Cognitive Effects of Oral p38 Alpha Kinase Inhibitor Neflamapimod in Dementia With Lewy Bodies

Phase 2

Completed

• Conditions: Dementia With Lewy Bodies (DLB)
• Interventions: Drug: Neflamapimod

• Registration Number: NCT04001517
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-06-07
• Study First Submitted QC: 2019-06-26
• Study First Posted: 2019-06-28
• Study Start: 2019-09-30
• Primary Completion: 2020-06-30
• Study Completion: 2020-06-30
• Results First Submitted: 2021-06-29
• Results First Submitted QC: 2021-10-28
• Results First Posted: 2021-11-02
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-10
• Last Update Posted: 2023-06-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 91

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Neflamapimod	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
Neflamapimod	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

Primary Outcome Measures

Name	Time	Method
Composite Z-score of a Study-specific Neuropsychological Test Battery (NTB) Including Tests From Cogstate Battery, Letter Fluency Test and Category Fluency Test	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

Name	Time	Method
International Shopping List Test (ISLT) - Immediate Recall	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.
Timed Up and Go Test (TUG)	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.
Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB)	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.
Mini-Mental State Examination (MMSE)	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.
Neuropsychiatric Inventory (NPI-10) - Mean Change in Hallucinations Domain Score	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.
Quantitative Electroencephalogram (qEEG)m - Dominant Peak Frequency Over Parietal Lobe	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.

Trial Locations

Locations (23)

The Ohio State University; 🇺🇸 Columbus, Ohio, United States

University of California San Diego (UCSD); 🇺🇸 La Jolla, California, United States

Massachusetts General Hospital; 🇺🇸 Charlestown, Massachusetts, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

New York Presbyterian Hospital - Columbia University Medical Center; 🇺🇸 New York, New York, United States

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

National Clinical Research, Inc.; 🇺🇸 Richmond, Virginia, United States

Northwest Clinical Research Center; 🇺🇸 Bellevue, Washington, United States

Inland Northwest Research; 🇺🇸 Spokane, Washington, United States

University of Rochester; 🇺🇸 Rochester, New York, United States

University of North Carolina; 🇺🇸 Chapel Hill, North Carolina, United States

Brain Research Center; 🇳🇱 Den Bosch, Netherlands

Pacific Neuroscience Institute; 🇺🇸 Santa Monica, California, United States

University of Virginia; 🇺🇸 Charlottesville, Virginia, United States

Elite Clinical Research; 🇺🇸 Miami, Florida, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

University of Colorado; 🇺🇸 Aurora, Colorado, United States

Cleveland Clinic - Lou Ruvo Center for Brain Health; 🇺🇸 Las Vegas, Nevada, United States

Summit Research Network; 🇺🇸 Portland, Oregon, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

University of Washington; 🇺🇸 Seattle, Washington, United States

University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States

Thomas Jefferson University; 🇺🇸 Philadelphia, Pennsylvania, United States