Extracorporeal Photopheresis in Early Diffuse Cutaneous Systemic Sclerosis

Diffuse Cutaneous Systemic Sclerosis Clinical Trial

Official title:

The Effectiveness of ECP in Diffuse Cutaneous Systemic Sclerosis

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04986605
• Other study ID #: ECR-CAN-011068
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: September 1, 2024
• Est. completion date: June 2027

Study information

• Verified date: February 2024
• Source: Lawson Health Research Institute
• Contact: Dr. Janet E Pope, MD PhD
• Phone: 519-646-6332
• Email: janet.pope[@]sjhc.london.on.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 15
• Est. completion date: June 2027
• Est. primary completion date: December 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Diffuse Cutaneous Systemic Sclerosis
• Scleroderma, Diffuse
• Scleroderma, Systemic
• Sclerosis

Intervention

Device:
• Extracorporeal Photopheresis (ECP)
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).

Drug:
• UVADEX
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.

Locations

Country	Name	City	State
Canada	Rheumatology Clinic, St. Joseph's Health Care	London	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Lawson Health Research Institute	Mallinckrodt

Country where clinical trial is conducted

Canada, 

References & Publications (29)

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Khanna D, Denton CP, Lin CJF, van Laar JM, Frech TM, Anderson ME, Baron M, Chung L, Fierlbeck G, Lakshminarayanan S, Allanore Y, Pope JE, Riemekasten G, Steen V, Muller-Ladner U, Spotswood H, Burke L, Siegel J, Jahreis A, Furst DE. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis. 2018 Feb;77(2):212-220. doi: 10.1136/annrheumdis-2017-211682. Epub 2017 Oct 24. — View Citation

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Komocsi A, Vorobcsuk A, Faludi R, Pinter T, Lenkey Z, Kolto G, Czirjak L. The impact of cardiopulmonary manifestations on the mortality of SSc: a systematic review and meta-analysis of observational studies. Rheumatology (Oxford). 2012 Jun;51(6):1027-36. doi: 10.1093/rheumatology/ker357. Epub 2012 Jan 5. — View Citation

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Merkel PA, Silliman NP, Clements PJ, Denton CP, Furst DE, Mayes MD, Pope JE, Polisson RP, Streisand JB, Seibold JR; Scleroderma Clinical Trials Consortium. Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2012 Oct;64(10):3420-9. doi: 10.1002/art.34427. — View Citation

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Pope J, McBain D, Petrlich L, Watson S, Vanderhoek L, de Leon F, Seney S, Summers K. Imatinib in active diffuse cutaneous systemic sclerosis: Results of a six-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study at a single center. Arthritis Rheum. 2011 Nov;63(11):3547-51. doi: 10.1002/art.30549. — View Citation

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Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, Mayes MD, Nash RA, Crofford LJ, Eggleston B, Castina S, Griffith LM, Goldstein JS, Wallace D, Craciunescu O, Khanna D, Folz RJ, Goldin J, St Clair EW, Seibold JR, Phillips K, Mineishi S, Simms RW, Ballen K, Wener MH, Georges GE, Heimfeld S, Hosing C, Forman S, Kafaja S, Silver RM, Griffing L, Storek J, LeClercq S, Brasington R, Csuka ME, Bredeson C, Keever-Taylor C, Domsic RT, Kahaleh MB, Medsger T, Furst DE; SCOT Study Investigators. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med. 2018 Jan 4;378(1):35-47. doi: 10.1056/nejmoa1703327. — View Citation

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* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Regimen-related toxicities	Adverse Events (AEs) >= Grade 3 and assessed by the investigator as 1 of the following: related or unrelated to treatment	assessed for duration of treatment up to 48 weeks, and up to 12 weeks post-treatment
Other	Infectious complications		assessed for duration of treatment up to 48 weeks, and up to 1 month post-treatment
Other	Change in peripheral levels of T-cell activation marker - sIL-2R	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.	12, 24, 36 and 48 weeks
Other	Change in peripheral levels of fibrillogenesis - amino terminal propeptide of type III collagen	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	12, 24, 36 and 48 weeks
Other	Change in CD3-positive cell count (T-cell marker) in skin biopsies of involved forearm skin	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)	24 and 48 weeks
Other	Change in myofibroblast count in skin biopsies of involved forearm skin	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	24 and 48 weeks
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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