An Open-Label Extension of XPro1595 in Patients With Alzheimer's Disease

Study Overview
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Brief Summary
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The goal of this Phase 2 Open Label study is to evaluate long-term safety, tolerability, and efficacy of XPro1595 on measures of cognition, function and brain quality in individuals with Alzheimer's Disease.

Detailed Description
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This study is designed as a Phase 2, open label study investigating the safety, tolerability, and efficacy of XPro1595 in patients with Alzheimer's Disease (AD). The planned dose is 1.0 mg/kg of XPro1595 for all subjects that completed a previous Phase 1 or Phase 2 study with XPro1595. Each enrolled patient will be treated with 1.0 mg/kg of XPro1595 as a subcutaneous injection once a week for 55 or 74 weeks, for a total exposure to XPro1595 of up to 78 weeks (18 months), depending on their previous study. Blood sampling for clinical lab analyses, physical exam findings, ECG and C-SSRS will be collected throughout the study to assess the safety and tolerability of XPro1595. Imaging endpoints (MRI), blood sampling for neuroinflammatory and neurodegenerative biomarkers, clinical ratings (CDR-SB, ADCS-MCI ADL, NPI-12) and cognitive performance assessed via the EMACC will be collected at screening and at Weeks 12, 24, 36, and 48. Depending on the parent study, some or all of these assessments may also be made at Weeks 55, 60 or 74. All patients that completed 4 weeks of dosing and the week 5 PK draw in the Phase 1 PK Lead-In or completed the treatment period and End of Study (EOS) assessments in a Phase 2 study are eligible to enroll into the OLE study. All patients enrolled, including those treated with placebo in the parent study, will receive 1.0 mg/kg XPro1595. Randomized treatment will remain blinded until the parent study database is locked, the study is unblinded and results for their prior study are released.

Official Title
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An Open Label Extension of XPro1595 in Patients With Alzheimer's Disease That Have Completed a Phase 1 or Phase 2 Study With XPro1595

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

Intervention / Treatment
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* Drug: XPro1595


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients are eligible to be included in the study only if all the following criteria apply: Participated and completed the full duration of the study intervention and all procedures at the End of Study (EOS) visit in a previous XPro1595 study. Concomitant medications for the management of MCI/AD and/or behavior symptoms which were ongoing during the double-blind study should remain at a constant dose throughout this study. Patient must be willing and able to provide informed consent prior to any study procedures being performed. If the patient is not competent, a LAR (Legally Authorized Representative) must provide informed consent on their behalf, and the patient must provide assent. Has a study partner willing to participate 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 informant assessments are performed. This study partner should agree to monitor and report on concomitant medications, understand the study requirements, and assist the participant in meeting study requirements. Patients with study partners that do not meet this criterion but are determined by the investigator as able to provide an adequate assessment of the patient may also participate with prior approval from the sponsor (However, this is not a requirement for patients coming from the AD-02 PK Lead-In Study). All male subjects who are sexually active with a female of childbearing potential (FCBP) must agree to use a highly effective method of contraception during the treatment period and until 90 days after the last dose of treatment. All females of childbearing potential (FCBP) must have a negative urine pregnancy test and agree to use a highly effective method of contraception during the treatment period and 30 days after the last dose of treatment. Exclusion Criteria: Any clinically significant abnormalities that in the opinion of the Investigator require further investigation or treatment or may interfere with study procedures and assessments or affect patient safety. These include but are not limited to, laboratory tests, electrocardiogram (ECG), physical examination, or vital signs at Screening or other medical conditions (e.g., cardiac, respiratory, gastrointestinal, psychiatric, renal disease) which are not adequately and stably controlled. Unable to comply with the study procedures and assessments.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 86 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
Intervention Model: Single Group Assignment
Interventional Model Description: An Open-Label Extension of XPro1595 in Patients with Alzheimer's Disease (AD) That Have Completed a Phase 2 Study with XPro1595
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: 1.0 mg/kg XPro1595<br>Patients will receive XPro1595. | Drug: XPro1595<br>* Each enrolled patient will be treated with 1.0 mg/kg of XPro1595 as a subcutaneous injection once a week for 55, or 74 weeks, for a total exposure to XPro1595 of up to 78 weeks (18 months), depending on their previous study.<br>* Other names: DN-TNF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who experience adverse events and serious adverse events | Change from Baseline to Weeks 55, or 74 in the OLE Study Clinically significant abnormalities of laboratory values, physical findings, electrocardiogram (ECG) findings and other safety assessments will be recorded as adverse events if the findings meet the defined criteria for adverse events. | Weeks 55, or 74 in the OLE Study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the change in cognitive performance following administration of open-label XPro1595 | Change from Baseline on the Early and Mild Alzheimer's Cognitive Composite (EMACC) (Jaeger 2017) made up of the following tests: The Grocery List Test- Immediate recall (Word List Learning Test-Immediate recall) Trail Making Test Part A and B Digit Symbol Coding Test Digit Span Forward and Backward Category Fluency Test (DKEFS) Letter Fluency Test (DKEFS) | Week 55 in the OLE Study | 
| To evaluate the change in cognition and global function following administration of open-label XPro1595 | Change from Baseline in the double-blind study (for those on XPro1595 during the double-blind study) or Change from Baseline in the OLE Study (for those on placebo during the double-blind study) to Week 55 in the OLE study for the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) | Week 55 in the OLE Study | 
| To evaluate the change in non-cognitive behavioral symptoms following open-label administration of XPro1595 | Change from Baseline in the double-blind study (for those on XPro1595 during the double-blind study) or Change from Baseline in the OLE Study (for those on placebo during the double-blind study) to Week 55 in the OLE study on the Neuropsychiatric Inventory (NPI-12) study partner items. The NPI-12 total score is calculated by adding the scores of the domains (each domain score ranges from 0 to 12). The NPI-12 total score is based upon the first 10 items and ranges from (0 to 10) with higher scores indicating greater behavioral impairment. | Week 55 in the OLE Study | 
| To evaluate the change Change from Baseline on the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS- MCI- ADL) | Change from Baseline in the double-blind study (for those on XPro1595 during the double-blind study) or Change from Baseline in the OLE Study (for those on placebo during the double-blind study) to Week 55 in the OLE study on the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS- MCI- ADL) The 23-item Alzheimer's Disease Cooperative Study - Mild Cognitive Impairment Activities of Daily Living (ADCS-MCI-ADL) Scale has good test-retest reliability, will be utilized to assess performance functioning in MCI patients (Galasko et al., 1997; Douglas Galasko et al., 2006; Pedrosa et al., 2010). | Week 55 in the OLE Study | 
| To evaluate the change on blood inflammatory and neurodegeneration biomarkers following open-label administration of XPro1595 (on blood inflammatory and neurodegeneration biomarker amyloid) | Change from Baseline in the double-blind study (for those on XPro1595 during the double-blind study or for those in the PK Lead-In Study) or Change from Baseline in the OLE Study (for those on placebo during the double-blind study) to Weeks 55, or 74 in the OLE study on blood inflammatory and neurodegeneration biomarkers (on blood inflammatory and neurodegeneration biomarker amyloid). | Weeks 55, or 74 in the OLE Study | 
| To evaluate the change on blood inflammatory and neurodegeneration biomarkers following open-label administration of XPro1595 (on blood inflammatory and neurodegeneration biomarker pTau) | Change from Baseline in the double-blind study (for those on XPro1595 during the double-blind study or for those in the PK Lead-In Study) or Change from Baseline in the OLE Study (for those on placebo during the double-blind study) to Weeks 55, or 74 in the OLE study on blood inflammatory and neurodegeneration biomarkers (on blood inflammatory and neurodegeneration biomarker pTau). | Weeks 55, or 74 in the OLE Study | 
| To evaluate the change on imaging neuroinflammation following open-label administration of XPro1595 | Change from Baseline in the double-blind study (for those on XPro1595 during the double-blind study or for those in the PK Lead-In Study) or Change from Baseline in the OLE Study (for those on placebo during the double-blind study) to Weeks 55, or 74 in the OLE study in Magnetic Resonance Imaging (MRI) neuroinflammation (White matter Free Water). | Weeks 55, or 74 in the OLE Study | 
| To evaluate the change on axonal integrity following open-label administration of XPro1595 | Change from Baseline in the double-blind study (for those on XPro1595 during the double-blind study or for those in the PK Lead-In Study) or Change from Baseline in the OLE Study (for those on placebo during the double-blind study) to Weeks 55, or 74 or in the OLE study in MRI Apparent Fiber Density (AFD). | Weeks 55, or 74 in the OLE Study | 
| To evaluate the change in Everyday Cognition (ECog) following open-label administration of XPro1595 | Change from Baseline in the double-blind study (for those on XPro1595 during the double-blind study) or Change from Baseline in the OLE Study (for those on placebo during the double-blind study) to Week 55 in the OLE study on Everyday Cognition (ECog). | Week 55 in the OLE Study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inflammation, Biomarker, Tumor Necrosis Factor (TNF)