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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Posiphen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). 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. Must speak English, Spanish, or Korean fluently. Exclusion Criteria: 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).

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate Rates of Enrollment | 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. | Up to 25 days | 
| Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate %CSF Samples With Enough Volume for Testing | The % of cerebrospinal fluid samples with sufficient volume for testing will be determined across study participants during the SILK sampling procedure | Up to 25 days | 
| Feasibility of CSF Catheter Study With SILK™ Technology to Evaluate Research Satisfaction | 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 | Up to 25 days | 
| Pharmacodynamic and PK-PD Effects on CSF Alzheimer's Disease Biomarkers | 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. | 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 | 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. | 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. | 
| Assessment of Neuropsychiatric Effects | 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. | 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. | 
| Assessment of Cognitive Effects | 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SILK™, Pharmacodynamics, Safety, Pharmacokinetics, Alzheimer's Disease