Ignite Creation Date:
2024-05-06 @ 3:46 PM
Last Modification Date:
2024-10-26 @ 1:56 PM
Study NCT ID:
NCT04752397
Status:
COMPLETED
Last Update Posted:
2022-11-17
First Post:
2021-02-09
Brief Title:
The Influence of Extracorporeal Photopheresis on Skin Sclerosis
Sponsor:
Charite University Berlin Germany
Organization:
Charite University Berlin Germany
Study Overview
Official Title:
The Influence of Extracorporeal Photopheresis on Skin Sclerosis - an Exploratory Clinical Study
Status:
COMPLETED
Status Verified Date:
2022-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Extracorporeal photopheresis ECP also known as extracorporeal photoimmunotherapy or photochemotherapy is a leukapheresis-based therapy that has been in clinical use for over three decades after receiving FDA approval in 1988 Extracorporeal photopheresis was initially used for the treatment of T-cell lymphoma Since its introduction indications for initiating ECP were continuously extended to the treatment of Graft-versus-Host Disease GvHD systemic sclerosis and in the field of solid organ transplantation There is also evidence supporting the use of ECP in generalized morphea a form of scleroderma limited to the skin and in eosinophilic fasciitis which is a rare localized fibrosing disorder of the fascia
Concluding the results of the published studies there is evidence that ECP has a positive effect on fibrosing disorders of the skin Furthermore in clinical practice it has been observed that patients with systemic sclerosis who undergo ECP treatment show improvement of the skin lesions or a deceleration in the formation progress of such lesions during the therapy Same findings can be observed in patients with sclerotic skin lesions of the skin for example in the context of a GvHD
There are no clinical studies so far that describe these processes using objective measuring methods Furthermore the mechanism of action of ECP in systemic sclerosis and other fibrosing disorders with skin manifestations has not yet been conclusively clarified Serological markers for monitoring the progress of the therapy and determining the prognosis are also missing Thus a consensus regarding the frequency and duration of ECP for the therapy of systemic scleroderma or sclerotic diseases has not yet been reached
This study aims at evaluating the influence of Extracorporeal Photopheresis on the quality and functionality of sclerotic skin lesions assessed by several objective methods Furthermore potential biomarkers which are being investigated in current studies are to be determined in order to evaluate the influence of ECP on those biomarkers and better understand the mechanism of action of ECP on systemic sclerosis and fibrosing disorders involving the skin
Concluding the results of the published studies there is evidence that ECP has a positive effect on fibrosing disorders of the skin Furthermore in clinical practice it has been observed that patients with systemic sclerosis who undergo ECP treatment show improvement of the skin lesions or a deceleration in the formation progress of such lesions during the therapy Same findings can be observed in patients with sclerotic skin lesions of the skin for example in the context of a GvHD
There are no clinical studies so far that describe these processes using objective measuring methods Furthermore the mechanism of action of ECP in systemic sclerosis and other fibrosing disorders with skin manifestations has not yet been conclusively clarified Serological markers for monitoring the progress of the therapy and determining the prognosis are also missing Thus a consensus regarding the frequency and duration of ECP for the therapy of systemic scleroderma or sclerotic diseases has not yet been reached
This study aims at evaluating the influence of Extracorporeal Photopheresis on the quality and functionality of sclerotic skin lesions assessed by several objective methods Furthermore potential biomarkers which are being investigated in current studies are to be determined in order to evaluate the influence of ECP on those biomarkers and better understand the mechanism of action of ECP on systemic sclerosis and fibrosing disorders involving the skin
Detailed Description:
Background and Rationale
Extracorporeal photopheresis
In this immunomodulatory therapy the apheresis leukocytes of the patients are irradiated with ultraviolet UV A in the presence of a photosensitizing agent 8-methoxypsoralen prior to reinfusion to the patient The mechanism of action of ECP has not yet been conclusively clarified However it has been shown that ECP modulates dendritic cells modifies the cytokine profile and stimulates several T cell subpopulations in particular regulatory T cells Treg The accumulated experience shows ECP to be well tolerated with no clinically significant side effects and no long-term complications Extracorporeal photopheresis is available as first-line as well as second-line therapy and can be combined with systemic drug therapies
Scleroderma and ECP
Scleroderma comprises a spectrum of autoimmune fibrosing disorders characterized by vascular alterations fibrosis and subsequent atrophy of the skin subcutaneous tissue and muscles Depending on the form of the disease internal organs may also be affected in various degrees eg alimentary tract lungs heart kidney central nervous system It is usually classified into systemic sclerosis generalized scleroderma and morphea localized scleroderma distinguished by visceral involvement in the generalized form and disease limited to the skin and subcutaneous tissue in the localized form Prognosis depends mainly on renal cardiac and pulmonary manifestations
The pathogenesis of scleroderma is not well understood However it is assumed that there is an initial damage to endothelial cells a subsequent inflammatory reaction in which mainly T-lymphocytes macrophages and mast cells are pathologically altered and an activation of fibroblasts causing increased and disturbed collagen production which finally leads to fibrosis In addition alterations in the innate and acquired immune response a disturbed microcirculation and fibroblast dysfunction are also involved
The therapy of patients with scleroderma is very limited It is based on immunosuppression which includes systemic steroids azathioprine cyclophosphamide methotrexate mycophenolate mofetil or interferons Phototherapy is also a major component in the treatment of Scleroderma and ranges from narrowband to broadband UVB UVA UVA1 Psoralen-UVA PUVA and ECP The key advantage of ECP for the treatment of scleroderma is the improvement of its skin manifestations Nevertheless there is also emerging evidence that suggests that ECP may play a role improving oral aperture size joint mobility skin ulcers and functional status Furthermore in contrast to the available immunosuppressive therapies ECP has a low side effect profile Τhe European Dermatology Forum recommends ECP as a second-line therapy or as part of adjuvant therapy in patients with scleroderma There is currently no consensus on the duration and frequency of ECP for the treatment of scleroderma
Graft-versus-Host Disease and ECP
Graft-versus-host disease is a complex multiorgan disease which can occur as a complication following allogeneic stem cell transplantation Involvement of the skin represents the most common appearance of GvHD According to the Consensus of National Institute of health further sub-classification can be done into acute and chronic GvHDCorticosteroids are first-line therapy for both acute and chronic GvHD but due to its significant toxicity and an increasing number of patients developing steroid-refractory disease many rescue therapies are currently available ECP is a widely recommended treatment approach as a second-line treatment especially in steroid refractory form of GvHD
Eosinophilic fasciitis and ECP
Eosinophilic fasciitis is a rare sclerodermiform syndrome of unknown etiology characterized by the fibrosis of the muscular fascia and subcutaneous tissue accompanied with infiltration of eosinophils There is little data regarding ECP in Eosinophilic fasciitis however ECP may be beneficial
Objectives
The aim of this study is to investigate the influence of ECP on patients with autoimmune fibrosing disorders including systemic sclerosis morphea sclerodermiform GvHD and eosinophilic fasciitis More specifically the following topics are going to be investigated
1 Quality and functionality of skin lesions
1 Examination of lesional and clinically uninvolved skin during ECP treatment using clinical evaluation and skin functional parameters If possible the examinations will take place before the initiation and during the ECP treatment This depends on the stage of therapy of the participants at the time they get included in the study
2 Evaluation of the influence of the frequency and the duration of ECP on the progress of the disease
2 Alteration of biomarkers during the ECP treatment
1 Observation of specific potential biomarkers during the treatment in order to understand the mechanism of action of ECP as well as its influence in those biomarkers
2 Evaluation of biomarkers as possible prognostic markers
Study design
Prospective monocentric exploratory study with a single group of 10 subjects Ten patients with sclerotic skin lesions due to systemic sclerosis or morphea or sclerodermiform GvHD or eosinophilic fasciitis will be enrolled in this clinical study Subjects not having started first ECP treatment yet will be preferred for inclusion The modified Rodnan skin score is widely accepted as a validated method to evaluate skin sclerosis therefore its results will be considered as the primary outcome in this study The study will include 8 visits for each included patient
Screening visit between week -2 and week 0
Baselineinclusion visit week 0
Intermediate visits every 4 weeks 2
End of study visit week 24 2
Study setting
The study will be conducted by the Clinical Research Center for Hair and Skin Science Department of Dermatology and Allergy Charité - Universitätsmedizin Berlin
Patients with systemic sclerosis or sclerotic skin lesions who already receive or are planned to receive ECP treatment will be recruited in this study In other words they will receive the treatment regardless of their inclusion in the study Normally a 3-day inpatient stay in the clinic is required for a cycle of ECP treatment The study visits will be carried out during this inpatient stay at the Department of Dermatology and Allergy Charité - Universitätsmedizin Berlin If necessary additional appointments with the subjects will be made in the same setting
Recruitment strategies
Patients who receive ECP in the Department of Dermatology Venerology and Allergology - Charité - Universitätsmedizin Berlin will be informed about the study by the study investigators
Data collection methods
1 Demographic data medical history An extended interview of the patient on his demographics medical history treatments and medications will be performed by an investigator during the inclusion visit
2 Modified Rodnan skin score The modified Rodnan skin score is a validated method to evaluate skin thickening in SSc worldwideIt will be performed by an investigator
3 Skin physiological and functional parameters Skin functional parameters will be determined at the uninvolved skin of the volar forearm or the gluteal area control and at one lesional skin area target lesion which may differ among the subjects but preferably would be in a contralateral area to the uninvolved skin area chosen Before measurements are performed subjects will rest for 30 minutes in a room with controlled environmental conditions room temperature 22 C 2 C relative humidity 50 10 for acclimatization The skin of the investigational sites must be open to air
Following parameters will be determined
Stratum corneum hydration SCH SCH will be measured using the Corneometer CM 825 Courage Khazaka Colonge Germany which measures the hydration level of the stratum corneum as electrical capacitance The measurement is based on the differences of the dielectric constant of water and other substances The arbitrary units range from 0 to 120 higher readings indicate higher stratum corneum hydration
Transepidermal water loss TEWL TEWL will be measured using the Tewameter TM 300 Courage Khazaka Colonge Germany The probe of the instrument measures the density gradient of the water evaporation from the skin indirectly by the two pairs of sensors temperature and relative humidity inside the hollow cylinder Water evaporation is captured in gram per hour per m² Higher values indicate a higher transepidermal water loss
Skin firmness A Cutometer Dual MPA 580 Courage Khazaka Colonge Germany will be used The instrument measures skin deformation after repeated cycles of suction and release The resistance of the skin to the negative pressure and its ability to return into its original position are displayed as curves penetration depth in mmtime in real time during the measurement
Skin surface sebum level A Sebumeter SM 815 Courage Khazaka Colonge Germany will be used The measurement is based on grease spot photometry The measurement cassette contains a special tape that becomes transparent when it comes into contact with sebum on the surface of the skin In order to make a measurement the cassette is inserted into an aperture on the device where the transparency of the tape is measured The transparency is measured by sending light through the tape using a light source in the aperture The light is reflected by a mirror behind the tape and a photocell measures the transparency The change in the amount of light transmission represents the sebum content of the tape which is displayed in units from 0-350 Higher values indicate a higher lipid level
Skin thickness A Dermascan C ultrasound scanner Cortex Technology Denmark with a 20MHz probe will be used
4 Biomarkers Biomarkers will be determined via blood sampling Two CPDa tubes and two serum tubes will be used at each blood collection Blood samples will be collected at three time-points during an inpatient stay immediately before the start of ECP on day one immediately after the ECP treatment on day one and at the patients discharge on day three Serum levels of specific cytokines and chemokines will be determined using ELISA Percentage counts of specific T-cell subpopulations will be obtained by fluorescence-activated cell sorting analysis FACS using the following surface markers CD3 CD4 CD45RA CD127 CD25 CXCR3 CXCR5 and CCR6
Data management
A paper source data will be created for this study Data including demographics medical history measurement results and clinical score results will be completed during the study visits in written form Data from the source data will be extracted and entered into a data file by the data manager using the software IBM SPSS Statistics 26 The database will be stored on a secured digital server of the Charité - Universitätsmedizin Berlin
Statistical methods
Descriptive comparative statistical analysis will be conducted All parameters will be described using measures of central tendency and measures of variability or dispersion This is an exploratory study therefore a formal sample size calculation is not planned
Monitoring
Data Monitoring Planned
Harms The participants will not be monitored for adverse events because the study is considered as non-interventional All subjects will receive ECP treatment regardless of their inclusion in this study Furthermore all non-invasive measurements as well as the blood sampling will be conducted during the subjects planned hospitalization
Auditing Not planned
Extracorporeal photopheresis
In this immunomodulatory therapy the apheresis leukocytes of the patients are irradiated with ultraviolet UV A in the presence of a photosensitizing agent 8-methoxypsoralen prior to reinfusion to the patient The mechanism of action of ECP has not yet been conclusively clarified However it has been shown that ECP modulates dendritic cells modifies the cytokine profile and stimulates several T cell subpopulations in particular regulatory T cells Treg The accumulated experience shows ECP to be well tolerated with no clinically significant side effects and no long-term complications Extracorporeal photopheresis is available as first-line as well as second-line therapy and can be combined with systemic drug therapies
Scleroderma and ECP
Scleroderma comprises a spectrum of autoimmune fibrosing disorders characterized by vascular alterations fibrosis and subsequent atrophy of the skin subcutaneous tissue and muscles Depending on the form of the disease internal organs may also be affected in various degrees eg alimentary tract lungs heart kidney central nervous system It is usually classified into systemic sclerosis generalized scleroderma and morphea localized scleroderma distinguished by visceral involvement in the generalized form and disease limited to the skin and subcutaneous tissue in the localized form Prognosis depends mainly on renal cardiac and pulmonary manifestations
The pathogenesis of scleroderma is not well understood However it is assumed that there is an initial damage to endothelial cells a subsequent inflammatory reaction in which mainly T-lymphocytes macrophages and mast cells are pathologically altered and an activation of fibroblasts causing increased and disturbed collagen production which finally leads to fibrosis In addition alterations in the innate and acquired immune response a disturbed microcirculation and fibroblast dysfunction are also involved
The therapy of patients with scleroderma is very limited It is based on immunosuppression which includes systemic steroids azathioprine cyclophosphamide methotrexate mycophenolate mofetil or interferons Phototherapy is also a major component in the treatment of Scleroderma and ranges from narrowband to broadband UVB UVA UVA1 Psoralen-UVA PUVA and ECP The key advantage of ECP for the treatment of scleroderma is the improvement of its skin manifestations Nevertheless there is also emerging evidence that suggests that ECP may play a role improving oral aperture size joint mobility skin ulcers and functional status Furthermore in contrast to the available immunosuppressive therapies ECP has a low side effect profile Τhe European Dermatology Forum recommends ECP as a second-line therapy or as part of adjuvant therapy in patients with scleroderma There is currently no consensus on the duration and frequency of ECP for the treatment of scleroderma
Graft-versus-Host Disease and ECP
Graft-versus-host disease is a complex multiorgan disease which can occur as a complication following allogeneic stem cell transplantation Involvement of the skin represents the most common appearance of GvHD According to the Consensus of National Institute of health further sub-classification can be done into acute and chronic GvHDCorticosteroids are first-line therapy for both acute and chronic GvHD but due to its significant toxicity and an increasing number of patients developing steroid-refractory disease many rescue therapies are currently available ECP is a widely recommended treatment approach as a second-line treatment especially in steroid refractory form of GvHD
Eosinophilic fasciitis and ECP
Eosinophilic fasciitis is a rare sclerodermiform syndrome of unknown etiology characterized by the fibrosis of the muscular fascia and subcutaneous tissue accompanied with infiltration of eosinophils There is little data regarding ECP in Eosinophilic fasciitis however ECP may be beneficial
Objectives
The aim of this study is to investigate the influence of ECP on patients with autoimmune fibrosing disorders including systemic sclerosis morphea sclerodermiform GvHD and eosinophilic fasciitis More specifically the following topics are going to be investigated
1 Quality and functionality of skin lesions
1 Examination of lesional and clinically uninvolved skin during ECP treatment using clinical evaluation and skin functional parameters If possible the examinations will take place before the initiation and during the ECP treatment This depends on the stage of therapy of the participants at the time they get included in the study
2 Evaluation of the influence of the frequency and the duration of ECP on the progress of the disease
2 Alteration of biomarkers during the ECP treatment
1 Observation of specific potential biomarkers during the treatment in order to understand the mechanism of action of ECP as well as its influence in those biomarkers
2 Evaluation of biomarkers as possible prognostic markers
Study design
Prospective monocentric exploratory study with a single group of 10 subjects Ten patients with sclerotic skin lesions due to systemic sclerosis or morphea or sclerodermiform GvHD or eosinophilic fasciitis will be enrolled in this clinical study Subjects not having started first ECP treatment yet will be preferred for inclusion The modified Rodnan skin score is widely accepted as a validated method to evaluate skin sclerosis therefore its results will be considered as the primary outcome in this study The study will include 8 visits for each included patient
Screening visit between week -2 and week 0
Baselineinclusion visit week 0
Intermediate visits every 4 weeks 2
End of study visit week 24 2
Study setting
The study will be conducted by the Clinical Research Center for Hair and Skin Science Department of Dermatology and Allergy Charité - Universitätsmedizin Berlin
Patients with systemic sclerosis or sclerotic skin lesions who already receive or are planned to receive ECP treatment will be recruited in this study In other words they will receive the treatment regardless of their inclusion in the study Normally a 3-day inpatient stay in the clinic is required for a cycle of ECP treatment The study visits will be carried out during this inpatient stay at the Department of Dermatology and Allergy Charité - Universitätsmedizin Berlin If necessary additional appointments with the subjects will be made in the same setting
Recruitment strategies
Patients who receive ECP in the Department of Dermatology Venerology and Allergology - Charité - Universitätsmedizin Berlin will be informed about the study by the study investigators
Data collection methods
1 Demographic data medical history An extended interview of the patient on his demographics medical history treatments and medications will be performed by an investigator during the inclusion visit
2 Modified Rodnan skin score The modified Rodnan skin score is a validated method to evaluate skin thickening in SSc worldwideIt will be performed by an investigator
3 Skin physiological and functional parameters Skin functional parameters will be determined at the uninvolved skin of the volar forearm or the gluteal area control and at one lesional skin area target lesion which may differ among the subjects but preferably would be in a contralateral area to the uninvolved skin area chosen Before measurements are performed subjects will rest for 30 minutes in a room with controlled environmental conditions room temperature 22 C 2 C relative humidity 50 10 for acclimatization The skin of the investigational sites must be open to air
Following parameters will be determined
Stratum corneum hydration SCH SCH will be measured using the Corneometer CM 825 Courage Khazaka Colonge Germany which measures the hydration level of the stratum corneum as electrical capacitance The measurement is based on the differences of the dielectric constant of water and other substances The arbitrary units range from 0 to 120 higher readings indicate higher stratum corneum hydration
Transepidermal water loss TEWL TEWL will be measured using the Tewameter TM 300 Courage Khazaka Colonge Germany The probe of the instrument measures the density gradient of the water evaporation from the skin indirectly by the two pairs of sensors temperature and relative humidity inside the hollow cylinder Water evaporation is captured in gram per hour per m² Higher values indicate a higher transepidermal water loss
Skin firmness A Cutometer Dual MPA 580 Courage Khazaka Colonge Germany will be used The instrument measures skin deformation after repeated cycles of suction and release The resistance of the skin to the negative pressure and its ability to return into its original position are displayed as curves penetration depth in mmtime in real time during the measurement
Skin surface sebum level A Sebumeter SM 815 Courage Khazaka Colonge Germany will be used The measurement is based on grease spot photometry The measurement cassette contains a special tape that becomes transparent when it comes into contact with sebum on the surface of the skin In order to make a measurement the cassette is inserted into an aperture on the device where the transparency of the tape is measured The transparency is measured by sending light through the tape using a light source in the aperture The light is reflected by a mirror behind the tape and a photocell measures the transparency The change in the amount of light transmission represents the sebum content of the tape which is displayed in units from 0-350 Higher values indicate a higher lipid level
Skin thickness A Dermascan C ultrasound scanner Cortex Technology Denmark with a 20MHz probe will be used
4 Biomarkers Biomarkers will be determined via blood sampling Two CPDa tubes and two serum tubes will be used at each blood collection Blood samples will be collected at three time-points during an inpatient stay immediately before the start of ECP on day one immediately after the ECP treatment on day one and at the patients discharge on day three Serum levels of specific cytokines and chemokines will be determined using ELISA Percentage counts of specific T-cell subpopulations will be obtained by fluorescence-activated cell sorting analysis FACS using the following surface markers CD3 CD4 CD45RA CD127 CD25 CXCR3 CXCR5 and CCR6
Data management
A paper source data will be created for this study Data including demographics medical history measurement results and clinical score results will be completed during the study visits in written form Data from the source data will be extracted and entered into a data file by the data manager using the software IBM SPSS Statistics 26 The database will be stored on a secured digital server of the Charité - Universitätsmedizin Berlin
Statistical methods
Descriptive comparative statistical analysis will be conducted All parameters will be described using measures of central tendency and measures of variability or dispersion This is an exploratory study therefore a formal sample size calculation is not planned
Monitoring
Data Monitoring Planned
Harms The participants will not be monitored for adverse events because the study is considered as non-interventional All subjects will receive ECP treatment regardless of their inclusion in this study Furthermore all non-invasive measurements as well as the blood sampling will be conducted during the subjects planned hospitalization
Auditing Not planned
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None