Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis
NCT ID: NCT04464434
Last Updated: 2024-12-06
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
RECRUITING
PHASE4
50 participants
INTERVENTIONAL
2020-09-17
2030-10-01
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
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).
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
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.
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Keywords
Explore important study keywords that can help with search, categorization, and topic discovery.
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
Upfront autologous HSCT
Upfront autologous HSCT
HSCT comprises the following consecutive steps:
1. Mobilisation
* Infusions of CYC 2g/m2 on 1 day.
* Hyperhydration, alkalinisation of urine and mesna to prevent haemorrhagic cystitis.
* Filgrastim (G-CSF) 5-10 μg/kg/day subcutaneously for 5 days (or more when necessary).
2. Leukapheresis Prompt start of leukapheresis is required at a CD34+ cell count of ≥10-20/μL. Goal: at least 2 x 10\^6 CD34+ cells per kilogram body weight.
3. Conditioning
* CYC 50 mg/kg/day intravenously for 4 consecutive days (total 200 mg/kg)
* Rabbit Antithymocyte Globulin (rbATG), a total dose of 7.5 mg/kg i.v., from Genzyme.
Hyperhydration, alkalinisation of the urine and mesna will be given to prevent haemorrhagic cystitis.
I.v. methylprednisolone 2 mg/kg will be administered on the days ATG, to improve tolerability of the ATG.
4. Peripheral stem cell infusion The number of CD34+ cells to be reinfused should be ≥ 2.0 x 10\^6/kg.
Immunosuppressive therapy
12 monthly i.v. pulses CYC 750 mg/m2 (= 9 g/m2 cumulative) followed by at least 12 months of oral MMF daily (3 grams as maximum daily dosage) or mycophenolic acid (up to 2.160 grams daily).
Hyperhydration, alkalinisation of the urine and mesna is recommended, and will be given according to local protocols in order to prevent haemorrhagic cystitis.
Upfront autologous HSCT
HSCT comprises the following consecutive steps:
1. Mobilisation
* Infusions of CYC 2g/m2 on 1 day.
* Hyperhydration, alkalinisation of urine and mesna to prevent haemorrhagic cystitis.
* Filgrastim (G-CSF) 5-10 μg/kg/day subcutaneously for 5 days (or more when necessary).
2. Leukapheresis Prompt start of leukapheresis is required at a CD34+ cell count of ≥10-20/μL. Goal: at least 2 x 10\^6 CD34+ cells per kilogram body weight.
3. Conditioning
* CYC 50 mg/kg/day intravenously for 4 consecutive days (total 200 mg/kg)
* Rabbit Antithymocyte Globulin (rbATG), a total dose of 7.5 mg/kg i.v., from Genzyme.
Hyperhydration, alkalinisation of the urine and mesna will be given to prevent haemorrhagic cystitis.
I.v. methylprednisolone 2 mg/kg will be administered on the days ATG, to improve tolerability of the ATG.
4. Peripheral stem cell infusion The number of CD34+ cells to be reinfused should be ≥ 2.0 x 10\^6/kg.
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
Upfront autologous HSCT
HSCT comprises the following consecutive steps:
1. Mobilisation
* Infusions of CYC 2g/m2 on 1 day.
* Hyperhydration, alkalinisation of urine and mesna to prevent haemorrhagic cystitis.
* Filgrastim (G-CSF) 5-10 μg/kg/day subcutaneously for 5 days (or more when necessary).
2. Leukapheresis Prompt start of leukapheresis is required at a CD34+ cell count of ≥10-20/μL. Goal: at least 2 x 10\^6 CD34+ cells per kilogram body weight.
3. Conditioning
* CYC 50 mg/kg/day intravenously for 4 consecutive days (total 200 mg/kg)
* Rabbit Antithymocyte Globulin (rbATG), a total dose of 7.5 mg/kg i.v., from Genzyme.
Hyperhydration, alkalinisation of the urine and mesna will be given to prevent haemorrhagic cystitis.
I.v. methylprednisolone 2 mg/kg will be administered on the days ATG, to improve tolerability of the ATG.
4. Peripheral stem cell infusion The number of CD34+ cells to be reinfused should be ≥ 2.0 x 10\^6/kg.
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
2. Fulfilling the 2013 ACR-EULAR classification criteria for SSc
Either: 3.1 or 3.2 3.1. Disease duration ≤ 3 years (from onset of first non-Raynaud's symptoms) and diffuse cutaneous disease with
\- progressive skin involvement with a mRSS ≥ 15 (in a diffuse pattern: involvement of skin on the upper limbs, chest and/or abdomen)
and/or
\- major organ involvement as defined by either:
a. clinically significant respiratory involvement = i. DLCO and/or (F)VC ≤ 85% (of predicted) and evidence of interstitial lung disease on HR-CT scan with clinically relevant obstructive disease and emphysema excluded. ii. Patients with a DCLO and/or FVC \> 85%, but with a progressive course of lung disease: defined as rela-tive decline of \>10% in FVC predicted and/or TLC predicted, or \>15% in DLCO predicted and evidence of interstitial lung disease on HR-CT scan with clinically relevant obstructive disease and emphysema ex-cluded, within 12 months. Intercurrent infections excluded.
b. clinically significant renal involvement = i. new renal insufficiency (serum creatinine \> upper limit of normal) AND
1. persistent urinalysis abnormalities (proteinuria, haematuria, casts), AND/OR
2. microangiopathic haemolytic anaemia AND/OR
3. hypertension (two successive BP readings of either systolic ≥ 160 mm Hg or diastolic \> 110 mm Hg, at least 12 hours apart), ; non-scleroderma related causes (e.g. medication, infection etc.) must be reasonably excluded.
c. clinically significant cardiac involvement = any of the following criteria: i. reversible congestive heart failure, ii. atrial or ventricular rhythm disturbances such as atrial fibrillation or flutter, atrial paroxysmal tachycar-dia or ventricular tachycardia, 2nd or 3rd degree AV block, iii. pericardial effusion (not leading to hemodynamic problems), myocarditis; non-scleroderma related causes must have been reasonably excluded
3.2. Disease duration ≤ 1 year (from onset of first non-Raynaud's symptoms) and diffuse cutaneous disease with mRSS ≥ 10 and
1. High risk ANA for organ based disease: ATA or ARA positivity and/ or
2. Acute phase response (ESR \> 25 mm/h and/or CRP \> 10.0 mg/L )
4\. Written Informed consent
Exclusion Criteria
2. Concomitant severe disease =
1. respiratory: resting mean pulmonary artery pressure (mPAP) \> 25 mmHg (by right heart catheterisation), DLCO \< 40% predicted, respiratory failure as defined by the primary endpoint
2. renal: creatinine clearance \< 40 ml/min (measured or estimated)
3. cardiac: clinical evidence of refractory congestive heart failure; LVEF \< 45% by cardiac echo or cardiac MR; chronic atrial fibrillation necessitating oral anticoagulation; uncontrolled ventricular arrhythmia; pericardial effusion with hemodynamic consequences
4. liver failure as defined by a sustained 3-fold increase in serum transaminase or bilirubin, or a Child-Pugh score C
5. psychiatric disorders including active drug or alcohol abuse
6. concurrent neoplasms or myelodysplasia
7. bone marrow insufficiency defined as leukocytopenia \< 4.0 x 109/L, thrombocytopenia \< 50x 10\^9/L, anaemia \< 8 gr/dL, CD4+ T lymphopenia \< 200 x 106/L
8. uncontrolled hypertension
9. uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity
10. ZUBROD-ECOG-WHO Performance Status Scale \> 2
3. Previous treatments with immunosuppressants \> 12 months including MMF, methotrexate, azathioprine, rituximab, tocilizumab, glucocorticosteroids.
4. Previous treatments with TLI, TBI or alkylating agents including CYC.
5. Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica;
6. eosinophilic myalgia syndrome; eosinophilic fasciitis.
7. Poor compliance of the patient as assessed by the referring physicians.
18 Years
65 Years
ALL
No
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
ZonMw: The Netherlands Organisation for Health Research and Development
OTHER
Boehringer Ingelheim
INDUSTRY
Miltenyi Biotec, Inc.
INDUSTRY
UMC Utrecht
OTHER
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Jacob M van Laar
Principal Investigator, Clinical professor
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Jacob M van Laar, MD PhD
Role: PRINCIPAL_INVESTIGATOR
UMC Utrecht
Julia Spierings
Role: STUDY_DIRECTOR
UMC Utrecht
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
Gaetano Pini-CTO
Milan, , Italy
Ospedale San Raffaele
Milan, , Italy
University Hospital Rome
Roma, , Italy
Amsterdam Rheumatology Centre
Amsterdam, , Netherlands
University Medical Centre Leiden
Leiden, , Netherlands
Radboudumc Nijmegen
Nijmegen, , Netherlands
University Medical Centre Utrecht
Utrecht, , Netherlands
Skåne University Hospital Lund
Lund, , Sweden
Karolinska Institute/Karolinska University Hospital Solna
Stockholm, , Sweden
University Hospital Basel
Basel, , Switzerland
Inselspital, Universitätsspital Bern
Bern, , Switzerland
Sheffield Teaching Hospitals NHS Foundation Trust
Sheffield, , United Kingdom
Countries
Review the countries where the study has at least one active or historical site.
Central Contacts
Reach out to these primary contacts for questions about participation or study logistics.
Facility Contacts
Find local site contact details for specific facilities participating in the trial.
Nicoletta Del Papa, MD PhD
Role: primary
Rafaella Greco
Role: primary
Roberto Giacomelli, MD PhD
Role: primary
Alexandre Voskuyl
Role: primary
Jeska de Vries-Bouwstra
Role: primary
Madelon Vonk
Role: primary
Julia Spierings
Role: primary
Anne Karien Marijnissen
Role: backup
Dirk Wuttge
Role: primary
Karina Gheorge, MD PhD
Role: primary
Ulrich Walker
Role: primary
Britta Maurer
Role: primary
References
Explore related publications, articles, or registry entries linked to this study.
Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, Craig R, Hirano I, Marshall K, Ruderman E, Jovanovic B, Milanetti F, Jain S, Boyce K, Morgan A, Carr J, Barr W. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet. 2011 Aug 6;378(9790):498-506. doi: 10.1016/S0140-6736(11)60982-3. Epub 2011 Jul 21.
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.
van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, Schuerwegh AJ, Marijt EW, Vonk MC, Schattenberg AV, Matucci-Cerinic M, Voskuyl AE, van de Loosdrecht AA, Daikeler T, Kotter I, Schmalzing M, Martin T, Lioure B, Weiner SM, Kreuter A, Deligny C, Durand JM, Emery P, Machold KP, Sarrot-Reynauld F, Warnatz K, Adoue DF, Constans J, Tony HP, Del Papa N, Fassas A, Himsel A, Launay D, Lo Monaco A, Philippe P, Quere I, Rich E, Westhovens R, Griffiths B, Saccardi R, van den Hoogen FH, Fibbe WE, Socie G, Gratwohl A, Tyndall A; EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014 Jun 25;311(24):2490-8. doi: 10.1001/jama.2014.6368.
van Bijnen S, de Vries-Bouwstra J, van den Ende CH, Boonstra M, Kroft L, Geurts B, Snoeren M, Schouffoer A, Spierings J, van Laar JM, Huizinga TW, Voskuyl A, Marijt E, van der Velden W, van den Hoogen FH, Vonk MC. Predictive factors for treatment-related mortality and major adverse events after autologous haematopoietic stem cell transplantation for systemic sclerosis: results of a long-term follow-up multicentre study. Ann Rheum Dis. 2020 Aug;79(8):1084-1089. doi: 10.1136/annrheumdis-2020-217058. Epub 2020 May 14.
Spierings J, van Rhenen A, Welsing PM, Marijnissen AC, De Langhe E, Del Papa N, Dierickx D, Gheorghe KR, Henes J, Hesselstrand R, Kerre T, Ljungman P, van de Loosdrecht AA, Marijt EW, Mayer M, Schmalzing M, Schroers R, Smith V, Voll RE, Vonk MC, Voskuyl AE, de Vries-Bouwstra JK, Walker UA, Wuttge DM, van Laar JM. A randomised, open-label trial to assess the optimal treatment strategy in early diffuse cutaneous systemic sclerosis: the UPSIDE study protocol. BMJ Open. 2021 Mar 18;11(3):e044483. doi: 10.1136/bmjopen-2020-044483.
Related Links
Access external resources that provide additional context or updates about the study.
official trial website
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
NL72607.041.20
Identifier Type: -
Identifier Source: org_study_id