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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02925650
Recruitment Status : Active, not recruiting
First Posted : October 6, 2016
Last Update Posted : August 3, 2022
Alzheimer's Disease Cooperative Study (ADCS)
Information provided by (Responsible Party):
Annovis Bio Inc.

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 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 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

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

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 ]
    Reports of adverse events or study discontinuations related to Posiphen

  2. The levels of Posiphen and its metabolites will be determined in plasma [ Time Frame: Up to 25 days ]
    Mean plasma concentrations of levels of posiphen tartrate, N1 desmethyl posiphen , and N8 desmethyl Posiphen metabolite will be determined for each of the three dose cohorts (posiphen 60 mg, 120 mg, 180 mg)

  3. The levels of Posiphen and its metabolites will be determined in cerebrospinal fluid (CSF) [ Time Frame: Up to 25 days ]
    Mean cerebrospinal fluid concentrations of posiphen tartrate, and N1 desmethyl posiphen, and N8 desmethyl pospiphen will be determined for each of the three dose cohorts (posiphen 60 mg, 120 mg, 180 mg)

  4. Fractional synthesis rate of Aβ40 in CSF using the SILK™ technique with multiple doses of Posiphen [ Time Frame: Up to 25 days ]
    The fractional synthesis rate (FSR) of Aβ40 will be measured in the CSF using the SILK™ technique

Secondary Outcome Measures :
  1. Feasibility of CSF catheter study with SILK™ technology to evaluate rates of enrollment [ Time Frame: Up to 25 days ]
    Enrollment rates will be evaluated across 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: Up to 25 days ]
    Alzheimer's Disease biomarkers including Beta Amyloid 38 (Aβ38), Aβ40, Aβ42, Soluble Amyloid Precursor Protein alpha (sAPPα), Soluble Amyloid Precursor Protein beta (sAPPβ), and T-Tau, will be measured in the CSF to determine if Posiphen has an effect on their levels.

  5. Assessment of mental status effects [ Time Frame: Up to 25 days ]
    The short-term effects of Posiphen on mental status will be measured using the Mini-Mental State Examination (MMSE).

  6. Assessment of neuropsychiatric effects [ Time Frame: Up to 25 days ]
    The short-term effects of Posiphen on neuropsychiatric symptoms will be measured using the Neuropsychiatric Inventory (NPI).

  7. Assessment of cognitive effects [ Time Frame: Up to 25 days ]
    The short-term effects of Posiphen on cognition will be measured using the Alzheimer's Disease Assessment Scale (ADAS-Cog12).

Other Outcome Measures:
  1. Fractional synthesis rates with normalized SILK curve sampling [ Time Frame: Up to 25 days ]
    Exploratory analyses of the fractional synthesized rates with normalized SILK curve sampling; of Aβ38, Aβ42, Total Aβ, and ratio curve of Aβ42/40.

  2. Absolute synthesis and clearance rates [ Time Frame: Up to 25 days ]
    Measurements of newly generated Aβ38, Aβ40, Aβ42, Total Aβ, and ratio of Aβ42/40.

Information from the National Library of Medicine

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

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02925650

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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] September 24, 2019

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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    Key Record Dates
Last Update Posted: August 3, 2022
Last Verified: August 2022
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 March 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/

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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
Additional relevant MeSH terms:
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Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs