Comparing upfront autologous stem cell transplantation to immunosuppression for early diffuse systemic sclerosis

Upfront Autologous Hematopoietic Stem Cell Transplantation Versus Immunosuppressive Medication in Early Diffuse Cutaneous Systemic Sclerosis: an International Multicentre, Open-label, Randomized Con-trolled Trial

This study is testing whether giving stem cell transplants right away is better than starting with standard treatments for people with early diffuse systemic sclerosis.

Quick facts

• Phase: Phase 4
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: UMC Utrecht (Academic / other)
• Drugs / interventions: rituximab, tocilizumab, methotrexate, cyclophosphamide, chemotherapy
• Locations: 12 sites (Milan and 11 other locations)
• Trial ID: NCT04464434 on ClinicalTrials.gov

What this trial studies

This multicentre, randomized, open label trial aims to evaluate the effectiveness of upfront autologous hematopoietic stem cell transplantation (HSCT) compared to standard immunosuppressive therapy followed by HSCT as a rescue option in patients with early diffuse cutaneous systemic sclerosis (dcSSc). The study seeks to determine the optimal timing for HSCT, as current guidelines lack clarity on whether it should be administered early or only after conventional treatments fail. Participants will be monitored for disease progression and treatment response, with the goal of improving patient outcomes and optimizing healthcare resources.

Who should consider this trial

Good fit: Ideal candidates for this study are adults aged 18 to 65 with early diffuse cutaneous systemic sclerosis and significant skin or organ involvement.

Not a fit: Patients with advanced systemic sclerosis or those who do not meet the inclusion criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide a more effective treatment strategy for patients with early diffuse systemic sclerosis, potentially improving their long-term health outcomes.

How similar studies have performed: Previous studies have shown promising results for HSCT in systemic sclerosis, but this specific comparison of treatment timing is novel.

Eligibility criteria

Inclusion Criteria:

1. Age between 18 and 65 years.
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:

1. Pregnancy or unwillingness to use adequate contraception during study
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.

Where this trial is running

Milan and 11 other locations

• Gaetano Pini-CTO — Milan, Italy (Not_yet_recruiting)
• Ospedale San Raffaele — Milan, Italy (Recruiting)
• University Hospital Rome — Roma, Italy (Not_yet_recruiting)
• Amsterdam Rheumatology Centre — Amsterdam, Netherlands (Recruiting)
• University Medical Centre Leiden — Leiden, Netherlands (Recruiting)
• Radboudumc Nijmegen — Nijmegen, Netherlands (Recruiting)
• University Medical Centre Utrecht — Utrecht, Netherlands (Recruiting)
• Skåne University Hospital Lund — Lund, Sweden (Recruiting)
• Karolinska Institute/Karolinska University Hospital Solna — Stockholm, Sweden (Recruiting)
• University Hospital Basel — Basel, Switzerland (Not_yet_recruiting)
• Inselspital, Universitätsspital Bern — Bern, Switzerland (Not_yet_recruiting)
• Sheffield Teaching Hospitals NHS Foundation Trust — Sheffield, United Kingdom (Not_yet_recruiting)

Study contacts

• Principal investigator: Jacob M van Laar, MD PhD — UMC Utrecht
• Study coordinator: Julia Spierings, MD

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