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

NCT ID: NCT03658135

Last Updated: 2019-12-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-12
• Study Completion Date: 2019-12-13

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).

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

BIIB092

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

Group Type: EXPERIMENTAL

BIIB092

Intervention Type: DRUG

BIIB092 is an investigational monoclonal antibody directed at tau protein

Placebo

Inactive ingredient

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Inactive ingredient

Interventions

BIIB092

BIIB092 is an investigational monoclonal antibody directed at tau protein

Intervention Type: DRUG

Placebo

Inactive ingredient

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

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;

Exclusion Criteria

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.

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).

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Adam Boxer

Adam Boxer, MD, PhD, Professor of Neurology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Adam Boxer, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UCSF Memory and Aging Center

Locations

UCSF Memory and Aging Center

San Francisco, California, United States

Countries

United States

Other Identifiers

UCSF-001-AET-1

Identifier Type: -

Identifier Source: org_study_id