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

• ClinicalTrials.gov Identifier: NCT02925650
• Recruitment Status: Completed
• First Posted: October 6, 2016
• Results First Posted: May 9, 2023
• Last Update Posted: May 9, 2023
• Sponsor: Annovis Bio Inc.
• Collaborator: Alzheimer's Disease Cooperative Study (ADCS)
• Information provided by (Responsible Party): Annovis Bio Inc.

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Alzheimer's Disease	Drug: Posiphen; Drug: Placebo	Phase 1; Phase 2

Detailed Description:

Posiphen®, which was discovered by the US National Institute on Aging (NIA) is a small, orally active, experimental drug that specifically inhibits the synthesis of amyloid precursor protein (APP), Tau and α-Synuclein. It is distinct from other Alzheimer's disease drugs currently in development, because it inhibits the formation of several toxic proteins, rather than removing individual toxic protein after they are produced. Posiphen has potential utility as a disease modifying treatment for AD. The present study will confirm the pharmacokinetics (PK) of Posiphen and its metabolites in plasma and cerebral spinal fluid (CSF). It will also measure the effects of a 23-25 day treatment period with Posiphen on the CSF and plasma levels of a number of biomarkers, inflammatory factors and control proteins. It will also expand the safety data in humans by extending the treatment period from 10 days to a treatment period from 23-25 days. In addition, this study will measure concentrations of various soluble biomarkers in CSF and use the SILK™ assay methods to directly measure the effect of Posiphen on the fractional synthesis rate of Aβ40 in CSF, which will help guide the further development of Posiphen and determine the feasibility of SILK™ in a multicenter trial.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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 (AD)
• Actual Study Start Date: March 2, 2017
• Actual Primary Completion Date: December 10, 2021
• Actual Study Completion Date: December 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Low Dose; 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; oral solid dosage form capsule
Experimental: Medium Dose; 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; oral solid dosage form capsule
Experimental: High Dose; 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; oral solid dosage form capsule
Placebo Comparator: Placebo; The Placebo comparator is to be taken orally in divided doses, three times per day for a total 23-25 days.	Drug: Placebo; oral solid dosage form capsule

Outcome Measures

Primary Outcome Measures :

1. Safety and Tolerability of Multiple Ascending Doses of Posiphen: Reports of Adverse Events or Study Discontinuations [ Time Frame: Up to 25 days ]
   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)
2. The Levels of Posiphen and Its Metabolites Will be Determined in Plasma [ Time Frame: 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. ]
   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.
3. The Levels of Posiphen and Its Metabolites Will be Determined in Cerebrospinal Fluid (CSF) [ Time Frame: 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. ]
   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.
4. Fractional Synthesis Rate of Aβ40 in CSF Using the SILK™ Technique With Multiple Doses of Posiphen [ Time Frame: 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. ]
   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.

Secondary Outcome Measures :

1. Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate Rates of Enrollment [ Time Frame: Up to 25 days ]
   Feasibility of CSF Catheter Study with SILK™ Technology was determined by comparing the total number of participants enrolled, randomized and treated with study drug in the trial to the total number of participants who completed the CSF Catheter Study across all participating sites.
2. Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate %CSF Samples With Enough Volume for Testing [ Time Frame: Up to 25 days ]
   The % of cerebrospinal fluid samples with sufficient volume for testing will be determined across study participants during the SILK sampling procedure
3. Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate Research Satisfaction [ Time Frame: Up to 25 days ]
   Research satisfaction will be evaluated by qualitative response to 14 questions asked to participants about their experience with the study procedures. Responses will be grouped and reported by common themes
4. Pharmacodynamic and PK-PD Effects on CSF Alzheimer's Disease Biomarkers [ Time Frame: 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. ]
   Aβ38, Aβ40, Aβ42, sAPPα, sAPPβ, and T-Tau were sampled at Screening and at the start of the confinement visit. Results of these measures were reported as a least square means, calculated as the change between the measured values at the start of the confinement visit and Screening in ng/mL.
5. Assessment of Mental Status Effects [ Time Frame: 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. ]
   The short-term effects of Posiphen on mental status will be measured using the Mini-Mental State Examination (MMSE). The MMSE is a brief, global cognitive measure that includes orientation, memory, attention, concentration, naming, writing, repetition, comprehension, and construction. The total score ranges from 0 (worst) to 30 (best performance). Results of the MMSE for this trial were reported as a raw change score, calculated as the change between the total scores at two evaluation time points (Baseline, Pre-Confinement Visit) and where negative values are worse and positive values are better.
6. Assessment of Neuropsychiatric Effects [ Time Frame: NPI 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. ]
   The Neuropsychiatric Inventory (NPI) was used to measure the frequency and severity of neuropsychiatric symptoms. On this scale frequency ratings range from 0 (no symptoms) to 4 (very frequently, once or more per day or continuously). Severity ratings range from 0 (no severity) to 3 (severe). The score for each of 12 symptoms measured in the scale is the product of severity and frequency within that symptom. The total score for the NPI is the sum of all 12 symptom item scores, for a highest possible total score of 144 in individuals with maximal symptoms, and a lowest possible total score of zero (0) in fully asymptomatic individuals. Lower scores are better and higher scores indicate more neuropsychiatric symptoms. Results are calculated as the change between the total scores at two evaluation time points (Baseline, Pre-Confinement Visit) with negative scores being better and positive scores being worse.
7. Assessment of Cognitive Effects [ Time Frame: ADAS-Cog12 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, also allowing a +/- 2-day visit window. ]
   The short-term effects of Posiphen on cognition were measured using the The Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12). The ADAS-Cog is a structured scale that evaluates memory (word recall, word recognition), reasoning, language (naming, comprehension), orientation, ideational praxis and constructional praxis. The test is scored in terms of errors, with higher scores reflecting poorer performance and greater impairment. Total ADAS-Cog12 scores can range from 0 to 80, with lower scores being better and higher scores being worse. Results of the ADAS-Cog12 for this trial are reported as a raw change score, calculated as the change between the total scores at two evaluation time points (Baseline, Pre-Confinement Visit) with negative scores being better and positive scores being worse.

Eligibility Criteria

• Ages Eligible for Study: 55 Years to 89 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female aged 55 to 89 years (inclusive), in good health, no frailty.
2. 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.
3. Female participants will be given a urine pregnancy test at the screening visit for which they should test negative.
4. Clinical profile consistent with MCI or mild AD, consistent with the core clinical criteria outlined in the NIA-AA Guidelines (2011).
5. MMSE score between 17 and 30 (inclusive).
6. CDR global score of 0.5 with a memory score of 0.5 or greater, or CDR global score of 1.0.
7. Participant likely to tolerate all study procedures per PI judgment.
8. 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.
9. General cognition and functional performance sufficiently preserved that the subject can provide written informed consent.
10. A minimum of 6 years of education or good work history.
11. 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.
12. No evidence of current suicidal ideation or previous suicide attempt in the past month as evaluated in the Columbia Suicide Severity Rating Scale.
13. 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.
14. 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.
15. Adequate visual and hearing ability (physical ability to perform all the study assessments).
16. Good general health with no disease expected to interfere with the study. Subjects may have common age-related disorders (i.e., hypertension, type II diabetes, dyslipidemia, and hypothyroidism) as long as these disorders are being controlled by diet or medication.
17. Must speak English, Spanish, or Korean fluently.

Exclusion Criteria:

1. 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.
2. Other neurodegenerative diseases, including Parkinsons disease and Huntingtons disease, or cerebral tumor.
3. 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).
4. History of a seizure disorder.
5. Clinically significant abnormalities in screening laboratory or ECG results.
6. 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.
7. Has four or more microinfarcts as noted in the MRI scan.
8. 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).
9. According to the criteria of the most current version of the DSM, alcohol abuse, alcohol dependence, or drug abuse in the past 5 years.
10. 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).
11. Resides in a skilled nursing facility.
12. Subjects with infection or inflammation of the skin or skin disease at or in proximity to the lumbar puncture site.
13. History of lumbar spine surgery or chronic low back pain (CLBP).
14. Subjects whom the site PI deems to be otherwise ineligible.
15. Has a deep brain stimulator (DBS).

Contacts and Locations

Locations

United States, California

UCSD Alzheimer's Disease Research Center

La Jolla, California, United States, 92037

United States, Indiana

IU Health Partners, Adult Neurology Clinic

Indianapolis, Indiana, United States, 46202

United States, Maryland

Johns Hopkins Hospital

Baltimore, Maryland, United States, 21287

United States, Missouri

Washington University Sleep Medicine Center

Brentwood, Missouri, United States, 63144

United States, New York

Columbia University Medical Center Sergievsky Center Taub Institute

New York, New York, United States, 10032

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

Sponsors and Collaborators

Annovis Bio Inc.

Alzheimer's Disease Cooperative Study (ADCS)

  Study Documents (Full-Text)

Documents provided by Annovis Bio Inc.:

Study Protocol  [PDF] November 23, 2021

Statistical Analysis Plan  [PDF] February 7, 2022

Informed Consent Form  [PDF] July 7, 2021

More Information

• Responsible Party: Annovis Bio Inc.
• ClinicalTrials.gov Identifier: NCT02925650
• Other Study ID Numbers: QR15001; ADC-042-DISC ( Other Identifier: Alzheimer's Disease Cooperative Study (ADCS) )
• First Posted: October 6, 2016
• Results First Posted: May 9, 2023
• Last Update Posted: May 9, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data from this research will be shared with other researchers pursuant to the 02/26/2003 "NIH Final Statement on Sharing Research Data". The ADCS through its Data and Sample Sharing Committee (DSSC) will receive requests for sample and data sharing. The ADCS grants access to de-identified data to qualified scientists who complete the request process and agree to conditions in an ADCS/UCSD Data Use Agreement (DUA) and the ADCS Publications Policy. After approval and receipt of the fully executed DUA, applicants are authorized to acquire data. Non-compliance with the DUA, including the requirement to provide requested updates will jeopardize further access to data. The same process and Committee reviews and approves biosample requests. If a request for biosample sharing is approved, a Material Transfer Agreement (MTA) will be negotiated between UCSD/ADCS and the requesting researcher or organization.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (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.
• URL: https://www.adcs.org/data-sharing/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Annovis Bio Inc.:

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

Additional relevant MeSH terms:

Alzheimer Disease; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Dementia; Tauopathies; Phenserine; Cholinesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs