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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 : Recruiting
First Posted : June 28, 2019
Last Update Posted : December 17, 2019
Sponsor:
Collaborator:
Worldwide Clinical Trials
Information provided by (Responsible Party):
EIP Pharma Inc

Study Description
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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

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 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
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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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


Outcome Measures
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Primary Outcome Measures :
  1. Composite score of a study-specific Cogstate Neurological Test Battery (NTB) including the Cogstate Letter Fluency Test and Category Fluency Test [ Time Frame: 16 weeks ]
    Change from Baseline to Week 16 in the composite score of a study-specific Cog-state Neurological Test Battery (NTB), including assessments of attention, executive function, and visuospatial function in neflamapimod treated-subjects as compared to the placebo-treated subjects, as analyzed using the Mixed Model Repeated Measures (MMRM) analysis method. The following six tests will be included in the composite: (1) Cogstate Detection test (DET), (2) Cogstate Identification test (IDN), (3) Cogstate One Card Learning test (OCL), (4) Cogstate One Back test (ONB), (5) Letter Fluency Test, (6) Category Fluency Test (CFT). Each score on the individual tests will be converted to a z-score, and then a total z-score will be calculated, in which each test is weighted equally. The change in total z-score in neflamapimod vs. placebo-recipients will be analyzed. As the analysis is based on z-scores, there is no minimum or maximum value.


Secondary Outcome Measures :
  1. Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) [ Time Frame: 16 weeks ]
    Change in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score based on semi-quantitative scoring of each domain (box) evaluating cognitive impairment in milder and more progressive forms of dementia, in neflamapimod-treated subjects compared to placebo-recipients. The domain (box) scores will be calculated for a Sum of Boxes score. Secondary efficacy endpoints will utilize the same analysis method and model as the primary endpoint.

  2. Mini-Mental State Examination (MMSE) [ Time Frame: 16 weeks ]
    Change in Mini-Mental State Examination (MMSE) with respect to orientation, memory, concentration, language, and praxis (scores ranging from 0 to 30 with lower scores indicating greater cognitive impairment), in neflamapimod-treated subjects compared to placebo-recipients. Secondary efficacy endpoints will utilize the same analysis method and model as the primary endpoint.

  3. Neuropsychiatric Inventory (NPI-10) [ Time Frame: 16 weeks ]
    Change in Neuropsychiatric Inventory (NPI-10) domains, specifically depression (dysphoria), anxiety, hallucinations, and agitation/aggression, in neflamapimod-treated subjects compared to placebo-recipients. Responses indicating subject has a problem with a particular sub-domain lead to questions of the caregiver rating the frequency of the symptoms on a 4-point scale, severity on a 3-point scale, and the distress the symptoms cause them on a 5-point scale. Secondary efficacy endpoints will utilize the same analysis method and model as the primary endpoint.

  4. International Shopping List Test (ISLT) [ Time Frame: 16 weeks ]
    Change in International Shopping List Test (ISLT) immediate and delayed recall and recognition will be used to assess episodic memory in neflamapimod-treated subjects compared to placebo-recipients. Secondary efficacy endpoints will utilize the same analysis method as the primary endpoint.

  5. Timed Up and Go Test (TUG) [ Time Frame: 16 weeks ]
    Change in Timed Up and Go Test (TUG) to assess mobility (score of >15 seconds indicates subject has increased risk of falls) in neflamapimod-treated subjects compared to placebo-recipients. Secondary efficacy endpoints will utilize the same analysis method and model as the primary endpoint.

  6. Quantitative Electroencephalogram (qEEG) [ Time Frame: 16 weeks ]
    Change in quantitative electroencephalogram (qEEG) parameters (all waveforms, with particular focus on relative alpha and theta power) with the subject awake in accordance with the 10-20 International System of Electrode placement will be evaluated as a potential biomarker for DLB. Slowing of the dominant frequency band by qEEG over posterior aspects of the brain has been recognized to be prominent in DLB, and various patterns have been identified to differentiate DLB from AD. EEG will be analyzed at an academic center (VU Medical Center, Amsterdam), who will develop the specific parameters during the conduct of the study, and they will specify the analytic approach in the Statistical Analysis Plan (SAP) that will be implemented prior to the completion of subject enrollment.


Eligibility Criteria
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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.
Contacts and Locations
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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


Contacts
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Contact: John Alam, MD 617-863-3751 jalam@eippharma.com

Locations
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Sponsors and Collaborators
EIP Pharma Inc
Worldwide Clinical Trials
Investigators
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Study Director: John Alam, MD EIP Pharma
More Information
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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
Last Update Posted: December 17, 2019
Last Verified: August 2019
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