Safety, Tolerability, PK and PD of Posiphen® in Subjects With Early Alzheimer's Disease

NCT02925650 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: QR15001ADC-042-DISC
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 6

Brief Summary

This study evaluates the safety and pharmacological effects of 3 different doses of Posiphen® when compared to a placebo, in adult male and female patients with early Alzheimer's disease (AD).

Conditions

Alzheimer's Disease

Keywords

Alzheimer's Disease; SILK™; Pharmacodynamics; Safety; Pharmacokinetics

Outcome Measures

Primary Outcomes (4)

• Safety and Tolerability of Multiple Ascending Doses of Posiphen: Reports of Adverse Events or Study Discontinuations

  Number of adverse events or study discontinuations, broken down by dose arm (i.e. Low vs. Medium vs. High vs. Placebo), and further broken down by relatedness to Posiphen (Definitely Related, Probably Related, Possibly Related, Unlikely Related, Unrelated)

  Up to 25 days

• The Levels of Posiphen and Its Metabolites Will be Determined in Plasma

  Mean plasma concentrations of levels of posiphen tartrate, N1 desmethyl posiphen, and N8 desmethyl Posiphen metabolite were determined for each of the three dose cohorts (Low Dose, Medium Dose, High Dose) by a protein precipitation extraction method using a high performance liquid chromatographic mass spectrometric detection method, with a linear weighted regression to determine their concentrations.

  The confinement visit occurred following 21-23 days of treatment with either Posiphen or placebo, while also allowing a +/- 2-day visit window. Plasma was collected at 0, 2, 4, 8, 12, 16, 20, and 24hrs during the confinement visit.

• The Levels of Posiphen and Its Metabolites Will be Determined in Cerebrospinal Fluid (CSF)

  Mean CSF concentrations of levels of posiphen tartrate, N1 desmethyl posiphen, and N8 desmethyl Posiphen metabolite were determined for each of the three dose cohorts (Low Dose, Medium Dose, High Dose) by a protein precipitation extraction method using a high performance liquid chromatographic mass spectrometric detection method, with a linear weighted regression to determine the concentrations.

  The confinement visit occurred following 21-23 days of treatment with either Posiphen or placebo, while also allowing a +/- 2-day visit window. Plasma was collected at 0, 2, 4, 8, 12, 16, 20, and 24hrs during the confinement visit.

• Fractional Synthesis Rate of Aβ40 in CSF Using the SILK™ Technique With Multiple Doses of Posiphen

  The fractional synthesis rate (FSR) of Aβ40 was measured in the CSF using the SILK™ technique. FSR is a measure of the rate of Aβ synthesis in the brain. During 13C6-leucine infusion, 13C6-leucine is incorporated into newly synthesized proteins throughout the body, including the brain, in proportion to the available 13C6-leucine. This FSR is calculated as the rate of change of the ratio of 13C6-leucine-labeled Aβ proteins to unlabeled Aβ proteins in the lumbar CSF between 6 to 16 hours, normalized to the ratio of labeled to unlabeled leucine amino acid in plasma. It is reported as a fraction of 13C6-leucine-labeled to unlabeled Aβ proteins per hour. The ratio of Aβ in CSF containing 13C6-leucine to that containing unlabeled leucine is measured using mass spectrometry.

  The confinement visit occurred following 21-23 days of treatment with either Posiphen or placebo, while also allowing a +/- 2-day visit window. CSF was collected between 6 and 16hrs during the confinement visit.

Secondary Outcomes (7)

• Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate Rates of Enrollment

  Up to 25 days

• Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate %CSF Samples With Enough Volume for Testing

  Up to 25 days

• Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate Research Satisfaction

  Up to 25 days

• Pharmacodynamic and PK-PD Effects on CSF Alzheimer's Disease Biomarkers

  CSF was sampled at Screening and at the start of the confinement visit, which occurred following 21-23 days of treatment with either Posiphen or placebo, while also allowing a +/- 2-day visit window.

• Assessment of Mental Status Effects

  MMSE was administered at Baseline and at the Pre-Confinement Visit 1-3 days prior to the Confinement Visit. This confinement visit occurred following 21-23 days of treatment with either Posiphen or placebo, while also allowing a +/- 2-day visit window.

Study Arms (4)

Low Dose

EXPERIMENTAL

The study drug Posiphen dosage of 60mg is to be taken orally in divided doses, three times per day for a total 23-25 days.

Drug: Posiphen

Medium Dose

EXPERIMENTAL

The study drug Posiphen dosage of 120mg is to be taken orally in divided doses, three times per day for a total 23-25 days.

Drug: Posiphen

High Dose

EXPERIMENTAL

The study drug Posiphen dosage of 180mg is to be taken orally in divided doses, three times per day for a total 23-25 days.

Drug: Posiphen

Placebo

PLACEBO COMPARATOR

The Placebo comparator is to be taken orally in divided doses, three times per day for a total 23-25 days.

Drug: Placebo

Interventions

Posiphen DRUG

oral solid dosage form capsule

High Dose; Low Dose; Medium Dose

Placebo DRUG

oral solid dosage form capsule

Placebo

Eligibility Criteria

• Age: 55 Years - 89 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female aged 55 to 89 years (inclusive), in good health, no frailty.
• Female participants must be post-menopausal for at least 2 consecutive years or surgically sterile (bilateral tubal ligation, hysterectomy or bilateral oophorectomy) for at least 6 months prior to screening.
• Female participants will be given a urine pregnancy test at the screening visit for which they should test negative.
• Clinical profile consistent with MCI or mild AD, consistent with the core clinical criteria outlined in the NIA-AA Guidelines (2011).
• MMSE score between 17 and 30 (inclusive).
• CDR global score of 0.5 with a memory score of 0.5 or greater, or CDR global score of 1.0.
• Participant likely to tolerate all study procedures per PI judgment.
• To qualify for entry, subjects will have a CSF Abeta42-Abeta40 ratio below 0.131 that is consistent with Alzheimers disease as measured via mass spectrometry by C2N.
• General cognition and functional performance sufficiently preserved that the subject can provide written informed consent.
• A minimum of 6 years of education or good work history.
• Study partner is available who has frequent contact with the subject (e.g., average of 10 hours per week or more), and can accompany the subject to most visits to answer questions about the subject. The study partner is required to attend the entire screening visit and the baseline visit. The study drug is dispensed to the participant at the baseline visit and the study partner (or other individual) should also oversee study drug administration if needed to ensure compliance with dose regimen. At a minimum, the study partner should stay for the first 3 hours of the confinement visit and return at the discharge to drive the subject home.
• No evidence of current suicidal ideation or previous suicide attempt in the past month as evaluated in the Columbia Suicide Severity Rating Scale.
• MRI scan within the 12 months prior to screening without evidence of infection, infarction, or other focal lesions and without clinical symptoms suggestive of intervening neurological disease. Lacunes that are not believed to contribute to the subjects cognitive impairment are permissible. If there is no MRI available within a 12-month timeframe, then an MRI must be performed as part of the screening procedures for eligibility.
• Stability of permitted medications for 4 weeks prior to baseline. NOTE: Cholinesterase inhibitors and or memantine are allowable only if stable for 12 weeks prior to screen. If taking Arciept (donezepil), no more than 10 mg/day is permitted during the course of the study.
• Adequate visual and hearing ability (physical ability to perform all the study assessments).

You may not qualify if:

• Has a history of a psychiatric disorder such as schizophrenia, bipolar disorder or major depression according to the criteria of the most current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Mild depression or history of depression that is stable on treatment with a tricyclic antidepressant SSRI or SNRI medication at a stable dose is acceptable.
• Other neurodegenerative diseases, including Parkinsons disease and Huntingtons disease, or cerebral tumor.
• Dementia other than AD, such as Acquired Immunodeficiency Syndrome (AIDS), Creutzfeldt-Jakob disease (CJD), Lewy Bodies dementia (LBD), Cerebrovascular dementia (CVD), Progressive Supranuclear Palsy (PSP), or normal pressure hydrocephalus (NPH).
• History of a seizure disorder.
• Clinically significant abnormalities in screening laboratory or ECG results.
• Has current serious or unstable illness including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic, psychiatric, immunologic, or hematologic disease or other conditions that, in the investigators opinion, makes them ineligible for participation in this study.
• Has four or more microinfarcts as noted in the MRI scan.
• Has cancer or has had a malignant tumor within the past 3 years, except patients who underwent potentially curative therapy with no evidence of recurrence. (Patients with stable untreated prostate cancer or skin cancers are not excluded).
• According to the criteria of the most current version of the DSM, alcohol abuse, alcohol dependence, or drug abuse in the past 5 years.
• Participation in another clinical trial with an investigational agent and have taken at least one dose of study medication, unless unblinded on placebo, within 16 weeks prior to screening. (The end of a previous investigational trial is the date the last dose of an investigational agent was taken).
• Resides in a skilled nursing facility.
• Subjects with infection or inflammation of the skin or skin disease at or in proximity to the lumbar puncture site.
• History of lumbar spine surgery or chronic low back pain (CLBP).
• Subjects whom the site PI deems to be otherwise ineligible.
• Has a deep brain stimulator (DBS).

Sponsors & Collaborators

• Annovis Bio Inc.: lead
• Alzheimer's Disease Cooperative Study (ADCS): collaborator

Study Sites (6)

UCSD Alzheimer's Disease Research Center

La Jolla, California, 92037, United States

Location

IU Health Partners, Adult Neurology Clinic

Indianapolis, Indiana, 46202, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Washington University Sleep Medicine Center

Brentwood, Missouri, 63144, United States

Location

Columbia University Medical Center Sergievsky Center Taub Institute

New York, New York, 10032, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Related Publications (2)

• Galasko D, Farlow MR, Lucey BP, Honig LS, Elbert D, Bateman R, Momper J, Thomas RG, Rissman RA, Pa J, Aslanyan V, Balasubramanian A, West T, Maccecchini M, Feldman HH. A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer's Disease. Alzheimers Res Ther. 2024 Jul 5;16(1):151. doi: 10.1186/s13195-024-01490-z.

  PMID: 38970127 DERIVED

• Galasko D, Farlow MR, Lucey BP, Honig LS, Elbert D, Bateman R, Momper J, Thomas R, Rissman RA, Pa J, Aslanyan V, Balasubramanian A, West T, Maccecchini M, Feldman HH. A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with Early Alzheimer's Disease. medRxiv [Preprint]. 2024 Mar 22:2024.03.20.24304638. doi: 10.1101/2024.03.20.24304638.

  PMID: 38562783 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

phenserine

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Howard Feldman MDCM, FRCP(C)
• Organization: Alzheimer's Disease Cooperative Study

hhfeldman@health.ucsd.edu

858-246-1347

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2016
• First Posted: October 6, 2016
• Study Start: March 2, 2017
• Primary Completion: December 10, 2021
• Study Completion: December 31, 2021
• Last Updated: May 9, 2023
• Results First Posted: May 9, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: 01 August 2023
• Access Criteria: Data requestors must complete an ADCS Data and Sample Sharing request form which will be reviewed by the ADCS DSSC. Upon approval, requestors must complete a Data Use Agreement (DUA) prior to accessing the data.

Locations

US (6)