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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Placebo oral tablet
* Drug: Simufilam 100 mg tablet
* Drug: Simufilam 50 mg oral tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Approximately sixty (60) patients will be enrolled into the study and randomized to one of three cohorts. Cohorts will receive placebo or PTI-125 at 50 or 100 mg b.i.d. (n=20 per group)
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 |