Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.
  8. 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.
  9. History of previous neurosurgery to the brain.
  10. If male with female partner(s) of child-bearing potential, unwilling or unable to adhere to contraception requirements specified in the protocol.
  11. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04001517


Locations
Show Show 24 study locations
Sponsors and Collaborators
EIP Pharma Inc
Worldwide Clinical Trials
Investigators
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Study Director: John Alam, MD EIP Pharma
  Study Documents (Full-Text)

Documents provided by EIP Pharma Inc:
Study Protocol  [PDF] April 12, 2019
Statistical Analysis Plan  [PDF] June 30, 2020

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Responsible Party: EIP Pharma Inc
ClinicalTrials.gov Identifier: NCT04001517    
Other Study ID Numbers: EIP19-NFD-501
First Posted: June 28, 2019    Key Record Dates
Results First Posted: November 2, 2021
Last Update Posted: November 2, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Dementia
Lewy Body Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Neurodegenerative Diseases
Parkinsonian Disorders
Basal Ganglia Diseases
Movement Disorders
Synucleinopathies