Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis

• Register: ClinicalTrials.gov
• Last refreshed on: 9 October 2023
• Main ID: NCT04464434
• Date of registration: 25/06/2020
• Prospective Registration: Yes
• Primary sponsor: UMC Utrecht
• Public title: Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis UPSIDE
• Scientific 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
• Date of first enrolment: September 17, 2020
• Target sample size: 50
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT04464434
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 4

Countries of recruitment

Belgium, Croatia, Germany, Italy, Netherlands, Sweden, Switzerland, United Kingdom

Contacts

• Name: Jacob M van Laar, MD PhD
• Affiliation: UMC Utrecht

• Name: Julia Spierings
• Affiliation: UMC Utrecht

• Name: Julia Spierings, MD

Key inclusion & exclusion 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.



Age minimum: 18 Years
Age maximum: 65 Years
Gender: All

Health Condition(s) or Problem(s) studied

Systemic Scleroses, Diffuse

Mycophenolate Mofetil

Scleroderma

Treatment Strategy

Autologous Stem Cell Transplantation

Systemic Sclerosis

Scleroderma, Diffuse

Cyclophosphamide

Intervention(s)

Procedure: Upfront autologous HSCT

Primary Outcome(s)

Global Rank Composite Score (GRCS) [Time Frame: 24 months]

Secondary Outcome(s)

Changes in cardiac function(Left Ventricular Ejection Fraction) [Time Frame: 12 and 24 months]

Changes in health related quality of life EQ-5D-5L index [Time Frame: 24 months]

Changes in fatigue measured with the FACIT questionnaire [Time Frame: 12 and 24 months]

Changes in nailfold capillaroscopy [Time Frame: 12 and 24 months]

Changes in several subsets of the immune system [Time Frame: 12 months]

Changes in sexual functioning [Time Frame: 12 and 24 months]

Changes in ability to work, measured by the customized Productivity Cost Questionnaire (iPCQ) [Time Frame: 12 and 24 months]

Number of CTCAE toxicity advserse events [Time Frame: 24 months]

Changes in handmobility [Time Frame: 24 months]

Changes in pulmonary function [Time Frame: 12 and 24 months]

Number of patient alive after 24 months (Overall mortality) [Time Frame: 24 months]

The area under the curve (AUC) of the CRISS over time [Time Frame: 24 months]

Changes in 18F FDG-PET scan from the thorax [Time Frame: 12 months]

Changes in daily functioning [Time Frame: 12 and 24 months]

Changes in gastrointestinal complaints (UCLA SCTC GIT 2.0) [Time Frame: 12 and 24 months]

Changes in self-assessed skin thickness (PASTUL_) [Time Frame: 60 months]

Changes in skin involvement (modified Rodnan Skin Score) [Time Frame: 24 months]

Inflammatory and fibrotic characteristics and changes of the skin and composition of the microbiome of the skin [Time Frame: 12 months]

Number of patients who die due to complications related to the treatment (Treatment related mortality) [Time Frame: 24 months]

Number of patients who survive without disease progression (Progression-free survival) [Time Frame: 24 months]

Number of patients who survive without major events (event free survival) [Time Frame: 24 months]

Secondary ID(s)

NL72607.041.20

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

ZonMw: The Netherlands Organisation for Health Research and Development

Boehringer Ingelheim

Miltenyi Biotec, Inc.