Mild Cognitive Impairment
Conditions
Keywords
Intravenous immunotherapy, Conversion to Alzheimer Disease
Brief summary
Patients with mild cognitive impairment (MCI) are a group recognized at being at high risk of progressing to Alzheimer disease. Treatment of MCI with immunotherapy with intravenous immunoglobulins (IVIG) could potentially reduce the risk of progression to Alzheimer disease. This study will evaluate the efficacy of intravenous immunoglobulin in patients with MCI over 24 months after the first infusion. This study will also document conversion from MCI to Alzheimer's Disease.
Detailed description
Screening procedures at visit 1 will take place up to 28 days prior to Visit 2 (Day 1) dosing. Screening labs and assessments will be performed during the screening period. A brain MRI will be obtained as standard of care within 6 months prior to the screening period. The first dose of study drug is administered on Day 1. Visits 2 through 6 have a ±1 day window and occur every 14 days over two months. The investigator will determine if a subject is suitable to continue following the missed infusion. Visits 7 through 12 (Month 4 through Month 24) have a ±7 day window. All study screening data from Visit 1 including laboratory results must be reviewed for study eligibility prior to receiving first dose of study drug. Visit 2 physical exams and neurological exams prior to infusion may occur within 72 hours prior to the first infusion. Prior to infusion, a review of concomitant medications and adverse events takes place to ensure that no excluded medications have been added or medication discontinued or dose changed that were required to have been stable. If the subject continues to be eligible for enrollment, the subject will be randomized, infused with study medication and will remain in the infusion clinic for at least 4 hours following the start of the infusion for safety assessments on Visit 2 (Day 1).
Interventions
DRUGNewGam 10% IVIG
Subjects will be randomized to receive either an infusion of IVIG at 0.4 g/kg or every 14 days for two months for a total of five infusions. Fifty subjects will be enrolled and randomized in a 1:1 IVIG 2.0 g/kg: placebo ratio. Twenty-five subjects will receive IVIG and 25 subjects will receive placebo.
OTHERPlacebo
Subjects will be randomized to receive either an infusion of 0.9% saline solution (placebo) every 14 days for two months for a total of five infusions. Fifty subjects will be enrolled and randomized in a 1:1 IVIG 2.0 g/kg: placebo ratio.
Sponsors
Sutter Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 84 Years
Healthy volunteers
No
Inclusion criteria
1. Age from 50 to \< 85 years old. 2. Diagnosis of Mild Cognitive Impairment, Amnestic type (single or multi domain) according to Petersen criteria (Appendix B) and supported by a CDR score of 0.5. 3. Mini-Mental State Examination (MMSE) score of 24-30, inclusive. 4. Rosen Modified Hachinski Ischemic score ≤ 4. 5. Willing to consent to Apolipoprotein E (ApoE) testing and agree to disclose Apolipoprotein E4 (ApoE4) status. Previous ApoE testing will be accepted. 6. Receiving stable doses of medication(s) for the treatment of non-excluded medical condition(s) for at least 30 days prior to screening. 7. Ability to attend all clinical visits and have an informant capable of accompanying the subject on specific clinic visits for two years or the duration of the study. 8. The subject's collaborative informant (support person) must be someone who has known the subject for at least 4 years; agrees to have at least 2 separate communications with the study participant per month for the duration of the study (one of these communications must be in person); and attends and completes the CDR interview at 8 study visits along with the subject. 9. Fluency in English and evidence of adequate premorbid intellectual functioning. 10. Adequate manual dexterity, visual, and auditory abilities to perform all aspects of the cognitive and functional assessments. 11. Venous access suitable for repeated infusion and phlebotomy.
Exclusion criteria
1. Has significant neurological disease, other than a-MCI that may affect cognition. 2. History of clinically evident stroke or history of clinically significant carotid or vertebrobasilar stenosis or plaque. 3. History of seizures, excluding febrile seizures in childhood. 4. Brain MRI shows moderate or severe cortical or hippocampal atrophy. 5. Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, CSF shunts, claustrophobia, metal fragments or foreign objects in the eyes, skin, or body that would contraindicate a brain MRI scan. 6. Current presence of a clinically significant major psychiatric disorder according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR). 7. History of cancer within the last 5 years, with the exception of nonmetastatic basal cell carcinoma, and squamous cell carcinoma of the skin. 8. Uncontrolled hypertension (diastolic BP\> 100 mmHg or systolic BP\> 160 mmHg, sitting). 9. History or evidence of any clinically significant autoimmune disease or disorder of the immune system (eg., Crohn's Disease, Rheumatoid Arthritis) 10. Women of childbearing potential. 11. Weight greater than 120 kg (264 lbs). 12. Excessive smoking defined as more than 20 cigarettes per day. 13. History of alcohol or drug dependence or abuse as defined by DSM-IV criteria within the last 2 years. 14. Severe liver or kidney disease verified by the PI review of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine. 15. Known coagulopathy, thrombosis, or low platelet count. 16. Known deficiency to Immunoglobulin A (IgA). 17. Positive serology for Hepatitis B or C, or HIV. 18. Concurrent or prior treatment with cholinesterase inhibitors and/or memantine, or Axona for cognitive enhancement. Exceptions (e.g. brief exposure to one of these medications) may be authorized if agreed upon by PI and sub-I. 19. Concurrent use of anticholinergic drugs including diphenhydramine. 20. Current use of anticonvulsant drugs for seizures, antiparkinson drugs, anticoagulant medications (except the use of aspirin 325 mg/day or less, plavix, aggrenox, and persantine but not for stroke). 21. Concurrent use of opioid pain relievers and related synthetic derivatives. 22. Use of experimental medications for AD or any other investigational medications or devices within 60 days prior to screening or within 5 half-lives of use of such a medication prior to screening, whichever is longer. 23. Prior treatment with IVIG or other experimental immunotherapeutic or vaccine for MCI or AD, or prior treatment with a biological product for the treatment of a-MCI or AD.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Percent Change in Ventricular Volume (APCV) as Measured by MRI | Baseline, 12, and 24 month MRI evaluation | Change in ventricular volumetric as measured by MRI at baseline, 12, and 24 months following the first infusion of either 0.4 g/kg NewGam or 0.9% saline solution(placebo) every 14 days x 5. Participants will also be classified as early MCI (EMCI) if baseline CDR-SB is less than 1.5, and late MCI (LMCI) if CDR-SB is greater than or equal to 1.5. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Converted From Amnestic Mild Cognitive Impairment (a-MCI) to Alzheimer Disease (AD) | Baseline to 24 months | The National Institute of Neurological and Communicative Disorders and Stroke - Alzheimers Disease and Related Disorders Association (NINCDS-ADRDA) Alzheimer's Criteria were proposed in 1984 by NINCDS-ADRDA criteria for diagnosing Alzheimer Disease and Clinical Dementia Rating (CDR) will be used to determine conversion from a-MCI to AD. |
| Change in Ventricular Volume in Patients With Positive Cerebrospinal Fluid (CSF) Aβ1-42/CSF P-Tau181P Alzheimer Signature | Baseline to 24 months following infusion | Mean ventricular volume (cubic centimeters) in patients with positive cerebrospinal fluid (CSF) Aβ1-42/CSF P-Tau181P Alzheimer signature at 24 months following infusion |
| Mean Cognitive Performance at 12 Months | 12 months | 12 month cognitive performance in treatment (IVIG/placebo) is measured by: * Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) * Scale from 0 to 85 (0 is best cognitive performance) * Score is the sum of 12 sub-scales. * Mini Mental State Exam (MMSE) * Scale from 0 to 30 (30 is best cognitive performance) * Score is the sum of 11 sub-scales. * Clinical Dementia Rating - Sum of Boxes (CDR-SB) * Scale is 0 to 18 (0 is best cognitive performance) * Score is the sum of 6 sub-scales |
| Mean Cognitive Performance at 24 Months | 24 month | 24 month cognitive performance in treatment (IVIG/placebo) is measured by: * Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) * Scale from 0 to 85 (0 is best cognitive performance) * Score is the sum of 12 sub-scales. * Mini Mental State Exam (MMSE) * Scale from 0 to 30 (30 is best cognitive performance) * Score is the sum of 11 sub-scales. * Clinical Dementia Rating - Sum of Boxes (CDR-SB) * Scale is 0 to 18 (0 is best cognitive performance) * Score is the sum of 6 sub-scales |
Countries
United States
Participant flow
Pre-assignment details
Fifty-two participants were randomized; however, 2 participants in the IVIG group did not complete the series of 5 infusions, and 1 placebo participant was excluded due to significant language symptoms which were a barrier to cognitive testing. This resulted having a data set consisting of a total of 49 subjects.
Participants by arm
| Arm | Count |
|---|---|
| Intravenous Immunoglobulin (IVIG) IVIG (NewGam 10%)at 0.4 g/kg
NewGam 10% IVIG: Subjects will be randomized to receive either an infusion of IVIG at 0.4 g/kg or every 14 days for two months for a total of five infusions.
Fifty subjects will be enrolled and randomized in a 1:1 IVIG 2.0 g/kg: placebo ratio. Twenty-five subjects will receive IVIG and 25 subjects will receive placebo. | 24 |
| Saline Solution 0.9% saline solution
Placebo: Subjects will be randomized to receive either an infusion of 0.9% saline solution (placebo) every 14 days for two months for a total of five infusions. Fifty subjects will be enrolled and randomized in a 1:1 IVIG 2.0 g/kg: placebo ratio. | 25 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Saline Solution | Total | Intravenous Immunoglobulin (IVIG) |
|---|---|---|---|
| Age, Continuous | 72.40 years STANDARD_DEVIATION 7.36 | 72.32 years STANDARD_DEVIATION 7.56 | 72.26 years STANDARD_DEVIATION 7.91 |
| Mean Cognitive Performance ADAS-cog | 10.29 units on a scale STANDARD_DEVIATION 5.68 | 10.46 units on a scale STANDARD_DEVIATION 4.97 | 10.63 units on a scale STANDARD_DEVIATION 4.23 |
| Mean Cognitive Performance CDR_SB | 1.58 units on a scale STANDARD_DEVIATION 0.9 | 1.78 units on a scale STANDARD_DEVIATION 0.94 | 1.96 units on a scale STANDARD_DEVIATION 0.95 |
| Mean Cognitive Performance MMSE | 26.44 units on a scale STANDARD_DEVIATION 2.6 | 26.59 units on a scale STANDARD_DEVIATION 2.37 | 26.75 units on a scale STANDARD_DEVIATION 2.15 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 42 Participants | 21 Participants |
| Sex: Female, Male Female | 14 Participants | 28 Participants | 14 Participants |
| Sex: Female, Male Male | 11 Participants | 21 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 2 / 25 |
| other Total, other adverse events | 1 / 24 | 2 / 25 |
| serious Total, serious adverse events | 0 / 24 | 0 / 25 |
Outcome results
Primary
Annualized Percent Change in Ventricular Volume (APCV) as Measured by MRI
Change in ventricular volumetric as measured by MRI at baseline, 12, and 24 months following the first infusion of either 0.4 g/kg NewGam or 0.9% saline solution(placebo) every 14 days x 5. Participants will also be classified as early MCI (EMCI) if baseline CDR-SB is less than 1.5, and late MCI (LMCI) if CDR-SB is greater than or equal to 1.5.
Time frame: Baseline, 12, and 24 month MRI evaluation
Population: Annualized Percent Change in ventricular volume (APCV) at 12 and 24 months was computed as:~((12 or 24 month volume) - (Baseline volume))/(Baseline volume)/(Time (years) between Baseline and 12 or 24 month visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Immunoglobulin (IVIG) | Annualized Percent Change in Ventricular Volume (APCV) as Measured by MRI | APCV Baseline to12 months | 5.87 percent change per participant year | Standard Deviation 3.91 |
| Intravenous Immunoglobulin (IVIG) | Annualized Percent Change in Ventricular Volume (APCV) as Measured by MRI | APCV Baseline to 24 months | 6.26 percent change per participant year | Standard Deviation 4.17 |
| Saline Solution | Annualized Percent Change in Ventricular Volume (APCV) as Measured by MRI | APCV Baseline to12 months | 8.14 percent change per participant year | Standard Deviation 4.43 |
| Saline Solution | Annualized Percent Change in Ventricular Volume (APCV) as Measured by MRI | APCV Baseline to 24 months | 7.08 percent change per participant year | Standard Deviation 4.05 |
Secondary
Change in Ventricular Volume in Patients With Positive Cerebrospinal Fluid (CSF) Aβ1-42/CSF P-Tau181P Alzheimer Signature
Mean ventricular volume (cubic centimeters) in patients with positive cerebrospinal fluid (CSF) Aβ1-42/CSF P-Tau181P Alzheimer signature at 24 months following infusion
Time frame: Baseline to 24 months following infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Immunoglobulin (IVIG) | Change in Ventricular Volume in Patients With Positive Cerebrospinal Fluid (CSF) Aβ1-42/CSF P-Tau181P Alzheimer Signature | Aβ42 (cc) | 294.00 cubic centimeters (cc) | Standard Deviation 96.55 |
| Intravenous Immunoglobulin (IVIG) | Change in Ventricular Volume in Patients With Positive Cerebrospinal Fluid (CSF) Aβ1-42/CSF P-Tau181P Alzheimer Signature | tau (cc) | 107.47 cubic centimeters (cc) | Standard Deviation 58.65 |
| Intravenous Immunoglobulin (IVIG) | Change in Ventricular Volume in Patients With Positive Cerebrospinal Fluid (CSF) Aβ1-42/CSF P-Tau181P Alzheimer Signature | p-tau (cc) | 43.59 cubic centimeters (cc) | Standard Deviation 19.9 |
| Saline Solution | Change in Ventricular Volume in Patients With Positive Cerebrospinal Fluid (CSF) Aβ1-42/CSF P-Tau181P Alzheimer Signature | Aβ42 (cc) | 353.41 cubic centimeters (cc) | Standard Deviation 112.99 |
| Saline Solution | Change in Ventricular Volume in Patients With Positive Cerebrospinal Fluid (CSF) Aβ1-42/CSF P-Tau181P Alzheimer Signature | tau (cc) | 96.18 cubic centimeters (cc) | Standard Deviation 65.47 |
| Saline Solution | Change in Ventricular Volume in Patients With Positive Cerebrospinal Fluid (CSF) Aβ1-42/CSF P-Tau181P Alzheimer Signature | p-tau (cc) | 39.47 cubic centimeters (cc) | Standard Deviation 30.27 |
Secondary
Mean Cognitive Performance at 12 Months
12 month cognitive performance in treatment (IVIG/placebo) is measured by: * Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) * Scale from 0 to 85 (0 is best cognitive performance) * Score is the sum of 12 sub-scales. * Mini Mental State Exam (MMSE) * Scale from 0 to 30 (30 is best cognitive performance) * Score is the sum of 11 sub-scales. * Clinical Dementia Rating - Sum of Boxes (CDR-SB) * Scale is 0 to 18 (0 is best cognitive performance) * Score is the sum of 6 sub-scales
Time frame: 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Immunoglobulin (IVIG) | Mean Cognitive Performance at 12 Months | Mini Mental State Exam (MMSE) | 26.04 units on a scale | Standard Deviation 3.76 |
| Intravenous Immunoglobulin (IVIG) | Mean Cognitive Performance at 12 Months | Alzheimer's Disease Assessment Scale (ADAS-Cog) | 11.03 units on a scale | Standard Deviation 6.66 |
| Intravenous Immunoglobulin (IVIG) | Mean Cognitive Performance at 12 Months | Clinical Dementia Rating Sum of Boxes (CDR-SB) | 2.7 units on a scale | Standard Deviation 1.63 |
| Saline Solution | Mean Cognitive Performance at 12 Months | Mini Mental State Exam (MMSE) | 25.38 units on a scale | Standard Deviation 4.28 |
| Saline Solution | Mean Cognitive Performance at 12 Months | Alzheimer's Disease Assessment Scale (ADAS-Cog) | 11.00 units on a scale | Standard Deviation 9.14 |
| Saline Solution | Mean Cognitive Performance at 12 Months | Clinical Dementia Rating Sum of Boxes (CDR-SB) | 2.65 units on a scale | Standard Deviation 2.13 |
Secondary
Mean Cognitive Performance at 24 Months
24 month cognitive performance in treatment (IVIG/placebo) is measured by: * Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) * Scale from 0 to 85 (0 is best cognitive performance) * Score is the sum of 12 sub-scales. * Mini Mental State Exam (MMSE) * Scale from 0 to 30 (30 is best cognitive performance) * Score is the sum of 11 sub-scales. * Clinical Dementia Rating - Sum of Boxes (CDR-SB) * Scale is 0 to 18 (0 is best cognitive performance) * Score is the sum of 6 sub-scales
Time frame: 24 month
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravenous Immunoglobulin (IVIG) | Mean Cognitive Performance at 24 Months | Mini Mental State Exam (MMSE) | 24.00 units on a scale | Standard Deviation 4.91 |
| Intravenous Immunoglobulin (IVIG) | Mean Cognitive Performance at 24 Months | Alzheimer's Disease Assessment Scale (ADAS-Cog) | 15.39 units on a scale | Standard Deviation 10.55 |
| Intravenous Immunoglobulin (IVIG) | Mean Cognitive Performance at 24 Months | Clinical Dementia Rating Sum of Boxes (CDR-SB) | 4.33 units on a scale | Standard Deviation 3.48 |
| Saline Solution | Mean Cognitive Performance at 24 Months | Mini Mental State Exam (MMSE) | 24.46 units on a scale | Standard Deviation 4.79 |
| Saline Solution | Mean Cognitive Performance at 24 Months | Alzheimer's Disease Assessment Scale (ADAS-Cog) | 13.25 units on a scale | Standard Deviation 11.77 |
| Saline Solution | Mean Cognitive Performance at 24 Months | Clinical Dementia Rating Sum of Boxes (CDR-SB) | 3.37 units on a scale | Standard Deviation 2.73 |
Secondary
Number of Participants Who Converted From Amnestic Mild Cognitive Impairment (a-MCI) to Alzheimer Disease (AD)
The National Institute of Neurological and Communicative Disorders and Stroke - Alzheimers Disease and Related Disorders Association (NINCDS-ADRDA) Alzheimer's Criteria were proposed in 1984 by NINCDS-ADRDA criteria for diagnosing Alzheimer Disease and Clinical Dementia Rating (CDR) will be used to determine conversion from a-MCI to AD.
Time frame: Baseline to 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intravenous Immunoglobulin (IVIG) | Number of Participants Who Converted From Amnestic Mild Cognitive Impairment (a-MCI) to Alzheimer Disease (AD) | 16 participants |
| Saline Solution | Number of Participants Who Converted From Amnestic Mild Cognitive Impairment (a-MCI) to Alzheimer Disease (AD) | 10 participants |