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NCT Number: NCT04303416

Plasma Exchange With Albumin in AMN Patients

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.

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Key information

Conditions

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

Age range

18 year–65 year

Sex eligibility

Male

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Bellvitge University Hospital

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Albumin solution

Drug

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

Other names: plasma exchange

Primary outcomes

  1. Concentration of very long chain fatty acids

    Time frame: Change from baseline at 6 months

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

Secondary outcomes

  1. 2 Minute Walk Test

    Time frame: Months 0, 6 and 12

    It measures the distance an individual is able to walk over a total of two minutes on a hard, flat surface

  2. 6 Minute Walk Test

    Time frame: Months 0, 6 and 12

    It measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface

  3. Timed Up and Go (TUG) test

    Time frame: Months 0, 6 and 12

    It consists in standing up, walking 3 meters, turning around, walk back to the chair and sitting back down, at regular pace

  4. Time to walk 25 Feet (TW25)

    Time frame: Months 0, 6 and 12

    The patient should walk 7.62 meters (25 feet) as quickly, but safely, as possible without running

  5. Expanded disability status scale (EDSS)

    Time frame: Months 0, 6 and 12

    This scale measures motor function, ranging from 0 (normal neurological examination) to 10 (death)

  6. Ashworth scale

    Time frame: Months 0, 6 and 12

    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).

  7. SF-Qualiveen (Short-form Qualiveen)

    Time frame: Months 0, 6 and 12

    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.

Sponsors and collaborators

Lead sponsor

Pujol, Aurora, M.D.

Indiv

Registry information

Official study title

Effect of Plasma Exchange With Albumin in Patients With Adrenomyeloneuropathy: Unicentric, Single Arm, Proof of Concept Study.

Important dates

Study start
2020
Primary completion
2021
Study completion
2021
First posted
Mar 11, 2020
Registry last updated
Sep 22, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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