Clinical trial NCT03748706: PTI-125 for Mild-to-moderate Alzheimer's Disease Patients
Official title: A Phase 2a, Open-label, Multiple Dose, Safety, Pharmacokinetic and Biomarker Study of PTl-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: 2018-11-21
Enrollment: 13
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate Alzheimer's disease patients.

Detailed description: This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate AD patients, 50-85 years of age. A total of twelve (12) patients will be enrolled into the study. Patients will receive 100 mg b.i.d. of PTI-125. The objectives of this study are to investigate the safety, pharmacokinetics and effect on biomarkers of PTI-125 following 28-day repeat-dose 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 \<= 24 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-hour) 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 and with continuous dosing for at least 3 months. If receiving donepezil, receiving any dose lower than 23 mg once daily.
* The patient is a non-smoker for at least 12 months.
* 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/Abeta42 in cerebrospinal fluid \>= 0.30.
* 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
* Residence in a skilled nursing facility
* 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 or requiring insulin
* Renal insufficiency (serum creatinine \>2.0 mg/dL)
* 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) \>2 times the upper limit of normal or total bilirubin greater than the upper limit of normal.
* 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 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 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 or greater quaque die currently or within 3 months prior to enrollment in the study
* Discontinued AChEI \< 30 days prior to enrollment in the study
* 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 enrollment in the study
* 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 enrollment in the study
* 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 enrollment in the study
* Peripherally acting drugs with effects on cholinergic transmission
* 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
* Loss of a significant volume of blood (\> 450 mL) within 4 weeks prior to the study
* Metformin or cimetidine.

Primary outcomes:
measure: Maximum Plasma Concentration (Cmax)
timeFrame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
measure: Time to Maximum Plasma Concentration (Tmax)
timeFrame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
measure: Last Quantifiable Plasma Concentration (Clast)
timeFrame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
measure: Time to Last Quantifiable Plasma Concentration (Tlast)
timeFrame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
measure: Area Under the Curve (AUClast)
timeFrame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
measure: Plasma Half-life (T1/2)
timeFrame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
Secondary outcomes:
measure: SavaDx (Biomarker)
timeFrame: Study Day 1 and Day 28
measure: CSF Biomarkers
timeFrame: Change from Baseline to Day 28
Other outcomes:
Locations:
city: DeSoto
country: United States
facility: Insite Clinical Research
state: Texas
city: San Antonio
country: United States
facility: Clinical Trials of Texas
state: Texas
Study officials:
affiliation: Cassava Sciences, Inc.
name: Lindsay Burns, PhD
role: STUDY_DIRECTOR
References:
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.
citation: 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.
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.