Study to Assess the Efficacy of XPro1595 in Patients With Mild Alzheimer's Disease With Biomarkers of Inflammation

Study Overview
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Brief Summary
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The purpose of this study is to measure cognitive and biological biomarkers in subcutaneously administered XPro1595 or placebo in patients with mild ADi.

Detailed Description
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This study is designed as a double-blind randomized, placebo-controlled, study investigating the safety, tolerability, and efficacy of XPro1595 in patients with mild AD with inflammation (ADi). The planned dose is 1.0 mg/kg of XPro1595 and matching placebo.

Official Title
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A Phase 2, Randomized, Placebo-Controlled, Double-Blind Study of XPro1595 in Patients With Mild Alzheimer's Disease With Biomarkers of Inflammation

Conditions
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Dementia, Tauopathies, Brain Diseases, Alzheimer Disease, Central Nervous System Diseases, Nervous System Diseases, Neurodegenerative Diseases, Neurocognitive Disorders, Mental Disorders

Intervention / Treatment
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* Drug: XPro1595
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for study entry, patients must satisfy all of the following criteria: Adult patients ≥ 60 years to ≤ 85 years of age at the time of consent; Diagnosed with mild dementia as clinically described in McKhann, (2011) and corresponding to stage 4 of the revised AD staging system (Jack, 2018). Patients who have received previous therapy for Alzheimer's disease may still be eligible; 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 caregiver willing to serve as 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 received treatment on another AD clinical trial within the last 60 days from Day 1; A prior organ or stem cell transplant; Seated blood pressure of ≥ 165/105 mmHg at Screening.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: (2:1) XPro1595 (1mg/kg), placebo Weekly subcutaneous injections
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.0 mg/kg XPro1595<br>1.0 mg/kg of XPro1595 will be administered via subcutaneous injection once a week for 23 weeks. | Drug: XPro1595<br>* XPro1595 will be delivered by subcutaneous injection once a week<br>* Other names: DN-TNF;|
| Placebo Comparator: 1.0 mg/kg Placebo<br>1.0 mg/kg of Placebo will be administered via subcutaneous injection once a week for 23 weeks. | Drug: Placebo<br>* Placebo will be delivered by subcutaneous injection once a week<br>* Other names: Matching Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Early and Mild Alzheimer's Cognitive Composite (EMACC) | Change in the Early and Mild Alzheimer's cognitive composite (EMACC) from Baseline to Week 24 in the following assessments: International Shopping List Test-Immediate recall (Word List learning Test) Digit Span Forward and Backward Category Fluency Test (DKEFS) Letter Fluency Test (DKEFS) Trail Making Test Parts A and B Digit Symbol Coding Test To assess the efficacy of XPro1595 compared with placebo on cognitive performance in patients with mild AD | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Dementia Rating (CDR) | Change from Baseline to Week 24 in Clinical Dementia Rating Scale (CDR) The CDR scale is a clinician-rated dementia staging system that tracks the progression of cognitive impairment in 6 categories (memory, orientation, judgement, and problem solving, community affairs, home and hobbies, and personal care). Each category is scored on a 5-point scale in which None = 0, Questionable = 0.5, Mild = 1, Moderate = 2, and Severe = 3. The global CDR score is established by clinical scoring rules and has values of 0 (no dementia), 0.5, (questionable dementia), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia). The Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) is obtained by adding the ratings in each of the 6 categories and ranges from 0 to 18 with higher scores indicative of greater impairment. To assess the effect of XPro1595 compared with placebo on cognition and global function in patients with mild AD | 24 Weeks | 
| Change in apparent fiber density (AFD) | Change from Baseline to Week 24 in apparent fiber density (AFD) To assess the efficacy of XPro1595 compared with placebo on axonal integrity in patients with mild AD | 24 Weeks | 
| Change in Everyday Cognition (E-Cog) | Change from Baseline to Week 24 in Everyday Cognition (E-Cog) To evaluate the effect of XPro1595 compared with placebo on E-Cog | 24 Weeks | 
| Change in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) | Change from Baseline to Week 24 in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) To assess the effect of XPro1595 compared with placebo on ADL in patients with mild AD. | 24 Weeks | 
| Change in myelin content | Change from Baseline to Week 24 in free-water-corrected tissue Radial diffusivity and 1 of the following i) MRI-specific myelin contrast: ii) a magnetization transfer ratio (MTR) iii) an inhomogeneous magnetization transfer (MT) or iv) an myelin water fraction (MWF) map To assess the efficacy of XPro1595 compared with placebo on myelin in patients with mild AD. | 24 Weeks | 
| Change in non-cognitive behavioral symptoms | Change from Baseline to Week 24 in (Neuropsychiatric Inventory [NPI] caregiver items) To assess the effect of XPro1595 compared with placebo on noncognitive behavioral symptoms in patients with mild AD | 24 Weeks | 
| Change in gray matter integrity | Change from Baseline to Week 24 in Cortical Disarray Measurement (CDM®) To assess the efficacy of XPro1595 compared with placebo on gray matter integrity in patients with mild AD | 24 Weeks | 
| Change in blood inflammatory and neurodegeneration biomarkers (on blood inflammatory and neurodegeneration biomarker amyloid) | Number of participants with a reduction in blood inflammatory and neurodegeneration biomarkers (on blood inflammatory and neurodegeneration amyloid) from Baseline to Week 24. To assess the efficacy of XPro1595 compared with placebo on blood inflammatory and neurodegeneration biomarkers (on blood inflammatory and neurodegeneration biomarker amyloid). | 24 Weeks | 
| Change in blood inflammatory and neurodegeneration biomarkers (on blood inflammatory and neurodegeneration biomarker pTau) | Change from Baseline to Week 24 in blood inflammatory and neurodegeneration biomarkers (on blood inflammatory and neurodegeneration biomarker pTau) To assess the efficacy of XPro1595 compared with placebo on blood inflammatory and neurodegeneration biomarkers (on blood inflammatory and neurodegeneration biomarker pTau) | 24 Weeks | 
| Change in brain structure neurodegeneration | Changes from Baseline to Week 24 in volumetric magnetic resonance imaging (MRI) To assess the efficacy of XPro1595 compared with placebo on brain structure neurodegeneration | 24 Weeks | 
| Number of participants who experience adverse events and serious adverse events | Clinically significant abnormalities of laboratory values, physical findings, electrocardiogram findings and other safety assessments will be recorded as adverse events if the findings meet the defined criteria for adverse events. | Baseline up to 28 days post last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TNF, Inflammation, Biomarker