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

This study has been completed.
Sponsor:
Collaborator:
Grifols Biologicals Inc.
Information provided by (Responsible Party):
Grifols Biologicals Inc. ( Instituto Grifols, S.A. )
ClinicalTrials.gov Identifier:
NCT00742417
First received: August 25, 2008
Last updated: May 5, 2016
Last verified: May 2016
  Purpose
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.

Condition Intervention Phase
Alzheimer's Disease
Biological: Albutein 5%
Other: Control
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by Grifols Biologicals Inc.:

Primary Outcome Measures:
  • Change From Baseline in Aβ1-42 Cerebrospinal Fluid (CSF) Levels. [ Time Frame: Baseline and up to week 44 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • P-Tau and Tau CSF Levels Throughout the Study. [ Time Frame: Baseline, week 02, week 08, week 20, week 33 and week 44 ] [ Designated as safety issue: No ]
    Levels of Tau and P-tau in CSF throughout the treatment phase and the follow-up phase (week 44).

  • Aβ1−40 Plasma Levels Before and After Each Study Period (The Genetics Company). [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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).

  • Aβ1−42 Plasma Levels Before and After Each Study Period (The Genetics Company). [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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).

  • Aβ1−42 Plasma Levels Before and After Each Study Period (Innotest). [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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).

  • Change From Baseline to Week 44 in Cognitive, Functional and Neuropsychiatric Scores (MMSE, ADAS-Cog, NPS Battery and CSDD) [ Time Frame: Change from baseline at week 44 ] [ Designated as safety issue: No ]

    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 to Week 44 in Cognitive, Functional and Neuropsychiatric Scores (ADCS-ADL, NPI, CDR-Sb and ADCS-CGIC). [ Time Frame: Change from baseline at week 44 ] [ Designated as safety issue: No ]

    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)

  • Magnetic Resonance Imaging (MRI) Structural Changes Variations Versus Baseline. [ Time Frame: Week 00 (baseline), week 20 and week 44 ] [ Designated as safety issue: No ]
    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.

  • Variations in Hypoperfusion Based on Single Photon Emission Computed Tomography (SPECT) [ Time Frame: End of study ] [ Designated as safety issue: No ]
    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.


Enrollment: 42
Study Start Date: July 2007
Study Completion Date: March 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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)

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.

  Eligibility

Ages Eligible for Study:   55 Years to 85 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00742417

Locations
United States, District of Columbia
Howard University
Washington, District of Columbia, United States, 20059
United States, New Jersey
Mid-Atlantic Geriatric/ARC
Manchester Township, New Jersey, United States, 08759
Spain
Fundació ACE
Barcelona, Catalunya, Spain, 08028
Hospital General Universitario Gregorio Marañon
Madrid, Spain, 28007
Sponsors and Collaborators
Instituto Grifols, S.A.
Grifols Biologicals Inc.
Investigators
Principal Investigator: Merce Boada, MD Fundació ACE
Study Director: Laura Núñez Grifols Biologicals Inc.
Study Chair: Antonio Paez Grifols Biologicals Inc.
  More Information

Responsible Party: Instituto Grifols, S.A.
ClinicalTrials.gov Identifier: NCT00742417     History of Changes
Other Study ID Numbers: IG0602 
Study First Received: August 25, 2008
Results First Received: December 3, 2015
Last Updated: May 5, 2016
Health Authority: United States: Food and Drug Administration
Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Grifols Biologicals Inc.:
Alzheimer's
Dementia
Senile
Loss of cognitive abilities
Old age
Elderly
Aging
Albumin
Caregiver
amyloid
beta amyloid
Central Nervous System Diseases
Brain Disease
Mental Disorders
Plasma Exchange

Additional relevant MeSH terms:
Alzheimer Disease
Amyloidosis
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Proteostasis Deficiencies
Metabolic Diseases

ClinicalTrials.gov processed this record on September 26, 2016