Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis

NCT04464434 | Completed Phase 4 DMC

• 1 other identifier: NL72607.041.20
• Study Type: interventional
• Target: 60
• Locations: 3 countries
• Sites: 8

Brief 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).

Conditions

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

Keywords

Randomized controlled trial; Autologous stem cell transplantation; Systemic Sclerosis; Cyclophosphamide; Mycophenolate Mofetil; Upfront; Treatment strategy; Event Free survival

Outcome Measures

Primary Outcomes (1)

• Global Rank Composite Score (GRCS)

  The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. For this endpoint, seveal endpoints will be used: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of \>30% in DLCO % predicted or \>20% in FVC % predicted ), renal failure (chronic dialysis \> 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction \<30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).

  24 months

Secondary Outcomes (21)

• Number of patients who survive without disease progression (Progression-free survival)

  24 months

• Number of patients who die due to complications related to the treatment (Treatment related mortality)

  24 months

• Number of patient alive after 24 months (Overall mortality)

  24 months

• Number of CTCAE toxicity advserse events

  24 months

• The area under the curve (AUC) of the CRISS over time

  24 months

Study Arms (2)

Upfront autologous HSCT

EXPERIMENTAL

Procedure: Upfront autologous HSCT

Immunosuppressive therapy

ACTIVE COMPARATOR

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.

Procedure: Upfront autologous HSCT

Interventions

Upfront autologous HSCT PROCEDURE

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; Upfront autologous HSCT

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18 and 65 years.
• 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
• persistent urinalysis abnormalities (proteinuria, haematuria, casts), AND/OR
• microangiopathic haemolytic anaemia AND/OR
• 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
• Disease duration ≤ 1 year (from onset of first non-Raynaud's symptoms) and diffuse cutaneous disease with mRSS ≥ 10 and
• High risk ANA for organ based disease: ATA or ARA positivity and/ or
• Acute phase response (ESR \> 25 mm/h and/or CRP \> 10.0 mg/L )

You may not qualify if:

• Pregnancy or unwillingness to use adequate contraception during study
• Concomitant severe disease =
• respiratory: resting mean pulmonary artery pressure (mPAP) \> 25 mmHg (by right heart catheterisation), DLCO \< 40% predicted, respiratory failure as defined by the primary endpoint
• renal: creatinine clearance \< 40 ml/min (measured or estimated)
• 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
• liver failure as defined by a sustained 3-fold increase in serum transaminase or bilirubin, or a Child-Pugh score C
• psychiatric disorders including active drug or alcohol abuse
• concurrent neoplasms or myelodysplasia
• 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
• uncontrolled hypertension
• uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity
• ZUBROD-ECOG-WHO Performance Status Scale \> 2
• Previous treatments with immunosuppressants \> 12 months including MMF, methotrexate, azathioprine, rituximab, tocilizumab, glucocorticosteroids.
• Previous treatments with TLI, TBI or alkylating agents including CYC.
• Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica;

Sponsors & Collaborators

• UMC Utrecht: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Boehringer Ingelheim: collaborator
• Miltenyi Biotec, Inc.: collaborator

Study Sites (8)

Gaetano Pini-CTO

Milan, Italy

Location

Ospedale San Raffaele

Milan, Italy

Location

University Hospital Rome

Roma, Italy

Location

Amsterdam Rheumatology Centre

Amsterdam, Netherlands

Location

University Medical Centre Leiden

Leiden, Netherlands

Location

Radboudumc Nijmegen

Nijmegen, Netherlands

Location

University Medical Centre Utrecht

Utrecht, Netherlands

Location

Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, United Kingdom

Location

Related Publications (5)

• 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.

  PMID: 21777972 BACKGROUND

• 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.

  PMID: 29298160 BACKGROUND

• 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.

  PMID: 25058083 BACKGROUND

• 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.

  PMID: 32409324 BACKGROUND

• 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.

  PMID: 33737437 DERIVED

Related Links

• official trial website

MeSH Terms

Conditions

Scleroderma, Systemic; Scleroderma, Diffuse

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Study Officials

• Jacob M van Laar, MD PhD

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

• Julia Spierings

  UMC Utrecht

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, Clinical professor

Model Details: This multicentre, randomized, open label trial aims to compare two treatment strategies in early dcSSc: upfront autologous HSCT versus i.v. CYC pulse therapy followed by MMF and HSCT as rescue option.

Study Record Dates

• First Submitted: June 25, 2020
• First Posted: July 9, 2020
• Study Start: September 17, 2020
• Primary Completion: March 19, 2026
• Study Completion: March 19, 2026
• Last Updated: March 24, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (3); NL (4); GB (1)