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

A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multiple Dose, Biomarker and Safety Study of PTI-125 in Mild-to-moderate Alzheimer's Disease Patients

This is a Phase 2b, Randomized, Double-blind, Placebo-controlled, multiple dose study of PTI-125 in mild-to-moderate Alzheimer's disease patients.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Placebo oral tablet; Drug: Simufilam 50 mg oral tablet; Drug: Simufilam 100 mg tablet

Detailed Description

This is a Phase 2b, Randomized, Double-blind, Placebo-controlled, multiple dose study of PTI-125 in mild-to-moderate Alzheimer's disease patients. A total of sixty (60) patients will be enrolled in the study. Patients will receive Placebo, 50 mg or 100 mg b.i.d. of PTI-125. The objective of this study are to investigate the safety, and biomarkers of PTI-125 following 28-day repeat oral administration.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85296
      • Cognitive Clinical Trials
    • Surprise, Arizona, United States, 85374
      • Cognitive Clinical Trials
  • Florida
    • Miami, Florida, United States, 33125
      • Optimus U
    • Palmetto Bay, Florida, United States, 33157
      • IMIC, Inc.
  • Nebraska
    • Bellevue, Nebraska, United States, 68005
      • Cognitive Clinical Trials
    • Omaha, Nebraska, United States, 68116
      • Cognitive Clinical Trials
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Advanced Memory Research Institute
  • Texas
    • Houston, Texas, United States, 77058
      • Centex Studies, Inc.
    • McAllen, Texas, United States, 78504
      • Centex Studies, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 <= 26 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-h) 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. If receiving donepezil, any dose lower than 23 mg once daily.
• The patient is a non-smoker for at least 3 years.
• 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/Aβ42 in cerebrospinal fluid >= 0.28.
• 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
• Enrollment in the previous PTI-125 trial
• A medical condition that would interfere with a lumbar puncture
• Residence in a skilled nursing facility and requiring 24 h care.
• Clinically significant laboratory test results
• Clinically significant untreated hypothyroidism
• Insufficiently controlled diabetes mellitus
• Renal insufficiency (serum creatinine > ULN)
• 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) > ULN or total bilirubin > ULN.
• 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 interval 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 Central Nervous System 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 quaque die currently or within 3 months prior to randomization
• Discontinued AChEI < 30 days prior to randomization
• Antipsychotics; low doses are allowed only if the subject has received a stable dose for at least 3 months before randomization
• Tricyclic antidepressants and monoamine oxidase inhibitors
• Anxiolytics or sedative-hypnotics, including barbiturates (unless given in low doses for benign tremor); low doses of benzodiazepines and zolpidem are allowed
• 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
• Positive urine drug test at screening
• Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to the study
• Suicidality on C-SSRS at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Cohort; Subjects administered placebo oral tablets twice daily (BID)	Drug: Placebo oral tablet; Oral placebo tablet
Experimental: Simufilam (PTI-125) 100 mg tablets Cohort; Subjects administered simufilam (PTI-125) 100 mg oral tablets twice daily (BID)	Drug: Simufilam 50 mg oral tablet; Simufilam 50 mg oral tablet; Other Names: PTI-125
Experimental: Simufilam (PTI-125) 50 mg tablets Cohort; Subjects administered simufilam (PTI-125) 50 mg oral tablets twice daily (BID)	Drug: Simufilam 100 mg tablet; Simufilam 100 mg oral tablet; Other Names: PTI-125

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in CSF Abeta42	Change from Baseline (screening sample) to Day 28 in cerebrospinal fluid levels of Amyloid beta42	Screening to Day 28
Change From Baseline in CSF Total Tau.	Change from Baseline (screening sample) to Day 28 in cerebrospinal fluid total tau.	Screening to Day 28
Change From Baseline in CSF P-tau181	Change from Baseline (screening) to Day 28 in cerebrospinal fluid P-tau181	Screening to Day 28
Change From Baseline in CSF Neurogranin	Change from Baseline (screening) to Day 28 in cerebrospinal fluid neurogranin	Screening to Day 28
Change From Baseline in CSF Neurofilament Light Chain	Change from Baseline (screening) to Day 28 in cerebrospinal fluid neurofilament light chain	Screening to Day 28
Change From Baseline in CSF YKL-40	Change from Baseline (screening) in cerebrospinal fluid YKL-40	Screening to Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Paired Associates Learning Test	Cognitive test assessing episodic memory. Boxes are displayed on the screen and are "opened" in a randomized order. One or more of them contains a pattern. The patterns are then displayed in the middle of the screen, one at a time and the participant must select the box in which the pattern was originally located. If the participant makes an error, the boxes are opened in sequence again to remind the participant of the locations of the patterns. The number of boxes increases progressively to a total of 8.	Day 1 to Day 28
Spatial Working Memory Test	Cognitive assessment of spatial working memory: A number of colored squares (boxes) are shown on the screen. By selecting the boxes and using a process of elimination, the subject should find one yellow 'token' in each of a number of boxes and use them to fill up an empty column on the right-hand side of the screen. The number of boxes is gradually increased to a total of 8 for the subjects to search. The colors and positions of the boxes are changed from trial to trial to discourage stereotyped search strategies.	Day 1 to Day 28
CSF IL-6, sTREM2, HMGB1, Albumin, IgG	Change from Baseline (screening sample) to Day 28 in secondary CSF biomarkers of neuroinflammation and blood-brain barrier integrity	Screening to Day 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Target Engagement Assays: Change From Baseline in Filamin A (FLNA) Linkages to alpha7 Nicotinic Acetylcholine Receptor (alpha7nAChR) and Toll-like Receptor 4 (TLR4) in Subject Lymphocytes	FLNA linkages to these two receptors were assessed by densitometric quantitation of immunoblot bands of each receptor (detected by a specific antibody) in anti-FLNA precipitates. The measure is noted as a ratio to total FLNA.	Day 1 to Day 28
Plasma P-tau181	Percent change in plasma P-tau181	Day 1 to Day 28
Percent Change From Baseline in SavaDx, a Novel Plasma Biomarker	SavaDx is a novel plasma biomarker	Day 1 to Day 28

Collaborators and Investigators

• Sponsor: Cassava Sciences, Inc.
• Collaborators: National Institute on Aging (NIA)
• Investigators: Study Director: Lindsay Burns, PhD, Cassava Sciences, Inc.

Publications and helpful links

General Publications

• Sever S. Role of actin cytoskeleton in podocytes. Pediatr Nephrol. 2021 Sep;36(9):2607-2614. doi: 10.1007/s00467-020-04812-z. Epub 2020 Nov 13.

Helpful Links

• Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer's disease
• PTI-125 and Alzheimer's Publications

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2019
• Primary Completion (Actual): March 31, 2020
• Study Completion (Actual): March 31, 2020

Study Registration Dates

• First Submitted: August 26, 2019
• First Submitted That Met QC Criteria: September 4, 2019
• First Posted (Actual): September 6, 2019

Study Record Updates

• Last Update Posted (Actual): September 29, 2021
• Last Update Submitted That Met QC Criteria: September 7, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: PTI-125-02; R44AG060878 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No