Plasma Exchange With Albumin in AMN Patients

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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.

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.
    


Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Concentration of very long chain fatty acids

Secondary Outcome

 2 Minute Walk Test

Condition

Adrenomyeloneuropathy

Intervention

Albumin solution

Study Arms / Comparison Groups

 Patients
Description:  Patients before and after the treatment

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

5

Start Date

March 9, 2020

Completion Date

August 28, 2021

Primary Completion Date

February 24, 2021

Eligibility Criteria

        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
      

Gender

Male

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

Spain

Location Countries

Spain

Administrative Informations


NCT ID

NCT04303416

Organization ID

XAMNPEAP2019


Responsible Party

Sponsor

Study Sponsor

Onofre, Aurora Pujol, M.D.


Study Sponsor

, , 


Verification Date

June 2021