Post Approval Study of Lixelle for the Treament of Dialysis-Related Amyloidosis

Study Overview
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Brief Summary
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Dialysis-related amyloidosis (DRA) is a serious complication of long-term hemodialysis (HD). Its pathogenic mechanism involves accumulation of β2-microglobulin (β2M) in the blood. β2M is produced by most cells in the body and is metabolized in the kidney in healthy individuals. However, in HD patients with renal dysfunction, β2M which is not removed entirely by HD accumulates excessively in the blood. Then it forms amyloid fibrils that are deposited in bones, joints, and soft tissues. The fibrils are further modified by advanced glycation end products (AGE), inducing local macrophage infiltration and production of cytokines leading to chronic inflammation and activation of osteoclasts. Consequently, severe complications with various symptoms are developed, which are collectively referred to as DRA. Lixelle® is a whole-blood β2M apheresis column developed to adsorb and eliminate β2M selectively from the blood of DRA patients. The treatment is performed with Lixelle® connected upstream of the dialyzer in series on a HD circuit in every session. The Lixelle® column contains porous cellulose beads with covalently linked hexadecyl alkyl chain ligands, which selectively adsorb β2M, via a molecular sieving effect because of its porous structure and hydrophobic interaction with ligands. Lixelle® has been used to relieve symptoms and prevent the progression of DRA in Japan since 1996, when health insurance coverage and reimbursement for the treatment were approved by Japanese Ministry of Health, Labor, and Welfare. Improvement of the activities of daily living (ADL) and remission of arthralgia by Lixelle® treatment has been shown in several clinical studies.

Official Title
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Treatment of Dialysis-Related Amyloidosis Using Lixelle® β2-microglobulin Apheresis Column

Conditions
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Dialysis Amyloidosis

Intervention / Treatment
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* Device: Lixelle® treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients receiving thrice-weekly HD and diagnosed as DRA by one or more of the following 1 to 4 will be included. Biopsy of any tissue, showing Congo-red positive amyloid fibrils and immunohistochemical stains consistent with β2M Shoulder ultrasonography showing rotator cuffs greater than 8 mm in thickness, and /or echogenic pads between muscle groups of the rotator cuff Two or more diagnoses of the following (1) to (5) (1) Polyarthralgia (2) Carpal tunnel syndrome (3) Trigger finger (4) Dialysis-associated spondylosis ((i) or (ii)) (i) Destructive spondyloarthropathy (DSA) (ii) Spinal stenosis (5) Bone cysts (Bone cysts considered to be caused by other diseases such as osteoarthritis, aneurysmal bone cysts and unicameral bone cysts should be excluded.) Biopsy of any tissue, showing Congo-red positive amyloid fibrils, and one diagnosis or surgical history of criterion 3- (1) to (5) Exclusion Criteria: Patient who meets any of the following 1 to 7 will be excluded from the study. Patient diagnosed with rheumatoid arthritis Patient diagnosed with osteoporosis Patient diagnosed with osteoarthritis Patient planning to receive renal transplantation during the study Patient for whom adequate anticoagulation cannot be achieved Patient for whom extracorporeal circulation therapy is contraindicated, such as those with severe cardiac insufficiency, acute myocardial infarction, severe cardiac arrhythmia, acute seizure disorder, or severe uncontrolled hypertension or hypotension Patient planning to become pregnant, pregnant, or breast-feeding Patient unable to understand or answer the questionnaires even with a proper assistance
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lixelle® treatment<br>2 years of Lixelle® treatment in the patients with dialysis related amyloidosis (DRA) | Device: Lixelle® treatment<br>* The treatment will be performed with the Lixelle® column connected to upstream of the dialyzer in series on the routine HD circuit according to the description in the IFU. The dialyzer and the Kt/V urea in the conventional HD for each patient will be kept equal in Lixelle®-treatment. Since the maximum blood flow rate for Lixelle® is 250 ml/min, the dialysis time will be extended to achieve the target Kt/V urea. The study will not restrict the type of hemodialyzer and other conditions of HD as specified by the physician. However, any changes to the HD procedure should be recorded properly, and the Kt/V urea should be kept equal to that at the enrollment.<br>|
| No Intervention: natural history<br>2 years of natural history in the patients with dialysis related amyloidosis (DRA) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the rate of SAE | comparison of incidence of SAE between between the Lixelle® treatment group and the natural history during treatment period (2 years) | through 2 years of Lixelle® treatment during the study period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| β2M reduction rate in Lixelle® treatment (2 year) | to compare how much blood β2M level have decreased after after Lixelle® treatment against pre-treatment level. | comparison between baseline and 2 years (104 weeks) after Lixelle® treatment | 
| comparison of β2M reduction rate between Lixelle® treatment and natural history | to compare β2M reduction rate (see Description in Outcome 2) between the Lixelle® treatment grroup and tne natural history group. | comparison between baseline and 2 years (104 weeks) after Lixelle® treatment |