Plasma Exchange With Albumin in AMN Patients

NCT04303416 | Completed Phase 2

• 1 other identifier: XAMNPEAP2019
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

Adrenomyeloneuropathy; Adrenoleukodystrophy

Keywords

plasma exchange; albumin; VLCFA

Outcome Measures

Primary Outcomes (1)

• Concentration of very long chain fatty acids

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

  Change from baseline at 6 months

Secondary Outcomes (7)

• 2 Minute Walk Test

  Months 0, 6 and 12

• 6 Minute Walk Test

  Months 0, 6 and 12

• Timed Up and Go (TUG) test

  Months 0, 6 and 12

• Time to walk 25 Feet (TW25)

  Months 0, 6 and 12

• Expanded disability status scale (EDSS)

  Months 0, 6 and 12

Study Arms (1)

Patients

EXPERIMENTAL

Patients before and after the treatment

Drug: Albumin solution

Interventions

Albumin solution DRUG

plasma exchange with albumin, one per week for one month, then one per month for 5 months

Also known as: plasma exchange

Patients

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Pujol, Aurora, M.D.: lead

Study Sites (1)

Bellvitge University Hospital

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Location

MeSH Terms

Conditions

Adrenoleukodystrophy

Interventions

Plasma Exchange

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Demyelinating Diseases; X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heredodegenerative Disorders, Nervous System; Metabolism, Inborn Errors; Peroxisomal Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Blood Transfusion; Biological Therapy; Therapeutics; Plasmapheresis; Blood Component Removal; Sorption Detoxification; Extracorporeal Circulation; Surgical Procedures, Operative

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDIV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 6, 2020
• First Posted: March 11, 2020
• Study Start: March 9, 2020
• Primary Completion: February 24, 2021
• Study Completion: September 13, 2021
• Last Updated: September 22, 2022

Record last verified: 2022-09

Locations

ES (1)