Clinical trial NCT02925650: Safety, Tolerability, PK and PD of Posiphen® in Subjects With Early Alzheimer's Disease
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease
SILK™
Pharmacodynamics
Safety
Pharmacokinetics
Lead sponsor: Annovis Bio Inc.
Sponsor class: INDUSTRY
Collaborators: name: Alzheimer's Disease Cooperative Study (ADCS)
First posted: 2016-10-06
Enrollment: 18
Sex: ALL
Minimum age (years): 55
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility 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).

Primary outcomes:
measure: Safety and Tolerability of Multiple Ascending Doses of Posiphen: Reports of Adverse Events or Study Discontinuations
timeFrame: Up to 25 days
measure: The Levels of Posiphen and Its Metabolites Will be Determined in Plasma
timeFrame: 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.
measure: The Levels of Posiphen and Its Metabolites Will be Determined in Cerebrospinal Fluid (CSF)
timeFrame: 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.
measure: Fractional Synthesis Rate of Aβ40 in CSF Using the SILK™ Technique With Multiple Doses of Posiphen
timeFrame: 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:
measure: Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate Rates of Enrollment
timeFrame: Up to 25 days
measure: Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate %CSF Samples With Enough Volume for Testing
timeFrame: Up to 25 days
measure: Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate Research Satisfaction
timeFrame: Up to 25 days
measure: Pharmacodynamic and PK-PD Effects on CSF Alzheimer's Disease Biomarkers
timeFrame: 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.
measure: Assessment of Mental Status Effects
timeFrame: 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.
measure: Assessment of Neuropsychiatric Effects
timeFrame: 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.
measure: Assessment of Cognitive Effects
timeFrame: 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.
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UCSD Alzheimer's Disease Research Center
state: California
city: Indianapolis
country: United States
facility: IU Health Partners, Adult Neurology Clinic
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Brentwood
country: United States
facility: Washington University Sleep Medicine Center
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center Sergievsky Center Taub Institute
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
Study officials:
References: