Simufilam (PTI-125), 100 mg, for Mild-to-moderate Alzheimer's Disease Patients

Alzheimer Disease Clinical Trial

— PTI-125  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04388254
• Other study ID #: PTI-125-04
• Secondary ID: R44AG065152
• Status: Completed
• Phase: Phase 2
• Start date: March 24, 2020
• Est. completion date: November 9, 2023

Study information

• Verified date: December 2023
• Source: Cassava Sciences, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 220
• Est. completion date: November 9, 2023
• Est. primary completion date: November 9, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

INCLUSION CRITERIA:

1. Informed consent form (ICF) signed by the subject or legally acceptable representative.

2. Patient has a caregiver or legal representative responsible for administering the drug and recording the time.

3. Ages = 50 and = 85 years

4. 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.

5. If female, postmenopausal for at least 1 year

6. Patient living at home, senior residential setting, or an institutional setting without the need for continuous (i.e. 24-h) nursing care

7. General health status acceptable for participation in the study

8. Fluency (oral and written) in English or Spanish

9. 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.

10. The patient is a non-smoker for at least 3 years.

11. The patient or legal representative must agree to comply with the drawing of blood samples for the PK assessments, laboratory assessments and SavaDx.

12. MMSE-2 score = 16 and = 26 at screening, OR if > 26, must have evidence of AD pathology such as a prior CSF total tau/Aß42 ratio = 0.28, an amyloid positive PET scan or hippocampal volume loss consistent with AD.

EXCLUSION CRITERIA:

1. Anything that in the opinion of the Investigator would preclude participation in a 2-year study.

2. BMI < 18.5

3. Positive urine drug screen.

4. Positive HIV, HCV or HbsAg screen.

5. Suicidality on C-SSRS

6. Exposure to an experimental drug other than simufilam, experimental biologic or experimental medical device within 3 months before screening

7. A medical condition that would interfere with a lumbar puncture

8. Residence in a skilled nursing facility and requiring 24 h care.

9. Clinically significant laboratory test results

10. Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating hormone level and thyroid supplementation dose must be stable for at least 6 months before screening)

11. Insufficiently controlled diabetes mellitus, including requiring insulin or metformin >1000 mg/day.

12. 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)

13. 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)

14. History of ischemic colitis or ischemic enterocolitis

15. Unstable medical condition that is clinically significant in the judgment of the investigator

16. Alanine transaminase (ALT) or aspartate transaminase (AST) > ULN or total bilirubin > ULN and clinically significant in the opinion of PI and/or Sponsor.

17. History of myocardial infarction or unstable angina within 6 months before screening

18. History of more than 1 myocardial infarction within 5 years before screening

19. Clinically significant cardiac arrhythmia (including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are acceptable)

20. Symptomatic hypotension, or uncontrolled hypertension

21. 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.

22. Stroke within 18 months before screening, or history of a stroke concomitant with onset of dementia

23. History of brain tumor or other clinically significant space-occupying lesion on CT or MRI

24. Head trauma with clinically significant loss of consciousness within 12 months before screening or concurrent with the onset of dementia

25. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or resuscitation

26. Specific degenerative CNS disease diagnosis other than AD (e.g., Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's disease)

27. Wernicke's encephalopathy

28. Active acute or chronic CNS infection

29. Donepezil 23 mg or greater QD currently or within 3 months prior to randomization

30. Discontinued AChEI < 30 days prior to randomization

31. 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

32. 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

33. 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

34. Immunosuppressants, including systemic corticosteroids, if taken in clinically immunosuppressive doses (Steroid use for allergy or other inflammation is permitted.)

35. Antiepileptic medications if taken for control of seizures

36. Chronic intake of opioid-containing analgesics

37. Sedating H1 antihistamines

38. Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or similar therapeutic agent within 30 days before screening

39. Clinically significant illness within 30 days of enrollment

40. History of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease

41. Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to the study

42. COVID-19 infection within 3 months

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Drug:
• Simufilam 100 mg oral tablet
Simufilam 100 mg oral tablet for b.i.d. administration
• Placebo
Matching placebo oral tablets

Locations

Country	Name	City	State
Canada	Ottawa Memory Clinic	Ottawa	Ontario
Canada	Toronto Memory Program	Toronto	Ontario
United States	Senior Adults Specialty Research	Austin	Texas
United States	Cognitive Clinical Trials	Bellevue	Nebraska
United States	Brain Matters Research	Delray Beach	Florida
United States	Neuropsychiatric Research Center of Southwest Florida	Fort Myers	Florida
United States	Cognitive Clinical Trials	Gilbert	Arizona
United States	Centex Studies, Inc.	Houston	Texas
United States	Sun Valley Research Center, Inc.	Imperial	California
United States	Centex Studies	McAllen	Texas
United States	Optimus U	Miami	Florida
United States	Adaptive Clinical Research, Inc	Miami Lakes	Florida
United States	Neuro-Behavioral Clinical Research	North Canton	Ohio
United States	Cognitive Clinical Trials	Omaha	Nebraska
United States	IMIC, Inc.	Palmetto Bay	Florida
United States	Cognitive Clinical Trials	Surprise	Arizona
United States	Advanced Memory Research Institute	Toms River	New Jersey

Sponsors (2)

Lead Sponsor	Collaborator
Cassava Sciences, Inc.	National Institute on Aging (NIA)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and Tolerability	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
Primary	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	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
Primary	Change from baseline in ADAS-Cog-11 during open-label period 1	Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item: Change from baseline in cognition during open-label period 1	Day 1 to Month 12
Primary	Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-11)	Change in cognition vs. placebo during randomized withdrawal period	Month 12 to Month 18
Secondary	Neuropsychiatric Inventory (NPI)	Change from baseline in behavioral symptoms during open-label period 1	Day 1 to Month 12
Secondary	Neuropsychiatric Inventory (NPI)	Change in neuropsychiatric symptoms vs. placebo during randomized withdrawal period	Month 12 to Month 18
Secondary	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	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
Secondary	Change from baseline in plasma P-tau181 during open-label period 1	Change from baseline in plasma concentrations (pg/mL) of phospho-tau181 during open-label period 1	Day 1 to Month 12
Secondary	Change in plasma P-tau181 during randomized withdrawal period	Change in plasma concentrations (pg/mL) of phospho-tau181 vs. placebo during randomized withdrawal period	Month 12 to Mont 18
Secondary	Change from baseline in plasma SavaDx during open-label period 1	Change from baseline in a proprietary plasma biomarker during open-label period 1	Day 1 to Month 12
Secondary	Change in plasma SavaDx during randomized withdrawal period	Change in a proprietary plasma biomarker during the randomized withdrawal.	Month 12 to Month 18