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Alzheimer DiseasePhase 1/2SIGNAL-ADNCT04381468

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

A Phase 1/2 study testing Pepinemab in people with Alzheimer Disease, run by Vaccinex Inc. at 14 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

To investigate safety, tolerability, the effects on cognition and brain metabolism of pepinemab in early AD dementia (early AD) subjects. Read more about this study

Who is it for?
Ages 55 to 85 years
Conditions the study is for
Alzheimer Disease
What is being tested?
Pepinemab
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
50 participants
Where
14 sitesUnited States
Study dates
22 Jul 2021to 5 Jun 2024
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 55 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Written informed consent from the participant and legally acceptable representative (trial partner).
  • Have a reliable and competent trial partner who must have a close relationship with the participant, 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 participant 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).
  • Male and female participants between the ages of 55 to 85 (inclusive).
  • If female, not be of childbearing potential as indicated by one of the following:
  • 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.
  • If male, must agree to use a reliable method of birth control (condoms with contraceptive forms or sexual abstinence) during the study and for 6 months after the last dose of study drug.
Show all 18Show fewer
  • Must fulfill one of the following:
  • A documented amyloid PET scan (florbetaben F18, florbetapir F18, or flutametamol F18) determined as positive by the Investigator obtained at any time prior to the Screening visit; or
  • A documented positive amyloid CSF result obtained at any time prior to the Screening visit; or
  • Investigator has knowledge of positive amyloid PET scan or positive amyloid CSF result obtained previously; or
  • A positive amyloid CSF result at screening. The cut-off value for CSF Aβ1-42 or CSF Aβ1-42/Aβ1-40 ratio will be based on the value determined by Vaccinex
  • Evidence of cognitive impairment based on history and neuropsychological testing that meet the diagnostic criteria for probable Alzheimer's dementia.
  • Global Clinical Dementia Rating (CDR) of 0.5 or 1.0
  • MMSE score of 17-26, inclusive.
  • Adequate vision, hearing, and motor function to comply with testing.
  • If receiving medications for AD (including but not limited to donepezil, rivastigmine, galantamine, tacrine, and memantine), be on a stable dose for at least 8 weeks prior to Screening Visit.
  • If on stable doses of centrally-acting medications, be on a stable dose for 8 weeks prior to Screening Visit.
  • In the opinion of the Investigator, is in reasonably good health over the last 6 months and any chronic disease is stable based on medical history and screening assessments.

Who cannot join

  • Inability to comply with visit schedule or other protocol requirements.
  • 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 days or 5 half-lives, whichever occurs first.
  • Have a known allergy to any ingredient in the study drug formulation.
  • Have a body weight greater than 125 kg.
  • Are a suicide risk, as determined by meeting any of the following criteria:
  • Suicide attempt within one year prior to the Baseline Visit.
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  • Suicidal ideation as defined by a positive response to question 4 and 5 on the C-SSRS within 60 days of the Baseline Visit.
  • Have a history of substance abuse (based on DSMIV criteria) within the past 12 months prior to Screening.
  • 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) at Screening.
  • Have clinically significant laboratory or ECG abnormalities at Screening in the opinion of the Investigator.
  • Have clinically relevant hematologic, hepatic, cardiac, or renal disease.
  • Have a clinically significant medical, surgical, laboratory, or behavioral abnormality which in the judgment of the Investigator makes the participant 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.
  • Participants who have a diagnosis of a neurological condition causing cognitive impairment other than sporadic 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), history of frequent concussions or significant findings on brain MRI at screening inconsistent with AD (e.g., cerebrovascular disease or tumor).
  • Have any of the following conditions (which would exclude MRI or PET participation):
  • Participants 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.
  • 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).
  • Body habitus that would impede completion of imaging scans.
  • 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,
  • Any other clinically significant finding on MRI (e.g., any lesion that may account for their cognitive impairment, including but not limited to brain tumor, severe white matter disease 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.
  • 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.
  • 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.
  • Has received treatment with any FDA accelerated approval therapy for treatment of Alzheimer's Disease
  • Has a Screening MRI that shows Amyloid-related imaging abnormalities edema (ARIA-E)

Trial locations and contacts

14 sites in 1 country.

14 sites in 1 country

United States14 sites

  • Neurological Associates of Albany

    Albany, New York, 12212

  • Dent Neurological Associates

    Amherst, New York, 14226

  • Brain Matters Research

    Delray Beach, Florida, 33445

  • Re-Cognition Health

    Fairfax, Virginia, 22031

  • University of Kansas Medical Center

    Fairway, Kansas, 66205

  • Neuropsychiatric Research Center of Southwest Florida

    Fort Myers, Florida, 33912

  • Indiana University School of Medicine

    Indianapolis, Indiana, 46202

  • JEM Research Institute

    Lake Worth, Florida, 33462

  • Columbia University Irving Medical Center

    New York, New York, 10032

  • Premiere Research Institute of Palm Beach, Neurology

    Palm Beach, Florida, 33480

  • University of Rochester Medical Center

    Rochester, New York, 14620

  • Pacific Research Network, Inc

    San Diego, California, 92103

  • Brain Matters Research

    Stuart, Florida, 34997

  • Georgetown University

    Washington D.C., District of Columbia, 20057

Other trials in United States

About this study

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

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

Read the detailed description

To investigate safety, tolerability, the effects on cognition and brain metabolism of pepinemab, administered as IV infusions every 4 weeks for 44 weeks (12 infusions) in mild dementia due to Alzheimer's Disease (AD)) participants. Participants will be randomized 1:1 to receive 40 mg/kg pepinemab or placebo.

This is a randomized double-blind, placebo-controlled study of pepinemab in mild dementia due to AD. The study is 52 weeks in duration, including a safety and efficacy evaluation 4 weeks after the last dose of study drug. Participants with resolved adverse events at Week 48 will have a safety telephone call at Week 52. Participants with unresolved adverse events at Week 48 will have a safety in-office visit at Week 52. The study protocol will include two sentinel participants in each of the two blinded dose arms. Sentinel dosing will be implemented by randomly assigning one study participant to one of the two dose arms in a blinded manner, treating those participants with study drug. If no unexpected serious adverse events are observed within 48 hours after the first and second participants receive treatment, two additional participants will be enrolled, with one participant assigned randomly to each of the two dose arms. Again a 48-hour safety period will be observed following treatment of the fourth participant to document any unexpected safety events that may occur. Should no unexpected serious adverse events occur within 48 hours after the third and fourth participants receive treatment, the remaining participants will be assigned to the study dose arms according to the blinded randomization scheme and the 1:1 randomization ratio. Participants will be randomized to one of two treatment arms and will receive one dose of study drug every 4 weeks during the 44-week dosing period for a total of 12 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.

Being tested
Pepinemab, Placebo
Keywords
Mild Cognitive Impairment, Mild Alzheimer's Dementia, Early Alzheimer's Disease, VX15/2503, Semaphorin 4D, SEMA4D, monoclonal antibody
Medical subject headings
Alzheimer Disease, Cognitive Dysfunction

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PepinemabDrug

    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

  • PlaceboDrug

    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

Study groups in NCT04381468
Study groupRoleWhat they receive
pepinemab 40mg/kgExperimentalThe study drug, pepinemab, will be administered via monthly intravenous infusions.
Receives: Drug: Pepinemab
PlaceboPlacebo comparator.A placebo control will be administered via monthly intravenous infusions.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of subjects with treatment emergent adverse events (TEAEs)

    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.

    Measured: Up to 40 weeks

Secondary outcomes (8)

  1. Effects on brain metabolism

    As assessed by [18F]fluorodeoxyglucose (FDG)-PET in the resting state following administration of 20 mg/kg or 40 mg/kg pepinemab or placebo.

    Measured: Up to 36 weeks

  2. Alzheimer's Disease Assessment Scale- Cognitive subscale (ADAS-cog13)

    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.

    Measured: Up to 36 weeks

  3. Clinical Dementia Rating (CDR)

    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.

    Measured: Up to 36 weeks

  4. Mini Mental State Examination (MMSE)

    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.

    Measured: Up to 36 weeks

  5. Alzheimer's Disease Cooperative Study - Activities of Daily Living

    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.

    Measured: Up to 36 weeks

  6. Alzheimer's Disease Cooperative Study- Clinical Global Impression of Change (ADCS-CGIC)

    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.

    Measured: Up to 36 weeks

  7. Neuropsychiatric Inventory (NPI)

    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.

    Measured: Up to 36 weeks

  8. Immunogenicity of pepinemab in serum

    As assessed by the frequency and titer of anti-drug antibodies.

    Measured: Up to 36 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 May 2020
  2. Study start22 Jul 2021
  3. Primary completion5 Jun 2024
  4. Study completion5 Jun 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Participants will be randomized to one of two treatment arms and will receive one dose of study drug every 4 weeks during the 44-week dosing period for a total of 12 doses of study drug
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
50 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04381468
Sponsor's protocol ID
VX15/2503-11
Acronym
SIGNAL-AD
Status last verified
Aug 2024
First submitted
1 May 2020
Last updated
22 Aug 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992 Apr 10;256(5054):184-5. doi: 10.1126/science.1566067. No abstract available.

    PubMed 1566067

  • Selkoe DJ. Resolving controversies on the path to Alzheimer's therapeutics. Nat Med. 2011 Sep 7;17(9):1060-5. doi: 10.1038/nm.2460.

    PubMed 21900936

  • Moreau-Fauvarque C, Kumanogoh A, Camand E, Jaillard C, Barbin G, Boquet I, Love C, Jones EY, Kikutani H, Lubetzki C, Dusart I, Chedotal A. The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. J Neurosci. 2003 Oct 8;23(27):9229-39. doi: 10.1523/JNEUROSCI.23-27-09229.2003.

    PubMed 14534257

  • Fisher, T. L., J. E. Leonard, and E. Smith. 2019. Investigator's Brochure : pepinemab-Neurology. Version 4 ed. Vaccinex, Inc.

  • Basile JR, Gavard J, Gutkind JS. Plexin-B1 utilizes RhoA and Rho kinase to promote the integrin-dependent activation of Akt and ERK and endothelial cell motility. J Biol Chem. 2007 Nov 30;282(48):34888-95. doi: 10.1074/jbc.M705467200. Epub 2007 Sep 12.

    PubMed 17855350

  • Giraudon P, Vincent P, Vuaillat C, Verlaeten O, Cartier L, Marie-Cardine A, Mutin M, Bensussan A, Belin MF, Boumsell L. Semaphorin CD100 from activated T lymphocytes induces process extension collapse in oligodendrocytes and death of immature neural cells. J Immunol. 2004 Jan 15;172(2):1246-55. doi: 10.4049/jimmunol.172.2.1246.

    PubMed 14707103

  • Giraudon P, Vincent P, Vuaillat C. T-cells in neuronal injury and repair: semaphorins and related T-cell signals. Neuromolecular Med. 2005;7(3):207-16. doi: 10.1385/NMM:7:3:207.

    PubMed 16247181

  • Okuno T, Nakatsuji Y, Moriya M, Takamatsu H, Nojima S, Takegahara N, Toyofuku T, Nakagawa Y, Kang S, Friedel RH, Sakoda S, Kikutani H, Kumanogoh A. Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. J Immunol. 2010 Feb 1;184(3):1499-506. doi: 10.4049/jimmunol.0903302. Epub 2009 Dec 28.

    PubMed 20038643

  • Smith ES, Jonason A, Reilly C, Veeraraghavan J, Fisher T, Doherty M, Klimatcheva E, Mallow C, Cornelius C, Leonard JE, Marchi N, Janigro D, Argaw AT, Pham T, Seils J, Bussler H, Torno S, Kirk R, Howell A, Evans EE, Paris M, Bowers WJ, John G, Zauderer M. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol Dis. 2015 Jan;73:254-68. doi: 10.1016/j.nbd.2014.10.008. Epub 2014 Oct 18.

    PubMed 25461192

  • Van Raamsdonk JM, Gibson WT, Pearson J, Murphy Z, Lu G, Leavitt BR, Hayden MR. Body weight is modulated by levels of full-length huntingtin. Hum Mol Genet. 2006 May 1;15(9):1513-23. doi: 10.1093/hmg/ddl072. Epub 2006 Mar 28.

    PubMed 16571604

  • Van Raamsdonk JM, Murphy Z, Slow EJ, Leavitt BR, Hayden MR. Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease. Hum Mol Genet. 2005 Dec 15;14(24):3823-35. doi: 10.1093/hmg/ddi407. Epub 2005 Nov 8.

    PubMed 16278236

  • Carroll JB, Lerch JP, Franciosi S, Spreeuw A, Bissada N, Henkelman RM, Hayden MR. Natural history of disease in the YAC128 mouse reveals a discrete signature of pathology in Huntington disease. Neurobiol Dis. 2011 Jul;43(1):257-65. doi: 10.1016/j.nbd.2011.03.018. Epub 2011 Mar 31.

    PubMed 21458571

  • Southwell AL, Franciosi S, Villanueva EB, Xie Y, Winter LA, Veeraraghavan J, Jonason A, Felczak B, Zhang W, Kovalik V, Waltl S, Hall G, Pouladi MA, Smith ES, Bowers WJ, Zauderer M, Hayden MR. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol Dis. 2015 Apr;76:46-56. doi: 10.1016/j.nbd.2015.01.002. Epub 2015 Feb 3.

    PubMed 25662335

  • Patnaik A, Weiss GJ, Leonard JE, Rasco DW, Sachdev JC, Fisher TL, Winter LA, Reilly C, Parker RB, Mutz D, Blaydorn L, Tolcher AW, Zauderer M, Ramanathan RK. Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors. Clin Cancer Res. 2016 Feb 15;22(4):827-36. doi: 10.1158/1078-0432.CCR-15-0431. Epub 2015 Oct 7.

    PubMed 26446947

  • LaGanke C, Samkoff L, Edwards K, Jung Henson L, Repovic P, Lynch S, Stone L, Mattson D, Galluzzi A, Fisher TL, Reilly C, Winter LA, Leonard JE, Zauderer M. Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial. Neurol Neuroimmunol Neuroinflamm. 2017 Jun 16;4(4):e367. doi: 10.1212/NXI.0000000000000367. eCollection 2017 Jul.

    PubMed 28642891

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Pepinemab in people with Alzheimer Disease, run by Vaccinex Inc. at 14 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of subjects with treatment emergent adverse events (TEAEs) (time frame: Up to 40 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04381468, which also lists 32 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Aug 2024.

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