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

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.

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.

Population: All subjects with a baseline and at least one on-treatment NTB evaluation. As placebo given twice or three times a day would not be expected to differences in outcome, per the protocol and statistical analysis plan (SAP) the placebo group was considered as one group, regardless of whether they received placebo BID or TID.

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.

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.

Population: All subjects with a baseline and at least one on-treatment CDR-SB evaluation. As placebo given twice or three times a day would not be expected to differences in outcome, per the protocol and statistical analysis plan (SAP) the placebo group was considered as one group, regardless of whether they received placebo BID or TID.

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.

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.

Population: All participants with at least one on-treatment ISLT immediate recall evaluation available. As placebo given twice or three times a day would not be expected to differences in outcome, per the protocol and statistical analysis plan (SAP) the placebo group was considered as one group, regardless of whether they received placebo BID or TID.

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.

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.

Population: All subjects with a baseline and at least one on-treatment MMSE evaluation. As placebo given twice or three times a day would not be expected to differences in outcome, per the protocol and statistical analysis plan (SAP) the placebo group was considered as one group, regardless of whether they received placebo BID or TID.

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.

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.

Population: All subjects with a baseline and at least one on-treatment NPI-10 evaluation. As placebo given twice or three times a day would not be expected to differences in outcome, per the protocol and statistical analysis plan (SAP) the placebo group was considered as one group, regardless of whether they received placebo BID or TID.

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.

Time frame: 16 weeks

Population: All subjects with a baseline and week 16 EEG recording.

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.

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.

Population: All subjects with a baseline and at least one on-treatment TUG evaluation. As placebo given twice or three times a day would not be expected to differences in outcome, per the protocol and statistical analysis plan (SAP) the placebo group was considered as one group, regardless of whether they received placebo BID or TID.