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Plasma Exchange With Albumin in AMN Patients

Primary Purpose

Adrenomyeloneuropathy, Adrenoleukodystrophy

Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
Albumin solution
Sponsored by
Onofre, Aurora Pujol, M.D.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adrenomyeloneuropathy focused on measuring plasma exchange, albumin, VLCFA

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Men of 18 to 65 years old, inclusive
  2. Elevated plasma VLCFA and gene mutation identified
  3. Clinical signs of AMN with at least pyramidal signs in the lower limbs and difficulties to run
  4. Presence of motor deficit according to the EDSS scale
  5. Ability to perform the 2MWT
  6. Normal brain MRI or brain MRI showing the following abnormalities that can be observed in AMN patients without the cerebral form of X-ALD, obtained in the 6 months prior to screening:

    • abnormal hyperintensity of pyramidal tract fibers in the brain stem on FLAIR or T2 sequence
    • abnormal hyperintensity of pyramidal tract fibers in the internal capsules on FLAIR or T2 sequence
    • cerebellar atrophy
    • moderate cortical atrophy

Exclusion Criteria:

  1. Any contraindication for plasma exchange due to behavioral disorders or abnormal coagulation parameters, such for example:

    • Hypocalcemia (Ca++ < 8.7 mg/dl)
    • Thrombocytopenia (< 100.000/µl)
    • Fibrinogen < 1.5 g/l
    • Prothrombin time (Quick) p< 60% versus control (INR > 1.5)
    • Beta-blocker treatment and bradycardia < 55/min
    • Treatment with ACIs (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. Hipersensibility to albumin o allergies to any of the components of Albunorm® 5%
  6. Plasma creatine > 2 mg/dl
  7. Uncontrolled high blood pressure (systolic blood pressure of 160 mmHg or higher and/or diastolic blood pressure of 100 mmHg or higher despite regular treatment during the last 3 months)
  8. Liver cirrhosis or any liver problem with GPT > 2.5 x ULN, or bilirubin > 2 mg/dl
  9. Heart diseases as evidenced by myocardial infarction, severe or unstable angina, or heart failure in the past 12 months
  10. Gadolinium enhancement on T1 sequence of any abnormal hypersignal of white matter, including myelinated pyramidal tracts, visible at brain MRI on FLAIR sequences
  11. Significant peripheral edema (2+ or more on the Assessment Chart for Pitting Edema) of the extremities of any etiology
  12. Any evolutive malignancy during the last five years or any condition complicating adherence to the study protocol
  13. Smokers (one pack/ day or more for at least 20 years), current or former
  14. Any psychiatric disease
  15. Present participation to another therapeutic clinical trial for X-ALD, or the receipt of any other investigational drug in the three months prior to the start of the study
  16. Patients being treated with anticoagulants or antiplatelet therapy
  17. Not easily contactable by the investigator in case of emergency or not capable to call the investigator

Sites / Locations

  • Bellvitge University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Patients

Arm Description

Patients before and after the treatment

Outcomes

Primary Outcome Measures

Concentration of very long chain fatty acids
Concentration of C26:0, C24:0 fatty acids and C26:0/C22:0 ratio in plasma

Secondary Outcome Measures

2 Minute Walk Test
It measures the distance an individual is able to walk over a total of two minutes on a hard, flat surface
6 Minute Walk Test
It measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface
Timed Up and Go (TUG) test
It consists in standing up, walking 3 meters, turning around, walk back to the chair and sitting back down, at regular pace
Time to walk 25 Feet (TW25)
The patient should walk 7.62 meters (25 feet) as quickly, but safely, as possible without running
Expanded disability status scale (EDSS)
This scale measures motor function, ranging from 0 (normal neurological examination) to 10 (death)
Ashworth scale
The Modified Ashworth Scale measures spasticity in patients with lesions of the CNS or neurological disorders. It ranges from 0 (no increase in tone) to 4 (affected part(s) rigid in flexion or extension).
SF-Qualiveen (Short-form Qualiveen)
The Qualiveen is a specific patients' health-related quality of life developed to assess the impact of urinary disorders in patients with neurological conditions. Response options are framed as 5-point Likert-type scales, with 0 indicating no impact of urinary problems on health-related quality of life and 4 indicating a high adverse impact.

Full Information

First Posted
March 6, 2020
Last Updated
September 21, 2022
Sponsor
Onofre, Aurora Pujol, M.D.
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1. Study Identification

Unique Protocol Identification Number
NCT04303416
Brief Title
Plasma Exchange With Albumin in AMN Patients
Official Title
Effect of Plasma Exchange With Albumin in Patients With Adrenomyeloneuropathy: Unicentric, Single Arm, Proof of Concept Study.
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
March 9, 2020 (Actual)
Primary Completion Date
February 24, 2021 (Actual)
Study Completion Date
September 13, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Onofre, Aurora Pujol, M.D.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Adrenoleukodystrophy (X-ALD) is the most common genetic disorder of the brain white matter with an incidence of 1:14,700 births. It is caused by mutations in the ABCD1 gene, which encodes a transporter of very long-chain fatty acids (VCLFA) into the peroxisome for degradation. As a consequence VLCFA accumulate in tissues and plasma being the pathognomonic biomarker for diagnosis. The excess of VLCFA produces mitochondrial ROS and oxidative damage, a major factor driving X-ALD pathogenesis. Other key dysregulated pathways are energy production, mitochondrial biogenesis and respiration, proteostasis, and ER stress. Current therapeutic options are unsatisfactory, restricted to bone marrow transplant and gene therapy, for which most patients do not qualify. The encouraging results of plasma exchange (PE) with albumin replacement for Alzheimer's Disease prompted us to start this study. Our rationale is the following: In plasma, VLCFA are transported by lipoproteins and albumin. Albumin is the major transporter of fatty acids (FA) to the brain. ABCD1 deficiency induces inflammation and increases blood-brain barrier leakage, which could facilitate increased permeability to albumin. We posit that replacement of albumin would lower VLCFA levels in plasma through peripheral sink mechanisms, diminishing the quantity of VLCFA reaching the brain, and would prevent lipid peroxidation. A pilot proof-of-concept study in 5 X-ALD patients will be carried out to replace endogenous albumin through PE applied, once a week the first month and monthly for 5 months. A 6 months follow-up after the end of the treatment will be carried out.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adrenomyeloneuropathy, Adrenoleukodystrophy
Keywords
plasma exchange, albumin, VLCFA

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Patients
Arm Type
Experimental
Arm Description
Patients before and after the treatment
Intervention Type
Drug
Intervention Name(s)
Albumin solution
Other Intervention Name(s)
plasma exchange
Intervention Description
plasma exchange with albumin, one per week for one month, then one per month for 5 months
Primary Outcome Measure Information:
Title
Concentration of very long chain fatty acids
Description
Concentration of C26:0, C24:0 fatty acids and C26:0/C22:0 ratio in plasma
Time Frame
Change from baseline at 6 months
Secondary Outcome Measure Information:
Title
2 Minute Walk Test
Description
It measures the distance an individual is able to walk over a total of two minutes on a hard, flat surface
Time Frame
Months 0, 6 and 12
Title
6 Minute Walk Test
Description
It measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface
Time Frame
Months 0, 6 and 12
Title
Timed Up and Go (TUG) test
Description
It consists in standing up, walking 3 meters, turning around, walk back to the chair and sitting back down, at regular pace
Time Frame
Months 0, 6 and 12
Title
Time to walk 25 Feet (TW25)
Description
The patient should walk 7.62 meters (25 feet) as quickly, but safely, as possible without running
Time Frame
Months 0, 6 and 12
Title
Expanded disability status scale (EDSS)
Description
This scale measures motor function, ranging from 0 (normal neurological examination) to 10 (death)
Time Frame
Months 0, 6 and 12
Title
Ashworth scale
Description
The Modified Ashworth Scale measures spasticity in patients with lesions of the CNS or neurological disorders. It ranges from 0 (no increase in tone) to 4 (affected part(s) rigid in flexion or extension).
Time Frame
Months 0, 6 and 12
Title
SF-Qualiveen (Short-form Qualiveen)
Description
The Qualiveen is a specific patients' health-related quality of life developed to assess the impact of urinary disorders in patients with neurological conditions. Response options are framed as 5-point Likert-type scales, with 0 indicating no impact of urinary problems on health-related quality of life and 4 indicating a high adverse impact.
Time Frame
Months 0, 6 and 12

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men of 18 to 65 years old, inclusive Elevated plasma VLCFA and gene mutation identified Clinical signs of AMN with at least pyramidal signs in the lower limbs and difficulties to run Presence of motor deficit according to the EDSS scale Ability to perform the 2MWT Normal brain MRI or brain MRI showing the following abnormalities that can be observed in AMN patients without the cerebral form of X-ALD, obtained in the 6 months prior to screening: abnormal hyperintensity of pyramidal tract fibers in the brain stem on FLAIR or T2 sequence abnormal hyperintensity of pyramidal tract fibers in the internal capsules on FLAIR or T2 sequence cerebellar atrophy moderate cortical atrophy Exclusion Criteria: Any contraindication for plasma exchange due to behavioral disorders or abnormal coagulation parameters, such for example: Hypocalcemia (Ca++ < 8.7 mg/dl) Thrombocytopenia (< 100.000/µl) Fibrinogen < 1.5 g/l Prothrombin time (Quick) p< 60% versus control (INR > 1.5) Beta-blocker treatment and bradycardia < 55/min Treatment with ACIs (increased risk of allergic reactions) Hemoglobin < 10 g/dl Difficult venous access precluding plasma exchange A history of frequent adverse reactions (serious or otherwise) to blood products Hipersensibility to albumin o allergies to any of the components of Albunorm® 5% Plasma creatine > 2 mg/dl Uncontrolled high blood pressure (systolic blood pressure of 160 mmHg or higher and/or diastolic blood pressure of 100 mmHg or higher despite regular treatment during the last 3 months) Liver cirrhosis or any liver problem with GPT > 2.5 x ULN, or bilirubin > 2 mg/dl Heart diseases as evidenced by myocardial infarction, severe or unstable angina, or heart failure in the past 12 months Gadolinium enhancement on T1 sequence of any abnormal hypersignal of white matter, including myelinated pyramidal tracts, visible at brain MRI on FLAIR sequences Significant peripheral edema (2+ or more on the Assessment Chart for Pitting Edema) of the extremities of any etiology Any evolutive malignancy during the last five years or any condition complicating adherence to the study protocol Smokers (one pack/ day or more for at least 20 years), current or former Any psychiatric disease Present participation to another therapeutic clinical trial for X-ALD, or the receipt of any other investigational drug in the three months prior to the start of the study Patients being treated with anticoagulants or antiplatelet therapy Not easily contactable by the investigator in case of emergency or not capable to call the investigator
Facility Information:
Facility Name
Bellvitge University Hospital
City
L'Hospitalet de Llobregat
State/Province
Barcelona
ZIP/Postal Code
08908
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Plasma Exchange With Albumin in AMN Patients

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