Clinical trial NCT04079803: PTI-125 for Mild-to-moderate Alzheimer's Disease Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer Disease
Lead sponsor: Cassava Sciences, Inc.
Sponsor class: INDUSTRY
Collaborators: name: National Institute on Aging (NIA)
First posted: 2019-09-06
Enrollment: 64
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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)
Primary purpose: TREATMENT

Brief summary: 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: 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.

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 \<= 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

Primary outcomes:
measure: Change From Baseline in CSF Abeta42
timeFrame: Screening to Day 28
measure: Change From Baseline in CSF Total Tau.
timeFrame: Screening to Day 28
measure: Change From Baseline in CSF P-tau181
timeFrame: Screening to Day 28
measure: Change From Baseline in CSF Neurogranin
timeFrame: Screening to Day 28
measure: Change From Baseline in CSF Neurofilament Light Chain
timeFrame: Screening to Day 28
measure: Change From Baseline in CSF YKL-40
timeFrame: Screening to Day 28
Secondary outcomes:
measure: Paired Associates Learning Test
timeFrame: Day 1 to Day 28
measure: Spatial Working Memory Test
timeFrame: Day 1 to Day 28
measure: CSF IL-6, sTREM2, HMGB1, Albumin, IgG
timeFrame: Screening to Day 28
Other outcomes:
measure: 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
timeFrame: Day 1 to Day 28
measure: Plasma P-tau181
timeFrame: Day 1 to Day 28
measure: Percent Change From Baseline in SavaDx, a Novel Plasma Biomarker
timeFrame: Day 1 to Day 28
Locations:
city: Gilbert
country: United States
facility: Cognitive Clinical Trials
state: Arizona
city: Surprise
country: United States
facility: Cognitive Clinical Trials
state: Arizona
city: Miami
country: United States
facility: Optimus U
state: Florida
city: Palmetto Bay
country: United States
facility: IMIC, Inc.
state: Florida
city: Bellevue
country: United States
facility: Cognitive Clinical Trials
state: Nebraska
city: Omaha
country: United States
facility: Cognitive Clinical Trials
state: Nebraska
city: Toms River
country: United States
facility: Advanced Memory Research Institute
state: New Jersey
city: Houston
country: United States
facility: Centex Studies, Inc.
state: Texas
city: McAllen
country: United States
facility: Centex Studies, Inc.
state: Texas
Study officials:
affiliation: Cassava Sciences, Inc.
name: Lindsay Burns, PhD
role: STUDY_DIRECTOR
References:
citation: 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.