Autologous Stem Cell Transplantation in Patients with Systemic Sclerosis: First-Line Therapy or Last Resort?

ICTRP Trial ID
NCT04464434 (ICTRP)

Official title (approved by ethics committee)
Upfront autologous hematopoietic stem cell transplantation versus immunosuppressive medication in early diffuse cutaneous systemic sclerosis: an international multicentre, open-label, randomized controlled trial (BASEC)

Academic 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 (ICTRP)

Public title
Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis (ICTRP)

Disease under investigation
Systemic Sclerosis;Systemic Scleroses, Diffuse;Scleroderma;Scleroderma, Diffuse;Autologous Stem Cell Transplantation;Cyclophosphamide;Mycophenolate Mofetil;Treatment Strategy (ICTRP)

Intervention under investigation
Procedure: Upfront autologous HSCT (ICTRP)

Type of trial
Interventional (ICTRP)

Trial design
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Inclusion/Exclusion criteria
Gender: All
Maximum age: 65 Years
Minimum age: 18 Years
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. (ICTRP)

not available

Primary and secondary end points
Global Rank Composite Score (GRCS) (ICTRP)

Number of patients who survive without disease progression (Progression-free survival);Number of patients who die due to complications related to the treatment (Treatment related mortality);Number of patient alive after 24 months (Overall mortality);Number of CTCAE toxicity advserse events;The area under the curve (AUC) of the CRISS over time;Changes in skin involvement (modified Rodnan Skin Score);Changes in cardiac function(Left Ventricular Ejection Fraction);Changes in pulmonary function;Changes in health related quality of life EQ-5D-5L index;Changes in nailfold capillaroscopy;Changes in 18F FDG-PET scan from the thorax;Changes in gastrointestinal complaints (UCLA SCTC GIT 2.0);Changes in several subsets of the immune system;Changes in self-assessed skin thickness (PASTUL_);Inflammatory and fibrotic characteristics and changes of the skin and composition of the microbiome of the skin;Changes in sexual functioning;Changes in daily functioning;Changes in ability to work, measured by the customized Productivity Cost Questionnaire (iPCQ);Changes in fatigue measured with the FACIT questionnaire;Changes in handmobility;Number of patients who survive without major events (event free survival) (ICTRP)

Registration date
not available

Incorporation of the first participant
not available

Secondary sponsors
ZonMw: The Netherlands Organisation for Health Research and Development;Boehringer Ingelheim;Miltenyi Biotec, Inc. (ICTRP)

Additional contacts
Jacob M van Laar, MD PhD;Julia Spierings;Julia Spierings, MD, J.Spierings@umcutrecht.nl, +31641888582, UMC Utrecht,UMC Utrecht, (ICTRP)

Secondary trial IDs
NL72607.041.20 (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://clinicaltrials.gov/ct2/show/NCT04464434 (ICTRP)