Efficacy and Safety of Plasma Exchange With 5% Albumin in Beta-amyloid Peptide Clearance in Cerebral Spinal Fluid

Phase II Study to Evaluate the Efficacy and Safety of Plasma Exchange With 5% Albumin in Beta-amyloid Peptide Clearance in Cerebral Spinal Fluid, and Its Effects in Patients With Mild-moderate Alzheimer's Disease.

The purpose of this study was to evaluate the efficacy and safety of plasma exchange with 5% albumin in beta-amyloid peptide clearance in cerebrospinal fluid, and its effects in patients with mild-moderate Alzheimer's disease.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Biological: Albutein 5%; Other: Control

Detailed Description

A phase II study was conducted primarily to determine whether plasma exchange with 5% human albumin is able to modify the concentration of beta-amyloid peptide in cerebrospinal fluid (CSF) in patients with AD.

• There was two weeks for screening and randomization of both groups (treatment and control).
• The subjects were randomized in a 1:1 proportion.

After screening and randomization, treatment proceeded as follows:

• three weeks of intensive treatment with two plasma exchanges per week
• followed by a month and a half of maintenance treatment with one weekly plasma exchange, and
• finally, three months of treatment with one plasma exchange every two weeks.

The control group followed the same program, except for the plasma exchanges. After the treatment period ended, subjects followed-up for a 6-month period of time.

The trial comprises a global multicenter (Spain and US), blind, randomized, controlled design. The trials key coordination is based in Spain where Dr. Boada (see Study Officials/Investigators) is the main study official.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Catalunya
    • Barcelona, Catalunya, Spain, 08028
      • Fundacio ACE
• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20059
      • Howard University
  • New Jersey
    • Manchester Township, New Jersey, United States, 08759
      • Mid-Atlantic Geriatric/ARC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• A diagnosis of AD ( National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criterion), and Mini-mental Status Examination (MMSE) score between ≥18 and ≤26.
• Current stable treatment with acetylcholine esterase inhibitors (AChEIs) for the previous three months.
• A stable care taker must be available, and must attend the patient study visits.
• The patient and a close relative or 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).
• 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.
• 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, must be available.

Exclusion Criteria:

• Any contraindication for plasma exchange due to behavioral disorders or abnormal coagulation parameters
• A history of frequent adverse reactions (serious or otherwise) to blood products.
• Hypersensitivity to albumin or allergies to any of the components of Albutein 5% Human Albumin.
• Plasma creatinine > 2 mg/dL.
• Uncontrolled high blood pressure.
• Liver cirrhosis or any liver problem with alanine aminotransferase (GPT) > 2.5 x upper limit of normal (ULN), or bilirubin > 2 mg/dL.
• Heart diseases, including antecedents of coronary disease and heart failure.
• Difficult venous access precluding plasma exchange.
• Participation in other clinical trials, or the reception of any other investigational drug in the three months prior to the start of the study.
• Any condition complicating adherence to the study protocol (illness with less than one year of expected survival, toxic habits, etc.).
• Pregnant or nursing women or women not using effective contraceptive methods for at least one month after plasma exchange.
• Fewer than six years of education.
• Prior behavioral disorders requiring pharmacological treatment, including insomnia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Control	Other: Control; Control group followed the same schedule; however, they did not undergo plasma replacement (it was subjected to simulated plasma replacements)
Experimental: Albutein 5%; Patients allocated to this arm underwent plasma exchange with Albutein 5%.	Biological: Albutein 5%; 18 Plasma Exchanges using Albutein 5%: three weeks of intensive treatment with two plasma exchanges per week; six weeks of maintenance treatment with one weekly plasma exchange; three months of maintenance treatment with one plasma exchange every two weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Aβ1-42 Cerebrospinal Fluid (CSF) Levels.	Change in levels of Aβ1-42 in CSF in the period between baseline lumbar puncture (before the start of treatment) and lumbar puncture immediately after the end of the last plasma exchange (whenever this may be). Separate assays of Aβ1-42 were performed with Innotest and The Genetics Company commercial kits.	Baseline and up to week 44

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
P-Tau and Tau CSF Levels Throughout the Study.	Levels of Tau and P-tau in CSF throughout the treatment phase and the follow-up phase (week 44).	Baseline, week 02, week 08, week 20, week 33 and week 44
Aβ1-40 Plasma Levels Before and After Each Study Period (The Genetics Company).	Plasma levels of Aβ1-40 before and after the Intensive period, Maintenance period I, Maintenance period II and the Follow-up phase (using The Genetics Company commercial kits).	Baseline, pre-plasma exchange 1 (PRE-PE1), post-plasma exchange 6 (POST-PE6), pre-plasma exchange 7 (PRE-PE7), post-plasma exchange 12 (POST-PE12), pre-plasma exchange 13 (PRE-PE13), post-plasma exchange 18 (POST-PE18), week 33 and week 44.
Aβ1-42 Plasma Levels Before and After Each Study Period (The Genetics Company).	Plasma levels of Aβ1-42 before and after the Intensive period, Maintenance period I, Maintenance period II and the Follow-up phase (using The Genetics Company commercial kits).	Baseline, pre-plasma exchange 1 (PRE-PE1), post-plasma exchange 6 (POST-PE6), pre-plasma exchange 7 (PRE-PE7), post-plasma exchange 12 (POST-PE12), pre-plasma exchange 13 (PRE-PE13), post-plasma exchange 18 (POST-PE18), week 33 and week 44
Aβ1-42 Plasma Levels Before and After Each Study Period (Innotest).	Plasma levels of Aβ1-42 before and after the Intensive period, Maintenance period I, Maintenance period II and the Follow-up phase (using Innotest commercial kits).	Baseline, pre-plasma exchange 1 (PRE-PE1), post-plasma exchange 6 (POST-PE6), pre-plasma exchange 7 (PRE-PE7), post-plasma exchange 12 (POST-PE12), pre-plasma exchange 13 (PRE-PE13), post-plasma exchange 18 (POST-PE18), week 33 and week 44.
Change From Baseline to Week 44 in Cognitive, Functional and Neuropsychiatric Scores (MMSE, ADAS-Cog, NPS Battery and CSDD)	Change in the cognitive, functional and neuropsychiatric scores and overall development.; MMSE: Mini Mental State Examination Score (range = 0 to 30, with lower values indicating impairment); ADAS-Cog: Alzheimer's Disease Assessment Scale, Cognitive Subscale (range = 0 to 70, with higher values indicating impairment); NPS (Neuropsychological battery): •SDMT (Symbol Digit Modalities Test, range = 0 to 110, with lower values indicating impairment), •SVF (Semantic Verbal Fluency Test, with a maximum of 44 words in 60 seconds), •PVF F, A and S (Phonetic Verbal Fluency Test, with a maximum of 44 words in 60 seconds), •BNT (Boston Naming Test, with a maximum of 15 pictures), •RAVLT (Rey Auditory Verbal Learning Test, with 15 words the patient should listen and remind); CSDD (Cornell Scale for Depression in Dementia, 0 = none; 1 =mild or intermittent; 2 = severe)	Change from baseline at week 44
Change From Baseline to Week 44 in Cognitive, Functional and Neuropsychiatric Scores (ADCS-ADL, NPI, CDR-Sb and ADCS-CGIC).	Change in the cognitive, functional and neuropsychiatric scores and overall development.; ADCS-ADL: Alzheimer's Disease Cooperative Study/Activities Of Daily Living (23 questions describing daily activity of the subject and requests the informer to describe the actions or behaviors observed. Increased autonomy associated to higher scores, maximum of 78 points and minimum of 0); NPI: Neuropsychiatric Inventory Questions (12 symptom domains scored by frequency [range=0 to 4, higher values being more frequent] and severity [range=1 to 3, higher values being more severe], total score is sum of frequency x severity of all domains); CDR-Sb: Clinical Dementia Rating (range=0 to 3, higher values being more severe); ADCS-CGIC: Alzheimer's Disease Cooperative Study/Clinical Global Impression of Change (7-point Likert scale, 0=not assessed, 1=marked improvement, 2=moderate improvement, 3=minimal improvement, 4=no change, 5=minimal worsening, 6=moderate worsening and 7=marked worsening)	Change from baseline at week 44
Magnetic Resonance Imaging (MRI) Structural Changes Variations Versus Baseline.	Structural changes in volume of the hippocampus, posterior cingular area, and other associated areas by Magnetic Resonance Imaging (MRI). Three measurements were made (week -2 or -1, 20 and 44). It was measured the variations versus the baseline.	Week 00 (baseline), week 20 and week 44
Variations in Hypoperfusion Based on Single Photon Emission Computed Tomography (SPECT)	Percentage of patients with improved perfusion at the end of the study compared to their initial perfusion. Frontal, parietal and temporal lobes were evaluated from the quantified NeuroGam images. This rendered parametric images showed brain alterations with more than 2 standard deviations with respect to a normal data base. Initial parametric images were compared to the final ones and it was considered perfusion improvement those patients that showed less stretch and/or defect intensity.	End of study

Collaborators and Investigators

• Sponsor: Instituto Grifols, S.A.
• Collaborators: Grifols Biologicals, LLC
• Investigators: Principal Investigator: Merce Boada, MD, Fundacio ACE; Study Director: Laura Núñez, Grifols Biologicals, LLC; Study Chair: Antonio Paez, Grifols Biologicals, LLC

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: August 25, 2008
• First Submitted That Met QC Criteria: August 25, 2008
• First Posted (Estimate): August 27, 2008

Study Record Updates

• Last Update Posted (Estimate): June 14, 2016
• Last Update Submitted That Met QC Criteria: May 5, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Elderly; amyloid; Dementia; Aging; Caregiver; Brain Disease; Central Nervous System Diseases; Mental Disorders; Old age; Alzheimer's; Albumin; Senile; Loss of cognitive abilities; beta amyloid; Plasma Exchange
• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Proteostasis Deficiencies; Dementia; Tauopathies; Amyloidosis; Alzheimer Disease
• Other Study ID Numbers: IG0602