Ignite Creation Date:
2024-05-06 @ 2:54 PM
Last Modification Date:
2024-10-26 @ 1:39 PM
Study NCT ID:
NCT04464434
Status:
RECRUITING
Last Update Posted:
2023-09-28
First Post:
2020-06-25
Brief Title:
Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis
Sponsor:
UMC Utrecht
Organization:
UMC Utrecht
Study Overview
Official Title:
Upfront Autologous Hematopoietic Stem Cell Transplantation Versus Immunosuppressive Medication in Early Diffuse Cutaneous Systemic Sclerosis an International Multicentre Open-label Randomized Con-trolled Trial
Status:
RECRUITING
Status Verified Date:
2023-09
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:
UPSIDE
Brief Summary:
HSCT has been implemented in international treatment guidelines for diffuse cutaneous systemic sclerosis dcSSc and is offered in clinical care and reimbursed by national health insurance in several European countries However data and specific guidelines on the best timing of HSCT in the course of dcSSc are lacking In particular it is unclear whether HSCT should be positioned as upfront therapy or as rescue treatment for patients not responding to conventional immunosuppressive therapy
This multicentre randomized open label trial aims to compare two treatment strategies used in usual care upfront autologous HSCT versus usual care with intravenous iv cyclophosphamide CYC pulse therapy followed by mycophenolate mofetil MMF and HSCT as rescue option
This multicentre randomized open label trial aims to compare two treatment strategies used in usual care upfront autologous HSCT versus usual care with intravenous iv cyclophosphamide CYC pulse therapy followed by mycophenolate mofetil MMF and HSCT as rescue option
Detailed Description:
Rationale This multicentre randomized open label trial aims to compare two treatment strategies used in usual care upfront autologous HSCT versus usual care with intravenous iv cyclophosphamide CYC pulse thera-py followed by mycophenolate mofetil MMF and HSCT as rescue option HSCT has been implemented in international treatment guidelines for diffuse cutaneous systemic sclerosis dcSSc and is offered in clinical care and reimbursed by national health insurance in several European countries However data and specific guidelines on the best timing of HSCT in the course of dcSSc are lacking
In particular it is unclear whether HSCT should be positioned as upfront therapy or as rescue treatment for patients not responding to conventional im-munosuppressive therapy Given the risks and costs associated with HSCT it may be preferable to evaluate the patients response to immunosuppressive therapy before proceeding to HSCT Considering HSCT as a rescue treatment could significantly delay the need for a potentially harmful treatment and may be an efficient approach from a health economic perspective as HSCT is a highly specialized resource intensive and expensive medical procedure On the other hand in the time frame needed to evaluate the effect of immunosuppressive therapy pulmonary and cardiac involvement may develop negatively influencing a patients prognosis and possibly leading to a contra-indication for HSCT We hypothesize that upfront HSCT results in less toxicity and medical costs in the long run Therefore we propose a multicentre randomized open label trial in chemotherapy naive patients with early dcSSc
Objective To determine the optimal treatment strategy in early dcSSc the effect of HSCT as upfront therapy compared with that of immunosuppressive medication in early dcSSc with respect to survival and prevention of major organ failure referred to as event-free survival which is considered as primary endpoint safety and the impact on skin thickening visceral involvement functional status and quality of life
Secondary goals are to evaluate in both treatment arms whether disease activity correlates with immunological parameters including immunopathology of skin immune reconstitution and autoantibodies We will also de-termine the cost-effectiveness of HSCT as first line treatment versus usual care and try to identify factors associated with response to treatment
Study design This investigation is an international multicentre prospective randomized open label trial com-paring two treatment strategies used in regular care upfront autologous HSCT versus immunosuppressive thera-py with iv CYC pulse therapy followed by MMF and HSCT as rescue option
Study population Patients aged between 18 - 65 years with an established diagnosis of dcSSc according to the ACREULAR criteria Patients disease duration non-Raynauds symptoms should be 3 years and mRSS 15 diffuse skin pattern and or clinically significant organ involvement heart and lung involvement
Intervention One group A receives upfront autologous HSCT and the other group B receives 12 monthly iv pulses CYC 750 mgm2 followed by at least 12 months of oral MMF max 3 grams daily at one year after start of treatment Rescue therapy may be considered in both arms in case of insufficient response or clinically relevant flare but preferably not within the first 3 months after randomisation For patients from Arm A methotrexate mycophenolate mofetil or mycophenolic acid or rituximab can be reinstituted according to local preference Based on earlier studies the clinical benefits of iv pulse cyclophosphamide may take between 6-12 months Therefore it is recommended to then switch patients from arm B to HSCT only in case of rapidly progressive disease which is arbitrarily defined as 30 increase in mRSS or 20 relative decline in FVC TLC or DLCO predicted
Main study parametersendpoints Global Rank Composit score at 24 months follow-up
Secondary efficacy endpoints Event-free survival after randomisationtreatment overall survival OS progression-free survival number of participants that need rescue therapy ie the alternative treatment due to treatment failure Treatment related mortality treatment toxicity and changes in mRSS FVC TLC and DLCO nailfold microscopy immunological markers in skin and blood cardiac MR and 18FDG-PET The CRISS at 12 months Safety and tolerability outcomes according to CTC-criteria CTCAE v50 Patient reported outcomes at 12 and 24 months include Quality of life EQ-5D SHAQ Gastrointestinal complaints UCLA SCTC GIT 20 sexual functioning
In particular it is unclear whether HSCT should be positioned as upfront therapy or as rescue treatment for patients not responding to conventional im-munosuppressive therapy Given the risks and costs associated with HSCT it may be preferable to evaluate the patients response to immunosuppressive therapy before proceeding to HSCT Considering HSCT as a rescue treatment could significantly delay the need for a potentially harmful treatment and may be an efficient approach from a health economic perspective as HSCT is a highly specialized resource intensive and expensive medical procedure On the other hand in the time frame needed to evaluate the effect of immunosuppressive therapy pulmonary and cardiac involvement may develop negatively influencing a patients prognosis and possibly leading to a contra-indication for HSCT We hypothesize that upfront HSCT results in less toxicity and medical costs in the long run Therefore we propose a multicentre randomized open label trial in chemotherapy naive patients with early dcSSc
Objective To determine the optimal treatment strategy in early dcSSc the effect of HSCT as upfront therapy compared with that of immunosuppressive medication in early dcSSc with respect to survival and prevention of major organ failure referred to as event-free survival which is considered as primary endpoint safety and the impact on skin thickening visceral involvement functional status and quality of life
Secondary goals are to evaluate in both treatment arms whether disease activity correlates with immunological parameters including immunopathology of skin immune reconstitution and autoantibodies We will also de-termine the cost-effectiveness of HSCT as first line treatment versus usual care and try to identify factors associated with response to treatment
Study design This investigation is an international multicentre prospective randomized open label trial com-paring two treatment strategies used in regular care upfront autologous HSCT versus immunosuppressive thera-py with iv CYC pulse therapy followed by MMF and HSCT as rescue option
Study population Patients aged between 18 - 65 years with an established diagnosis of dcSSc according to the ACREULAR criteria Patients disease duration non-Raynauds symptoms should be 3 years and mRSS 15 diffuse skin pattern and or clinically significant organ involvement heart and lung involvement
Intervention One group A receives upfront autologous HSCT and the other group B receives 12 monthly iv pulses CYC 750 mgm2 followed by at least 12 months of oral MMF max 3 grams daily at one year after start of treatment Rescue therapy may be considered in both arms in case of insufficient response or clinically relevant flare but preferably not within the first 3 months after randomisation For patients from Arm A methotrexate mycophenolate mofetil or mycophenolic acid or rituximab can be reinstituted according to local preference Based on earlier studies the clinical benefits of iv pulse cyclophosphamide may take between 6-12 months Therefore it is recommended to then switch patients from arm B to HSCT only in case of rapidly progressive disease which is arbitrarily defined as 30 increase in mRSS or 20 relative decline in FVC TLC or DLCO predicted
Main study parametersendpoints Global Rank Composit score at 24 months follow-up
Secondary efficacy endpoints Event-free survival after randomisationtreatment overall survival OS progression-free survival number of participants that need rescue therapy ie the alternative treatment due to treatment failure Treatment related mortality treatment toxicity and changes in mRSS FVC TLC and DLCO nailfold microscopy immunological markers in skin and blood cardiac MR and 18FDG-PET The CRISS at 12 months Safety and tolerability outcomes according to CTC-criteria CTCAE v50 Patient reported outcomes at 12 and 24 months include Quality of life EQ-5D SHAQ Gastrointestinal complaints UCLA SCTC GIT 20 sexual functioning
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?:
False
Is an FDA AA801 Violation?:
None