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Safety Study of TPI-287 to Treat CBS and PSP (TPI-287-4RT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02133846
Recruitment Status : Completed
First Posted : May 8, 2014
Last Update Posted : April 15, 2020
Sponsor:
Collaborators:
CBD Solutions
Tau Consortium
Information provided by (Responsible Party):
Adam Boxer, University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE May 6, 2014
First Posted Date  ICMJE May 8, 2014
Last Update Posted Date April 15, 2020
Study Start Date  ICMJE May 2014
Actual Primary Completion Date September 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2014)
Maximum tolerated dose of TPI-287 in patients with primary 4RT; CBS or PSP. [ Time Frame: 21 months (first subject enrolled to last subject completed) ]
To determine the safety and tolerability [maximum tolerated dose (MTD) within planned dosing range] of intravenous (IV) infusions of TPI 287 administered once every 3 weeks for 9 weeks (for a total of 4 infusions) in patients with primary four repeat tauopathies (4RT): corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2014)
TPI-287 levels in blood plasma and cerebrospinal fluid [ Time Frame: 21 months (first subject enrolled to last subject completed) ]
To determine the pharmacokinetic (PK) profile of TPI 287 in plasma after a single IV infusion of TPI 287 and the steady-state cerebrospinal (CSF) concentration of TPI 287 1 week after completion of the fourth infusion.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: May 7, 2014)
  • CSF biomarkers [ Time Frame: Screening and 1 Week after completion of the fourth study infusion ]
    A lumbar puncture will be performed at the screening and final visits to obtain cerebrospinal fluid (CSF). CSF biomarkers of neurodegeneration (neurofilament light chain), total tau, tau isoforms and fragments, and tau phosphopeptides.
  • Brain MRI scan [ Time Frame: Screening and 2 Weeks after last double-blind infusion ]
    Brain MRI scans will be performed to explore effects of changes in brain network functional and structural connectivity, as well as perfusion after administration of study drug.
  • Degree of disability [ Time Frame: Baseline and 1 Week after completion 4th infusion ]
    The Progressive Supranuclear Palsy Rating Scale (PSPRS), Schwab and England Activities of Daily Living (SEADL), clinical dementia rating scale sum of boxes (CDR-SB-FTLD) will be conducted.
  • Cognition [ Time Frame: Baseline and 1 Week after 4th study infusion ]
    One-minute phonemic verbal fluency (PVC) test for works starting in "F", "A" and "S", Mini-Mental State Examination (MMSE)
  • Behavior [ Time Frame: Screening and 2 Weeks after last infusion ]
    The Geriatric Depression Scale (GDS) will be conducted to determine effect a
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Safety Study of TPI-287 to Treat CBS and PSP
Official Title  ICMJE A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential Cohort, Dose-Ranging Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of TPI 287 in Patients With Primary Four Repeat Tauopathies: Corticobasal Syndrome or Progressive Supranuclear Palsy
Brief Summary The purpose of this study is to determine the safety and tolerability [maximum tolerated dose (MTD) within planned dosing range] of intravenous (IV) infusions of TPI 287 administered once every 3 weeks for 9 weeks (for a total of 4 infusions) in patients with primary four repeat tauopathies (4RT), corticobasal syndrome (CBS; also called corticobasal degeneration, CBD) or progressive supranuclear palsy (PSP).
Detailed Description

The maximum tolerated dose of TPI-287 will be determined through a planned dose escalation over 3 sequential cohorts, each comprising of 11 participants randomized to either TPI-287 or placebo. TPI-287 or placebo will be administered as an intravenous infusion once every 3 weeks for 9 weeks, for a total of 4 infusions. Participants who successfully complete this phase will have the option of entering into the open label extension phase during which TPI-287 will be administered once every 3 weeks for an additional 6 weeks, for a total of 3 extra infusions.

The dose of TPI 287 will be escalated in sequential cohorts. In the low dose cohort 11 subjects each diagnosis (i.e., separate dose escalations will be performed for CBS and PSP) will be enrolled. The medium and high dose cohorts will be comprised of 11 subjects; combined CBS and PSPdiagnoses. Subjects will be assigned to cohorts in the order of study entry.

Pre-medications of diphenhyramine 25 mg (Benadryl), dexamethasone 10 mg, and famotidine 20 mg (or the H2 blocker ranitidine 50 mg) will be given IV within 60 minutes prior to each study infusion.

Safety and tolerability will be assessed through reporting of adverse events, physical and neurological testing, ECGs, as well as blood and urine analyses. Baseline and end-point measures of cognition and function, MRI brain scans, and cerebrospinal fluid (CSF) biomarker analyses will be used to determine preliminary efficacy of TPI-287 in mild-moderate AD. Pharmacokinetic and pharmacodynamic properties of TPI-287 will be calculated from blood plasma collected after the first infusion, and from CSF collected on the last visit of the placebo-controlled phase.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Primary Four Repeat Tauopathies (4RT)
  • Corticobasal Syndrome (CBS)
  • Progressive Supranuclear Palsy (PSP)
  • Corticobasal Degeneration (CBD)
Intervention  ICMJE
  • Drug: TPI 287 2 mg/m2
    2 mg/m2 of TPI-287 diluted with 500mL 0.9% sodium chloride. TPI-287 is a microtubule inhibitor belonging to the taxane diterpenoid (taxoid) family, and specifically to the abeotaxane class.Drug: Placebo Drug: Placebo 500mL 0.9% sodium chloride.
  • Drug: TPI-287 20 mg/m2
    20 mg/m2 of TPI-287 diluted with 500mL 0.9% sodium chloride. TPI-287 is a microtubule inhibitor belonging to the taxane diterpenoid (taxoid) family, and specifically to the abeotaxane class
  • Drug: Placebo
    500mL 0.9% sodium chloride
  • Drug: TPI-287 6.3 mg/m2
    6.3 mg/m2 of TPI-287 diluted with 500mL 0.9% sodium chloride. TPI-287 is a microtubule inhibitor belonging to the taxane diterpenoid (taxoid) family, and specifically to the abeotaxane class
Study Arms  ICMJE
  • Experimental: TPI-287 low dose
    2 mg/m2 of TPI-287 administered as a 1-hour intravenous infusion once every 3 weeks for 9 weeks (for a total of 4 infusions)
    Interventions:
    • Drug: TPI 287 2 mg/m2
    • Drug: Placebo
  • Experimental: TPI-287 moderate dose
    6.3 mg/m2 of TPI-287 administered as a 1-hour intravenous infusion once every 3 weeks for 9 weeks (for a total of 4 infusions).
    Interventions:
    • Drug: Placebo
    • Drug: TPI-287 6.3 mg/m2
  • Experimental: TPI-287 high dose
    20 mg/m2 of TPI-287 administered as a 1-hour intravenous infusion once every 3 weeks for 9 weeks (for a total of 4 infusions)
    Interventions:
    • Drug: TPI-287 20 mg/m2
    • Drug: Placebo
  • Placebo Comparator: Placebo
    0.9% sodium chloride as a 1-hour intravenous infusion once every 3 weeks for 9 weeks (for a total of 4 infusions)
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 26, 2015)
44
Original Estimated Enrollment  ICMJE
 (submitted: May 7, 2014)
66
Actual Study Completion Date  ICMJE September 2019
Actual Primary Completion Date September 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Between 50 and 85 years of age (inclusive);
  2. Able to walk 5 steps with minimal assistance (stabilization of one arm or use of cane/walker);
  3. MRI at Screening is consistent with CBS or PSP (≤ 4 microhemorrhages, and no large strokes or severe white matter disease);
  4. MMSE at Screening is between 14 and 30 (inclusive);
  5. FDA-approved AD medications are sometimes prescribed for CBS and PSP subjects, and are allowed as long as the dose is stable for 2 months prior to Screening. Other medications (except those listed under exclusion criteria) are allowed as long as the dose is stable for 30 days prior to Screening;
  6. FDA-approved Parkinson's medications are allowed as long as the dose is stable for 2 months prior to Screening;
  7. Has a reliable study partner who agrees to accompany the subject to visits, and spends at least 5 hours per week with the subject;
  8. Agrees to 2 lumbar punctures;
  9. Signed and dated written informed consent obtained from the subject and the subject's caregiver in accordance with local IRB regulations;
  10. Males and all WCBP agree to abstain from sex or use an adequate method of contraception for the duration of the study and for 30 days after the last dose of study drug.

    Adequate contraceptive methods include those with a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as complete abstinence from sexual intercourse with a potentially fertile partner, and some double barrier methods (condom with spermicide) in conjunction with use by the partner of an intrauterine device (IUD), diaphragm with spermicide, oral contraceptives, birth control patch or vaginal ring, oral, or injectable or implanted contraceptives.

    For this study, a woman who has been surgically sterilized or who has been in a state of amenorrhea for more than two years will be deemed not to be of childbearing potential;

    For PSP Only

  11. Meets National Institute of Neurological Disorders and Stroke - Society for Progressive Supranuclear Palsy (NINDS-SPSP) probable or possible PSP criteria (Litvan et al. 1996a), as modified for the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) clinical trial (Bensimon et al. 2009).

For CBS Only

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

Exclusion Criteria:

  1. Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD (McKhann et al. 2011);
  2. Any medical condition other than CBS or PSP that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia);
  3. A prominent and sustained response to levodopa therapy;
  4. History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof);
  5. History of significant peripheral neuropathy;
  6. History of major psychiatric illness or untreated depression;
  7. 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 INR >1.2 at Screening evaluations;
  8. Evidence of any clinically significant findings on Screening or baseline evaluations which, in the opinion of the Investigator would pose a safety risk or interfere with appropriate interpretation of study data;
  9. Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection;
  10. Current clinically significant viral infection;
  11. Major surgery within four weeks prior to Screening;
  12. Unable to tolerate MRI scan at Screening;
  13. 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;
  14. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with the dosing schedule or study evaluations;
  15. Previous exposure to microtubule inhibitors (including TPI 287) within 5 years of Screening. Treatment with microtubule inhibitors other than TPI 287 while on study will not be allowed;
  16. Participation in another interventional clinical trial within 3 months of Screening;
  17. Treatment with another investigational drug within 30 days of Screening. Treatment with investigational drugs other than TPI 287 while on study will not be allowed;
  18. Known hypersensitivity to the inactive ingredients in the study drug;
  19. Pregnant or lactating;
  20. Positive pregnancy test at Screening or Baseline (Day 1);
  21. Cancer within 5 years of Screening, except for non-metastatic skin cancer or non-metastatic prostate cancer not expected to cause significant morbidity or mortality within one year of baseline.

    For CBS Only:

  22. History or evidence at Screening of cortical amyloid levels on 18F florbetapir PET scans consistent with underlying AD;
  23. History of serum or plasma progranulin level less than one standard deviation below the normal subject mean for the laboratory performing the assay;
  24. History or evidence at Screening of known disease-associated mutations in GRN or C9ORF72 genes to rule out CBS due to TDP-43 pathology;
  25. History of known disease-associated mutations in ribosomal protein L3 [TDP- 43 gene (TARBP)], chromatin modifying protein 2B (CHMPB2) or valosin containing protein (VCP) genes or any other frontotemporal lobar degeneration (FTLD) causative genes discovered during the course of the trial and not associated with underlying tau pathology.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02133846
Other Study ID Numbers  ICMJE TPI287-4RT-001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Adam Boxer, University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE
  • CBD Solutions
  • Tau Consortium
Investigators  ICMJE
Principal Investigator: Adam Boxer, MD, PhD UCSF Memory and Aging Center
PRS Account University of California, San Francisco
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP