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

Phase 2

Completed

Conditions: Alzheimer Disease

Interventions: Drug: PTI-125, 100 mg tablets

Registration Number: NCT03748706

Lead Sponsor: Pain Therapeutics

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 13

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Simufilam (PTI-125)	PTI-125, 100 mg tablets	Simufilam (PTI-125) 100 mg oral tablets administered twice daily (BID)

Primary Outcome Measures

Name	Time	Method
Plasma Half-life (T1/2)	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	Assessment of the half-life in plasma of PTI-125
Time to Last Quantifiable Plasma Concentration (Tlast)	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	Levels of PTI-125 will be assessed to determine the elapsed time to where PTI-125 can last be detected in the plasma.
Time to Maximum Plasma Concentration (Tmax)	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	Levels of PTI-125 will be assessed to determine how long it takes to reach the Cmax
Maximum Plasma Concentration (Cmax)	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	Blood draws will be done to evaluate levels of PTI-125 in the plasma using non-compartmental methods in WinNonlin.
Last Quantifiable Plasma Concentration (Clast)	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	Levels of PTI-125 will be assessed to determine the last time point where PTI-125 can be detected.
Area Under the Curve (AUClast)	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	AUC for PTI-125 plasma concentration from time zero to the last quantifiable plasma concentration.

Secondary Outcome Measures

Name	Time	Method
CSF Biomarkers	Change from Baseline to Day 28	A cerebrospinal fluid sample collection will be performed for Aβ42, tau, YKL40 and other potential CSF biomarkers
SavaDx (Biomarker)	Study Day 1 and Day 28	Blood samples will be tested for the complementary diagnostic/biomarker for Alzheimer's disease.