Corticobasal Degeneration Syndrome, Frontotemporal Lobar Degeneration With Tau Inclusions, MAPT Mutation Carriers, Symptomatic, Nonfluent Aphasia, Progressive, Primary Tauopathies, Traumatic Encephalopathy Syndrome
Conditions
Keywords
CBS, CBD, nfvPPA, FTD, sMAPT, TES
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).
Interventions
DRUGBIIB092
BIIB092 is an investigational monoclonal antibody directed at tau protein
OTHERPlacebo
Inactive ingredient
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind - only investigational pharmacist is unblinded
Intervention 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).
Eligibility
Sex/Gender
ALL
Age
35 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events | 20 weeks | Assess adverse events during 20 weeks administration BIIB092 or Placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Pharmacokinetic properties of BIIB092 in Plasma | 20 weeks | Measure steady-state plasma concentrations of BIIB092 and its metabolites |
| Changes in Pharmacokinetic properties of BIIB092 in Cerebrospinal Fluid | 20 weeks | Measure steady-state Cerebrospinal fluid concentrations of BIIB092 and its metabolites |
| Changes in Pharmacodynamic effects of BIIB092 on Cerebrospinal Fluid | 20 weeks | Measure CSF concentrations of free extracellular tau (eTau) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Cerebrospinal Fluid Biomarkers of neurofilament light chain | 20 weeks | Measure CSF concentrations of neurofilament light chain protein (NfL) pg/mL |
| Change in Cerebrospinal Fluid Biomarkers of total tau | 20 weeks | Measure CSF concentrations of total tau protein (t-tau) pg/mL |
| Change in Schwab and England Activities of Daily Living (SEADL) scale | 20 weeks | 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. |
| Change in whole brain volume on brain MRI | 20 weeks | Measure of global volume of interest (whole brain) |
| Change in Montreal Cognitive Assessment (MoCA) | 20 weeks | 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. |
| Change in Neuropsychiatric Inventory-Questionnaire (NPI-Q) | 20 weeks | 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. |
| Changes in Functional Activities Questionnaire (FAQ) | 20 weeks | 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) |
| Change in regional brain volume on brain MRI | 20 weeks | Measure of regional volumes of interest (such as ventricles, hippocampus) |
| Change in functional connectivity on brain MRI | 20 weeks | Connectivity between brain regions measured using arterial spin labeling (ASL) |
| Change in Cerebrospinal Fluid Biomarkers of phosphorylated tau | 20 weeks | Measure CSF concentrations of phosphorylated tau protein (p-tau) pg/mL |
Countries
United States
Outcome results
None listed