A Study in Subjects With Late Prodromal & Early Manifest HD to Assess the Safety, Tolerability, pk, and Efficacy of Pepi (SIGNAL-HD)

• ClinicalTrials.gov Identifier: NCT02481674
• Recruitment Status: Completed
• First Posted: June 25, 2015
• Last Update Posted: May 2, 2022
• Sponsor: Vaccinex Inc.
• Collaborator: Huntington Study Group
• Information provided by (Responsible Party): Vaccinex Inc.

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety, tolerability, PK, and efficacy of Pepinemab in subjects with late prodromal and early manifest Huntington's disease.

Condition or disease	Intervention/treatment	Phase
Huntington's Disease	Drug: VX15/2503; Drug: Placebo	Phase 2

Detailed Description:

VX15/2503-N-131 (SIGNAL-HD) is a Phase 2, multi-center, randomized, double-blind, placebo controlled study of VX15/2503 (pepinemab) in subjects with late prodromal and early manifest Huntington's disease. The primary objective is to evaluate the safety and tolerability of monthly IV administration of a single dosage of pepinemab (or placebo). Efficacy endpoints include determining the effect of pepinemab on brain volumes (MRI), FDG-PET imaging, 11C-PBR28 (TSPO) PET imaging (subset of Cohort B only) and clinical features of HD including cognition, motor function, behavior, functional abilities, global function and global measurement of change. Additional endpoints include PK / PD, immunogenicity, and exploratory biomarkers. Subjects in Cohort B that have received 12 months of pepinemab who volunteer will undergo a lumbar puncture at V13 to collect cerebral spinal fluid (CSF) to evaluate pepinemab mAb concentrations, total sSEMA4D levels, and other biomarkers in their CSF. Enrollment will involve approximately 276 individuals who are 21 years of age or older with late prodromal (CAG-age product score (CAP score) of greater than 200 and Diagnostic Confidence Level (DCL) of 2 or 3) or early manifest HD (Total Functional Capacity (TFC) greater than or equal to 11). The study will be divided into Cohort A and Cohort B. Cohort A is now complete and an unblinded analysis has been performed. Cohort A subjects were treated for 6 months with either drug or placebo (1:1) and then all subjects were treated with drug for 6 months, followed by 3 months of follow up. Treatment duration for each subject in Cohort A was 12 months. Participation in Cohort A included a Screening visit, a Baseline visit within 30 days of screening; 12 monthly treatment visits beginning at baseline and continuing through Month 12; follow-up safety phone call at one month and a follow-up safety visit three months after the final infusion. Cohort A subjects participated in the study for approximately 16 months. Based on the analysis of Cohort A, it was decided to extend the duration of treatment for a subset of subjects in Cohort B to evaluate the clinical response to pepinemab after 36 months. Additional enrolled subjects in Cohort B will be treated with drug or placebo (1:1). Participation in Cohort B will include a Screening visit, a Baseline visit within 30 days of screening; 18 or 36 monthly visits beginning at baseline and continuing through Month 18 or Month 36; follow-up safety phone call or visit, and for a subset of subjects, a follow-up safety visit three and six months after the final infusion. Cohort B subjects will participate in the study for approximately 19 and up to 37 months.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 301 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multi-center, Randomized, Double-blind, Placebo Controlled Study in Subjects With Late Prodromal and Early Manifest Huntington's Disease to Assess the Safety, Tolerability, pk, and Efficacy of Pepinemab
• Study Start Date: July 2015
• Actual Primary Completion Date: August 2020
• Actual Study Completion Date: August 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: VX15/2503; The study drug VX15/2503 will be administered via monthly intravenous infusions	Drug: VX15/2503; VX15/2503 (pepinemab) is a humanized IgG4 monoclonal antibody and will be administered intravenously at a dose of 20 mg/kg. 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.; Other Name: pepinemab
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.

Outcome Measures

Primary Outcome Measures :

1. Revisions to SAP were made prior to un-blinding, on June 30, 2020, upon consultation with FDA. [ Time Frame: Prior to DBL/Study Completion ]
   If primary outcome, listed below (Outcome 3), does not reach its critical p-value, the secondary outcomes will not be formally tested. If both co-primary outcomes are statistically significant, the five secondary outcomes will be formally tested following a hierarchical testing procedure.
2. Safety and tolerability of monthly intravenous (IV) administration of pepinemab relative to placebo in subjects with early HD (Cohort B pooled, includes Cohort B1 Early Manifest and Cohort B2 Late Prodromal HD). [ Time Frame: Up to 18 months ]
   Measured by drug related adverse event frequency and laboratory test abnormalities in all subjects.
3. Efficacy of monthly IV administration of pepinemab relative to placebo in Early Manifest HD (Cohort B1) [ Time Frame: Up to 18 months ]
   Co-primary outcome measured by the change from baseline in the Huntington's Disease Two-item Cognitive Family (PTAP and OTS) selected from the Huntington's Disease

Secondary Outcome Measures :

1. Clinical feature of Early Manifest HD: motor function (Q-Motor) [ Time Frame: Up to 18 months ]
   Measured by change from baseline of Q-Motor Tap Speed IOI duration mean in Cohort B1
2. Clinical feature of Early Manifest HD: functional capacity (UHDRS-TFC) [ Time Frame: Up to 18 months ]
   Measured by change from baseline of UHDRS-TFC score in Cohort B1
3. Clinical feature of Early HD: functional capacity (UHDRS-TFC) [ Time Frame: Up to 18 months ]
   Measured by time to 1-point change in UHDRS-TFC score in Cohort B pooled
4. Clinical Feature of Early HD: motor function (Q-Motor) [ Time Frame: Up to 18 months ]
   Measured by change from baseline of Q-Motor Tap Speed IOI duration mean in Cohort B pooled
5. Clinical Feature of Early HD: cognition (Huntington's Disease Two-item Cognitive Family). [ Time Frame: Up to 18 months ]
   Measured by change from baseline in the two-item HD-CAB family (PTAP and OTS) in Cohort B pooled

Other Outcome Measures:

1. Clinical feature of HD: cognition [ Time Frame: Up to 18 months ]
   Measured by change from baseline in the HD-CAB composite score
2. Impact of monthly IV administration of pepinemab relative to placebo on change in brain metabolic activity [ Time Frame: Up to 18 months ]
   Measured by change from baseline [18F]-Fluoro-2-Deoxy-D-Glucose positron emission tomography (FDG-PET) standardized uptake value ratio (SUVR) Cortical Composite Index averaging results over the right and left sides of the brain in a subset of both late prodromal and early manifest subjects
3. Impact of monthly IV administration of pepinemab relative to placebo on change in brain volume [ Time Frame: Up to 18 months ]
   Measured by change from baseline in volumetric magnetic resonance imaging (MRI) averaging results over the right and left sides of the brain (BBSI, CBSI, VBSI, and change in white matter)
4. Brain metabolic activity [ Time Frame: Up to 18 months ]
   Measured by change from baseline in [11C]-PBR28 translocator protein positron emission tomography (TSPO-PET) in a small subset of late prodromal subjects (Cohort B2)
5. pepinemab and total sSEMA4D levels in cerebral spinal fluid (CSF) [ Time Frame: Up to 18 months ]
   PK parameter
6. Immunogenicity of monthly IV administration of pepinemab relative to placebo [ Time Frame: Up to 18 months ]
   Measured by the frequency and titer of anti-drug antibodies and human anti-human antibodies
7. Immunophenotyping of monthly IV administration of pepinemab relative to placebo [ Time Frame: Up to 18 months ]
   Measured by the levels of peripheral immune subsets in whole blood, including such lymphocyte subsets as B cells, T cells, and NK cells
8. Peak serum concentration (Cmax) of monthly IV administration of pepinemab [ Time Frame: Up to 18 months ]
   PK parameter
9. Area under the serum concentration versus time curve (AUC) of monthly IV administration of pepinemab [ Time Frame: Up to 18 months ]
   PK parameter
10. Half-life of VX15/2503 of monthly IV administration of pepinemab [ Time Frame: Up to 18 months ]
    PK parameter
11. SEMA4D saturation in whole blood of monthly IV administration of pepinemab [ Time Frame: Up to 18 months ]
    PD parameter to determine T-cell receptor occupancy
12. T-cell SEMA4D levels in whole blood of monthly IV administration of pepinemab [ Time Frame: Up to 18 months ]
    PD parameter
13. Total soluble SEMA4D levels in serum of monthly IV administration of pepinemab [ Time Frame: Up to 18 months ]
    PD parameter to determine the levels of total soluble SEMA4D
14. Clinical feature of HD: functional abilities [ Time Frame: Up to 18 months ]
    Measured by change from baseline in UHDRS core functional assessments
15. Clinical Feature of HD: Patient Reported Outcome [ Time Frame: Up to 18 months ]
    Measured by the overall response to therapy using patient reported impression of change (PGIC)
16. Clinical feature of HD: behavior [ Time Frame: Up to 18 months ]
    Measured by change from baseline in the Problem Behavioral Assessment-Short (PBA) questionnaire
17. Clinical feature of HD: Patient Reported Outcome [ Time Frame: Up to 18 months ]
    Measured by change from baseline in the Huntington Disease Health Index (HD-HI) Index
18. Clinical Safety and Non-Safety Laboratory Assessments (Clinical, Imaging, PK, PD and/or Immunogenicity) [ Time Frame: Up to 36 months ]
    Dataset analysis

Eligibility Criteria

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria Highlights:

1. Male or female and are at least greater than or equal to 21 years of age at Screening.

2. Must fulfill one of the following criteria at Screening:

   1. Late prodromal HD as defined by a CAP score of greater than 200 and DCL 2 or 3.
   2. Early manifest HD as defined by a TFC greater than or equal to 11. Subject must have been determined to have a clinical diagnosis of HD by the Site Investigator as defined by a DCL of 4.

3. Must fulfill both of the following criteria at Screening:

   1. Have undergone genetic testing with a known CAG repeat greater than or equal to 36.
   2. No features of juvenile HD (Westphal variant).
4. If female must be either surgically sterile, postmenopausal, or nonlactating and nonpregnant. Female subjects of childbearing potential must practice a highly effective method of contraception.
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. Are willing and capable of providing informed consent for study participation, CAG genotyping (all subjects).
7. Are capable of reading, writing, and communicating effectively with others.
8. Are taking stable doses of any concomitant medications (including tetrabenazine and deutetrabenazine) during the 1 month prior to the Baseline Visit, with the exception of newly prescribed anxiolytics for the use of pre-medication prior to imaging at screening, which will be permitted on a case-by-case basis.
9. Must meet all criteria required to move forward with the Randomization Authorization Flow (RAF) and be considered eligible by the RAF Reviewer.

Exclusion Criteria Highlights:

1. Have participated in an investigational drug or device study within 30 days of the Baseline Visit, or 180 days if previous investigational drug was a MAb therapeutic, or previously participated in SIGNAL Cohort A. This does not apply to Cohort B subjects who are being offered the option to participate in the extension of Cohort B.
2. Have had previous neurosurgery for Huntington's disease or other movement disorders.

3. 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 5 on the C-SSRS (Baseline visit form) suicidal ideation section, within 60 days of the Baseline Visit.
   3. significant risk of suicide, as judged by the site Investigator.
4. Have marked cognitive impairment with a Montreal Cognitive Assessment (MoCA) Score less than or equal to 22.
5. Have a presence of clinically significant psychosis and/or confusional states, in the opinion of the site Investigator.
6. Have clinically significant laboratory or ECG abnormalities at Screening, in the opinion of the site Investigator.
7. Have clinically relevant hematologic, hepatic, cardiac, or renal disease.
8. Have a medical history of infection with human immunodeficiency virus, hepatitis C and/or hepatitis B, or found to have an abnormality at Screening.
9. Have a history of substance abuse (based on DSMIV criteria) within the past 12 months prior to Screening.
10. If female are pregnant or breastfeeding.
11. Have a known allergy to any ingredient in the study drug.
12. Have a history of malignancy of any type within 2 years prior to Screening. A history of surgically excised non-melanoma skin cancers, and superficial bladder or prostate cancer is permitted.
13. 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.
14. Have any significant findings not related to HD on the screening MRI which in the judgment of the site Investigator makes the subject unsuitable for the study.

15. Have any of the following conditions (which would exclude MRI participation):

    1. 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).
    2. Body habitus that would impede completion of MRI scan. (Subject weight above 158 kg should be discussed with the Medical Monitor).

    NOTE: If PET is done on PET-MRI all the above conditions apply for PET-MRI.

16. Are undergoing FDG-PET and have received research-related radiation exposure that exceeds institutional guidelines in the prior year if applicable.
17. 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.
18. 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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35233

United States, California

University of California, San Diego

La Jolla, California, United States, 92037

University of California San Francisco

San Francisco, California, United States, 94143

United States, Colorado

University of Colorado - Denver

Aurora, Colorado, United States, 80045

United States, District of Columbia

Georgetown University

Washington, District of Columbia, United States, 20007

United States, Florida

University of Florida Gainesville

Gainesville, Florida, United States, 32611

United States, Georgia

Emory University School of Medicine

Atlanta, Georgia, United States, 30329

United States, Indiana

Indiana University School of Medicine

Indianapolis, Indiana, United States, 46202

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Kentucky

University of Louisville

Louisville, Kentucky, United States, 40202

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21218

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

Massachusetts General Hospital

Charlestown, Massachusetts, United States, 02129

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48105

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63110

United States, New York

Columbia University

New York, New York, United States, 10027

Columbia University

New York, New York, United States, 10032

University of Rochester

Rochester, New York, United States, 14618

United States, North Carolina

Duke University Health Center

Durham, North Carolina, United States, 27705

Wake Forest University

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

University of Cincinnati

Cincinnati, Ohio, United States, 45267

Ohio State University

Columbus, Ohio, United States, 43210

University of Toledo

Toledo, Ohio, United States, 43614

United States, Tennessee

Vanderbilt University

Nashville, Tennessee, United States, 37232

United States, Texas

University of Texas Houston Medical School

Houston, Texas, United States, 77030

United States, Vermont

University of Vermont

Burlington, Vermont, United States, 05401

United States, Virginia

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

United States, Washington

University of Washington and VA Puget Sound Health Care System

Seattle, Washington, United States, 98195

University of Washington

Seattle, Washington, United States, 98195

Canada, Alberta

University of Alberta

Edmonton, Alberta, Canada, T6G 2R3

Canada, British Columbia

University of British Columbia

Vancouver, British Columbia, Canada, V6T 1Z4

Canada, Quebec

Centre hospitalier de l'Université de Montréal (CHUM)

Montréal, Quebec, Canada, H2X 0C1

Sponsors and Collaborators

Vaccinex Inc.

Huntington Study Group

Investigators

• Principal Investigator: Andrew Feigin, MD; The Marlene & Paolo Fresco Institute for Parkinson's & Movement Disorders-NYU Langone Medical Center

More Information

Additional Information:

Nonclinical research article: Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. 

Publications:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Feigin A, Evans EE, Fisher TL, Leonard JE, Smith ES, Reader A, Mishra V, Manber R, Walters KA, Kowarski L, Oakes D, Siemers E, Kieburtz KD, Zauderer M; Huntington Study Group SIGNAL investigators. Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial. Nat Med. 2022 Oct;28(10):2183-2193. doi: 10.1038/s41591-022-01919-8. Epub 2022 Aug 8. Erratum In: Nat Med. 2022 Oct 4;:

Rodrigues FB, Wild EJ. Huntington's Disease Clinical Trials Corner: August 2018. J Huntingtons Dis. 2018;7(3):279-286. doi: 10.3233/JHD-189003.

• Responsible Party: Vaccinex Inc.
• ClinicalTrials.gov Identifier: NCT02481674
• Other Study ID Numbers: VX15/2503-N-131
• First Posted: June 25, 2015
• Last Update Posted: May 2, 2022
• Last Verified: April 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Vaccinex Inc.:

Prodromal Stage; Early Manifest Stage

Additional relevant MeSH terms:

Huntington Disease; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Cognition Disorders; Neurocognitive Disorders; Mental Disorders