Extracorporeal Photopheresis in Early Diffuse Cutaneous Systemic Sclerosis

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess feasibility, safety and preliminary efficacy of Extracorporeal Photopheresis in the treatment of active diffuse cutaneous systemic sclerosis (dcSSc). This pilot study will help to determine if further study (a RCT) is justified.

Detailed Description
-----------------
Systemic sclerosis (SSc, Scleroderma) is a multisystem autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs. There is no effective treatment for the majority of patients with diffuse scleroderma (diffuse cutaneous systemic sclerosis; dcSSc). Only few therapies have shown modest benefits in regard to some specific organ pathologies. In the early stage of dcSSc, it may be possible to reverse inflammation and reduce the probability of irreversible fibrosis via significant immune modulation as later, often the fibrosis doesn't improve with treatment. This is a pilot study that will treat 15 participants with dcSSc who meet the eligibility criteria. The objective of the study is to determine if the benefit of Extracorporeal photopheresis (ECP) and safety are favorable in order to consider and help in the design of a randomized controlled trial (RCT). This is a Phase II study that is uncontrolled and patients will remain on their background immunosuppressive treatment unless if contraindicated for safety or drug interactions. The trial is powered to show a mean change in skin thickness measured with modified Rodnan skin score (mRSS) of ≥5 over one year, in an uncontrolled, unblinded study. The Health Assessment Questionnaire Disability Index (HAQ-DI), patient and physician global scores, inflammatory markers, and combined response index in SSc (CRISS) will all be exploratory outcomes. Other outcomes such as changes in cells on skin biopsies from baseline to end of the trial will be explored if the study is positive.

Official Title
-----------------
The Effectiveness of ECP in Diffuse Cutaneous Systemic Sclerosis

Conditions
-----------------
Diffuse Cutaneous Systemic Sclerosis

Intervention / Treatment
-----------------
* Device: Extracorporeal Photopheresis (ECP)
* Drug: UVADEX


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with SSc, aged 18 years or older, and: Subjects must meet the ACR/EULAR classification criteria for SSc (2013). Early dcSSc (within 5 years of first non-Raynaud's phenomenon symptom) or any other dcSSc patients who have at least one of the signs of disease activity: mRSS of 15 or more, presence of tendon friction rubs, elevated inflammatory markers thought to be due to active dcSSc and not related to other issues such as infection or ILD with FVC% predicted <80% or HRCT showing ILD thought to be from SSc. Able to give informed consent. Exclusion Criteria: Poor pulmonary function (FVC<40% and/or DLCO<30%). Class IV PAH or PH. Clinically significant cardiac disease. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, cardiac, hepatic, pancreatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease; and cancer (i.e. co-existing melanoma, basal cell, or squamous cell skin carcinoma). Chronic or ongoing active infectious disease requiring systemic treatment, including active tuberculosis (TB) infection. Seropositivity for human immunodeficiency virus (HIV) at study entry. Active viral infection with viral replication of hepatitis B or C virus at study entry. Thrombophilia. Contraindications to heparin including history of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITTS), history of thrombocytopenia with pentosan polysulfate, known hypersensitivity to heparin or pork products. Low Platelet count (less than 100,000 per mm3). Aphakia (absence or loss of the eye's lens and has not been replaced with an artificial lens), because of the significantly increased risk of retinal damage due to the absence of lenses. Severe anemia (hemoglobin <70g/L). High white blood cell count (greater than 25000 mm3). A history of surgical spleen removal. A history of a light sensitive disease state, i.e. lupus erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma pigmentosum and albinism. Previous idiosyncratic reactions to psoralen compounds. Patients who are using photosensitizing drugs such as anthralin, coal tar or coal tar derivatives, griseofulvin, phenothiazines, nalidixic acid, halogenated salicylanilides (bacteriostatic soaps), sulfonamides, tetracyclines, thiazides, and certain organic staining dyes such as methylene blue, toluidine blue, rose bengal and methyl orange. Treatment with more than 2 immunosuppressants (including mofetil mycophenolate, methotrexate, cyclophosphamide, biologics) at study entry. Pregnancy, breast feeding or child bearing potential without practicing highly effective contraception (and partners for men in the study). Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder). Participation in another clinical trial within six weeks before randomization in this study. Previous use of Extracorporeal photopheresis.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Administration of Extracorporeal Photopheresis Treatment<br>Duration of treatment: 48 weeks. Treatments occur on 2 consecutive days every 4 weeks. Dose of UVADEX: Treatment Volume x 0.017 = mL of UVADEX for each treatment Treatment Volume (TV) is defined as: The total volume of Buffy Coat plus prime solution that will undergo photoactivation. Route of administration: Extracorporeal | Device: Extracorporeal Photopheresis (ECP)<br>* Drug Intervention using a medical device. The ECP device is already licensed in Canada. License No.7703. ECP treatment, using the drug UVADEX, will be given on 2 consecutive days every 4 weeks for a total of 26 treatment days (48 weeks).<br>* Other names: 8-mop;Drug: UVADEX<br>* The phase II aspect of the study refers to the drug, methoxsalen. Methoxsalen is being used off label from the currently approved indications in the monograph. The study is proposing to use methoxsalen in combination with with extracorporeal photopheresis for the treatment of diffuse cutaneous systemic sclerosis. Treatment will be given in addition to standard of care medications for SSc.<br>* Other names: 8-mop;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in skin thickness measured by modified Rodnan Skin Score | modified Rodnan Skin Score (mRSS): is a standard outcome measure for skin disease in SSc and calculated by measuring skin thickness in 17 different body sites (each site scored 0-3, with a total possible additive score of 51). A higher skin score (or a higher skin thickness) and progression of this score, is predictive of internal organ involvement and mortality. While a lower or improving (lessening) score is associated with favorable outcomes, including better survival. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the modified Rodnan Skin Score | modified Rodnan Skin Score (mRSS): is a standard outcome measure for skin disease in SSc and calculated by measuring skin thickness in 17 different body sites (each site scored 0-3, with a total possible additive score of 51). A higher skin score (or a higher skin thickness) and progression of this score, is predictive of internal organ involvement and mortality. While a lower or improving (lessening) score is associated with favorable outcomes, including better survival. | 12, 24 and 36 weeks | 
| Combined Response Index in diffuse cutaneous systemic sclerosis score | CRISS score: It is calculated according to changes from the start of a study, compared to an endpoint, by using the modified Rodnan Skin Score (mRSS), the Health Assessment Questionnaire - Disability Index (HAQ-DI), patient and physician global assessment of scleroderma-related health, and forced vital capacity. A CRISS score of ≥ 0.6 indicates likelihood that a patient improved on treatment. Will be calculated with baseline data and to define disease progression at 6 months. | 24 weeks | 
| Change in Forced Vital Capacity | Change in Pulmonary Function as measured by percentage of Improving or worsening FVC. The FVC (Forced vital Capacity) is the total amount of air exhaled during the FEV (Forced expiratory volume) test. | 6 and 12 months | 
| Change in the diffusing capacity for carbon monoxide | Change in Pulmonary Function as measured by percentage of Improving or worsening DLCO. The DLCO (diffusing capacity of the lungs for carbon monoxide) measures the ability of the lungs to transfer gas from inhaled air to the red blood cells in pulmonary capillaries. | 6 and 12 months | 
| Change in physician global assessment of disease activity | Measured on a Visual Analogue Scale (VAS) from 0-10, with 0 being no disease activity and 10 being the worst possible disease activity. | 12, 24, 36 and 48 weeks | 
| Change in physician global assessment of disease severity | Measured on a Visual Analogue Scale (VAS) from 0-10, with 0 being no disease severity and 10 being the worst possible disease severity. | 12, 24, 36 and 48 weeks | 
| Change in physician global assessment of disease damage | Measured on a Visual Analogue Scale (VAS) from 0-10, with 0 being no disease damage and 10 being the worst possible disease damage. | 12, 24, 36 and 48 weeks | 
| Change in patient global assessment of health status | Measured on a Visual Analogue Scale (VAS) from 0-100, with 0 being no overall effect of disease on participant, and 100 being the worst possible overall effect of disease on participant. This is a patient reported outcome. | 12, 24, 36 and 48 weeks | 
| Change in Scleroderma Health Assessment Questionnaire | The SHAQ combines the disability and pain scales of the HAQ (HAQ-DI), with five scleroderma-specific Visual Analogue Scales for: digital ulcers, Raynaud's phenomenon, gastrointestinal (GI) symptoms, lung symptoms, and overall disease severity. The HAQ-DI yields a score of 0-3, that indicates the extent of the respondent's functional limitations. Each VAS score is scaled from 0 to 3, with 0 being no symptoms and 3 being the worst possible symptom severity. A composite VAS score is not created nor are the individual VAS scores incorporated into the HAQ DI score. Typically, each VAS score is reported individually. There is a proposed way to obtain a combined score obtained by pooling the 8 domains of the HAQ DI and the 5 VASs; however, this approach has not yet been widely accepted. This is a patient reported outcome. | 12, 24, 36 and 48 weeks | 
| Change in serum concentrations C-Reactive Protein | Change in serum concentrations of the acute phase reactant, CRP CRP aids in the evaluation of stress, trauma, infection, inflammation, surgery & associated diseases. Blood levels of C-Reactive Protein (CRP) are known to rise in acute disease to a level of up to 50 mg/L in the presence of slight to moderate inflammatory process. Values >50 mg/L indicate high and extensive inflammatory activity. | 12, 24, 36 and 48 weeks | 
| Change in serum concentrations of Erythrocyte Sedimentation Rate | Change in serum concentrations of the acute phase reactant, ESR Reference ranges: Male: 0-10 mm/h Female: 0-20 mm/h A faster-than-normal rate may indicate inflammation in the body. Inflammation is part of the immune response system. The higher the number, the higher the likelihood of inflammation. | 12, 24, 36 and 48 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
systemic sclerosis, scleroderma, extracorporeal photopheresis, connective tissue diseases, skin diseases