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A Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy Study of TPI-287 in Alzheimer's Disease

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: NCT01966666
Recruitment Status : Active, not recruiting
First Posted : October 21, 2013
Last Update Posted : April 5, 2019
Sponsor:
Information provided by (Responsible Party):
Adam Boxer, University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE October 14, 2013
First Posted Date  ICMJE October 21, 2013
Last Update Posted Date April 5, 2019
Study Start Date  ICMJE November 2013
Estimated Primary Completion Date August 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 16, 2013)
Maximum tolerated dose of TPI-287 [ Time Frame: up to 13 weeks post initial dosing ]
Planned dose range of intravenous infusions of TPI-287 administered once every 3 weeks for 9 weeks. The dose will be escalated in 3 sequential cohorts and participants will be monitored for adverse events to determine safety and tolerability.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01966666 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2013)
TPI-287 levels in blood plasma and cerebrospinal fluid [ Time Frame: Screening and Week 10 ]
Blood plasma will be collected at specified time-points before and following the first infusion of study drug (TPI-287 or placebo) to measure TPI-287 levels. Steady-state levels of TPI-287 will be estimated from cerebrospinal fluid collected at end-point visit of placebo-controlled phase. These levels will be used to estimate the pharmacokinetic properties of TPI-287.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 16, 2013)
  • CSF biomarkers of Alzheimer's disease [ Time Frame: Screening and Week 10 ]
    A lumbar puncture will be performed at the screening and final visits to obtain cerebrospinal fluid (CSF). CSF will be analyzed for changes to concentration of biomarkers of Alzheimer's disease - beta amyloid (1-42), total tau, phosphorylated tau, tau isoforms and fragments, and tau phosphopeptides.
  • Brain MRI scan [ Time Frame: Screening and Week 11 ]
    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.
  • Cognition [ Time Frame: Screening and Week 11 ]
    The Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) and Mini Mental State Examination (MMSE) will be conducted to determine effect and preliminary efficacy of the drug on cognition.
  • Degree of disability [ Time Frame: Screening and Week 11 ]
    The Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) will be conducted to determine effect and preliminary efficacy of the drug on degree of disability.
  • Behavior [ Time Frame: Screening and Week 11 ]
    The Geriatric Depression Scale (GDS) will be conducted to determine effect and preliminary efficacy of the drug on behavior.
  • Number of participants with adverse events as a measure of safety and tolerability of extended administration of TPI-287 [ Time Frame: up to 20 weeks post initial dosing ]
    Participants who successfully complete the placebo controlled phase will be offered the option to enter an open label extension phase comprising of 3 additional infusions of TPI-287, administered once every 3 weeks for 6 weeks. Participants will be monitored for adverse events to determine drug safety and tolerability.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy Study of TPI-287 in Alzheimer's Disease
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 Mild to Moderate Alzheimer's Disease
Brief Summary The purpose of the study is to determine the highest dose of TPI-287 that is safe and tolerable when administered as an intravenous infusion to participants with mild to moderate Alzheimer's disease (AD), to measure pharmacokinetic properties of the drug as well as to gauge preliminary efficacy of TPI-287 on disease progression.
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.

Pre-medication of diphenhyramine 25 mg (Benadryl) will be given IV within 30 to 60 minutes prior to each study infusion in the study.

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: Other
Condition  ICMJE Alzheimer's Disease
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: 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.
  • 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.
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: TPI-287 6.3 mg/m2
    • Drug: Placebo
  • 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
    Intervention: Drug: Placebo
Publications * Not Provided

*   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 Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: October 16, 2013)
33
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2019
Estimated Primary Completion Date August 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria (all must be met):

  1. Between 50 and 82 years of age (inclusive)
  2. Meets National Institute on Aging-Alzheimer's Association Workgroups criteria for probable AD dementia (McKhann et al. 2011)
  3. MRI at Screening is consistent with AD (≤ 4 microhemorrhages, and no large strokes or severe white matter disease)
  4. MHIS at Screening is ≤ 4
  5. MMSE at Screening is between 14 and 26 (inclusive)
  6. FDA-approved AD medications 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
  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.

Exclusion Criteria (any one of the following will exclude a subject from being enrolled into the study):

  1. Any medical condition other than AD that could account for cognitive deficits (e.g., active seizure disorder, stroke, vascular dementia)
  2. History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof)
  3. History of significant peripheral neuropathy
  4. History of major psychiatric illness or untreated depression
  5. 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 or baseline evaluations
  6. 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
  7. Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection
  8. Current clinically significant viral infection
  9. Major surgery within four weeks prior to Screening
  10. Unable to tolerate MRI scan at Screening
  11. 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
  12. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with the dosing schedule or study evaluations
  13. Any previous exposure to microtubule inhibitors (including TPI 287) within 5 years of Screening. Treatment with microtubule inhibitors other than TPI287 while on study will not be allowed
  14. Participation in another AD clinical trial within 3 months of Screening
  15. 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
  16. Known hypersensitivity to the inactive ingredients in the study drug
  17. Pregnant or lactating
  18. Positive pregnancy test at Screening or Baseline (Day 1)
  19. Cancer within 5 years of Screening, except for non-metastatic skin cancer.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 82 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 NCT01966666
Other Study ID Numbers  ICMJE TPI287-AD-001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
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 Not Provided
Investigators  ICMJE
Principal Investigator: Adam L Boxer, M.D., Ph.D. University of California, San Francisco
PRS Account University of California, San Francisco
Verification Date April 2019

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