Systemic Sclerosis
Conditions
Interventions
Arm A. Upfront autologous HSCT
Autologous, non-myeloablative HSCT comprises the following consecutive steps:
a. Mobilisation: PBSCs will be mobilised using a regimen consisting of one-hour infusions o
Sponsors
University Medical Centre Utrecht
Eligibility
Inclusion criteria
Inclusion criteria: 1. Age between 18 and 65 years. 2. Fulfilling the 2013 ACR-EULAR classification criteria for SSc (appendix B). 3. Disease duration = 2 years (from onset of first non-Raynaud’s symptoms) and diffuse cutaneous disease with - mRSS = 15 and/or - clinically significant organ involvement as defined by either: a) 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 relative 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 excluded, within 12 months. Intercurrent infections excluded. b) renal involvement = any of the following criteria: hypertension (two successive BP readings of either systolic = 160 mm Hg or diastolic > 110 mm Hg, at least 12 hours apart), persistent urinalysis abnormalities (proteinuria, haematuria, casts), microangiopathic haemolytic anaemia, new renal insufficiency (serum creatinine > upper limit of normal); non-scleroderma related causes (e.g. medication, infection etc.) must be reasonably excluded. c) cardiac involvement = any of the following criteria: reversible congestive heart failure, atrial or ventricular rhythm disturbances such as atrial fibrillation or flutter, atrial paroxysmal tachycardia or ventricular tachycardia, 2nd or 3rd degree AV block, pericardial effusion (not leading to hemodynamic problems), myocardi-tis; non-scleroderma related causes must have been reasonably excluded. 4. Written Informed consent
Exclusion criteria
Exclusion criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: 1. Pregnancy or unwillingness to use adequate contraception during study 2. Concomitant severe disease = a) respiratory: resting mean pulmonary artery pressure (mPAP) > 20 mmHg (by right heart catheterisa tion), DLCO 2 3. Previous treatments with immunosuppressants > 6 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary endpoint is event-free survival. Event-free survival is defined as the time in days from the day of randomisation until the occurrence of death due to any cause or the development of persistent major organ failure (heart, lung, kidney) defined as follows: •Heart: left ventricular ejection fraction 6.7 kPa (> 50 mmHg) without oxygen supply •Kidney: need for renal replacement therapy Note 1. When major organ failure has occurred, its persistence is to be confirmed by repeated evaluation after 3 months. Note 2. Cardiac MR is considered the gold standard for assessment of LVEF. LVEF measurements by cardiac echo (instead of cardiac MR) will be accepted when baseline and follow-up eval-uations have been performed by the same experienced echocardiologist. | — |
Secondary
| Measure | Time frame |
|---|---|
| - Progression-free survival, defined as the time in days since the day of randomisation until any of the following relative changes from baseline has been documented: • death, • = 10% drop in (F)VC predicted and/or = 15% drop in DLCO predicted, • = 15% drop in LVEF by echo or cardiac MR, • = 15% drop in body weight, • = 30% drop in creatinine clearance, • = 30% increase in skin score, • = 0.5 increase in SHAQ. - Treatment related mortality is defined as any death during the study period following randomisation that cannot be attributed to progression of the disease according to the consensus opinion of the DSMB. - Treatment toxicity will be assessed using WHO toxicity parameters (adverse events =/> grade 3) in consecutive 3-month periods following randomisation until two years follow-up. - The area under the curve (AUC) of the CRISS over time, measuring the ‘predicted probability of being im-proved’ over 2 years.(22) This AUC is calculated based on 4 repeated measures (6, 12, 18 and 24 months) with back translation to the original scale between 0 and 1. The CRISS is a composite score, measuring the CRISS is a two-step process: Step 1: Subjects who develop new or worsening of cardiopulmonary and/or renal involvement due to SSc are considered as not improved (irrespective of improvement in other core items) and assigned a probability of im-proving equal to 0.0. Specifically if a subject develops either: 1) New scleroderma renal crisis, 2) Decline in forced vital capacity (FVC)% predicted =15% (relative), confirmed by another FVC% within a month, high resolution computer tomography (HRCT) to confirm interstitial lung disease (ILD; if previous high resolution computer tomography of chest did not show ILD) and FVC% predicted below 80% predicted, 3) New onset of left ventricular failure (defined as left ventricular ejection fraction =45%) requiring treatment, or, 4) New onset of pulmonary arterial hypertension (PAH) on right heart catheterization requiring treatmen | — |
Contacts
Public ContactJulia Spierings
UMC Utrecht
Outcome results
None listed