A Study to Evaluate Albumin and Immunoglobulin in Alzheimer's Disease

A Multicenter, Randomized, Controlled Study To Evaluate The Efficacy and Safety of Short-Term Plasma Exchange Followed by Long-Term Plasmapheresis With Infusion of Human Albumin Combined With Intravenous Immunoglobulin In Patients With Mild-Moderate Alzheimer's Disease

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.

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.

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 (exclusion criteria under medical criterion).

17. Less than three months with stable treatment for behavioral disorders or insomnia.

18. Patients being treated with anticoagulants or antiplatelet therapy (antiaggregants) should not be recruited in the study.