Alzheimer's Disease
Conditions
Keywords
Alzheimer's disease, Amyloid Beta (AB) peptide, Albumin, Intravenous immunoglobulin, IVIG
Brief summary
The purpose of this study is to evaluate the changes in the cognitive, functional, behavioral and global domains based on the different applicable psychometric batteries and scales.
Detailed description
A clinical trial comprised of 350 subjects with probable mild to moderate Alzheimer's Disease (AD) will be conducted primarily to determine whether plasmapheresis with infusion of human albumin combined with intravenous immunoglobulin (IVIG) is able to modify patient's cognitive, functional, behavioral and global domains. There will be 3 treatment groups and 1 control group. The subjects will be randomized in a 1:1:1:1 proportion.
Interventions
BIOLOGICALAlbumin 5%
Therapeutic plasma exchange with human albumin 5%
BIOLOGICALAlbumin 20%
Low volume plasma exchange with human albumin 5%
BIOLOGICALImmunoglobulin
Intravenous human immunoglobulin 5%
Sponsors
Grifols Biologicals, LLC
Instituto Grifols, S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: 1. Males or females between 55-85 years of age at the time of signing of the informed consent document. 2. A diagnosis of Alzheimer's disease (NINCDS-ADRDA criterion), and mini-mental status examination (MMSE) score between \>/=18 and \</=26. 3. Current stable treatment with acetylcholine esterase inhibitors (AChEIs) and/or memantine for the previous three months. 4. The patient and a close relative or the legal representative must read the patient information sheet, agree to participation in the trial, and then sign the informed consent document (the patient personally and the close relative/legal representative). 5. The patient must be able to follow the study protocol, receive the treatment in the established time period, and continue during the follow-up interval. 6. A brain computed axial tomography (CAT) or magnetic resonance imaging (MRI) study, obtained in the 12 months prior to recruitment, showing the absence of cerebrovascular disease, should be available. Nevertheless, it is mandatory to use the MRI obtained during the screening period to rule out any cerebrovascular disease. 7. A stable care taker must be available, and must attend the patient study visits. Main
Exclusion criteria
1. Any contraindication for plasma exchange due to behavioral disorders or abnormal coagulation parameters, such as for example: * Hypocalcemia (Ca++ \< 8.7 mg/dL) * Thrombocytopenia (\<100,000/µL) * Fibrinogen \<1.5 g/L * Prothrombin time (Quick) p\<60% versus control (international normalized ratio (INR) \>1.5) * Beta-blocker treatment and bradycardia \<55/min * Treatment with angiotension-converting enzyme inhibitors (ACEIs) (increased risk of allergic reactions) 2. Hemoglobin \< 10 g/dL 3. Difficult venous access precluding plasma exchange. 4. A history of frequent adverse reactions (serious or otherwise) to blood products. 5. Hypersensitivity to albumin or allergies to any of the components of Albutein. 6. History of immunoglobulin A (IgA) deficiency. 7. Known allergies to Flebogamma DIF components such as sorbitol. 8. History of thromboembolic complications of intravenous immunoglobulins. 9. Plasma creatinine \> 2 mg/dl. 10. Uncontrolled high blood pressure (systolic blood pressure of 160 mmHg or higher and/or diastolic blood pressure of 100 mmHg or higher despite treatment during the last 3 months). 11. Liver cirrhosis or any liver problem with glutamic pyruvic transaminase (GPT) \> 2.5 x upper limit of normal (ULN), or bilirubin \> 2 mg/dL. 12. Heart diseases, as evidenced by myocardial infarction, severe or unstable angina, or heart failure (New York Association Class II, III or IV) in the past 12 months. 13. Participation in other clinical trials, or the receipt of any other investigational drug in the three months prior to the start of the study. 14. Any condition complicating adherence to the study protocol (illness with less than one year of expected survival, known drug or alcohol abuse, etc.). 15. Pregnant or nursing women or women not using effective contraceptive methods for at least one month after plasma exchange. 16. Fewer than six years of education (
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score (Changes From Baseline to 14 Months) | Baseline and 14 months | ADAS-Cog total score as a change from baseline to 14 months The ADAS-Cog Scale is a questionnaire that assesses cognitive performance in 12 different domains. The domains are: word recall, commands, constructional praxis, delayed word-recall task, naming objects/figures, ideational praxis, orientation, word recognition, remembering test instructions, comprehension, word finding difficulty, and spoken language ability. The total score ranges from 0-80 where a higher score indicates more cognitive impairment. |
| Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score (Changes From Baseline to 14 Months) | Baseline and 14 Months | ADCS-ADL total score as a change from baseline to 14 months The ADCS-ADL comprises 23 questions covering a wide array of activities of daily living. Many of the activities begin with an assessment of whether that activity is relevant and then, if yes, follow with an assessment of the difficulty. The total score over all activities ranges from 0-78 where a higher score indicates more autonomy (better outcome). |
Other
| Measure | Time frame | Description |
|---|---|---|
| ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | Baseline and 14 months | ADAS-Cog total score as a change from baseline to 14 months in patients with baseline Mini-Mental State Examination (MMSE):22-26 The ADAS-Cog Scale is a questionnaire that assesses cognitive performance in 12 different domains. The domains are: word recall, commands, constructional praxis, delayed word-recall task, naming objects/figures, ideational praxis, orientation, word recognition, remembering test instructions, comprehension, word finding difficulty, and spoken language ability. The total score ranges from 0-80 where a higher score indicates more cognitive impairment. |
| ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | Baseline and 14 months | ADCS-ADL total score as a change from baseline to 14 months in patients with baseline Mini-Mental State Examination (MMSE):22-26 The ADCS-ADL comprises 23 questions covering a wide array of activities of daily living. Many of the activities begin with an assessment of whether that activity is relevant and then, if yes, follow with an assessment of the difficulty. The total score over all activities ranges from 0-78 where a higher score indicates more autonomy (better outcome). |
| ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | Baseline and 14 months | ADAS-Cog score as a change from baseline to 14 months in patients with baseline Mini-Mental State Examination (MMSE):18-21 The ADAS-Cog Scale is a questionnaire that assesses cognitive performance in 12 different domains. The domains are: word recall, commands, constructional praxis, delayed word-recall task, naming objects/figures, ideational praxis, orientation, word recognition, remembering test instructions, comprehension, word finding difficulty, and spoken language ability. The total score ranges from 0-80 where a higher score indicates more cognitive impairment |
| ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | Baseline and 14 months | ADCS-ADL total score as a change from baseline to 14 months in patients with baseline Mini-Mental State Examination (MMSE):18-21 The ADCS-ADL comprises 23 questions covering a wide array of activities of daily living. Many of the activities begin with an assessment of whether that activity is relevant and then, if yes, follow with an assessment of the difficulty. The total score over all activities ranges from 0-78 where a higher score indicates more autonomy (better outcome). |
Countries
Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High Albumin + Immunoglobulin Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with high dose of albumin 20% or immunoglobulin 5% (maintenance treatment period) | 78 |
| Low Albumin + Immunoglobulin Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% or immunoglobulin 5% (maintenance treatment period) | 86 |
| Low Albumin Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period) | 78 |
| Control (Sham) Group Simulated plasma exchange procedure | 80 |
| Total | 322 |
Baseline characteristics
| Characteristic | Low Albumin + Immunoglobulin | Low Albumin | Control (Sham) Group | High Albumin + Immunoglobulin | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 69 Participants | 52 Participants | 51 Participants | 56 Participants | 228 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 26 Participants | 29 Participants | 22 Participants | 94 Participants |
| Age, Continuous | 69.47 years STANDARD_DEVIATION 6.924 | 68.47 years STANDARD_DEVIATION 7.476 | 68.44 years STANDARD_DEVIATION 8.378 | 69.54 years STANDARD_DEVIATION 7.895 | 68.99 years STANDARD_DEVIATION 7.655 |
| Baseline Mini-Mental State Examination total score | 22.09 units on a scale STANDARD_DEVIATION 2.633 | 21.24 units on a scale STANDARD_DEVIATION 2.408 | 21.69 units on a scale STANDARD_DEVIATION 2.559 | 21.41 units on a scale STANDARD_DEVIATION 2.616 | 21.62 units on a scale STANDARD_DEVIATION 2.566 |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 48 Participants | 43 Participants | 36 Participants | 47 Participants | 174 Participants |
| Sex: Female, Male Male | 38 Participants | 35 Participants | 44 Participants | 31 Participants | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 79 | 2 / 86 | 0 / 78 | 0 / 79 |
| other Total, other adverse events | 67 / 79 | 77 / 86 | 72 / 78 | 56 / 79 |
| serious Total, serious adverse events | 16 / 79 | 19 / 86 | 8 / 78 | 8 / 79 |
Outcome results
Primary
Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score (Changes From Baseline to 14 Months)
ADAS-Cog total score as a change from baseline to 14 months The ADAS-Cog Scale is a questionnaire that assesses cognitive performance in 12 different domains. The domains are: word recall, commands, constructional praxis, delayed word-recall task, naming objects/figures, ideational praxis, orientation, word recognition, remembering test instructions, comprehension, word finding difficulty, and spoken language ability. The total score ranges from 0-80 where a higher score indicates more cognitive impairment.
Time frame: Baseline and 14 months
Population: Evaluable population with ADAS-Cog measurement at 14 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High Albumin + Immunoglobulin | Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score (Changes From Baseline to 14 Months) | 0.8 units on a scale | Standard Error 1.28 |
| Low Albumin + Immunoglobulin | Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score (Changes From Baseline to 14 Months) | 0.8 units on a scale | Standard Error 1.09 |
| Low Albumin | Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score (Changes From Baseline to 14 Months) | 1.5 units on a scale | Standard Error 1.02 |
| Control (Sham) Group | Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score (Changes From Baseline to 14 Months) | 3.2 units on a scale | Standard Error 0.95 |
| All Treated | Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score (Changes From Baseline to 14 Months) | 1.0 units on a scale | Standard Error 0.64 |
Primary
Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score (Changes From Baseline to 14 Months)
ADCS-ADL total score as a change from baseline to 14 months The ADCS-ADL comprises 23 questions covering a wide array of activities of daily living. Many of the activities begin with an assessment of whether that activity is relevant and then, if yes, follow with an assessment of the difficulty. The total score over all activities ranges from 0-78 where a higher score indicates more autonomy (better outcome).
Time frame: Baseline and 14 Months
Population: Evaluable population with ADCS-ADL measurement at 14 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High Albumin + Immunoglobulin | Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score (Changes From Baseline to 14 Months) | -3.5 units on a scale | Standard Error 1.8 |
| Low Albumin + Immunoglobulin | Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score (Changes From Baseline to 14 Months) | -2.0 units on a scale | Standard Error 1.03 |
| Low Albumin | Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score (Changes From Baseline to 14 Months) | -3.9 units on a scale | Standard Error 1.24 |
| Control (Sham) Group | Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score (Changes From Baseline to 14 Months) | -6.7 units on a scale | Standard Error 1.5 |
| All Treated | Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score (Changes From Baseline to 14 Months) | -3.2 units on a scale | Standard Error 0.78 |
Other Pre-specified
ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21
ADAS-Cog score as a change from baseline to 14 months in patients with baseline Mini-Mental State Examination (MMSE):18-21 The ADAS-Cog Scale is a questionnaire that assesses cognitive performance in 12 different domains. The domains are: word recall, commands, constructional praxis, delayed word-recall task, naming objects/figures, ideational praxis, orientation, word recognition, remembering test instructions, comprehension, word finding difficulty, and spoken language ability. The total score ranges from 0-80 where a higher score indicates more cognitive impairment
Time frame: Baseline and 14 months
Population: Evaluable population with baseline MMSE:18-21 and with ADAS-Cog measurement at 14 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High Albumin + Immunoglobulin | ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | 2.4 units on a scale | Standard Error 1.95 |
| Low Albumin + Immunoglobulin | ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | 1.9 units on a scale | Standard Error 2.44 |
| Low Albumin | ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | 3.3 units on a scale | Standard Error 1.49 |
| Control (Sham) Group | ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | 6.4 units on a scale | Standard Error 1.34 |
| All Treated | ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | 2.6 units on a scale | Standard Error 1.07 |
Other Pre-specified
ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26
ADAS-Cog total score as a change from baseline to 14 months in patients with baseline Mini-Mental State Examination (MMSE):22-26 The ADAS-Cog Scale is a questionnaire that assesses cognitive performance in 12 different domains. The domains are: word recall, commands, constructional praxis, delayed word-recall task, naming objects/figures, ideational praxis, orientation, word recognition, remembering test instructions, comprehension, word finding difficulty, and spoken language ability. The total score ranges from 0-80 where a higher score indicates more cognitive impairment.
Time frame: Baseline and 14 months
Population: Evaluable population with baseline MMSE:22-26 and with ADAS-Cog measurement at 14 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High Albumin + Immunoglobulin | ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | -0.9 units on a scale | Standard Error 1.51 |
| Low Albumin + Immunoglobulin | ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | -0.3 units on a scale | Standard Error 1.04 |
| Low Albumin | ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | -0.6 units on a scale | Standard Error 1.12 |
| Control (Sham) Group | ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | 0.6 units on a scale | Standard Error 1.12 |
| All Treated | ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | -0.6 units on a scale | Standard Error 0.68 |
Other Pre-specified
ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21
ADCS-ADL total score as a change from baseline to 14 months in patients with baseline Mini-Mental State Examination (MMSE):18-21 The ADCS-ADL comprises 23 questions covering a wide array of activities of daily living. Many of the activities begin with an assessment of whether that activity is relevant and then, if yes, follow with an assessment of the difficulty. The total score over all activities ranges from 0-78 where a higher score indicates more autonomy (better outcome).
Time frame: Baseline and 14 months
Population: Evaluable population with baseline MMSE:18-21 and with ADCS-ADL measurement at 14 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High Albumin + Immunoglobulin | ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | -4.5 units on a scale | Standard Error 2.97 |
| Low Albumin + Immunoglobulin | ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | -5.7 units on a scale | Standard Error 2.11 |
| Low Albumin | ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | -6.0 units on a scale | Standard Error 1.75 |
| Control (Sham) Group | ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | -14.1 units on a scale | Standard Error 2.67 |
| All Treated | ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21 | -5.5 units on a scale | Standard Error 1.33 |
Other Pre-specified
ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26
ADCS-ADL total score as a change from baseline to 14 months in patients with baseline Mini-Mental State Examination (MMSE):22-26 The ADCS-ADL comprises 23 questions covering a wide array of activities of daily living. Many of the activities begin with an assessment of whether that activity is relevant and then, if yes, follow with an assessment of the difficulty. The total score over all activities ranges from 0-78 where a higher score indicates more autonomy (better outcome).
Time frame: Baseline and 14 months
Population: Evaluable population with baseline MMSE:22-26 and with ADCS-ADL measurement at 14 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High Albumin + Immunoglobulin | ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | -2.4 units on a scale | Standard Error 1.68 |
| Low Albumin + Immunoglobulin | ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | 0.8 units on a scale | Standard Error 0.98 |
| Low Albumin | ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | -0.9 units on a scale | Standard Error 1.43 |
| Control (Sham) Group | ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | -1.3 units on a scale | Standard Error 1.29 |
| All Treated | ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26 | -0.6 units on a scale | Standard Error 0.75 |