Corticobasal Degeneration (CBD), Corticobasal Syndrome (CBS), Primary Four Repeat Tauopathies (4RT), Progressive Supranuclear Palsy (PSP)
Conditions
Keywords
4RT, CBS, PSP, CBD, TPI-287
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.
Interventions
DRUGTPI 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.
DRUGTPI-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
DRUGPlacebo
500mL 0.9% sodium chloride
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
Sponsors
CBD Solutions
Tau Consortium
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose of TPI-287 in patients with primary 4RT; CBS or PSP. | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TPI-287 levels in blood plasma and cerebrospinal fluid | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Degree of disability | 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. |
| CSF biomarkers | 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. |
| Behavior | Screening and 2 Weeks after last infusion | The Geriatric Depression Scale (GDS) will be conducted to determine effect a |
| Cognition | 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) |
| Brain MRI scan | 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. |
Countries
United States
Outcome results
None listed