Alzheimer Disease, Brain Diseases, Central Nervous System Diseases, Dementia, Mental Disorders, Mild Cognitive Impairment, Nervous System Diseases, Neurocognitive Disorders, Neurodegenerative Diseases, Tauopathies
Conditions
Keywords
Inflammation, Biomarker, TNF
Brief summary
The goal of this Phase 2 Alzheimer's study is to determine whether 1.0 mg/kg XPro1595 confers a benefit on cognition, function, and biomarkers of white matter and to further evaluate safety and tolerability. The objectives of this study are to determine the safety, tolerability, and efficacy of XPro1595 in patients with early ADi.
Detailed description
This trial is a randomized clinical study using XPro1595 to treat patients with Early Alzheimer's Disease with biomarkers of inflammation (ADi). Early ADi patients are defined as patients with Mild Alzheimer's Disease or Mild Cognitive Impairment (MCI) with a biomarker of inflammation.
Interventions
DRUGXPro1595
XPro1595 will be delivered by subcutaneous injection once a week
DRUGPlacebo
Placebo will be delivered by subcutaneous injection once a week
Sponsors
Inmune Bio, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
* (2:1) XPro1595 (1mg/kg), placebo * Weekly subcutaneous injections
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
The screening window for this trial is 45 days. Inclusion Criteria: To be eligible for study entry, patients must satisfy all of the following criteria: * Adult patients 50 years to ≤ 85 years of age at the time of consent; * Meets the diagnostic criteria of MCI of probable Alzheimer's disease (Jack et al. 2018; NIA-AA) or mild dementia as clinically described in McKhann, (2011) and corresponding to stages 3 or 4 of the revised AD staging system (Jack, 2018). (NIA-AA); * Amyloid positive (documented in medical history or assessed during screening through blood test); * Either currently or previously (in pre-AD condition) literate and capable of reading, writing, and communicating effectively with others; * Residence in an assisted living is allowed as is personal assistances provided in the home, however at time of enrollment participant must be able to perform most ADL with minimal assistance, and participant must be permitted sufficient independence to allow assessment of change in ADL; * Has a study partner for the duration of the trial who either lives in the same household or interacts with the patient at least 4 hours per day and on at least 4 days per week, who is knowledgeable about the patient's daytime and night-time behaviors and who can be available to attend all clinic visits in person at which caregiver assessments are performed.
Exclusion criteria
Patients will be excluded from the study if 1 or more of the following criteria are applicable: * Have any contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants (e.g., in-skull and cardiac devices other than those approved as safe for use in MRI scanners); * Receives considerable help to carry out basic ADL living either in the home or as a resident in a nursing home or similar facility; * Lifetime history of a major psychiatric disorder including schizophrenia and bipolar disorder. Major depressive disorder that has resulted in 2 or more hospitalizations in a lifetime. Major depressive episode during the past 5 years that is judged by the clinical team unlikely to have been part of Alzheimer's prodrome. History of suicidality. * History of substance abuse within 12 months; use of cannabis or cannabis products within 6 months of consent; * Enrolled in another clinical trial where patients receive treatment with an investigational drug or treatment device or have had previous treatment with any investigational medicinal product within 60 days or 5 half-lives (whichever is longer) prior to study drug treatment; * A prior organ or stem cell transplant; * Seated blood pressure of ≥ 165/105 mmHg at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Early and Mild Alzheimer's Cognitive Composite (EMACC) | 24 Weeks | Change from Baseline to Week 24 in the Early and Mild Alzheimer's Cognitive Composite (EMACC), a z-score composite of six neuropsychological tests (International Shopping List Test-Immediate Recall; Digit Span Forward/Backward; Category Fluency; Letter Fluency \[D-KEFS\]; Trail Making Test A and B; Digit Symbol Coding). Each component is standardized to the pooled baseline mean (0) and SD (1), then averaged. Higher scores indicate better cognitive performance; a positive change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in CDR-SB | 24 Weeks | Change from Baseline to Week 24 in the Clinical Dementia Rating - Sum of Boxes (CDR-SB), the sum of the six CDR domain box scores (each 0, 0.5, 1, 2, or 3); total range 0 to 18, with higher scores indicating greater impairment (worse outcome). A negative change favors XPro1595 (less decline). |
| Change in Everyday Cognition (E-Cog) | 24 Weeks | Change from Baseline to Week 24 in the Everyday Cognition (E-Cog) total score, a 39-item informant-report questionnaire that asks the study partner to rate the participant's current performance on cognitively relevant everyday activities relative to 10 years prior (i.e., before illness onset). Activities span memory, language, visuospatial/perceptual abilities, planning, organization, and divided attention. Each item is rated on a 4-point scale from 1 (better or no change) to 4 (consistently much worse). The total score is the mean of all rated items and ranges from 1 to 4, with higher scores indicating greater decline since prior to illness onset. |
| Change in Neuropsychiatric Inventory (NPI-12) Total Score at Week 24 | 24 Weeks | Change from Baseline to Week 24 in the Neuropsychiatric Inventory, 12-domain version (NPI-12), a structured interview administered to the study partner (informant) assessing 12 neuropsychiatric domains (delusions; hallucinations; agitation/aggression; depression/dysphoria; anxiety; elation/euphoria; apathy/indifference; disinhibition; irritability/lability; aberrant motor behavior; nighttime behaviors; appetite/eating). Each domain is scored as frequency (1-4) × severity (1-3); the total score is the sum of domain scores and ranges from 0 to 144. Higher scores indicate greater neuropsychiatric burden (worse outcome); a negative change from baseline favors XPro1595. The total score is reported; domain or subfactor scores, where applicable, are interpreted only within the context of the full instrument. |
Countries
Australia, Canada, Czechia, France, Germany, Poland, Spain, United Kingdom
Contacts
STUDY_DIRECTORTherese Blomberg
INmune Bio
Participant flow
Pre-assignment details
Of 721 screened, 514 did not meet eligibility. Criteria: MCI or mild AD dementia (McKhann; CDR global 0.5-1.0), age 50-85, MMSE ≥22, amyloid positivity (with protocol-amendment flexibility during operational constraints), and ≥1 of 4 inflammatory biomarkers (hsCRP \>1.5 mg/L, ESR \>10 mm/h, HbA1C \>6.0 DCCT%, or ≥1 APOE4 allele). 207 were randomized 2:1 to XPro1595 or placebo, stratified by clinical stage (MCI vs. mild AD) and sex. One randomized participant did not receive study drug.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 175 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Age, Continuous | 72.90 years STANDARD_DEVIATION 6.34 |
| APOE E4 status Heterozygote (APOE ε3/ε4) | 78 Participants |
| APOE E4 status Homozygote (APOE ε4/ε4) | 25 Participants |
| APOE E4 status Noncarrier | 22 Participants |
| APOE E4 status Unknown | 2 Participants |
| Biologically confirmed amyloid positive Negative | 14 Participants |
| Biologically confirmed amyloid positive Positive | 103 Participants |
| Biologically confirmed amyloid positive Unknown | 14 Participants |
| Clinical Dementia Rating (CDR) Global Score 0.5 | 161 Participants |
| Clinical Dementia Rating (CDR) Global Score 1.0 | 10 Participants |
| Clinical Dementia Rating - Sum of Boxes (CDR-SB) | 3.05 units on a scale STANDARD_DEVIATION 1.52 |
| Diagnosis Mild Alzheimer's Dementia (mAD) | 35 Participants |
| Diagnosis Mild Cognitive Impairment (MCI) | 59 Participants |
| Early and Mild Alzheimer's Cognitive Composite (EMACC) | 0.00 z-score STANDARD_DEVIATION 0.72 |
| Mini-Mental State Examination (MMSE) | 26.09 units on a scale STANDARD_DEVIATION 2.17 |
| Number of enrichment inflammatory biomarkers 1 Biomarker | 72 Participants |
| Number of enrichment inflammatory biomarkers 2 Biomarker | 30 Participants |
| Number of enrichment inflammatory biomarkers 3 Biomarkers | 33 Participants |
| Number of enrichment inflammatory biomarkers 4 Biomarkers | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 126 Participants |
| Region of Enrollment Australia | 10 participants |
| Region of Enrollment Canada | 5 participants |
| Region of Enrollment Czechia | 2 participants |
| Region of Enrollment France | 3 participants |
| Region of Enrollment Poland | 16 participants |
| Region of Enrollment Spain | 10 participants |
| Region of Enrollment United Kingdom | 89 participants |
| Sex: Female, Male Female | 68 Participants |
| Sex: Female, Male Male | 66 Participants |
| Time since AD diagnosis | 1.20 years STANDARD_DEVIATION 1.52 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 139 | 0 / 67 |
| other Total, other adverse events | 131 / 139 | 59 / 67 |
| serious Total, serious adverse events | 8 / 139 | 5 / 67 |
Outcome results
None listed