Diffuse Cutaneous Systemic Sclerosis
Conditions
Keywords
systemic sclerosis, scleroderma, extracorporeal photopheresis, connective tissue diseases, skin diseases
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.
Interventions
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).
DRUGUVADEX
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.
Sponsors
Mallinckrodt
London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with SSc, aged 18 years or older, and: 2. Subjects must meet the ACR/EULAR classification criteria for SSc (2013). 3. 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. 4. Able to give informed consent.
Exclusion criteria
1. Poor pulmonary function (FVC\<40% and/or DLCO\<30%). 2. Class IV PAH or PH. 3. Clinically significant cardiac disease. 4. 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). 5. Chronic or ongoing active infectious disease requiring systemic treatment, including active tuberculosis (TB) infection. 6. Seropositivity for human immunodeficiency virus (HIV) at study entry. 7. Active viral infection with viral replication of hepatitis B or C virus at study entry. 8. Thrombophilia. 9. 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. 10. Low Platelet count (less than 100,000 per mm3). 11. 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. 12. Severe anemia (hemoglobin \<70g/L). 13. High white blood cell count (greater than 25000 mm3). 14. A history of surgical spleen removal. 15. A history of a light sensitive disease state, i.e. lupus erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma pigmentosum and albinism. 16. Previous idiosyncratic reactions to psoralen compounds. 17. 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. 18. Treatment with more than 2 immunosuppressants (including mofetil mycophenolate, methotrexate, cyclophosphamide, biologics) at study entry. 19. Pregnancy, breast feeding or child bearing potential without practicing highly effective contraception (and partners for men in the study). 20. Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder). 21. Participation in another clinical trial within six weeks before randomization in this study. 22. Previous use of Extracorporeal photopheresis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in skin thickness measured by modified Rodnan Skin Score | 48 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the diffusing capacity for carbon monoxide | 6 and 12 months | 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. |
| Change in physician global assessment of disease severity | 12, 24, 36 and 48 weeks | Measured on a Visual Analogue Scale (VAS) from 0-10, with 0 being no disease severity and 10 being the worst possible disease severity. |
| Change in physician global assessment of disease damage | 12, 24, 36 and 48 weeks | Measured on a Visual Analogue Scale (VAS) from 0-10, with 0 being no disease damage and 10 being the worst possible disease damage. |
| Change in patient global assessment of health status | 12, 24, 36 and 48 weeks | 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. |
| Change in Scleroderma Health Assessment Questionnaire | 12, 24, 36 and 48 weeks | 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. |
| Change in serum concentrations C-Reactive Protein | 12, 24, 36 and 48 weeks | 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. |
| Change in serum concentrations of Erythrocyte Sedimentation Rate | 12, 24, 36 and 48 weeks | 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. |
| Change in the modified Rodnan Skin Score | 12, 24 and 36 weeks | 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. |
| Combined Response Index in diffuse cutaneous systemic sclerosis score | 24 weeks | 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. |
| Change in Forced Vital Capacity | 6 and 12 months | 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. |
| Change in physician global assessment of disease activity | 12, 24, 36 and 48 weeks | Measured on a Visual Analogue Scale (VAS) from 0-10, with 0 being no disease activity and 10 being the worst possible disease activity. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in peripheral levels of T-cell activation marker - sIL-2R | 12, 24, 36 and 48 weeks | interleukin 2 receptor (sIL-2R) Serum sIL-2R level is a sensitive and quantitative marker of circulating peripheral blood mononuclear cell activation. Normal range of serum sIL-2R is below 2500 pg/ml. High levels may be found in conditions associated with T-cell activation. |
| Change in peripheral levels of fibrillogenesis - amino terminal propeptide of type III collagen | 12, 24, 36 and 48 weeks | Amino-terminal propeptide of procollagen type III (PIIINP) is generated during the synthesis of type III collagen. PIIINP is a non-specific marker of soft tissue injury. PIIINP in serum has been shown to correlate with fibrillogenesis, and thus to be a potential direct marker of type III collagen deposition. PIIINP reference range Adult (\>19 years): 1.2 - 4.2 ug/L |
| Change in CD3-positive cell count (T-cell marker) in skin biopsies of involved forearm skin | 24 and 48 weeks | Measured by immunohistochemistry (IHC) as the percentage of CD3-positive cells per total number of cells/mm2. Reference rage not established (there is no range, we are looking for a stat significant change (decrease) from baseline) |
| Change in myofibroblast count in skin biopsies of involved forearm skin | 24 and 48 weeks | Myofibroblasts are cells involved in the inflammatory response to injury. Myofibroblasts play an active role in collagen synthesis, and correlate with clinical measures of disease activity in SSc. Measured by immunohistochemistry (IHC) as the percentage of alpha-SMA-positive cells per total number of cells/mm2. Reference range not established |
| Infectious complications | assessed for duration of treatment up to 48 weeks, and up to 1 month post-treatment | — |
| Regimen-related toxicities | assessed for duration of treatment up to 48 weeks, and up to 12 weeks post-treatment | Adverse Events (AEs) \>= Grade 3 and assessed by the investigator as 1 of the following: related or unrelated to treatment |
Countries
Canada
Contacts
Primary ContactDr. Janet E Pope, MD PhD
Backup ContactAmanda Philip
Outcome results
None listed