Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis — UPSIDE  

Systemic Sclerosis Clinical Trial

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

Clinical Trial Summary

HSCT has been implemented in (inter)national 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 (i.v.) cyclophosphamide (CYC) pulse therapy followed by mycophenolate mofetil (MMF) and HSCT as rescue option).

Clinical Trial 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 (i.v.) cyclophosphamide (CYC) pulse thera-py followed by mycophenolate mofetil (MMF) and HSCT as rescue option). HSCT has been implemented in (inter)national 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 patient's 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 patient's 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 i.v. 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 ACR/EULAR criteria. Patients disease duration (non-Raynaud's 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 i.v. pulses CYC (750 mg/m2), 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 (re)instituted, according to local preference. Based on earlier studies, the clinical benefits of i.v. 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 parameters/endpoints: Global Rank Composit score at 24 months follow-up.

Secondary efficacy endpoints: Event-free survival after randomisation/treatment, overall survival (OS), progression-free survival, number of participants that need rescue therapy (i.e. 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 v5.0). Patient reported outcomes at 12 and 24 months include: Quality of life (EQ-5D), SHAQ, Gastrointestinal complaints (UCLA SCTC GIT 2.0), sexual functioning. ;

Related Conditions & MeSH terms

• Autologous Stem Cell Transplantation
• Cyclophosphamide
• Mycophenolate Mofetil
• Scleroderma
• Scleroderma, Diffuse
• Scleroderma, Localized
• Scleroderma, Systemic
• Sclerosis
• Systemic Scleroses, Diffuse
• Systemic Sclerosis
• Treatment Strategy

• NCT number: NCT04464434
• Study type: Interventional
• Source: UMC Utrecht
• Contact: Julia Spierings, MD
• Phone: +31641888582
• Email: J.Spierings@umcutrecht.nl
• Status: Recruiting
• Phase: Phase 4
• Start date: September 17, 2020
• Completion date: October 1, 2030