Rheopheresis as Adjuvant Treatment of Calciphylaxis

Study Overview
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Brief Summary
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We propose to set up a prospective randomized controlled trial to control the security and assess the efficacy of adjuvant treatment by rheopheresis in necrotizing-ulcered calciphylaxis in the hemodialysis population.

Detailed Description
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Calciphylaxis, also known as uremic calcifying arteriolopathy (UCA), is a rare disease that causes painful ischemic skin lesions due to microvascular calcification and thrombosis of the dermis and subcutaneous adipose tissue. Patients with end-stage renal disease (ESRD) are the main target for calciphylaxis. Rheopheresis is a therapeutic apheresis to treat microcirculatory disorders. This double filtration plasmapheresis eliminates a defined spectrum of high molecular weight proteins from human plasma including relevant factors for vascular inflammation and thrombose. We propose a prospective randomized controlled trial to compared the efficacy of rheopheresis as adjuvant treatment to the standard of care compared to standard care with Sham-apheresis.

Official Title
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Efficacy of Rheopheresis as Adjuvant Treatment of Calciphylaxis in Hemodialysis Patients : a Prospective Randomized Controled Single-blind Trial

Conditions
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Metabolic Disorder, End Stage Renal Disease, Rare Diseases

Intervention / Treatment
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* Procedure: Rheopheresis procedure
* Procedure: Sham-apheresis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Calciphylaxis with at least one ulcerated or necrotizing lesion End stage renal disease requiring hemodialysis Weight superior to 30kg Subject affiliated to or beneficiary of a social security system Subject having signed written informed consent A patient with progressing calciphylaxis to ulcerate or necrosis despite conventional treatment may also be included. Exclusion Criteria: KARNOFSKY Performance Status Scale inferior to 30% Life expectancy (independently of calciphylaxis) estimated < 6 months according to a referring physician expert in hemodialysis Uncontrolled infection (persistence of fever despite appropriate antibiotic therapy) Common variable immunodeficiency Albumin allergy Contra-indication to stop anti-vitamin K treatment Severe cognitive or psychiatric disorders, patients unable to give an informed consent or unwilling to participate in the study Pregnancy or breastfeeding and all the other categories of people with special protection according to the French Code de la Santé Publique (CSP): patients under legal supervision, patients hospitalized without contentment, patients admitted in social or sanitary structures for care and not research, and patients in emergency situations.

Ages Eligible for Study
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Minimum Age: 18 Years

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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rheopheresis group<br>In addition to the standards of care, the experimental group will carry out the rheopheresis in two stages: Stage 1: induction treatment: 3 apheresis sessions during the first week (w0; i.e. between D1 and D7) and then 2 apheresis sessions each week for 3 weeks (from w1 to w3; i.e. between D8 and D28) ; Step 2: maintenance treatment with 1 apheresis session per week until the 11th week (i.e. between D29 and D84). | Procedure: Rheopheresis procedure<br>* rheopheresis is performed using an automated monitor (Plasauto, company HemaT) in a double-filtration cascade. Plasma purify from of high molecular weight proteins<br>|
| Sham Comparator: Sham-apheresis group<br>In addition to the standards of care, the comparator group will carry out Sham-apheresis sessions according to the same scheme as the rheopheresis sessions of the experimental group. | Procedure: Sham-apheresis<br>* Sham-apheresis is performed with the same automated monitor (Plasauto, HemaT company). Extracted plasma is not treated through the secondary filter (Rheofilter) and return to the patient.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with complete wound healing of the calciphylaxis-mediated ischemic lesions after 12 weeks of rheopheresis treatment (a total of 17 sessions). | Complete wound healing is defined as the absence of livedoid peri-lesional inflammation with presence of granulation tissue (stage 3 healing process) and/or epithelization (stage 4) over the entire ulcer surface of calciphylactic lesions. The healing of the lesions will be illustrated with a photographic support. And the pictures will be examined a second time in a centralized and blind way by two referring dermatologists. In case of multiple calciphylaxis skin lesions, monitoring and evaluation will be done on the largest lesion at the time of patient's inclusion. | at 12 weeks of treatement | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patient with partial wound healing of the calciphylaxis mediated lesions after rheopheresis treatment. | The partial healing is defined by a partial reepithelialization (validated if 3 of following 4 criteria are present: 1-absence of necrosis; 2- granulation; 3 less inflammatory bordering 4- 20% decrease of the lesion size). The evolution of the size of the lesions and the partial healing of the wound will be illustrated by a photographic support. | At 4 weeks and 12 weeks of rheopheresis treatment. | 
| Occurrence of new ulcerated calciphylaxis lesions | Occurrence of new ulcerated calciphyalxis lesions frome Baseline to 4 and 12 weeks of treatment. | At 4 weeks and 12 weeks of rheopheresis treatment. | 
| Evolution of the self-reporting pain using Numeric Rating Scale (NRS) | The Numeric Rating Scale (NRS) describes the pain intensity at 11-point numeric scale ranges from '0' representing one pain extreme (e.g. no pain) to '10' representing the other pain extreme | from baseline (V0) to 12 weeks of rheopheresis (V2) | 
| Evolution of the level of antalgic consumed according to World Health Organisation (WHO) classification | The level of consumed antalgic is defined according to the World Health Organization (WHO) classification Level I analgesics = peripheral analgesics or not morphine have the lowest analgesic power Level II analgesics = weak morphine. Level III analgesics = strong morphine agonists and antagonists. | from baseline (V0) to 12 weeks of rheopheresis (V2) | 
| Number of days without antibiotics | Number of days the patient receives antibiotics, regardless of the route of administration, whether the patient is treated on an outpatient or inpatient basis. | during the 12 weeks of rheopheresis treatment | 
| Quality of life by the Wound quality of life score (Wound-Qol) | The Wound-QoL measures the disease-specific, health-related quality of life of patients with chronic wounds. It consists of 17 items on impairments which are always assessed in retrospect to the preceding seven days. | form baseline (V0) and at 12 weeks | 
| Number of days discharged from hospital | Number of days the patient is treated on an outpatient basis. | during the 12 weeks of rheopheresis treatment | 
| Overall survival | Survival of patients, whether or not calciphylaxis is cured. | at 12 weeks and 12 months after first rheopheresis. | 
| Change in inflammatory proteins | Change in the plasmatic rates of C-reactive protein (CRP) and fibrinogen. | from baseline to 12 weeks-rheopheresis treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Calciphylaxis, Rheopheresis, Hemodialysis, Chronic kidney disease