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SEMA4D Blockade Safety and Brain Metabolic Activity in Alzheimer's Disease (AD) (SIGNAL-AD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04381468
Recruitment Status : Recruiting
First Posted : May 8, 2020
Last Update Posted : September 17, 2020
Sponsor:
Collaborators:
Alzheimer's Drug Discovery Foundation
Alzheimer's Association
Information provided by (Responsible Party):
Vaccinex Inc.

Brief Summary:
To investigate safety, tolerability, the effects on cognition and brain metabolism of pepinemab in early AD dementia (early AD) subjects.

Condition or disease Intervention/treatment Phase
Alzheimer Disease Drug: Pepinemab Drug: Placebo Phase 1 Phase 2

Detailed Description:

This is a randomized double-blind, placebo-controlled, parallel-group study of pepinemab in early AD dementia defined as MCI and mild Alzheimer's dementia. The study is 40 weeks in duration, including a safety and efficacy evaluation 4 weeks after the last dose of study drug. Subjects with resolved adverse events at Week 36 will have a safety telephone call at Week 40. Subjects with unresolved adverse events at Week 36 will have a safety in-office visit at Week 40.

The study protocol will include two sentinel subjects in each of the three blinded dose arms. Sentinel dosing will be implemented by randomly assigning one study subject to each of the three dose arms in a blinded manner, treating those subjects with study drug, and observing them for at least 48 hours after treatment. If no unexpected serious adverse events are observed within 48 hours after the third subject receives treatment, three additional subjects will be enrolled, with one subject each assigned randomly to each of the three dose arms. Again a 48-hour observation period will be observed following treatment to document any unexpected safety events that may occur. Should no unexpected serious adverse events occur within 48 hours after the sixth subject receives treatment, the remaining subjects will be assigned to the study dose cohorts according to the blinded randomization scheme and the 1:1:1 randomization ratio.

Subjects will be randomized to one of three treatment arms and will receive one dose of study drug every 4 weeks during the 32-week dosing period for a total of 9 doses of study drug. The primary objective is the safety and tolerability of study drug. A key secondary objective is the change in brain metabolism as assessed by [18F]fluorodeoxyglucose (FDG)-PET in the resting state.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Subjects will be randomized to one of three treatment arms and will receive one dose of study drug every 4 weeks during the 32-week dosing period for a total of 9 doses of study drug.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: SEMA4D Blockade Safety and Brain Metabolic Activity in Alzheimer's Disease (AD): A Multi-center, Randomized, Double-Blind, Placebo-Controlled Safety and Biomarker Study of Pepinemab Anti-SEMA4D Antibody in Early-AD
Actual Study Start Date : September 3, 2020
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: pepinemab 40mg/kg
The study drug, pepinemab, will be administered via monthly intravenous infusions.
Drug: Pepinemab
Pepinemab is a humanized IgG4 monoclonal antibody. The antibody is formulated at 20 mg/mL in 20 mM Sodium Acetate buffer, pH 5.4, containing 130 mM Sodium Chloride and 0.02% Polysorbate 80

Experimental: pepinemab 20mg/kg
The study drug, pepinemab, will be administered via monthly intravenous infusions.
Drug: Pepinemab
Pepinemab is a humanized IgG4 monoclonal antibody. The antibody is formulated at 20 mg/mL in 20 mM Sodium Acetate buffer, pH 5.4, containing 130 mM Sodium Chloride and 0.02% Polysorbate 80

Placebo Comparator: Placebo
.A placebo control will be administered via monthly intravenous infusions.
Drug: Placebo
Placebo consists of formulation buffer only which is 20 mM Sodium Acetate buffer, pH 5.4, containing 130 mM Sodium Chloride and 0.02% Polysorbate 80




Primary Outcome Measures :
  1. Number of subjects with treatment emergent adverse events (TEAEs) [ Time Frame: Up to 40 weeks ]
    TEAEs are defined as Adverse events (AEs) with onset after date-time of first dose, or medical conditions present prior to the start of IP but increased in severity or relationship after date-time of first dose of IP.


Secondary Outcome Measures :
  1. Effects on brain metabolism [ Time Frame: Up to 36 weeks ]
    As assessed by [18F]fluorodeoxyglucose (FDG)-PET in the resting state following administration of 20 mg/kg or 40 mg/kg pepinemab or placebo.

  2. Alzheimer's Disease Assessment Scale- Cognitive subscale (ADAS-cog13) [ Time Frame: Up to 36 weeks ]
    The Alzheimer's Disease Assessment Scale (ADAS-cog13) will be performed to test the cognition of subjects. The score ranges from 0 to 75,and higher values represent a better outcome.

  3. Clinical Dementia Rating (CDR) [ Time Frame: Up to 36 weeks ]
    The CDR assesses 3 domains of cognition (memory, orientation, judgment/problem solving) and 3 domains of function (community affairs, home/hobbies, personal care) using semi-structured interviews of both the study subject and an informant carried out by a trained rater. The CDR is scored using a standard methodology. Each domain is rated on a 5-point scale and lower numbers represent a better outcome.

  4. Mini Mental State Examination (MMSE) [ Time Frame: Up to 36 weeks ]
    Mini-Mental State Examination scores(MMSE) will be performed to test the cognition of subjects. The score ranges from 0 to 30,and higher values represent a better outcome.

  5. Alzheimer's Disease Cooperative Study - Activities of Daily Living [ Time Frame: Up to 36 weeks ]
    The ADCS-ADL assesses the competence of participants with AD in basic and instrumental activities of daily living (ADLs). It is administered by a clinician as a structured interview with a caregiver. The maximum score is 30. A higher score is better.

  6. Alzheimer's Disease Cooperative Study- Clinical Global Impression of Change (ADCS-CGIC) [ Time Frame: Up to 36 weeks ]
    The ADCS-CGIC focuses on clinicians' observations of change in the patient's cognitive, functional, and behavioral performance since the beginning of a trial. The ADCS-CGIC gives a discrete score that ranges from 1-7 with 7 being the worst outcome.

  7. Neuropsychiatric Inventory (NPI) [ Time Frame: Up to 36 weeks ]
    The NPI is a trial partner interview-based rating scale assessing 12 behavioral disturbances occurring in dementia subjects. Items are scored for both frequency and severity. Total scores range from 0-144 with higher scores indicating greater behavioral disturbances. For each item, the associated trial partner distress is also assessed.

  8. Immunogenicity of pepinemab in serum [ Time Frame: Up to 36 weeks ]
    As assessed by the frequency and titer of anti-drug antibodies.


Other Outcome Measures:
  1. Peak serum concentration (Cmax) [ Time Frame: Up to 36 weeks ]
    PK parameter

  2. Area under the serum concentration vs. time curve (AUC) [ Time Frame: Up to 36 weeks ]
    PK parameter

  3. Half-life of pepinemab [ Time Frame: Up to 36 weeks ]
    PK parameter

  4. Serum and CSF levels of neuroinflammatory cytokines [ Time Frame: Up to 36 weeks ]
    IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL13,IFNγ, TNF-α, TGFβ

  5. T- and B-Cell Quantitation by Flow Cytometry (TBNK) [ Time Frame: Up to 36 weeks ]
    B cells, total count; Natural killer (NK) cells, total count; T cells, total count; Absolute CD4/CD8 count with ratio

  6. Plasma and CSF concentration of neurofilament light chain (NfL) [ Time Frame: Up to 36 weeks ]
  7. Plasma and CSF concentrations of Aβ1-42/Aβ1-40 [ Time Frame: Up to 36 weeks ]
  8. CSF levels of pepinemab [ Time Frame: Up to 36 weeks ]
  9. CSF concentrations of tau and p-tau [ Time Frame: Up to 36 weeks ]
  10. CSF concentrations of YKL-40 [ Time Frame: Up to 36 weeks ]
  11. Cellular SEMA4D levels [ Time Frame: Up to 36 weeks ]
    PD parameter to determine the level of SEMA4D expression on T lymphocytes

  12. Total soluble SEMA4D levels [ Time Frame: Up to 36 weeks ]
    PD parameter to determine levels of total soluble SEMA4D

  13. Effects on brain volume [ Time Frame: Up to 36 weeks ]
    As measured by MRI



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   55 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion

  1. Written informed consent from subject and legally acceptable representative (trial partner).
  2. Have a reliable and competent trial partner who must have a close relationship with the subject, who has face to face contact at least three days a week for a minimum of ten waking hours a week and is willing to accompany the subject to all trial visits. The trial partner should understand the nature of the trial and adhere to trial requirements (e.g., dose, visit schedules, receive phone calls, and evaluations).
  3. Male and female subjects between the ages of 55 to 85 (inclusive).
  4. If female, not be of childbearing potential as indicated by one of the following:

    a) Has reached natural menopause defined as either: i) ≥ 12 months of spontaneous amenorrhea or ii) ≥ 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/ml as determined by the central laboratory; b) Has had a hysterectomy; or c) Has had a bilateral tubal ligation; or d) Has had a bilateral oophorectomy (with or without a hysterectomy) and more than 6 weeks have passed since the surgery.

  5. If male must agree to use a reliable method of birth control (condoms with contraceptive foams or sexual abstinence) during the study and for 6 months after the last dose of study drug.
  6. Must fulfill one of the following:

    1. A documented amyloid PET scan (florbetaben F18, florbetapir F18, or flutametamol F18) determined as positive by the investigator obtained prior to the Screening visit.
    2. A documented positive amyloid CSF result obtained prior to the Screening visit.
    3. If documentation is not available in the subject's record that states that the subject has had a positive amyloid PET scan or positive amyloid CSF result prior to the Screening visit, a positive amyloid CSF result is required at screening. The cut-off value for CSF Aβ1-42 or CSF Aβ1-42/Aβ1-40 ratio will be based on the value established by the central CSF screening laboratory and specified in a separate laboratory manual.
  7. Evidence of cognitive impairment based on history and neuropsychological testing that meet the diagnostic criteria for Mild Cognitive Impairment or probable Alzheimer's dementia.
  8. Global Clinical Dementia Rating (CDR) of 0.5 or 1.0
  9. MMSE score ≥22.
  10. Adequate vision and motor function to comply with testing.
  11. Use of AD medications (including but not limited to donepezil, rivastigmine, galantamine, tacrine, and memantine) at doses that have been stable for at least 8 weeks prior to Screening Visit.
  12. Subjects on stable doses of centrally-acting medications for 8 weeks prior to Screening Visit.
  13. In the opinion of the Investigator, subjects should be in reasonably good health over the last 6 months and any chronic disease should be stable, based on medical history and screening assessments.

Exclusion

  1. Have participated in an investigational drug or device study within 30 days of the Baseline Visit. If previous investigational drug was a monoclonal antibody, antibody-drug conjugate or similar protein therapeutic, 180 or days or 5 half-lives, whichever occurs first.
  2. Have a known allergy to any ingredient in the study drug formulation.
  3. Have a body weight greater than 125kg.
  4. Are a suicide risk, as determined by meeting any of the following criteria:

    1. suicide attempt within one year prior to Baseline.
    2. suicidal ideation as defined by a positive response to question 4 and 5 on the C-SSRS within 60 days of the Baseline Visit.
  5. Have a history of substance abuse (based on DSMIV criteria) within the past 12 months prior to Screening.
  6. Significant acute or chronic infection at Screening. including, among others: Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as, HBV surface antigen positive or positive HCV antibody with reflex to positive HCV RNA).
  7. Have clinically significant laboratory or ECG abnormalities at Screening, in the opinion of the Investigator.
  8. Have clinically relevant hematologic, hepatic, cardiac, or renal disease.
  9. Have a clinically significant medical, surgical, laboratory, or behavioral abnormality which in the judgment of the site Investigator makes the subject unsuitable for the study. as well as anyone with a history of malignancy of any type within 2 years of Screening. Persons with a history of surgically-excised non-melanoma skin cancers, superficial bladder or prostate cancer are permitted.
  10. Subjects that have a diagnosis of a neurological condition causing cognitive impairment other than sporadic MCI/mild dementia due to AD (e.g. Lewy body disease or frontotemporal dementia), a primary psychiatric diagnosis (e.g. Cognitive Impairment due to Schizophrenia, CIAS), or significant findings on brain MRI at screening inconsistent with AD (e.g. cerebrovascular disease or tumor).
  11. Have any of the following conditions (which would exclude MRI or PET participation):

    1. Subjects deemed unable to cooperate due to claustrophobia, inability to lie on scanner bed for 45 minutes, or inability to achieve venous access sufficient for tracer or pepinemab administration.
    2. An implant/device/condition that is contraindicated for MRI (e.g. pacemaker, severe claustrophobia, prosthetic heart valve, any metal fragments in the eyes or body--in some cases, an X-ray may be needed before an MRI scan, to ensure it is safe to enter the scanner).
    3. Body habitus that would impede completion of imaging scans.
  12. Has an MRI scan obtained at Screening that shows evidence of a neurological disorder other than early AD or > 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as "possible" or "definite"), a single area of superficial siderosis, or any other clinically significant finding (e.g., any lesion that may account for their cognitive impairment, including but not limited to brain tumor, severe white matter disease with a rating of 3 on the age-related white matter changes (ARWMC) scale, arteriovenous malformation, cavernous hemangioma, or any infarct in a strategic cortical or subcortical location). Are undergoing FDG-PET and have received research-related radiation exposure that exceeds institutional guidelines in the prior year if applicable.
  13. Are undergoing a LP for CSF collection and have any of the following conditions: uncorrected bleeding or clotting disorders, skin infections near the site of the LP, suspicion of increased intracranial pressure, allergies to numbing medications (local anesthetics), acute spinal trauma, history of migraines.
  14. Are undergoing a LP for CSF collection and taking any of the following types of anticoagulants: coumarins and indandiones, Factor Xa inhibitors, heparins, or thrombin inhibitors.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04381468


Contacts
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Contact: John Leonard, PhD 585-271-2700 JLeonard@vaccinex.com
Contact: Alisha Reader 585-271-2700 AReader@vaccinex.com

Locations
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United States, California
Pacific Research Network, Inc Recruiting
San Diego, California, United States, 92103
Contact: Dixie Creager         
United States, District of Columbia
Georgetown University Not yet recruiting
Washington, District of Columbia, United States, 20057
Contact: Kelly McCann         
United States, Florida
Brain Matters Research Not yet recruiting
Delray Beach, Florida, United States, 33445
Contact: Jennifer Blasi         
Neuropsychiatric Research Center of Southwest Florida Not yet recruiting
Fort Myers, Florida, United States, 33912
Contact: Melissa Schaerf         
JEM Research Institute Recruiting
Lake Worth, Florida, United States, 33462
Contact: Jayne Drew         
Brain Matters Research Not yet recruiting
Stuart, Florida, United States, 34997
Contact: Gina Collazo         
United States, Indiana
Indiana University School of Medicine Not yet recruiting
Indianapolis, Indiana, United States, 46202
Contact: Kala Hall         
United States, Kansas
University of Kansas Medical Center Not yet recruiting
Fairway, Kansas, United States, 66205
Contact: Rebecca Bothwell         
United States, Maryland
Johns Hopkins University Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Megan Schultz         
United States, Massachusetts
Boston Memory Clinic Not yet recruiting
Newton, Massachusetts, United States, 02459
Contact: Paula Levin         
United States, New York
Columbia University Irving Medical Center Not yet recruiting
New York, New York, United States, 10032
Contact: Katrina Cuasay         
University of Rochester Medical Center Not yet recruiting
Rochester, New York, United States, 14620
Contact: Susan Salem-Spencer         
Richmond Behavioral Associates Not yet recruiting
Staten Island, New York, United States, 10312
Contact: Adam Smith         
United States, Virginia
Re-Cognition Health Not yet recruiting
Fairfax, Virginia, United States, 22031
Contact: Monica Bland         
Sponsors and Collaborators
Vaccinex Inc.
Alzheimer's Drug Discovery Foundation
Alzheimer's Association
Investigators
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Study Director: Eric Siemers, MD Vaccinex Inc.
Additional Information:
Publications:
Fisher, T. L., J. E. Leonard, and E. Smith. 2019. Investigator's Brochure : pepinemab-Neurology. Version 4 ed. Vaccinex, Inc.

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Responsible Party: Vaccinex Inc.
ClinicalTrials.gov Identifier: NCT04381468    
Other Study ID Numbers: VX15/2503-11
First Posted: May 8, 2020    Key Record Dates
Last Update Posted: September 17, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Vaccinex Inc.:
Mild Cognitive Impairment
Mild Alzheimer's Dementia
Early Alzheimer's Disease
VX15/2503
Semaphorin 4D
SEMA4D
monoclonal antibody
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders