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

• Sponsor: Instituto Grifols, S.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01561053
• Collaborator: Grifols Biologicals, LLC (Industry)
• Enrollment: 347
• Locations: 40
• Arms: 4
• Actual Duration (Months): 70.5
• Patients Per Site: 8.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Biological: Albumin 5%; Biological: Albumin 20%; Biological: Immunoglobulin	Phase 2/Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 347 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Apr 19, 2012
• Actual Primary Completion Date: Mar 6, 2018
• Actual Study Completion Date: Mar 6, 2018

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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).

3. 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

4. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

1. Hemoglobin < 10 g/dL

2. Difficult venous access precluding plasma exchange.

3. A history of frequent adverse reactions (serious or otherwise) to blood products.

4. Hypersensitivity to albumin or allergies to any of the components of Albutein.

5. History of immunoglobulin A (IgA) deficiency.

6. Known allergies to Flebogamma DIF components such as sorbitol.

7. History of thromboembolic complications of intravenous immunoglobulins.

8. Plasma creatinine > 2 mg/dl.

9. 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).

10. Liver cirrhosis or any liver problem with glutamic pyruvic transaminase (GPT) > 2.5 x upper limit of normal (ULN), or bilirubin > 2 mg/dL.

11. 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.

12. Participation in other clinical trials, or the receipt of any other investigational drug in the three months prior to the start of the study.

13. Any condition complicating adherence to the study protocol (illness with less than one year of expected survival, known drug or alcohol abuse, etc.).

14. Pregnant or nursing women or women not using effective contraceptive methods for at least one month after plasma exchange.

15. Fewer than six years of education (exclusion criteria under medical criterion).

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northern California Research	Sacramento	California	United States	95821
2	Mountain View Clinical Research, Inc	Denver	Colorado	United States	80209
3	Howard University	Washington	District of Columbia	United States	20059
4	Bradenton Research Center, Inc.	Bradenton	Florida	United States	34205
5	Quantum Laboratories	Deerfield Beach	Florida	United States	33064
6	Galiz Research, LLC	Hialeah	Florida	United States	33016
7	Largo Medical Center	Largo	Florida	United States	33770
8	L&L Research Choices, Inc	Miami	Florida	United States	33144
9	Allied Biomedical Research Institute	Miami	Florida	United States	33155
10	Miami Dade Medical Research Institute, LLC	Miami	Florida	United States	33176
11	Neurology Associates of Osmond Beach	Ormond Beach	Florida	United States	32174
12	PharmaSeek LLC (DMI Research)	Pinellas Park	Florida	United States	33782
13	iResearch Atlanta, LLC	Decatur	Georgia	United States	30030
14	RTR Medical Group	Savannah	Georgia	United States	31419
15	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
16	Mid-Atlantic Geriatric/ARC	Manchester	New Jersey	United States	08759
17	The NeuroCognitive Institute	Mount Arlington	New Jersey	United States	08756
18	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
19	Neurology Specialists Inc	Dayton	Ohio	United States	45417
20	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
21	Roper St. Francis Healthcare	Charleston	South Carolina	United States	29401
22	Wesley Neurology Clinic	Cordova	Tennessee	United States	38018
23	Hospital General de Elche	Elche	Alicante	Spain	03203
24	Hospital Universitario del Vinalopó	Elche	Alicante	Spain	03293
25	Hospital Universitari de Bellvitge	Hospitalet de Llobregat	Barcelona	Spain	08907
26	Hospital General de Catalunya	Sant Cugat Del Vallès	Barcelona	Spain	08190
27	Hospital Universitari Mútua de Terrassa	Terrassa	Barcelona	Spain	08221
28	Hospital Universitario Nuestra Señora de Candelaria	Santa Cruz de Tenerife	Canary Islands	Spain	38010
29	Hospital Universitario de Getafe	Getafe	Madrid	Spain	28905
30	Fundació ACE	Barcelona		Spain	08028
31	Hospital Vall d'Hebrón	Barcelona		Spain	08035
32	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain	08041
33	Hospital Universitario de Burgos	Burgos		Spain	09005
34	Parc Hospitalari Martí i Julià	Girona		Spain	17190
35	Hospital Universitari de Santa Maria	Lleida		Spain	25198
36	Hospital General Universitario Gregorio Marañón	Madrid		Spain	28007
37	Hospital Clínico San Carlos	Madrid		Spain	28040
38	Hospital Universitario Doctor Peset	Valencia		Spain	46017
39	Hospital Universitario y Politécnico La Fe	Valencia		Spain	46026
40	Hospital Viamed Montecanal	Zaragoza		Spain	50012

Sponsors and Collaborators

• Instituto Grifols, S.A.
• 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.

Study Documents (Full-Text)

• Study Protocol - Feb 21, 2018
• Statistical Analysis Plan - Jul 31, 2018

More Information

Publications

None provided.

• Responsible Party: Instituto Grifols, S.A.
• ClinicalTrials.gov Identifier: NCT01561053
• Other Study ID Numbers: IG1002
• First Posted: Mar 22, 2012
• Last Update Posted: Jul 31, 2019
• Last Verified: Jul 1, 2019

• Keywords provided by Instituto Grifols, S.A.: Alzheimer's disease; Amyloid Beta (AB) peptide; Albumin; Intravenous immunoglobulin; IVIG
• Additional relevant MeSH terms: Alzheimer Disease; Immunoglobulins; Immunoglobulins, Intravenous; Antibodies

Study Results

Participant Flow

Arm/Group Title	High Albumin + Immunoglobulin	Low Albumin + Immunoglobulin	Low Albumin	Control (Sham) Group
Arm/Group Description	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)	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)	Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period)	Simulated plasma exchange procedure
Period Title: Overall Study
STARTED	86	92	82	87
Patients With Baseline MMSE:18-21	47	40	47	42
Patients With Baseline MMSE:22-26	39	52	35	45
Randomized Not Treated	8	6	4	7
Evaluable Subjects	78	86	78	80
COMPLETED	51	56	61	64
NOT COMPLETED	35	36	21	23

Baseline Characteristics

Arm/Group Title	High Albumin + Immunoglobulin	Low Albumin + Immunoglobulin	Low Albumin	Control (Sham) Group	Total
Arm/Group Description	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)	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)	Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period)	Simulated plasma exchange procedure	Total of all reporting groups
Overall Participants	78	86	78	80	322
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	22 28.2%	17 19.8%	26 33.3%	29 36.3%	94 29.2%
>=65 years	56 71.8%	69 80.2%	52 66.7%	51 63.8%	228 70.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.54 (7.895)	69.47 (6.924)	68.47 (7.476)	68.44 (8.378)	68.99 (7.655)
Sex: Female, Male (Count of Participants)
Female	47 60.3%	48 55.8%	43 55.1%	36 45%	174 54%
Male	31 39.7%	38 44.2%	35 44.9%	44 55%	148 46%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Baseline Mini-Mental State Examination total score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	21.41 (2.616)	22.09 (2.633)	21.24 (2.408)	21.69 (2.559)	21.62 (2.566)

Outcome Measures

1. Primary Outcome

Title	Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Total Score (Changes From Baseline to 14 Months)
Description	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

Outcome Measure Data

Analysis Population Description

Evaluable population with ADAS-Cog measurement at 14 months

Arm/Group Title	High Albumin + Immunoglobulin	Low Albumin + Immunoglobulin	Low Albumin	Control (Sham) Group	All Treated
Arm/Group Description	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)	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)	Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period)	Simulated plasma exchange procedure	All patients Treatment groups 1, 2 and 3 combined
Measure Participants	50	57	61	64	168
Least Squares Mean (Standard Error) [units on a scale]	0.8 (1.28)	0.8 (1.09)	1.5 (1.02)	3.2 (0.95)	1.0 (0.64)

2. Primary Outcome

Title	Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score (Changes From Baseline to 14 Months)
Description	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

Outcome Measure Data

Analysis Population Description

Evaluable population with ADCS-ADL measurement at 14 months

Arm/Group Title	High Albumin + Immunoglobulin	Low Albumin + Immunoglobulin	Low Albumin	Control (Sham) Group	All Treated
Arm/Group Description	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)	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)	Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period)	Simulated plasma exchange procedure	All patients Treatment groups 1, 2 and 3 combined
Measure Participants	51	57	61	64	169
Least Squares Mean (Standard Error) [units on a scale]	-3.5 (1.80)	-2.0 (1.03)	-3.9 (1.24)	-6.7 (1.50)	-3.2 (0.78)

3. Other Pre-specified Outcome

Title	ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26
Description	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

Outcome Measure Data

Analysis Population Description

Evaluable population with baseline MMSE:22-26 and with ADAS-Cog measurement at 14 months

Arm/Group Title	High Albumin + Immunoglobulin	Low Albumin + Immunoglobulin	Low Albumin	Control (Sham) Group	All Treated
Arm/Group Description	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)	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)	Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period)	Simulated plasma exchange procedure	All patients Treatment groups 1, 2 and 3 combined
Measure Participants	23	37	25	38	85
Least Squares Mean (Standard Error) [units on a scale]	-0.9 (1.51)	-0.3 (1.04)	-0.6 (1.12)	0.6 (1.12)	-0.6 (0.68)

4. Other Pre-specified Outcome

Title	ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:22-26
Description	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

Outcome Measure Data

Analysis Population Description

Evaluable population with baseline MMSE:22-26 and with ADCS-ADL measurement at 14 months

Arm/Group Title	High Albumin + Immunoglobulin	Low Albumin + Immunoglobulin	Low Albumin	Control (Sham) Group	All Treated
Arm/Group Description	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)	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)	Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period)	Simulated plasma exchange procedure	All patients Treatment groups 1, 2 and 3 combined
Measure Participants	23	37	25	38	85
Least Squares Mean (Standard Error) [units on a scale]	-2.4 (1.68)	0.8 (0.98)	-0.9 (1.43)	-1.3 (1.29)	-0.6 (0.75)

5. Other Pre-specified Outcome

Title	ADAS-Cog Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21
Description	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

Outcome Measure Data

Analysis Population Description

Evaluable population with baseline MMSE:18-21 and with ADAS-Cog measurement at 14 months

Arm/Group Title	High Albumin + Immunoglobulin	Low Albumin + Immunoglobulin	Low Albumin	Control (Sham) Group	All Treated
Arm/Group Description	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)	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)	Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period)	Simulated plasma exchange procedure	All patients Treatment groups 1, 2 and 3 combined
Measure Participants	27	20	36	26	83
Least Squares Mean (Standard Error) [units on a scale]	2.4 (1.95)	1.9 (2.44)	3.3 (1.49)	6.4 (1.34)	2.6 (1.07)

6. Other Pre-specified Outcome

Title	ADCS-ADL Total Score (Changes From Baseline to 14 Months) in Patients With Baseline MMSE:18-21
Description	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

Outcome Measure Data

Analysis Population Description

Evaluable population with baseline MMSE:18-21 and with ADCS-ADL measurement at 14 months

Arm/Group Title	High Albumin + Immunoglobulin	Low Albumin + Immunoglobulin	Low Albumin	Control (Sham) Group	All Treated
Arm/Group Description	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)	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)	Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period)	Simulated plasma exchange procedure	All patients Treatment groups 1, 2 and 3 combined
Measure Participants	28	20	36	26	84
Least Squares Mean (Standard Error) [units on a scale]	-4.5 (2.97)	-5.7 (2.11)	-6.0 (1.75)	-14.1 (2.67)	-5.5 (1.33)

Adverse Events

Time Frame	14 Months
Adverse Event Reporting Description	1 randomized subject in the control group was implanted by error with a real central catheter and was then transfered and treated as high albumin + immunoglobulin subject. Therefore, this subject was considered for evaluable population as control (control group [n=80] and high albumin + immunoglobulin group [n=78]), but moved to high albumin + immunoglobulin group for safety analysis (control group [n=79] and high albumin + immunoglobulin group [n=79]).
Arm/Group Title	High Albumin + Immunoglobulin		Low Albumin + Immunoglobulin		Low Albumin		Control (Sham) Group
Arm/Group Description	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)		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)		Therapeutic plasma exchange with albumin 5% (intensive treatment period) + Low volume plasma exchange with low dose of albumin 20% (maintenance treatment period)		Simulated plasma exchange procedure
All Cause Mortality
	High Albumin + Immunoglobulin		Low Albumin + Immunoglobulin		Low Albumin		Control (Sham) Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/79 (0%)		2/86 (2.3%)		0/78 (0%)		0/79 (0%)
Serious Adverse Events
	High Albumin + Immunoglobulin		Low Albumin + Immunoglobulin		Low Albumin		Control (Sham) Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/79 (20.3%)		19/86 (22.1%)		8/78 (10.3%)		8/79 (10.1%)
Blood and lymphatic system disorders
Anaemia	0/79 (0%)	0	0/86 (0%)	0	0/78 (0%)	0	1/79 (1.3%)	1
Cardiac disorders
Myocardial infarction	0/79 (0%)	0	0/86 (0%)	0	1/78 (1.3%)	1	0/79 (0%)	0
Sinus tachycardia	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Eye disorders
Retinal detachment	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/79 (0%)	0	0/86 (0%)	0	0/78 (0%)	0	1/79 (1.3%)	1
Diarrhoea	0/79 (0%)	0	0/86 (0%)	0	0/78 (0%)	0	1/79 (1.3%)	1
Pancreatitis acute	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
General disorders
Chest pain	2/79 (2.5%)	2	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Intentional medical device removal by patient	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Non-cardiac chest pain	0/79 (0%)	0	0/86 (0%)	0	0/78 (0%)	0	1/79 (1.3%)	1
Pyrexia	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Thrombosis in device	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Immune system disorders
Anaphylactic reaction	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Infections and infestations
Bronchitis	0/79 (0%)	0	0/86 (0%)	0	0/78 (0%)	0	1/79 (1.3%)	1
Device related infection	1/79 (1.3%)	1	1/86 (1.2%)	1	3/78 (3.8%)	3	0/79 (0%)	0
Device related sepsis	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Diverticulitis	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Endocarditis staphylococcal	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Lobar pneumonia	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Sepsis	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Injury, poisoning and procedural complications
Anaesthetic complication cardiac	0/79 (0%)	0	0/86 (0%)	0	0/78 (0%)	0	1/79 (1.3%)	1
Femur fracture	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Hip fracture	1/79 (1.3%)	1	1/86 (1.2%)	1	0/78 (0%)	0	1/79 (1.3%)	1
Humerus fracture	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Post lumbar puncture syndrome	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Procedural intestinal perforation	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/79 (0%)	0	0/86 (0%)	0	1/78 (1.3%)	1	0/79 (0%)	0
Hypovolaemia	0/79 (0%)	0	1/86 (1.2%)	1	1/78 (1.3%)	1	0/79 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal adenocarcinoma	0/79 (0%)	0	0/86 (0%)	0	0/78 (0%)	0	1/79 (1.3%)	1
Nervous system disorders
Amyloid related imaging abnormalities	2/79 (2.5%)	2	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Cerebrovascular accident	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	1/79 (1.3%)	1
Headache	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Lacunar infarction	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Metabolic encephalopathy	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Presyncope	1/79 (1.3%)	1	0/86 (0%)	0	0/78 (0%)	0	0/79 (0%)	0
Syncope	2/79 (2.5%)	2	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Transient ischaemic attack	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Psychiatric disorders
Completed suicide	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Self injurious behaviour	0/79 (0%)	0	0/86 (0%)	0	1/78 (1.3%)	1	0/79 (0%)	0
Respiratory, thoracic and mediastinal disorders
Apnoea	0/79 (0%)	0	0/86 (0%)	0	1/78 (1.3%)	1	0/79 (0%)	0
Dyspnoea	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Rhinitis allergic	0/79 (0%)	0	0/86 (0%)	0	0/78 (0%)	0	1/79 (1.3%)	1
Surgical and medical procedures
Bladder neoplasm surgery	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Knee operation	0/79 (0%)	0	0/86 (0%)	0	0/78 (0%)	0	1/79 (1.3%)	1
Vascular disorders
Jugular vein thrombosis	0/79 (0%)	0	1/86 (1.2%)	1	0/78 (0%)	0	0/79 (0%)	0
Other (Not Including Serious) Adverse Events
	High Albumin + Immunoglobulin		Low Albumin + Immunoglobulin		Low Albumin		Control (Sham) Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	67/79 (84.8%)		77/86 (89.5%)		72/78 (92.3%)		56/79 (70.9%)
Blood and lymphatic system disorders
Anaemia	17/79 (21.5%)	17	17/86 (19.8%)	19	16/78 (20.5%)	20	4/79 (5.1%)	5
Iron deficiency anaemia	5/79 (6.3%)	5	1/86 (1.2%)	1	3/78 (3.8%)	3	1/79 (1.3%)	1
Cardiac disorders
Bradycardia	4/79 (5.1%)	6	3/86 (3.5%)	3	1/78 (1.3%)	1	0/79 (0%)	0
Gastrointestinal disorders
Diarrhoea	4/79 (5.1%)	6	6/86 (7%)	7	3/78 (3.8%)	3	2/79 (2.5%)	2
Nausea	5/79 (6.3%)	6	5/86 (5.8%)	8	8/78 (10.3%)	11	0/79 (0%)	0
Vomiting	3/79 (3.8%)	4	6/86 (7%)	6	5/78 (6.4%)	5	3/79 (3.8%)	3
General disorders
Catheter site erythema	3/79 (3.8%)	4	3/86 (3.5%)	3	4/78 (5.1%)	6	0/79 (0%)	0
Device connection issue	0/79 (0%)	0	0/86 (0%)	0	0/78 (0%)	0	4/79 (5.1%)	8
Extravasation	10/79 (12.7%)	15	7/86 (8.1%)	13	7/78 (9%)	12	0/79 (0%)	0
Infusion site extravasation	7/79 (8.9%)	10	4/86 (4.7%)	6	2/78 (2.6%)	3	0/79 (0%)	0
Oedema peripheral	1/79 (1.3%)	2	0/86 (0%)	0	3/78 (3.8%)	3	5/79 (6.3%)	5
Catheter site pain	2/79 (2.5%)	2	0/86 (0%)	0	9/78 (11.5%)	11	0/79 (0%)	0
Infections and infestations
Catheter site infection	1/79 (1.3%)	1	4/86 (4.7%)	5	4/78 (5.1%)	4	0/79 (0%)	0
Nasopharyngitis	6/79 (7.6%)	6	3/86 (3.5%)	3	7/78 (9%)	7	3/79 (3.8%)	5
Respiratory tract infection	1/79 (1.3%)	1	4/86 (4.7%)	4	3/78 (3.8%)	3	4/79 (5.1%)	4
Upper respiratory tract infection	6/79 (7.6%)	6	1/86 (1.2%)	1	6/78 (7.7%)	6	5/79 (6.3%)	6
Urinary tract infection	5/79 (6.3%)	6	6/86 (7%)	7	1/78 (1.3%)	1	3/79 (3.8%)	3
Injury, poisoning and procedural complications
Contusion	3/79 (3.8%)	4	9/86 (10.5%)	10	4/78 (5.1%)	4	4/79 (5.1%)	4
Vascular access complication	6/79 (7.6%)	11	4/86 (4.7%)	5	4/78 (5.1%)	7	0/79 (0%)	0
Investigations
Blood fibrinogen decreased	3/79 (3.8%)	4	5/86 (5.8%)	8	1/78 (1.3%)	1	0/79 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	3/79 (3.8%)	3	3/86 (3.5%)	3	4/78 (5.1%)	4	1/79 (1.3%)	1
Muscle spasms	18/79 (22.8%)	34	5/86 (5.8%)	6	9/78 (11.5%)	18	3/79 (3.8%)	3
Pain in extremity	4/79 (5.1%)	5	4/86 (4.7%)	4	2/78 (2.6%)	2	1/79 (1.3%)	1
Nervous system disorders
Dizziness	11/79 (13.9%)	12	12/86 (14%)	16	8/78 (10.3%)	10	3/79 (3.8%)	7
Headache	12/79 (15.2%)	13	4/86 (4.7%)	4	7/78 (9%)	9	14/79 (17.7%)	20
Paraesthesia	5/79 (6.3%)	12	1/86 (1.2%)	1	9/78 (11.5%)	16	0/79 (0%)	0
Presyncope	10/79 (12.7%)	14	14/86 (16.3%)	18	8/78 (10.3%)	9	2/79 (2.5%)	2
Syncope	4/79 (5.1%)	4	4/86 (4.7%)	5	4/78 (5.1%)	5	1/79 (1.3%)	1
Psychiatric disorders
Anxiety	6/79 (7.6%)	11	2/86 (2.3%)	4	6/78 (7.7%)	6	1/79 (1.3%)	1
Skin and subcutaneous tissue disorders
Erythema	0/79 (0%)	0	1/86 (1.2%)	1	4/78 (5.1%)	4	1/79 (1.3%)	1
Vascular disorders
Haematoma	3/79 (3.8%)	3	5/86 (5.8%)	6	3/78 (3.8%)	4	0/79 (0%)	0
Hypertension	0/79 (0%)	0	0/86 (0%)	0	3/78 (3.8%)	4	5/79 (6.3%)	7
Hypotension	16/79 (20.3%)	34	16/86 (18.6%)	39	21/78 (26.9%)	43	1/79 (1.3%)	1
Poor venous access	7/79 (8.9%)	10	6/86 (7%)	7	4/78 (5.1%)	6	0/79 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A 18-month post-study period is reserved for a joint, multi-center publication of study results. After this period, individual sites may publish results provided that the Sponsor is allowed 60 days to review any proposed publication for removal of confidential, protected, and trademarked material prior to submission with an option to delay publication up to 120 days if needed to protect its interests. The Sponsor shall retain the option to receive acknowledgment for its sponsorship of the study.