PTI-125 for Mild-to-moderate Alzheimer's Disease Patients

• ClinicalTrials.gov Identifier: NCT03748706
• Recruitment Status: Completed
• First Posted: November 21, 2018
• Results First Posted: April 1, 2021
• Last Update Posted: July 7, 2021
• Sponsor: Pain Therapeutics
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Cassava Sciences, Inc. ( Pain Therapeutics )

Tracking Information

• First Submitted Date: November 13, 2018
• First Posted Date: November 21, 2018
• Results First Submitted Date: March 3, 2021
• Results First Posted Date: April 1, 2021
• Last Update Posted Date: July 7, 2021
• Actual Study Start Date: March 7, 2019
• Actual Primary Completion Date: May 8, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 31, 2021)

• Maximum Plasma Concentration (Cmax) [ Time Frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose ]
  Blood draws will be done to evaluate levels of PTI-125 in the plasma using non-compartmental methods in WinNonlin.
• Time to Maximum Plasma Concentration (Tmax) [ Time Frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose ]
  Levels of PTI-125 will be assessed to determine how long it takes to reach the Cmax
• Last Quantifiable Plasma Concentration (Clast) [ Time Frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose ]
  Levels of PTI-125 will be assessed to determine the last time point where PTI-125 can be detected.
• Time to Last Quantifiable Plasma Concentration (Tlast) [ Time Frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose ]
  Levels of PTI-125 will be assessed to determine the elapsed time to where PTI-125 can last be detected in the plasma.
• Area Under the Curve (AUClast) [ Time Frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose ]
  AUC for PTI-125 plasma concentration from time zero to the last quantifiable plasma concentration.
• Plasma Half-life (T1/2) [ Time Frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose ]
  Assessment of the half-life in plasma of PTI-125

Original Primary Outcome Measures (submitted: November 18, 2018)

• Maximum Plasma Concentration (Cmax) [ Time Frame: Study Days 1, 2, 28 and 29 ]
  Blood draws will be done to evaluate levels of PTI-125 in the plasma using non-compartmental methods in WinNonlin.
• Time to Maximum Plasma Concentration (Tmax) [ Time Frame: Study Days 1, 2, 28 and 29 ]
  Levels of PTI-125 will be assessed to determine how long it takes to reach the Cmax
• Last Quantifiable Plasma Concentration (Clast) [ Time Frame: Study Day 1, 2, 28 and 29 ]
  Levels of PTI-125 will be assessed to determine the last time point where PTI-125 can be detected.
• Time to Last Quantifiable Plasma Concentration (Tlast) [ Time Frame: Study Days 1, 2, 28 and 29 ]
  Levels of PTI-125 will be assessed to determine the elapsed time to where PTI-125 can last be detected in the plasma.
• Area Under the Curve (AUC) [ Time Frame: Study Days 1, 2, 28 and 29 ]
  AUC for PTI-125 plasma concentration from time zero to the last quantifiable plasma concentration.
• Minimum Plasma Concentration (Cmin) [ Time Frame: Study Days 7 and 14 ]
  Assessment of the lowest plasma concentration of PTI-125

Current Secondary Outcome Measures (submitted: March 3, 2021)

• SavaDx (Biomarker) [ Time Frame: Study Day 1 and Day 28 ]
  Blood samples will be tested for the complementary diagnostic/biomarker for Alzheimer's disease.
• CSF Biomarkers [ Time Frame: Change from Baseline to Day 28 ]
  A cerebrospinal fluid sample collection will be performed for Aβ42, tau, YKL40 and other potential CSF biomarkers

Original Secondary Outcome Measures (submitted: November 18, 2018)

• PTI-125DX (biomarker) [ Time Frame: Study Days 1, 7, 14 and 29 ]
  Blood samples will be tested for the companion dignostic/biomarker for Alzheimer's disease.
• Biomarker assay [ Time Frame: Day 28 ]
  A CSF sample collection will be performed for Aβ/tau, YKL40 and other potential CSF biomarkers

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: PTI-125 for Mild-to-moderate Alzheimer's Disease Patients
• Official Title: A Phase 2a, Open-label, Multiple Dose, Safety, Pharmacokinetic and Biomarker Study of PTl-125 in Mild-to-moderate Alzheimer's Disease Patients
• Brief Summary: This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate Alzheimer's disease patients.
• Detailed Description: This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate AD patients, 50-85 years of age. A total of twelve (12) patients will be enrolled into the study. Patients will receive 100 mg b.i.d. of PTI-125. The objectives of this study are to investigate the safety, pharmacokinetics and effect on biomarkers of PTI-125 following 28-day repeat-dose oral administration.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Alzheimer Disease

Intervention

Drug: PTI-125, 100 mg tablets

PTI-125, 100 mg tablets taken twice a day for 28 days

Study Arms

Experimental: Simufilam (PTI-125)

Simufilam (PTI-125) 100 mg oral tablets administered twice daily (BID)

Intervention: Drug: PTI-125, 100 mg tablets

Publications *

• Wang HY, Lee KC, Pei Z, Khan A, Bakshi K, Burns LH. PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. Neurobiol Aging. 2017 Jul;55:99-114. doi: 10.1016/j.neurobiolaging.2017.03.016. Epub 2017 Mar 31.
• Wang HY, Bakshi K, Frankfurt M, Stucky A, Goberdhan M, Shah SM, Burns LH. Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A. J Neurosci. 2012 Jul 18;32(29):9773-84. doi: 10.1523/JNEUROSCI.0354-12.2012. Erratum In: J Neurosci. 2021 Dec 15;41(50):10405. J Neurosci. 2022 Jan 19;42(3):529.
• Wang HY, Pei Z, Lee KC, Lopez-Brignoni E, Nikolov B, Crowley CA, Marsman MR, Barbier R, Friedmann N, Burns LH. PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients. J Prev Alzheimers Dis. 2020;7(4):256-264. doi: 10.14283/jpad.2020.6.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 3, 2021): 13
• Original Estimated Enrollment (submitted: November 18, 2018): 12
• Actual Study Completion Date: May 8, 2019
• Actual Primary Completion Date: May 8, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Ages >= 50 and <= 85 years
• Informed consent form (ICF) signed by the subject or legally acceptable representative.
• Clinical diagnosis of dementia due to possible or probable Alzheimer's disease
• Mini-Mental State Examination score >= 16 and <= 24 at screening
• If female, postmenopausal for at least 1 year
• Patient living at home, senior residential setting, or an institutional setting without the need for continuous (i.e. 24-hour) nursing care
• General health status acceptable for participation in the study
• Fluency (oral and written) in English or Spanish
• If receiving memantine, rivastigmine, galantamine or an AChEI, receiving a stable dose for at least 3 months (90 days) before screening and with continuous dosing for at least 3 months. If receiving donepezil, receiving any dose lower than 23 mg once daily.
• The patient is a non-smoker for at least 12 months.
• The patient or legal representative must agree to comply with the drawing of blood samples and with a lumbar puncture and the drawing of cerebrospinal fluid samples.
• The patient has a ratio of total tau/Abeta42 in cerebrospinal fluid >= 0.30.
• Patient has a caregiver or legal representative responsible for administering the drug and recording the time.

Exclusion Criteria:

• Exposure to an experimental drug, experimental biologic or experimental medical device within the longer of 5 half-lives or 3 months before screening
• Residence in a skilled nursing facility
• Clinically significant laboratory test results
• Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating hormone level and thyroid supplementation dose must be stable for at least 6 months before screening)
• Insufficiently controlled diabetes mellitus or requiring insulin
• Renal insufficiency (serum creatinine >2.0 mg/dL)
• Malignant tumor within 3 years before screening (except squamous and basal cell carcinoma or cervical carcinoma in situ or localized prostate cancer or localized stage 1 bladder cancer)
• History of ischemic colitis or ischemic enterocolitis
• Unstable medical condition that is clinically significant in the judgment of the investigator
• Alanine transaminase (ALT) or aspartate transaminase (AST) >2 times the upper limit of normal or total bilirubin greater than the upper limit of normal.
• History of myocardial infarction or unstable angina within 6 months before screening
• History of more than 1 myocardial infarction within 5 years before screening
• Clinically significant cardiac arrhythmia (including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are acceptable)
• Symptomatic hypotension, or uncontrolled hypertension
• Clinically significant abnormality on screening electrocardiogram (ECG), including but not necessarily limited to a confirmed corrected QT value >= 450 msec for males or >= 470 msec for females.
• Stroke within 18 months before screening, or history of a stroke concomitant with onset of dementia
• History of brain tumor or other clinically significant space-occupying lesion on CT or MRI
• Head trauma with clinically significant loss of consciousness within 12 months before screening or concurrent with the onset of dementia
• Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or resuscitation
• Specific degenerative CNS disease diagnosis other than Alzheimer's disease (eg, Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's disease)
• Wernicke's encephalopathy
• Active acute or chronic Central Nervous System infection
• Donepezil 23 mg or greater quaque die currently or within 3 months prior to enrollment in the study
• Discontinued AChEI < 30 days prior to enrollment in the study
• Antipsychotics; low doses are allowed only if given for sleep disturbances, agitation and/or aggression, and only if the subject has received a stable dose for at least 3 months before enrollment in the study
• Tricyclic antidepressants and monoamine oxidase inhibitors; all other antidepressants are allowed only if the subject has received a stable dose for at least 3 months before enrollment in the study
• Anxiolytics or sedative-hypnotics, including barbiturates (unless given in low doses for benign tremor); low doses of benzodiazepines and zolpidem are allowed only if given for insomnia/sleep disturbance, and only if the subject has received a stable dose for at least 3 months before enrollment in the study
• Peripherally acting drugs with effects on cholinergic transmission
• Immunosuppressants, including systemic corticosteroids, if taken in clinically immunosuppressive doses (Steroid use for allergy or other inflammation is permitted.)
• Antiepileptic medications if taken for control of seizures
• Chronic intake of opioid-containing analgesics
• Sedating H1 antihistamines
• Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or similar therapeutic agent within 30 days before screening
• Clinically significant illness within 30 days of enrollment
• History of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease
• Positive serum hepatitis B surface antigen (HBsAg) or positive hepatitis C virus (HCV) antibody test at screening
• Positive HIV test at screening
• Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to the study
• Metformin or cimetidine.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03748706
• Other Study ID Numbers: PTI-125-03; R44AG060878 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

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

• Plan to Share IPD: No

• Current Responsible Party: Cassava Sciences, Inc. ( Pain Therapeutics )
• Original Responsible Party: Same as current
• Current Study Sponsor: Pain Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: National Institute on Aging (NIA)

Investigators

• Study Director: Lindsay Burns, PhD; Cassava Sciences, Inc.

• PRS Account: Cassava Sciences, Inc.
• Verification Date: June 2021