Subjective Memory Loss in Older Persons
Conditions
Keywords
memory loss
Brief summary
The purpose of this six-month research study is to determine if Cerefolin NAC reduces levels of substances in the blood that may be associated with thinking ability and the health of brain cells in subjects with memory concerns when compared to a standard multivitamin. Cerefolin NAC is available as a dietary supplement via a prescription from a physician. The multivitamin used in the study contains the Recommended Daily Intake recommended for older persons.
Detailed description
Study Phase: Exploratory Indication: Memory Complaints Study Design: A single-center, double-blind, placebo-controlled study with 100 subjects with memory complaints followed for 6 months (4 visits)using Cerefolin® NAC or placebo once a day in addition to a standardized multivitamin. Sample Size: 100 subjects as follows: 1. 50 on Cerefolin® NAC + multivitamin; and, 2. 50 on Placebo + multivitamin. Primary Objective: To determine if Cerefolin® NAC (compared to multivitamin) decreases the blood level of homocysteine, increases the blood level of glutathione (a marker for oxidative stress), and increases the ratio of Aβ42 to Aβ40 (a marker for beta-amyloid) that may be related to neuronal injury and inflammation. Secondary Objectives: 1. To determine if Cerefolin® NAC reduces hs-CRP and TNF-α blood levels, and increases IL-6 blood levels. 2. To determine if Cerefolin® NAC (compared to Placebo) reduces plasma F2 isoprostane and increases potential antioxidant (PAO) levels. 3. To assess the tolerability of Cerefolin® NAC 4. To explore the effects of Cerefolin® NAC on a 6-month change in: (a)global and specific cognitive domains in a standardized neuropsychological test battery,(b) quality of life as measured by SF-36, (c)instrumental and basic activities of daily living, (d)MADRS; and (e)performance-based physical function. 5. To explore if a change in homocysteine level is related to a change in the plasma glutathione, hs-CRP, IL-6, TNF-α, F2-isoprostane, and PAO levels and to a change in the ratio of Aβ42 to Aβ40. 6. To explore the effects of MS AG2756, APOE and MFTHR on the relationship examined in Secondary Objective #5. 7. To explore the relationship of B12 status and status to cognition NOTE: For individuals successfully completing the 6-month blinded phase, there is an 12-month open-label extension of Cerefolin NAC + multivitamin. The primary purpose of the exploratory, open-label extension phase of the CERE-001 study is to systematically collect long-term safety data on CEREFOLIN NAC usage over an additional 12-month period.
Interventions
OTHERCerefolin NAC (a medical food)
Cerefolin NAC one tablet each day
OTHERCerefolin NAC placebo
Placebo tablet once a day
Sponsors
Pamlab, Inc.
Rush University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than 60; * Memory complaints as defined by two questions: 1. Do The subject think your have memory problems?; and, 2. Has there been a decline in your memory over the last 10 years? * Fluency in English; * Ability to ingest oral medications; and, * Willing to replace current vitamin intake with a standardized multivitamin provided for the study.
Exclusion criteria
* Clinical stroke or Parkinson's disease; * Taking FDA approved drug for symptomatic treatment of Alzheimer's disease (Aricept, Razadyne, Exelon, and/or Namenda); * History of significant renal insufficiency (creatinine ≥1.5); * History of renal stones or peptic ulcer disease; * Use of vitamin supplements containing more than 400mcg of folic acid per day within 2 months of Screen Visit; * As determined by the study physician, clinically significant serum folate and vitamin B12 deficiency on screening blood tests that would require further clinical evaluation and treatment * As determined by the study physician, clinically significant medical conditions, physical exam findings or abnormal blood tests at screening that would require further clinical evaluation and treatment * B12 injections 6 months prior to the Screen Visit; * Confirmed clinical diagnosis of Mild Cognitive Impairment (MCI), vascular dementia or Alzheimer's Disease (AD); and, * Known hypersensitivity to L-methylfolate, methyl-cobalamin or N-acetylcysteine. * Use of any other investigational agent used during the 30 days prior to Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Six Month Blood Levels of Homocysteine, Glutathione, and the Ratio of Aβ42 to Aβ40 (as a Percent of Baseline Levels) After Daily Intake of Cerefolin NAC Plus a Multivitamin Versus a Multivitamin Only | 6 months | Primary outcome markers were plasma homocysteine (tHcy), glutathione, and the ratio of amyloid proteins, Aβ42 and Aβ40. Plasma tHcy and glutathione were assayed using a high performance liquid chromatography (HPLC) with fluorescence detection method. Enzyme-linked immunosorbent assays (ELISA) were used for Aβ42 (Wako Chemicals USA, Inc., Richmond, VA) and Aβ40 (Invitrogen Corporation, Canarillo, CA) detection. Primary analyses utilized Last Observation Carried Forward (LOCF) to assess the primary biomarker level at 6 months versus baseline. Six month levels in biomarker outcomes were compared using t-tests of the logarithmically transformed values and the antilogarithm was applied to the SDs obtain 95% confidence intervals (95% CIs). A significant difference between treatments was needed for at least one of the primary outcome variables (tHcy, glutathione, or the Aβ42 to Aβ40 ratio) to declare the study positive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tolerability of Cerefolin NAC and a Multivitamin Versus a Multivitamin Only | 6 months | Mean study product compliance was measured as the actual number of study product tablets taken as a percent of the maximum study product tablets that could have been taken during the intervention period. |
| Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6 months | Outcome measures were 6-month levels of highly sensitive c-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), malondialdehyde, and potential anti-oxidant (PAO)in blood samples as a percent of baseline value. |
Countries
United States
Participant flow
Recruitment details
Between March 2008 and September 2009, persons expressing study interest at community presentations or at the Rush Memory Clinic were contacted. Of 524 persons expressing interest, 400 were excluded before consenting for having excluding clinical diagnoses(227), participation refusal (119), and other exclusions medication (54).
Pre-assignment details
Consented participants underwent a screening evaluation to ensure inclusion criteria were met prior to study treatment assignment and one month run-in treatment with a multivitamin only. Of 124 consented individuals, 20 discontinued prior to randomization due to new medical conditions (9), declining participation (5), and for other reasons (6).
Participants by arm
| Arm | Count |
|---|---|
| Cerefolin NAC + Multivitamin On Cerefolin NAC and open-label multivitamin supplement
Cerefolin NAC (a medical food) : Cerefolin NAC one tablet each day | 51 |
| Cerefolin NAC Placebo + Multivitamin On placebo and open label multivitamin supplement
Cerefolin NAC placebo : Placebo tablet once a day | 53 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Cerefolin NAC Placebo + Multivitamin | Total | Cerefolin NAC + Multivitamin |
|---|---|---|---|
| Age Continuous | 79.4 years STANDARD_DEVIATION 8.7 | 80.1 years STANDARD_DEVIATION 7.7 | 80.9 years STANDARD_DEVIATION 6.6 |
| Education Level | 15 years STANDARD_DEVIATION 3 | 15 years STANDARD_DEVIATION 3 | 15 years STANDARD_DEVIATION 3 |
| glutathione | 4.02 micromol/L STANDARD_DEVIATION 1.59 | 4.02 micromol/L STANDARD_DEVIATION 1.63 | 4.01 micromol/L STANDARD_DEVIATION 1.67 |
| highly sensitive c-Reactive Protein | 0.23 mg/mL STANDARD_DEVIATION 22.37 | 0.22 mg/mL STANDARD_DEVIATION 20.68 | 0.20 mg/mL STANDARD_DEVIATION 18.93 |
| interleukin-6 | 2.12 pg/mL STANDARD_DEVIATION 2.35 | 2.12 pg/mL STANDARD_DEVIATION 2.17 | 2.12 pg/mL STANDARD_DEVIATION 1.98 |
| malondialdehyde | 0.93 micromol/L STANDARD_DEVIATION 1.75 | 0.92 micromol/L STANDARD_DEVIATION 1.71 | 0.90 micromol/L STANDARD_DEVIATION 1.67 |
| potential anti-oxidant (PAO) | 1016 micromol/L STANDARD_DEVIATION 2 | 997 micromol/L STANDARD_DEVIATION 2 | 979 micromol/L STANDARD_DEVIATION 2 |
| ratio of amyloid beta 1-42 to 1-40 | 0.034 pmol/L:pmol/L STANDARD_DEVIATION 1.81 | 0.031 pmol/L:pmol/L STANDARD_DEVIATION 1.77 | 0.027 pmol/L:pmol/L STANDARD_DEVIATION 1.73 |
| Region of Enrollment United States | 53 participants | 104 participants | 51 participants |
| Sex: Female, Male Female | 42 Participants | 88 Participants | 46 Participants |
| Sex: Female, Male Male | 11 Participants | 16 Participants | 5 Participants |
| total plasma homocysteine | 8.10 micromol/L STANDARD_DEVIATION 1.33 | 8.22 micromol/L STANDARD_DEVIATION 1.33 | 8.35 micromol/L STANDARD_DEVIATION 1.32 |
| tumor necrosis factor alpha | 1.37 pg/mL STANDARD_DEVIATION 1.53 | 1.41 pg/mL STANDARD_DEVIATION 1.57 | 1.45 pg/mL STANDARD_DEVIATION 1.61 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 51 | 28 / 53 |
| serious Total, serious adverse events | 11 / 51 | 8 / 53 |
Outcome results
Primary
Six Month Blood Levels of Homocysteine, Glutathione, and the Ratio of Aβ42 to Aβ40 (as a Percent of Baseline Levels) After Daily Intake of Cerefolin NAC Plus a Multivitamin Versus a Multivitamin Only
Primary outcome markers were plasma homocysteine (tHcy), glutathione, and the ratio of amyloid proteins, Aβ42 and Aβ40. Plasma tHcy and glutathione were assayed using a high performance liquid chromatography (HPLC) with fluorescence detection method. Enzyme-linked immunosorbent assays (ELISA) were used for Aβ42 (Wako Chemicals USA, Inc., Richmond, VA) and Aβ40 (Invitrogen Corporation, Canarillo, CA) detection. Primary analyses utilized Last Observation Carried Forward (LOCF) to assess the primary biomarker level at 6 months versus baseline. Six month levels in biomarker outcomes were compared using t-tests of the logarithmically transformed values and the antilogarithm was applied to the SDs obtain 95% confidence intervals (95% CIs). A significant difference between treatments was needed for at least one of the primary outcome variables (tHcy, glutathione, or the Aβ42 to Aβ40 ratio) to declare the study positive.
Time frame: 6 months
Population: The Intent-to-Treat (ITT) cohort included randomized subjects taking at least one study treatment dose. Primary analyses utilized Last Observation Carried Forward (LOCF) to assess 6 month levels in the primary biomarkers. 2-sided, t-test p-value for group differences was only significant (\<0.05) for 6-month homocysteine level.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cerefolin NAC + Multivitamin | Six Month Blood Levels of Homocysteine, Glutathione, and the Ratio of Aβ42 to Aβ40 (as a Percent of Baseline Levels) After Daily Intake of Cerefolin NAC Plus a Multivitamin Versus a Multivitamin Only | 6-Month Homocysteine Level | 71 percent of baseline level |
| Cerefolin NAC + Multivitamin | Six Month Blood Levels of Homocysteine, Glutathione, and the Ratio of Aβ42 to Aβ40 (as a Percent of Baseline Levels) After Daily Intake of Cerefolin NAC Plus a Multivitamin Versus a Multivitamin Only | 6-Month Glutathione Level | 115 percent of baseline level |
| Cerefolin NAC + Multivitamin | Six Month Blood Levels of Homocysteine, Glutathione, and the Ratio of Aβ42 to Aβ40 (as a Percent of Baseline Levels) After Daily Intake of Cerefolin NAC Plus a Multivitamin Versus a Multivitamin Only | 6-Month AB42/AB40 Ratio | 101 percent of baseline level |
| Cerefolin NAC Placebo + Multivitamin | Six Month Blood Levels of Homocysteine, Glutathione, and the Ratio of Aβ42 to Aβ40 (as a Percent of Baseline Levels) After Daily Intake of Cerefolin NAC Plus a Multivitamin Versus a Multivitamin Only | 6-Month Homocysteine Level | 101 percent of baseline level |
| Cerefolin NAC Placebo + Multivitamin | Six Month Blood Levels of Homocysteine, Glutathione, and the Ratio of Aβ42 to Aβ40 (as a Percent of Baseline Levels) After Daily Intake of Cerefolin NAC Plus a Multivitamin Versus a Multivitamin Only | 6-Month Glutathione Level | 101 percent of baseline level |
| Cerefolin NAC Placebo + Multivitamin | Six Month Blood Levels of Homocysteine, Glutathione, and the Ratio of Aβ42 to Aβ40 (as a Percent of Baseline Levels) After Daily Intake of Cerefolin NAC Plus a Multivitamin Versus a Multivitamin Only | 6-Month AB42/AB40 Ratio | 104 percent of baseline level |
Secondary
Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only
Outcome measures were 6-month levels of highly sensitive c-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), malondialdehyde, and potential anti-oxidant (PAO)in blood samples as a percent of baseline value.
Time frame: 6 months
Population: All participants in Intent-to-Treat were included with last observation carried forward.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cerefolin NAC + Multivitamin | Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6-month TNF-alpha Level | 99 percent of baseline level |
| Cerefolin NAC + Multivitamin | Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6-month Malondialdehyde Level | 93 percent of baseline level |
| Cerefolin NAC + Multivitamin | Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6-month IL-6 Level | 114 percent of baseline level |
| Cerefolin NAC + Multivitamin | Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6-month PAO Level | 109 percent of baseline level |
| Cerefolin NAC + Multivitamin | Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6-month hs-CRP Level | 110 percent of baseline level |
| Cerefolin NAC Placebo + Multivitamin | Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6-month PAO Level | 115 percent of baseline level |
| Cerefolin NAC Placebo + Multivitamin | Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6-month hs-CRP Level | 111 percent of baseline level |
| Cerefolin NAC Placebo + Multivitamin | Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6-month TNF-alpha Level | 108 percent of baseline level |
| Cerefolin NAC Placebo + Multivitamin | Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6-month IL-6 Level | 105 percent of baseline level |
| Cerefolin NAC Placebo + Multivitamin | Six Month Levels of Inflammation and Oxidative Stress Markers(as a Percent of Baseline Levels) After Daily Treatment With Cerefolin NAC and a Multivitamin or a Multivitamin Only | 6-month Malondialdehyde Level | 90 percent of baseline level |
Secondary
Tolerability of Cerefolin NAC and a Multivitamin Versus a Multivitamin Only
Mean study product compliance was measured as the actual number of study product tablets taken as a percent of the maximum study product tablets that could have been taken during the intervention period.
Time frame: 6 months
Population: All participants in Intent-to-Treat cohort were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cerefolin NAC + Multivitamin | Tolerability of Cerefolin NAC and a Multivitamin Versus a Multivitamin Only | 88 percent of study drug taken | Standard Error 15 |
| Cerefolin NAC Placebo + Multivitamin | Tolerability of Cerefolin NAC and a Multivitamin Versus a Multivitamin Only | 88 percent of study drug taken | Standard Error 21 |