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

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Biological: Albumin 5%; Biological: Albumin 20%; Biological: Immunoglobulin

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.

• Study Type: Interventional
• Enrollment (Actual): 347
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Barcelona, Spain, 08041
    • Hospital de La Santa Creu I Sant Pau
  • Barcelona, Spain, 08028
    • Fundacio ACE
  • Burgos, Spain, 09005
    • Hospital Universitario de Burgos
  • Girona, Spain, 17190
    • Parc Hospitalari Martí i Julià
  • Lleida, Spain, 25198
    • Hospital Universitari de Santa Maria
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico La Fe
  • Valencia, Spain, 46017
    • Hospital Universitario Doctor Peset
  • Zaragoza, Spain, 50012
    • Hospital Viamed Montecanal
  • Alicante
    • Elche, Alicante, Spain, 03203
      • Hospital General de Elche
    • Elche, Alicante, Spain, 03293
      • Hospital Universitario del Vinalopó
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Hospital Universitari de Bellvitge
    • Sant Cugat Del Vallès, Barcelona, Spain, 08190
      • Hospital General de Catalunya
    • Terrassa, Barcelona, Spain, 08221
      • Hospital Universitari Mutua de Terrassa
  • Canary Islands
    • Santa Cruz de Tenerife, Canary Islands, Spain, 38010
      • Hospital Universitario Nuestra Señora de Candelaria
  • Madrid
    • Getafe, Madrid, Spain, 28905
      • Hospital Universitario de Getafe
• United States
  • California
    • Sacramento, California, United States, 95821
      • Northern California Research
  • Colorado
    • Denver, Colorado, United States, 80209
      • Mountain View Clinical Research, Inc
  • District of Columbia
    • Washington, District of Columbia, United States, 20059
      • Howard University
  • Florida
    • Bradenton, Florida, United States, 34205
      • Bradenton Research Center, Inc.
    • Deerfield Beach, Florida, United States, 33064
      • Quantum Laboratories
    • Hialeah, Florida, United States, 33016
      • Galiz Research, LLC
    • Largo, Florida, United States, 33770
      • Largo Medical Center
    • Miami, Florida, United States, 33155
      • Allied Biomedical Research Institute
    • Miami, Florida, United States, 33176
      • Miami Dade Medical Research Institute, LLC
    • Miami, Florida, United States, 33144
      • L&L Research Choices, Inc
    • Ormond Beach, Florida, United States, 32174
      • Neurology Associates of Osmond Beach
    • Pinellas Park, Florida, United States, 33782
      • PharmaSeek LLC (DMI Research)
  • Georgia
    • Decatur, Georgia, United States, 30030
      • iResearch Atlanta, LLC
    • Savannah, Georgia, United States, 31419
      • RTR Medical Group
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Manchester, New Jersey, United States, 08759
      • Mid-Atlantic Geriatric/ARC
    • Mount Arlington, New Jersey, United States, 08756
      • The NeuroCognitive Institute
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Dayton, Ohio, United States, 45417
      • Neurology Specialists Inc
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29401
      • Roper St. Francis Healthcare
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Wesley Neurology Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 53 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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)	Biological: Albumin 5%; Therapeutic plasma exchange with human albumin 5%; Other Names: Albutein® 5%; Human Albumin Grifols 5%; Biological: Albumin 20%; Low volume plasma exchange with human albumin 5%; Other Names: Albutein® 20%; Human Albumin Grifols 20%; Biological: Immunoglobulin; Intravenous human immunoglobulin 5%; Other Names: Flebogamma® 5% DIF
Experimental: 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)	Biological: Albumin 5%; Therapeutic plasma exchange with human albumin 5%; Other Names: Albutein® 5%; Human Albumin Grifols 5%; Biological: Albumin 20%; Low volume plasma exchange with human albumin 5%; Other Names: Albutein® 20%; Human Albumin Grifols 20%; Biological: Immunoglobulin; Intravenous human immunoglobulin 5%; Other Names: Flebogamma® 5% DIF
Experimental: Low Albumin; Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period)	Biological: Albumin 5%; Therapeutic plasma exchange with human albumin 5%; Other Names: Albutein® 5%; Human Albumin Grifols 5%; Biological: Albumin 20%; Low volume plasma exchange with human albumin 5%; Other Names: Albutein® 20%; Human Albumin Grifols 20%
No Intervention: Control (sham) group; Simulated plasma exchange procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and 14 months
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).	Baseline and 14 Months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and 14 months
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).	Baseline and 14 months
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	Baseline and 14 months
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).	Baseline and 14 months

Collaborators and Investigators

• Sponsor: Instituto Grifols, S.A.
• Collaborators: Grifols Biologicals, LLC
• Investigators: Principal Investigator: Merce Boada Rovira, MD, PhD, Fundació ACE. Barcelona. Spain; Study Chair: Antonio Páez, MD, Instituto Grifols, S.A.; Study Director: Laura Núñez, BSc, Instituto Grifols, S.A.

Publications and helpful links

General Publications

• Cuberas-Borros G, Roca I, Castell-Conesa J, Nunez L, Boada M, Lopez OL, Grifols C, Barcelo M, Pareto D, Paez A. Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer's disease: additional results from the AMBAR study. Eur J Nucl Med Mol Imaging. 2022 Nov;49(13):4589-4600. doi: 10.1007/s00259-022-05915-5. Epub 2022 Jul 22.

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2012
• Primary Completion (Actual): March 6, 2018
• Study Completion (Actual): March 6, 2018

Study Registration Dates

• First Submitted: March 16, 2012
• First Submitted That Met QC Criteria: March 21, 2012
• First Posted (Estimate): March 22, 2012

Study Record Updates

• Last Update Posted (Actual): July 31, 2019
• Last Update Submitted That Met QC Criteria: July 10, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Alzheimer's disease; IVIG; Intravenous immunoglobulin; Albumin; Amyloid Beta (AB) peptide
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous
• Other Study ID Numbers: IG1002