- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04388254
Simufilam (PTI-125), 100 mg, for Mild-to-moderate Alzheimer's Disease Patients (PTI-125)
December 22, 2023 updated by: Cassava Sciences, Inc.
A 12-Month, Open-Label Safety Study of Simufilam Followed by a 6-Month Randomized Withdrawal and 6 Additional Months Open-Label in Mild-to-moderate Alzheimer's Disease Patients
A two-year safety study of simufilam (PTI-125) 100 mg oral tablets twice daily for participants of the previous simufilam studies as wells as additional new mild-to-moderate Alzheimer's disease subjects for a total of 200 participants.
All participants will receive simufilam 100 mg tablets twice daily for one year, followed by a 6-month randomized, double-blind period where subjects will either continue on active treatment or be switched to placebo.
The study concludes with an additional 6-month open-label treatment period.
Clinic visits are every month or month and a half in the first year, and every 3 months in the second year with an additional visit at Month 13.
Cognition and neuropsychiatric symptoms are evaluated.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
The objectives of this study are to build the safety database for simufilam (PTI-125) and to investigate its effects on biomarkers, cognition and neuropsychiatric symptoms during 12-month twice-daily administration in mild-to-moderate AD patients.
Additional objectives are to assess differences in cognition and neuropsychiatric symptoms between active and placebo arms in the 6-month randomized period.
All subjects will undergo lumbar puncture at screening for baseline testing of cerebrospinal fluid (CSF) total tau and Abeta42, and the first 50 subjects will also provide a CSF sample at Month 6 or Month 12 for evaluation of change from baseline in CSF biomarkers.
CSF will not be required of subjects with prior CSF, PET or MRI evidence of Alzheimer's disease.
Plasma biomarkers will be evaluated in all subjects.
Safety will be assessed by blood tests, electrocardiograms, adverse event monitoring and, at Months 12 and 24, full physical examinations.
Study Type
Interventional
Enrollment (Actual)
220
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Ontario
-
Ottawa, Ontario, Canada, K1Z 1G3
- Ottawa Memory Clinic
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Toronto, Ontario, Canada, M3B 2S7
- Toronto Memory Program
-
-
-
-
Arizona
-
Gilbert, Arizona, United States, 85296
- Cognitive Clinical Trials
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Surprise, Arizona, United States, 85374
- Cognitive Clinical Trials
-
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California
-
Imperial, California, United States, 92251
- Sun Valley Research Center, Inc.
-
-
Florida
-
Delray Beach, Florida, United States, 33445
- Brain Matters Research
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Fort Myers, Florida, United States, 33912
- Neuropsychiatric Research Center of Southwest Florida
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Miami, Florida, United States, 33125
- Optimus U
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Miami Lakes, Florida, United States, 33016
- Adaptive Clinical Research, Inc
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Palmetto Bay, Florida, United States, 33157
- IMIC, Inc.
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Nebraska
-
Bellevue, Nebraska, United States, 68005
- Cognitive Clinical Trials
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Omaha, Nebraska, United States, 68130
- Cognitive Clinical Trials
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New Jersey
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Toms River, New Jersey, United States, 08755
- Advanced Memory Research Institute
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Ohio
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North Canton, Ohio, United States, 44720
- Neuro-Behavioral Clinical Research
-
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Texas
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Austin, Texas, United States, 78757
- Senior Adults Specialty Research
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Houston, Texas, United States, 77058
- Centex Studies, Inc.
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McAllen, Texas, United States, 78504
- Centex Studies
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-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
50 years to 85 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Description
INCLUSION CRITERIA:
- Informed consent form (ICF) signed by the subject or legally acceptable representative.
- Patient has a caregiver or legal representative responsible for administering the drug and recording the time.
- Ages ≥ 50 and ≤ 85 years
- Clinical diagnosis of dementia due to possible or probable AD consistent with criteria established by a workgroup of the National Institute on Aging and the Alzheimer's Disease Association.
- 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 (90 days) before screening. If receiving donepezil, receiving any dose lower than 23 mg once daily. Multiple medications are allowed.
- 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 for the PK assessments, laboratory assessments and SavaDx.
- MMSE-2 score ≥ 16 and ≤ 26 at screening, OR if > 26, must have evidence of AD pathology such as a prior CSF total tau/Aβ42 ratio ≥ 0.28, an amyloid positive PET scan or hippocampal volume loss consistent with AD.
EXCLUSION CRITERIA:
- Anything that in the opinion of the Investigator would preclude participation in a 2-year study.
- BMI < 18.5
- Positive urine drug screen.
- Positive HIV, HCV or HbsAg screen.
- Suicidality on C-SSRS
- Exposure to an experimental drug other than simufilam, experimental biologic or experimental medical device within 3 months before screening
- 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 (if treated, thyroid-stimulating hormone level and thyroid supplementation dose must be stable for at least 6 months before screening)
- Insufficiently controlled diabetes mellitus, including requiring insulin or metformin >1000 mg/day.
- Renal insufficiency (serum creatinine > ULN and clinically significant in the opinion of PI and/or Sponsor OR eGFR <60 ml/min/m2 as estimated by either the MDRD or CKD-EPI equation)
- 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 and clinically significant in the opinion of PI and/or Sponsor.
- 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 QTc (Fridericia correction method) 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 AD (e.g., Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's disease)
- Wernicke's encephalopathy
- Active acute or chronic CNS infection
- Donepezil 23 mg or greater QD currently or within 3 months prior to randomization
- Discontinued AChEI < 30 days prior to randomization
- 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 randomization
- 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 randomization
- 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 randomization
- 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
- Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to the study
- COVID-19 infection within 3 months
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Simufilam 100 mg oral tablets throughout
Simufilam 100 mg oral tablets administered twice daily (BID) for the full 24 months (including the randomized period Month 12 to Month 18)
|
Simufilam 100 mg oral tablet for b.i.d.
administration
Other Names:
|
Placebo Comparator: Simufilam 100 mg oral tablets / Placebo / Simufilam 100 mg oral tablets
This placebo arm is only for Month 12 to Month 18. Day 1 to Month 12, as well as Month 18 to Month 24 are open-label treatment periods of simufilam 100 mg b.i.d. for all subjects.
|
Simufilam 100 mg oral tablet for b.i.d.
administration
Other Names:
Matching placebo oral tablets
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Safety and Tolerability
Time Frame: Day 1 to Month 24
|
Safety and tolerability of simufilam (PTI-125) during the full study: Open-label period 1 (Day 1 to Month 12), the randomized withdrawal (Month 12 to Month 18), and open-label period 2 (Month 18 to Month 24)
|
Day 1 to Month 24
|
Change from baseline in CSF P-tau, Total Tau, Abeta42, neurofilament light chain, neurogranin, YKL-40, soluble TREM2 and HMGB1 during first 6 months of open-label period 1
Time Frame: Screening to Month 6
|
Change from baseline in cerebrospinal fluid biomarkers of AD pathology, neurodegeneration and neuroinflammation during first 6 months of open-label period 1 in a subset of 25 subjects
|
Screening to Month 6
|
Change from baseline in ADAS-Cog-11 during open-label period 1
Time Frame: Day 1 to Month 12
|
Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item: Change from baseline in cognition during open-label period 1
|
Day 1 to Month 12
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Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-11)
Time Frame: Month 12 to Month 18
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Change in cognition vs. placebo during randomized withdrawal period
|
Month 12 to Month 18
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Neuropsychiatric Inventory (NPI)
Time Frame: Day 1 to Month 12
|
Change from baseline in behavioral symptoms during open-label period 1
|
Day 1 to Month 12
|
Neuropsychiatric Inventory (NPI)
Time Frame: Month 12 to Month 18
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Change in neuropsychiatric symptoms vs. placebo during randomized withdrawal period
|
Month 12 to Month 18
|
Change from baseline in CSF P-tau, Total Tau, Abeta42, neurofilament light chain, neurogranin, YKL-40, soluble TREM2 and HMGB1 during open-label period 1
Time Frame: Screening to Month 12
|
Change from baseline in cerebrospinal fluid biomarkers of AD pathology, neurodegeneration and neuroinflammation during open-label period 1 in a subset of 25 subjects
|
Screening to Month 12
|
Change from baseline in plasma P-tau181 during open-label period 1
Time Frame: Day 1 to Month 12
|
Change from baseline in plasma concentrations (pg/mL) of phospho-tau181 during open-label period 1
|
Day 1 to Month 12
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Change in plasma P-tau181 during randomized withdrawal period
Time Frame: Month 12 to Mont 18
|
Change in plasma concentrations (pg/mL) of phospho-tau181 vs. placebo during randomized withdrawal period
|
Month 12 to Mont 18
|
Change from baseline in plasma SavaDx during open-label period 1
Time Frame: Day 1 to Month 12
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Change from baseline in a proprietary plasma biomarker during open-label period 1
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Day 1 to Month 12
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Change in plasma SavaDx during randomized withdrawal period
Time Frame: Month 12 to Month 18
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Change in a proprietary plasma biomarker during the randomized withdrawal.
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Month 12 to Month 18
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Study Chair: Lindsay Burns, PhD, Cassava Sciences
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General 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.
Helpful Links
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
March 24, 2020
Primary Completion (Actual)
November 9, 2023
Study Completion (Actual)
November 9, 2023
Study Registration Dates
First Submitted
May 11, 2020
First Submitted That Met QC Criteria
May 11, 2020
First Posted (Actual)
May 14, 2020
Study Record Updates
Last Update Posted (Actual)
December 26, 2023
Last Update Submitted That Met QC Criteria
December 22, 2023
Last Verified
December 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- PTI-125-04
- R44AG065152 (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
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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