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

Kaneka Medical America LLC40 enrolled

Overview

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.

In a post-market study on Lixelle® conducted between 1994 and 1997 in Japan, all adverse events in 183 patients (13, 476 treatments) at 58 centers were collected. The most frequent adverse events were temporary hypotension and anemia, which are common in dialysis or any extracorporeal therapy. Since the maximum blood flow rate for Lixelle® is less than the average blood flow rate for the conventional HD in the USA, Lixelle®- treatment requires a longer treatment time to achieve the same Kt/V urea as the conventional HD in the United States. However, the longer dialysis time and the lower blood flow rate are not likely to increase the rate of adverse events. Adverse events (including Serious Adverse Events) will be collected at each treatment whenever they occur and will be analyzed using descriptive statistics. This is a prospective double-armed study of 2 years of Lixelle®-treatment. The study consists of the study arm of 2 years of Lixelle®-treatment in 30 DRA patients and the natural history arm of 2 years of conventional HD in 10 DRA patients as the descriptive reference. The primary objective of this study is to assess the safety of Lixelle® in patients in the USA. The secondary objectives of this study are to assess the probable benefit of Lixelle® to increase the β2M reduction rate in a single dialysis session. Exploratory endpoints are to assess: 1. the changes of DRA symptoms and ADL of the patients treated with Lixelle® using DRAQ (Dialysis-Related Amyloidosis Questionnaire) 2. the changes of QOL of the patients treated with Lixelle® using KDQOL-SF (Kidney Disease Quality of Life Short Form) 3. the pre-treatment β2M levels at baseline, one and two years; and 4. bone cysts at baseline and two years

Interventions

Lixelle® treatmentDEVICE

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.

Eligibility

Sex: ALL

Medical Language ↔ Plain English

Inclusion Criteria: * Patients receiving thrice-weekly HD and diagnosed as DRA by one or more of the following 1 to 4 will be included. 1. Biopsy of any tissue, showing Congo-red positive amyloid fibrils and immunohistochemical stains consistent with β2M 2. Shoulder ultrasonography showing rotator cuffs greater than 8 mm in thickness, and /or echogenic pads between muscle groups of the rotator cuff 3. 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.) 4. 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. 1. Patient diagnosed with rheumatoid arthritis 2. Patient diagnosed with osteoporosis 3. Patient diagnosed with osteoarthritis 4. Patient planning to receive renal transplantation during the study 5. Patient for whom adequate anticoagulation cannot be achieved 6. 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 7. Patient planning to become pregnant, pregnant, or breast-feeding 8. Patient unable to understand or answer the questionnaires even with a proper assistance

Outcomes

Primary Outcomes

the rate of SAE

comparison of incidence of SAE between between the Lixelle® treatment group and the natural history during treatment period (2 years)

Time frame: through 2 years of Lixelle® treatment during the study period

Secondary Outcomes

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.

Time frame: 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.