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BIIB092 in Primary Tauopathies: CBS, nfvPPA, sMAPT, and TES (TauBasket)

Primary Purpose

Primary Tauopathies, Corticobasal Degeneration Syndrome, Frontotemporal Lobar Degeneration With Tau Inclusions

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
BIIB092
Placebo
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Tauopathies focused on measuring CBS, CBD, nfvPPA, FTD, sMAPT, TES

Eligibility Criteria

35 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • The inclusion criteria are listed below and are the same for each diagnostic cohort, except where noted. Participants must meet all of the specified inclusion criteria to be randomized to study drug (active or placebo) treatment.

    1. Between 35 and 80 years of age (inclusive);
    2. Able to walk at least 10 steps with minimal assistance (stabilization of one arm or use of cane/walker);
    3. MRI at Screening is consistent with the underlying neurodegenerative disease of the respective diagnostic cohort (i.e., CBS, nfvPPA, sMAPT, or TES), with no large strokes or severe white matter disease;
    4. Mini Mental State Exam (MMSE) at Screening is between 20 and 30 (inclusive);
    5. Amyloid beta (Aβ) positron emission tomography (PET) scan (florbetapir or equivalent) at Screening is not consistent with underlying Alzheimer's disease (AD).

      Previous Aβ PET scan negativity (assessed by a certified neuro radiologist) or previous AD CSF biomarker (Aβ)/tau level) negativity may be used instead of performing an Aβ PET scan at Screening at the PI's discretion;

    6. The following medications are allowed, but must be stable for 2 months prior to

      Screening:

      1. FDA-approved AD medications
      2. FDA-approved Parkinson's disease medications;
    7. Other medications (except those listed under exclusion criteria) are allowed as long as the dose is stable for 30 days prior to Screening;
    8. Has a reliable study partner who agrees to accompany the participant to visits, and spends at least 5 hours per week with the participant;
    9. Agrees to 3 lumbar punctures;
    10. Signed and dated written informed consent obtained from the participant and the participant's study partner in accordance with local IRB regulations;
    11. Women of childbearing potential (WCBP) must agree to abstain from sex or use an adequate method of contraception for the duration of the Screening period, the study drug treatment period, and for 155 days after the last dose of study drug;
    12. Males must agree to abstain from sex with WCBP or use an adequate method of contraception for the duration of the study drug treatment period and for 215 days after the last dose of study drug.

      For CBS Only

    13. Meets 2013 consensus criteria for possible or probable corticobasal degeneration (CBD), CBS subtype (Armstrong et al. 2013).

      For nfvPPA Only

    14. Meets 2011 consensus criteria for nfvPPA (Gorno-Tempini et al. 2011). Patients meeting 2013 Armstrong criteria for CBS-nfvPPA or 2017 Movement Disorder Society (MDS) criteria for progressive supranuclear palsy and speech/language disorders (PSP-SL) (Höglinger et al. 2017) would be assigned to this cohort since both of these definitions were derived from the 2011 Gorno-Tempini criteria.

      For sMAPT Only

    15. Has known frontotemporal lobar degeneration- (FTLD-) causative MAPT mutation confirmed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory (Ghetti et al. 2015);
    16. CDR-FTLD (Knopman et al. 2008) sum of boxes score ≥ 1.0. Sum of boxes is used instead of the global Clinical Dementia Rating Scale (CDR) because the global CDR does not take into account FTLD specific measures;
    17. Has any clinical phenotype of sMAPT.

      For TES Only

    18. Meets 2016 criteria for probable TES (Reams et al. 2016);
    19. At least 5 years or greater between symptom onset and 1st known traumatic brain injury/concussive episode.

Exclusion Criteria:

The exclusion criteria are listed below and are the same for each diagnostic cohort. Participants meeting any of the following exclusion criteria will be excluded from randomization to study drug (active or placebo) treatment.

  1. A diagnosis of probable AD (McKhann et al. 2011) or progressive supranuclear palsy- Richardson's syndrome (PSP-RS) (Höglinger et al. 2017). Since variants of progressive supranuclear palsy (PSP) are known to cause nfvPPA and CBS, a diagnosis of PSP-SL or progressive supranuclear palsy-corticobasal syndrome (PSP- CBS) would not be exclusionary;
  2. Any other medical condition other than CBS, nfvPPA, sMAPT or TES that could account for cognitive or motor deficits (e.g., active seizure disorder, stroke, vascular dementia, substance abuse or alcoholism);
  3. History of a prominent and sustained response to levodopa therapy in the opinion of the PI;
  4. History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof);
  5. History of major psychiatric illness or untreated depression that in the opinion of the PI would pose a safety risk or interfere with the appropriate interpretation of study data;
  6. Neutrophil count <1,500/mm3, platelets <100,000/mm3, serum creatinine >1.5 x upper limit of normal (ULN), total bilirubin >1.5 x ULN, alanine aminotransferase (ALT) >3 x ULN, aspartate aminotransferase (AST) >3 x ULN, or International Normalized Ratio (INR) >1.2 at Screening evaluations;
  7. Evidence of any clinically significant findings on Screening or baseline evaluations which, in the opinion of the PI would pose a safety risk or interfere with appropriate interpretation of study data;
  8. Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection;
  9. Current clinically significant viral infection;
  10. Major surgery within four weeks prior to Screening;
  11. Any contraindication for MRI or unable to tolerate MRI scan at Screening;
  12. Any contraindication to or unable to tolerate lumbar puncture at Screening, including use of anti-coagulant medications such as warfarin. Daily administration of 81 mg aspirin will be allowed as long as the dose is stable for 30 days prior to Screening;
  13. Participants who, in the opinion of the PI, are unable or unlikely to comply with the dosing schedule or study evaluations;
  14. Prior treatment with BIIB092;
  15. Treatment with another investigational drug within 30 days or 5 half-lives of drug before Screening, whichever is longer. Treatment with investigational drugs other than BIIB092 while on study will not be allowed;
  16. Treatment with systemic corticosteroids within 30 days or 5 half-lives of drug before Screening, whichever is longer. Treatment with systemic corticosteroids while on study will not be allowed;
  17. Known hypersensitivity to the inactive ingredients in the study drug (BIIB092 or placebo);
  18. Known to be pregnant or lactating; or positive pregnancy test at Screening or Baseline (Day 1);
  19. Cancer within 5 years of Screening, except for basal cell carcinoma;
  20. History of serum or plasma progranulin level less than one standard deviation below the normal participant mean for the laboratory performing the assay;
  21. History or evidence at Screening of known disease-associated mutations in GRN, TBK1, C9ORF72, TARBP, CHMPB2, or VCP genes (FTLD causative gene mutations not associated with underlying tau pathology).

Sites / Locations

  • UCSF Memory and Aging Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

BIIB092

Placebo

Arm Description

The investigational drug, BIIB092, will be given intravenously, every 4 weeks for 20 weeks

Inactive ingredient

Outcomes

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events
Assess adverse events during 20 weeks administration BIIB092 or Placebo

Secondary Outcome Measures

Changes in Pharmacokinetic properties of BIIB092 in Plasma
Measure steady-state plasma concentrations of BIIB092 and its metabolites
Changes in Pharmacokinetic properties of BIIB092 in Cerebrospinal Fluid
Measure steady-state Cerebrospinal fluid concentrations of BIIB092 and its metabolites
Changes in Pharmacodynamic effects of BIIB092 on Cerebrospinal Fluid
Measure CSF concentrations of free extracellular tau (eTau)

Full Information

First Posted
August 13, 2018
Last Updated
December 17, 2019
Sponsor
University of California, San Francisco
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1. Study Identification

Unique Protocol Identification Number
NCT03658135
Brief Title
BIIB092 in Primary Tauopathies: CBS, nfvPPA, sMAPT, and TES
Acronym
TauBasket
Official Title
A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Parallel Cohort Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy Study of Intravenously Infused BIIB092 in Patients With Four Different Primary Tauopathy Syndromes
Study Type
Interventional

2. Study Status

Record Verification Date
December 2019
Overall Recruitment Status
Terminated
Why Stopped
BIIB092 program discontinued
Study Start Date
September 12, 2018 (Actual)
Primary Completion Date
December 13, 2019 (Actual)
Study Completion Date
December 13, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of California, San Francisco

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Parallel Cohort Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy Study of Intravenously Infused BIIB092 in Patients with Four Different Primary Tauopathy Syndromes
Detailed Description
This is a phase 1b randomized, double-blind, safety, and tolerability clinical trial of an investigational drug, called BIIB092 in patients with four different primary tauopathy syndromes: amyloid PET (-) corticobasal syndrome (CBS), nonfluent variant primary progressive aphasia (nfvPPA), symptomatic patients with autosomal dominant genetic forms of frontotemporal lobar degeneration (FTD) due to the presence of a mutation in the microtubule-associated protein tau gene (sMAPT), and traumatic encephalopathy syndromes (TES). Primary tauopathies are neurodegenerative brain disorders in which tau is the only protein that accumulates at autopsy. While Alzheimer's disease (AD) is the most common tauopathy, it is considered a secondary tauopathy, because tau protein accumulates along with another pathogenic protein, amyloid beta. Primary tauopathies are rare diseases for which there is no treatment or cure. The purpose of the this study is to characterize the safety and tolerability profile of intravenous BIIB092 in four primary tauopathies. A basket design will be used for a parallel evaluation of BIIB092 in four heterogenous clinicopathological syndromes that share a common molecular target (tau).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Tauopathies, Corticobasal Degeneration Syndrome, Frontotemporal Lobar Degeneration With Tau Inclusions, MAPT Mutation Carriers, Symptomatic, Traumatic Encephalopathy Syndrome, Nonfluent Aphasia, Progressive
Keywords
CBS, CBD, nfvPPA, FTD, sMAPT, TES

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
This is a phase 1b, randomized, double-blind, placebo-controlled, parallel cohort study of the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of BIIB092 in patients with 4 different primary tauopathy syndromes: CBS, nfvPPA, sMAPT, and TES. A basket trial design will be used for a parallel evaluation of BIIB092 in four heterogeneous clinicopathological syndromes that share a common molecular target (tau). There will be four cohorts of approximately 8 participants each, one for each specific primary tauopathy syndrome listed above (for a total of approximately 32 participants). For each diagnostic cohort, eligible participants will be randomized 3:1 to active or placebo (i.e., 6 participants receiving BIIB092 and 2 participants receiving placebo). All eligible participants will be administered study drug (BIIB092 or placebo) as an 1-hour intravenous (IV) infusion q4w for 20 weeks (for a total of 6 infusions).
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double-blind - only investigational pharmacist is unblinded
Allocation
Randomized
Enrollment
22 (Actual)

8. Arms, Groups, and Interventions

Arm Title
BIIB092
Arm Type
Experimental
Arm Description
The investigational drug, BIIB092, will be given intravenously, every 4 weeks for 20 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Inactive ingredient
Intervention Type
Drug
Intervention Name(s)
BIIB092
Intervention Description
BIIB092 is an investigational monoclonal antibody directed at tau protein
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Inactive ingredient
Primary Outcome Measure Information:
Title
Incidence of Treatment-Emergent Adverse Events
Description
Assess adverse events during 20 weeks administration BIIB092 or Placebo
Time Frame
20 weeks
Secondary Outcome Measure Information:
Title
Changes in Pharmacokinetic properties of BIIB092 in Plasma
Description
Measure steady-state plasma concentrations of BIIB092 and its metabolites
Time Frame
20 weeks
Title
Changes in Pharmacokinetic properties of BIIB092 in Cerebrospinal Fluid
Description
Measure steady-state Cerebrospinal fluid concentrations of BIIB092 and its metabolites
Time Frame
20 weeks
Title
Changes in Pharmacodynamic effects of BIIB092 on Cerebrospinal Fluid
Description
Measure CSF concentrations of free extracellular tau (eTau)
Time Frame
20 weeks
Other Pre-specified Outcome Measures:
Title
Change in whole brain volume on brain MRI
Description
Measure of global volume of interest (whole brain)
Time Frame
20 weeks
Title
Change in regional brain volume on brain MRI
Description
Measure of regional volumes of interest (such as ventricles, hippocampus)
Time Frame
20 weeks
Title
Change in functional connectivity on brain MRI
Description
Connectivity between brain regions measured using arterial spin labeling (ASL)
Time Frame
20 weeks
Title
Change in functional connectivity on brain MRI
Description
Connectivity between brain regions measured using resting state functional MRI (rsfMRI)
Time Frame
20 weeks
Title
Change in functional connectivity on brain MRI
Description
Connectivity between brain regions measured using diffusion tensor MRI (DTI)
Time Frame
20 weeks
Title
Change in Cerebrospinal Fluid Biomarkers of phosphorylated tau
Description
Measure CSF concentrations of phosphorylated tau protein (p-tau) pg/mL
Time Frame
20 weeks
Title
Change in Cerebrospinal Fluid Biomarkers of neurofilament light chain
Description
Measure CSF concentrations of neurofilament light chain protein (NfL) pg/mL
Time Frame
20 weeks
Title
Change in Cerebrospinal Fluid Biomarkers of total tau
Description
Measure CSF concentrations of total tau protein (t-tau) pg/mL
Time Frame
20 weeks
Title
Change in Schwab and England Activities of Daily Living (SEADL) scale
Description
The SEADL assesses the subject's ability to perform daily activities as reported by the subject, caregiver, and clinician. Rated in 10% increments, with 100% = completely independent to 0% = bedridden and vegetative functions.
Time Frame
20 weeks
Title
Changes in Functional Activities Questionnaire (FAQ)
Description
The FAQ measures the subject's ability to perform common activities independently as reported by informant (such as paying bills, preparing a meal, keeping track of current events). Normal = 0 and dependent on others = 3; Sum scores (range 0-30, with higher score impaired function and possible cognitive impairment)
Time Frame
20 weeks
Title
Change in Montreal Cognitive Assessment (MoCA)
Description
The MoCA is a brief 30-question test assessing cognitive abilities (such as orientation, short-term memory, executive function/visuospatial ability). Scores range from zero to 30, with a higher score generally considered normal; lower scores indicate possible cognitive impairment.
Time Frame
20 weeks
Title
Change in Neuropsychiatric Inventory-Questionnaire (NPI-Q)
Description
The NPI-Q is a brief assessment of neuropsychiatric symptoms (such as delusions, hallucinations). Each symptom is rated (by informant/caregiver) for Severity on a 3-point scale (mild, moderate, severe) and Distress on a 5-point scale (0 to 5). The higher the total Severity and Distress scores the more impactful the symptoms.
Time Frame
20 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The inclusion criteria are listed below and are the same for each diagnostic cohort, except where noted. Participants must meet all of the specified inclusion criteria to be randomized to study drug (active or placebo) treatment. Between 35 and 80 years of age (inclusive); Able to walk at least 10 steps with minimal assistance (stabilization of one arm or use of cane/walker); MRI at Screening is consistent with the underlying neurodegenerative disease of the respective diagnostic cohort (i.e., CBS, nfvPPA, sMAPT, or TES), with no large strokes or severe white matter disease; Mini Mental State Exam (MMSE) at Screening is between 20 and 30 (inclusive); Amyloid beta (Aβ) positron emission tomography (PET) scan (florbetapir or equivalent) at Screening is not consistent with underlying Alzheimer's disease (AD). Previous Aβ PET scan negativity (assessed by a certified neuro radiologist) or previous AD CSF biomarker (Aβ)/tau level) negativity may be used instead of performing an Aβ PET scan at Screening at the PI's discretion; The following medications are allowed, but must be stable for 2 months prior to Screening: FDA-approved AD medications FDA-approved Parkinson's disease medications; Other medications (except those listed under exclusion criteria) are allowed as long as the dose is stable for 30 days prior to Screening; Has a reliable study partner who agrees to accompany the participant to visits, and spends at least 5 hours per week with the participant; Agrees to 3 lumbar punctures; Signed and dated written informed consent obtained from the participant and the participant's study partner in accordance with local IRB regulations; Women of childbearing potential (WCBP) must agree to abstain from sex or use an adequate method of contraception for the duration of the Screening period, the study drug treatment period, and for 155 days after the last dose of study drug; Males must agree to abstain from sex with WCBP or use an adequate method of contraception for the duration of the study drug treatment period and for 215 days after the last dose of study drug. For CBS Only Meets 2013 consensus criteria for possible or probable corticobasal degeneration (CBD), CBS subtype (Armstrong et al. 2013). For nfvPPA Only Meets 2011 consensus criteria for nfvPPA (Gorno-Tempini et al. 2011). Patients meeting 2013 Armstrong criteria for CBS-nfvPPA or 2017 Movement Disorder Society (MDS) criteria for progressive supranuclear palsy and speech/language disorders (PSP-SL) (Höglinger et al. 2017) would be assigned to this cohort since both of these definitions were derived from the 2011 Gorno-Tempini criteria. For sMAPT Only Has known frontotemporal lobar degeneration- (FTLD-) causative MAPT mutation confirmed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory (Ghetti et al. 2015); CDR-FTLD (Knopman et al. 2008) sum of boxes score ≥ 1.0. Sum of boxes is used instead of the global Clinical Dementia Rating Scale (CDR) because the global CDR does not take into account FTLD specific measures; Has any clinical phenotype of sMAPT. For TES Only Meets 2016 criteria for probable TES (Reams et al. 2016); At least 5 years or greater between symptom onset and 1st known traumatic brain injury/concussive episode. Exclusion Criteria: The exclusion criteria are listed below and are the same for each diagnostic cohort. Participants meeting any of the following exclusion criteria will be excluded from randomization to study drug (active or placebo) treatment. A diagnosis of probable AD (McKhann et al. 2011) or progressive supranuclear palsy- Richardson's syndrome (PSP-RS) (Höglinger et al. 2017). Since variants of progressive supranuclear palsy (PSP) are known to cause nfvPPA and CBS, a diagnosis of PSP-SL or progressive supranuclear palsy-corticobasal syndrome (PSP- CBS) would not be exclusionary; Any other medical condition other than CBS, nfvPPA, sMAPT or TES that could account for cognitive or motor deficits (e.g., active seizure disorder, stroke, vascular dementia, substance abuse or alcoholism); History of a prominent and sustained response to levodopa therapy in the opinion of the PI; History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof); History of major psychiatric illness or untreated depression that in the opinion of the PI would pose a safety risk or interfere with the appropriate interpretation of study data; Neutrophil count <1,500/mm3, platelets <100,000/mm3, serum creatinine >1.5 x upper limit of normal (ULN), total bilirubin >1.5 x ULN, alanine aminotransferase (ALT) >3 x ULN, aspartate aminotransferase (AST) >3 x ULN, or International Normalized Ratio (INR) >1.2 at Screening evaluations; Evidence of any clinically significant findings on Screening or baseline evaluations which, in the opinion of the PI would pose a safety risk or interfere with appropriate interpretation of study data; Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection; Current clinically significant viral infection; Major surgery within four weeks prior to Screening; Any contraindication for MRI or unable to tolerate MRI scan at Screening; Any contraindication to or unable to tolerate lumbar puncture at Screening, including use of anti-coagulant medications such as warfarin. Daily administration of 81 mg aspirin will be allowed as long as the dose is stable for 30 days prior to Screening; Participants who, in the opinion of the PI, are unable or unlikely to comply with the dosing schedule or study evaluations; Prior treatment with BIIB092; Treatment with another investigational drug within 30 days or 5 half-lives of drug before Screening, whichever is longer. Treatment with investigational drugs other than BIIB092 while on study will not be allowed; Treatment with systemic corticosteroids within 30 days or 5 half-lives of drug before Screening, whichever is longer. Treatment with systemic corticosteroids while on study will not be allowed; Known hypersensitivity to the inactive ingredients in the study drug (BIIB092 or placebo); Known to be pregnant or lactating; or positive pregnancy test at Screening or Baseline (Day 1); Cancer within 5 years of Screening, except for basal cell carcinoma; History of serum or plasma progranulin level less than one standard deviation below the normal participant mean for the laboratory performing the assay; History or evidence at Screening of known disease-associated mutations in GRN, TBK1, C9ORF72, TARBP, CHMPB2, or VCP genes (FTLD causative gene mutations not associated with underlying tau pathology).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adam Boxer, MD, PhD
Organizational Affiliation
UCSF Memory and Aging Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UCSF Memory and Aging Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States

12. IPD Sharing Statement

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BIIB092 in Primary Tauopathies: CBS, nfvPPA, sMAPT, and TES

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