<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04464434</url>
  </required_header>
  <id_info>
    <org_study_id>NL72607.041.20</org_study_id>
    <nct_id>NCT04464434</nct_id>
  </id_info>
  <brief_title>Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis</brief_title>
  <acronym>UPSIDE</acronym>
  <official_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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UMC Utrecht</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ZonMw: The Netherlands Organisation for Health Research and Development</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Miltenyi Biotec, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>UMC Utrecht</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      HSCT has been implemented in (inter)national treatment guidelines for diffuse cutaneous&#xD;
      systemic sclerosis (dcSSc) and is offered in clinical care and reimbursed by national health&#xD;
      insurance in several European countries. However, data and specific guidelines on the best&#xD;
      timing of HSCT in the course of dcSSc are lacking. In particular, it is unclear whether HSCT&#xD;
      should be positioned as upfront therapy or as rescue treatment for patients not responding to&#xD;
      conventional immunosuppressive therapy.&#xD;
&#xD;
      This multicentre, randomized, open label trial aims to compare two treatment strategies used&#xD;
      in usual care: upfront autologous HSCT versus usual care with (intravenous (i.v.)&#xD;
      cyclophosphamide (CYC) pulse therapy followed by mycophenolate mofetil (MMF) and HSCT as&#xD;
      rescue option).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale: This multicentre, randomized, open label trial aims to compare two treatment&#xD;
      strategies used in usual care: upfront autologous HSCT versus usual care with (intravenous&#xD;
      (i.v.) cyclophosphamide (CYC) pulse thera-py followed by mycophenolate mofetil (MMF) and HSCT&#xD;
      as rescue option). HSCT has been implemented in (inter)national treatment guidelines for&#xD;
      diffuse cutaneous systemic sclerosis (dcSSc) and is offered in clinical care and reimbursed&#xD;
      by national health insurance in several European countries. However, data and specific&#xD;
      guidelines on the best timing of HSCT in the course of dcSSc are lacking.&#xD;
&#xD;
      In particular, it is unclear whether HSCT should be positioned as upfront therapy or as&#xD;
      rescue treatment for patients not responding to conventional im-munosuppressive therapy.&#xD;
      Given the risks and costs associated with HSCT, it may be preferable to evaluate the&#xD;
      patient's response to immunosuppressive therapy before proceeding to HSCT. Considering HSCT&#xD;
      as a rescue treatment could significantly delay the need for a potentially harmful treatment&#xD;
      and may be an efficient approach from a health economic perspective as HSCT is a highly&#xD;
      specialized, resource intensive and expensive medical procedure. On the other hand, in the&#xD;
      time frame needed to evaluate the effect of immunosuppressive therapy, pulmonary and cardiac&#xD;
      involvement may develop, negatively influencing a patient's prognosis and possibly leading to&#xD;
      a contra-indication for HSCT. We hypothesize that upfront HSCT results in less toxicity and&#xD;
      medical costs in the long run. Therefore, we propose a multicentre randomized open label&#xD;
      trial in chemotherapy naive patients with early dcSSc.&#xD;
&#xD;
      Objective: To determine the optimal treatment strategy in early dcSSc: the effect of HSCT as&#xD;
      upfront therapy compared with that of immunosuppressive medication in early dcSSc, with&#xD;
      respect to survival and prevention of major organ failure (referred to as 'event-free&#xD;
      survival' which is considered as primary endpoint), safety and the impact on skin thickening,&#xD;
      visceral involvement, functional status, and quality of life&#xD;
&#xD;
      Secondary goals are to evaluate (in both treatment arms) whether disease activity correlates&#xD;
      with immunological parameters, including immunopathology of skin, immune reconstitution, and&#xD;
      autoantibodies. We will also de-termine the cost-effectiveness of HSCT as first line&#xD;
      treatment versus usual care and try to identify factors associated with response to&#xD;
      treatment.&#xD;
&#xD;
      Study design: This investigation is an international multicentre, prospective, randomized,&#xD;
      open label trial com-paring two treatment strategies used in regular care: upfront autologous&#xD;
      HSCT versus immunosuppressive thera-py with i.v. CYC pulse therapy followed by MMF and HSCT&#xD;
      as rescue option.&#xD;
&#xD;
      Study population: Patients aged between 18 - 65 years with an established diagnosis of dcSSc&#xD;
      according to the ACR/EULAR criteria. Patients disease duration (non-Raynaud's symptoms)&#xD;
      should be ≤ 3 years and mRSS ≥ 15 (diffuse skin pattern) and /or clinically significant organ&#xD;
      involvement (heart and lung involvement).&#xD;
&#xD;
      Intervention: One group (A) receives upfront autologous HSCT and the other group (B) receives&#xD;
      12 monthly i.v. pulses CYC (750 mg/m2), followed by at least 12 months of oral MMF (max 3&#xD;
      grams daily) at one year after start of treatment. Rescue therapy may be considered in both&#xD;
      arms in case of insufficient response or clinically relevant flare, but preferably not within&#xD;
      the first 3 months after randomisation. For patients from Arm A methotrexate, mycophenolate&#xD;
      mofetil or mycophenolic acid, or rituximab can be (re)instituted, according to local&#xD;
      preference. Based on earlier studies, the clinical benefits of i.v. pulse cyclophosphamide&#xD;
      may take between 6-12 months. Therefore it is recommended to then switch patients from arm B&#xD;
      to HSCT only in case of rapidly progressive disease, which is arbitrarily defined as ≥30%&#xD;
      increase in mRSS or ≥20% relative decline in FVC, TLC, or DLCO predicted.&#xD;
&#xD;
      Main study parameters/endpoints: The main study parameter is event-free survival after&#xD;
      randomisation/treatment start.&#xD;
&#xD;
      Secondary efficacy endpoints: Overall Survival (OS), progression-free survival, number of&#xD;
      participants that need rescue therapy (i.e. the alternative treatment) due to treatment&#xD;
      failure. Treatment related mortality, treatment toxicity, and changes in mRSS, FVC, TLC and&#xD;
      DLCO, nailfold microscopy, immunological markers in skin and blood, cardiac MR and 18FDG-PET.&#xD;
      The CRISS at 12 months. Safety and tolerability outcomes according to CTC-criteria (CTCAE&#xD;
      v5.0). Patient reported outcomes at 12 and 24 months include: Quality of life (EQ-5D), SHAQ,&#xD;
      Gastrointestinal complaints (UCLA SCTC GIT 2.0), sexual functioning.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 17, 2020</start_date>
  <completion_date type="Anticipated">February 1, 2026</completion_date>
  <primary_completion_date type="Anticipated">September 17, 2025</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>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.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients who survive without major events (event free survival)</measure>
    <time_frame>24 months</time_frame>
    <description>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:&#xD;
Heart: left ventricular ejection fraction &lt; 30% by cardiac MR (or cardiac echo)&#xD;
Lungs: respiratory failure = resting arterial oxygen tension (PaO2) &lt; 8 kPa (&lt; 60 mmHg) and/or resting arterial carbon dioxide tension (PaCO2) &gt; 6.7 kPa (&gt; 50 mmHg) without oxygen supply&#xD;
Kidney: need for renal replacement therapy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients who survive without disease progression (Progression-free survival)</measure>
    <time_frame>24 months</time_frame>
    <description>Defined as the time in days since the day of randomisation until any of the following relative changes from base-line has been documented:&#xD;
death,&#xD;
≥ 10% drop in (F)VC predicted and/or ≥ 15% drop in DLCO predicted,&#xD;
≥ 15% drop in LVEF by echo or cardiac MR,&#xD;
≥ 15% drop in body weight,&#xD;
≥ 30% drop in creatinine clearance,&#xD;
≥ 30% increase in skin score,&#xD;
≥ 0.5 increase in SHAQ.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who die due to complications related to the treatment (Treatment related mortality)</measure>
    <time_frame>24 months</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patient alive after 24 months (Overall mortality)</measure>
    <time_frame>24 months</time_frame>
    <description>Any death, regardless of relationship to treatment, between randomization and 24 months post-randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of CTCAE toxicity advserse events</measure>
    <time_frame>24 months</time_frame>
    <description>Number of CTCAE v5.0 toxicity advserse events =/&gt; grade 3 that occur in consecutive 3-month periods following randomisation until 24 months follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The area under the curve (AUC) of the CRISS over time</measure>
    <time_frame>24 months</time_frame>
    <description>The American College of Rheumatology Composite Response Index in Diffuse Cutaneous Systemic Sclerosis (ACR CRISS) was developed using expert consensus and data driven approaches for use in clinical trials (Khanna et al, 2016).&#xD;
The exponential algorithm determines the predicted probability of improvement from baseline, incorporating change in the mRSS, FVC percent predicted, physician and patient global assessments, and HAQ-DI. The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). A higher score indicates greater improvement. Subjects are not considered improved (ACR CRISS score = 0) if they develop new: 1) renal crisis; 2) decline in FVC% predicted by 15% (relative) from baseline and confirmed after 1 month; or 3) left ventricular failure (systolic ejection fraction &lt; 45%); or 4) new pulmonary artery hypertension on right heart catheterization requiring treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in skin involvement (modified Rodnan Skin Score)</measure>
    <time_frame>24 months</time_frame>
    <description>Modified Rodnan Skin Score (mRSS) The MRSS is a validated physical examination method for estimating skin induration. It is correlated with biopsy measures of skin thickness and reflects prognosis and visceral involvement, especially in early disease2, 4. It is scored on a 0 (normal) to 3+ (severe induration) ordinal scales over 17 body areas, with a maximum score of 51 and is used to categorize severity of SSc. Minimally clinically significant difference in MRSS is 3-5 points (Amjadi et al., American College of Rheumatology; Aug 2009; 2493-2494) It has been extensively used as primary/ secondary outcome in RCT with Scleroderma. This will be collected at every study visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in cardiac function(Left Ventricular Ejection Fraction)</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>LVEF is measured by cardiac echo and at baseline and 12 months with cardiac MRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in pulmonary function</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>Diffusion in liters of carbon monoxide (DLCO) is a measure of lung function. Predicted values for DLCO were computed using the Crapo Morris equations and adjusted per the Cotes formula for anemia, if a participant's hemoglobin was &lt;13 or &gt;17 gm/dL, and altitude (Calgary site only). Forced Vital Capacity (FVC) is the amount of air that can be forcibly exhaled after a full breath and is a measure of lung function. Predicted FVC was based on institutional standards.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in health related quality of life EQ-5D-5L index</measure>
    <time_frame>24 months</time_frame>
    <description>HR-QoL will be assessed using the validated EuroQol (EQ-5D-5L), the calculated index ranges from 0 (worse HR-QoL) to 1 (best HR-QoL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in nailfold capillaroscopy</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>Nailfold capillaroscopy (NFS) will be obtained by the local capillaroscopist pre- and post-ASCT (at baseline, at 6, 12 24 months and yearly after). The evaluation of the images will be done centrally. The NFS-findings will be described standardly according to the consensus of the EULAR study group on microcirculation in rheumatic diseases. As such, the images will be evaluated in a quantitative (density, di-mension, morphology and presence of haemorrhages) and a qualitative way (normal, aspecific abnormalities, early/active/late scleroderma pattern). As we will analyse 16 NFS-images per subject, an overall qualitative as-sessment per subject will be assigned, based on the most prevalent pattern per subject.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in 18F FDG-PET scan from the thorax</measure>
    <time_frame>12 months</time_frame>
    <description>Validation of semi-quantitative analysis method with respiratory gated and non-gated 18F FDG-PET prospec-tively and comparison of 18F FDG-PET with routine HR-CT thorax, pulmonary lung function and clinical symptoms, will be done at baseline and at 12 months follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in gastrointestinal complaints (UCLA SCTC GIT 2.0)</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>The UCLA SCTC GIT 2.0 is a standardized set of outcome measures developed through literature review, patient focus groups and cognitive debriefing among patients with a variety of gastrointestinal disorders including irritable bowel syndrome, inflammatory bowel disease, other common gastrointestinal disorders, SSc, and a census-based US general population control sample (Khanna et al, 2009). The scale consists of eight domains relating to gastroesophageal reflux (13 items), disrupted swallowing (7 items), diarrhea (5 items), bowel incontinence/soilage (4 items), nausea and vomiting (4 items), constipation (9 items), belly pain (6 items), and gas/bloat/flatulence (12 items). The scales correlated significantly with both generic and disease-targeted legacy instruments, and demonstrate evidence of reliability.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in several subsets of the immune system</measure>
    <time_frame>12 months</time_frame>
    <description>We will evaluate antibody repertoire pre- and post-treatment at dedicated timepoints and assess correlations to clinical disease course characteristics. Also, B cells will be characterized in terms of frequency, phenotype and functional capacities before and after treatment. Additionally, transcriptomics analysis on the immune cell (sub-)populations isolated will be done.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in self-assessed skin thickness (PASTUL_)</measure>
    <time_frame>60 months</time_frame>
    <description>Patients will assess their skin thickness using the validate PASTUL questionnaire every 3 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammatory and fibrotic characteristics and changes of the skin and composition of the microbiome of the skin</measure>
    <time_frame>12 months</time_frame>
    <description>Skin biopsies from affected skin will be used to investigate the inflammatory and fibrotic changes and the skin microbiome. Before taking the skin biopsies the skin will be anesthetized with lidocaine 1%. The biopsy used for analysis of the inflammatory and fibrotic characteristics, using immunohistochemistry, will be frozen in liquid nitrogen. 6S rRNA gene sequencing will be done to obtain the microbial profiles of the skin biopsies.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in sexual functioning</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>We will use the validated IIEF-5 and SFQ-28</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in daily functioning</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>SHAQ-DI The SHAQ-DI is a disease-targeted, musculoskeletal-targeted measure intended for assessing functional ability in scleroderma. It is a self-administered 20-question instrument that assesses a patient's level of functional ability and includes questions that involve both upper and lower extremities. The SHAQ-DI score ranges from 0 (no disability) to 3 (severe disability). It has a 7 day recall period and has been extensively used in SSc. Five visual analog scales are included in the scleroderma-HAQ assessing burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in ability to work, measured by the customized Productivity Cost Questionnaire (iPCQ)</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>The customized iPCQ is a selection of 5 questions derived from the full iPCQ</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in fatigue measured with the FACIT questionnaire</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>The FACIT questionnaire is a validated questionnaire for evaluating fatigue</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in handmobility</measure>
    <time_frame>24 months</time_frame>
    <description>assessment done using the mHAMIS</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Systemic Sclerosis</condition>
  <condition>Systemic Scleroses, Diffuse</condition>
  <condition>Scleroderma</condition>
  <condition>Scleroderma, Diffuse</condition>
  <condition>Autologous Stem Cell Transplantation</condition>
  <condition>Cyclophosphamide</condition>
  <condition>Mycophenolate Mofetil</condition>
  <condition>Treatment Strategy</condition>
  <arm_group>
    <arm_group_label>Upfront autologous HSCT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Immunosuppressive therapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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).&#xD;
Hyperhydration, alkalinisation of the urine and mesna is recommended, and will be given according to local protocols in order to prevent haemorrhagic cystitis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Upfront autologous HSCT</intervention_name>
    <description>HSCT comprises the following consecutive steps:&#xD;
Mobilisation&#xD;
Infusions of CYC 2g/m2 on 1 day.&#xD;
Hyperhydration, alkalinisation of urine and mesna to prevent haemorrhagic cystitis.&#xD;
Filgrastim (G-CSF) 5-10 μg/kg/day subcutaneously for 5 days (or more when necessary).&#xD;
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.&#xD;
Conditioning&#xD;
CYC 50 mg/kg/day intravenously for 4 consecutive days (total 200 mg/kg)&#xD;
Rabbit Antithymocyte Globulin (rbATG), a total dose of 7.5 mg/kg i.v., from Genzyme.&#xD;
Hyperhydration, alkalinisation of the urine and mesna will be given to prevent haemorrhagic cystitis.&#xD;
I.v. methylprednisolone 2 mg/kg will be administered on the days ATG, to improve tolerability of the ATG.&#xD;
Peripheral stem cell infusion The number of CD34+ cells to be reinfused should be ≥ 2.0 x 10^6/kg.</description>
    <arm_group_label>Immunosuppressive therapy</arm_group_label>
    <arm_group_label>Upfront autologous HSCT</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age between 18 and 65 years.&#xD;
&#xD;
          2. Fulfilling the 2013 ACR-EULAR classification criteria for SSc (appendix B).&#xD;
&#xD;
          3. Disease duration ≤ 2 years (from onset of first non-Raynaud's symptoms) and diffuse&#xD;
             cutaneous disease with&#xD;
&#xD;
               -  mRSS ≥ 15 and/or&#xD;
&#xD;
               -  clinically significant organ involvement as defined by either:&#xD;
&#xD;
                    1. respiratory involvement = i. DLCO and/or (F)VC ≤ 85% (of predicted) and&#xD;
                       evidence of interstitial lung disease on HR-CT scan with clinically relevant&#xD;
                       obstructive disease and emphysema excluded.&#xD;
&#xD;
                       ii. Patients with a DCLO and/or FVC &gt; 85%, but with a progressive course of&#xD;
                       lung disease: defined as relative decline of &gt;10% in FVC predicted and/or&#xD;
                       TLC predicted, or &gt;15% in DLCO predicted and evidence of interstitial lung&#xD;
                       disease on HR-CT scan with clinically relevant obstructive disease and&#xD;
                       emphysema excluded, within 12 months. Intercurrent infections excluded.&#xD;
&#xD;
                    2. renal involvement = any of the following criteria: hypertension (two&#xD;
                       successive BP readings of either systolic ≥ 160 mm Hg or diastolic &gt; 110 mm&#xD;
                       Hg, at least 12 hours apart), persistent urinalysis abnormalities&#xD;
                       (proteinuria, haematuria, casts), microangiopathic haemolytic anaemia, new&#xD;
                       renal insufficiency (serum creatinine &gt; upper limit of normal);&#xD;
                       non-scleroderma related causes (e.g. medication, infection etc.) must be&#xD;
                       reasonably excluded.&#xD;
&#xD;
                    3. cardiac involvement = any of the following criteria: reversible congestive&#xD;
                       heart failure, atrial or ventricular rhythm disturbances such as atrial&#xD;
                       fibrillation or flutter, atrial paroxysmal tachycardia or ventricular&#xD;
                       tachycardia, 2nd or 3rd degree AV block, pericardial effusion (not leading&#xD;
                       to hemodynamic problems), myocardi-tis; non-scleroderma related causes must&#xD;
                       have been reasonably excluded.&#xD;
&#xD;
          4. Written Informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnancy or unwillingness to use adequate contraception during study&#xD;
&#xD;
          2. Concomitant severe disease =&#xD;
&#xD;
               1. respiratory: resting mean pulmonary artery pressure (mPAP) &gt; 25 mmHg (by right&#xD;
                  heart catheterisation), DLCO &lt; 40% predicted, respiratory failure as defined by&#xD;
                  the primary endpoint&#xD;
&#xD;
               2. renal: creatinine clearance &lt; 40 ml/min (measured or estimated)&#xD;
&#xD;
               3. cardiac: clinical evidence of refractory congestive heart failure; LVEF &lt; 45% by&#xD;
                  cardiac echo or cardiac MR; chronic atrial fibrillation necessitating oral&#xD;
                  anticoagulation; uncontrolled ventricular arrhythmia; pericardial effusion with&#xD;
                  hemodynamic consequences&#xD;
&#xD;
               4. liver failure as defined by a sustained 3-fold increase in serum transaminase or&#xD;
                  bilirubin, or a Child-Pugh score C&#xD;
&#xD;
               5. psychiatric disorders including active drug or alcohol abuse&#xD;
&#xD;
               6. concurrent neoplasms or myelodysplasia&#xD;
&#xD;
               7. bone marrow insufficiency defined as leukocytopenia &lt; 4.0 x 109/L,&#xD;
                  thrombocytopenia &lt; 50x 10^9/L, anaemia &lt; 8 gr/dL, CD4+ T lymphopenia &lt; 200 x&#xD;
                  106/L&#xD;
&#xD;
               8. uncontrolled hypertension&#xD;
&#xD;
               9. uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity&#xD;
&#xD;
              10. ZUBROD-ECOG-WHO Performance Status Scale &gt; 2&#xD;
&#xD;
          3. Previous treatments with immunosuppressants &gt; 12 months including MMF, methotrexate,&#xD;
             azathioprine, rituximab, tocilizumab, glucocorticosteroids.&#xD;
&#xD;
          4. Previous treatments with TLI, TBI or alkylating agents including CYC.&#xD;
&#xD;
          5. Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride,&#xD;
             trichlorethylene or silica;&#xD;
&#xD;
          6. eosinophilic myalgia syndrome; eosinophilic fasciitis.&#xD;
&#xD;
          7. Poor compliance of the patient as assessed by the referring physicians.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jacob M van Laar, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UMC Utrecht</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Julia Spierings</last_name>
    <role>Study Director</role>
    <affiliation>UMC Utrecht</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Julia Spierings, MD</last_name>
    <phone>+31641888582</phone>
    <email>J.Spierings@umcutrecht.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Anne Karien Marijnissen, PhD</last_name>
    <email>A.C.A.Marijnissen@umcutrecht.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Gaetano Pini-CTO</name>
      <address>
        <city>Milan</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Nicoletta Del Papa, MD PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Ospedale San Raffaele</name>
      <address>
        <city>Milan</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rafaella Greco</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospital Rome</name>
      <address>
        <city>Roma</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Roberto Giacomelli, MD PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Amsterdam Rheumatology Centre</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alexandre Voskuyl</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Medical Centre Leiden</name>
      <address>
        <city>Leiden</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jeska de Vries-Bouwstra</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Radboudumc Nijmegen</name>
      <address>
        <city>Nijmegen</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Madelon Vonk</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Medical Centre Utrecht</name>
      <address>
        <city>Utrecht</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Julia Spierings</last_name>
    </contact>
    <contact_backup>
      <last_name>Anne Karien Marijnissen</last_name>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Skåne University Hospital Lund</name>
      <address>
        <city>Lund</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dirk Wuttge</last_name>
      <email>dirk.wuttge@med.lu.se</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Karolinska Institute/Karolinska University Hospital Solna</name>
      <address>
        <city>Stockholm</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Karina Gheorge, MD PhD</last_name>
      <email>karina.gheorghe@regionstockholm.se</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospital Basel</name>
      <address>
        <city>Basel</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Ulrich Walker</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Inselspital, Universitätsspital Bern</name>
      <address>
        <city>Bern</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Britta Maurer</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Sheffield Teaching Hospitals NHS Foundation Trust</name>
      <address>
        <city>Sheffield</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location_countries>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>Sweden</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
  </location_countries>
  <removed_countries>
    <country>Belgium</country>
    <country>Croatia</country>
    <country>Germany</country>
  </removed_countries>
  <link>
    <url>http://upsidetrial.com/</url>
    <description>official trial website</description>
  </link>
  <reference>
    <citation>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.</citation>
    <PMID>21777972</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>29298160</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>25058083</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>32409324</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 25, 2020</study_first_submitted>
  <study_first_submitted_qc>July 6, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 9, 2020</study_first_posted>
  <last_update_submitted>August 15, 2023</last_update_submitted>
  <last_update_submitted_qc>August 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>UMC Utrecht</investigator_affiliation>
    <investigator_full_name>Jacob M van Laar</investigator_full_name>
    <investigator_title>Principal Investigator, Clinical professor</investigator_title>
  </responsible_party>
  <keyword>Randomized controlled trial</keyword>
  <keyword>Autologous stem cell transplantation</keyword>
  <keyword>Systemic Sclerosis</keyword>
  <keyword>Cyclophosphamide</keyword>
  <keyword>Mycophenolate Mofetil</keyword>
  <keyword>Upfront</keyword>
  <keyword>Treatment strategy</keyword>
  <keyword>Event Free survival</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Scleroderma, Systemic</mesh_term>
    <mesh_term>Scleroderma, Diffuse</mesh_term>
    <mesh_term>Scleroderma, Localized</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is not a plan to make IPD available.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04464434
org study id: NL72607.041.20
nct id: NCT04464434
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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).
Rationale: 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 thera-py followed by mycophenolate mofetil (MMF) and HSCT
      as rescue option). 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 im-munosuppressive therapy.
      Given the risks and costs associated with HSCT, it may be preferable to evaluate the
      patient's response to immunosuppressive therapy before proceeding to HSCT. Considering HSCT
      as a rescue treatment could significantly delay the need for a potentially harmful treatment
      and may be an efficient approach from a health economic perspective as HSCT is a highly
      specialized, resource intensive and expensive medical procedure. On the other hand, in the
      time frame needed to evaluate the effect of immunosuppressive therapy, pulmonary and cardiac
      involvement may develop, negatively influencing a patient's prognosis and possibly leading to
      a contra-indication for HSCT. We hypothesize that upfront HSCT results in less toxicity and
      medical costs in the long run. Therefore, we propose a multicentre randomized open label
      trial in chemotherapy naive patients with early dcSSc.

      Objective: To determine the optimal treatment strategy in early dcSSc: the effect of HSCT as
      upfront therapy compared with that of immunosuppressive medication in early dcSSc, with
      respect to survival and prevention of major organ failure (referred to as 'event-free
      survival' which is considered as primary endpoint), safety and the impact on skin thickening,
      visceral involvement, functional status, and quality of life

      Secondary goals are to evaluate (in both treatment arms) whether disease activity correlates
      with immunological parameters, including immunopathology of skin, immune reconstitution, and
      autoantibodies. We will also de-termine the cost-effectiveness of HSCT as first line
      treatment versus usual care and try to identify factors associated with response to
      treatment.

      Study design: This investigation is an international multicentre, prospective, randomized,
      open label trial com-paring two treatment strategies used in regular care: upfront autologous
      HSCT versus immunosuppressive thera-py with i.v. CYC pulse therapy followed by MMF and HSCT
      as rescue option.

      Study population: Patients aged between 18 - 65 years with an established diagnosis of dcSSc
      according to the ACR/EULAR criteria. Patients disease duration (non-Raynaud's symptoms)
      should be ≤ 3 years and mRSS ≥ 15 (diffuse skin pattern) and /or clinically significant organ
      involvement (heart and lung involvement).

      Intervention: One group (A) receives upfront autologous HSCT and the other group (B) receives
      12 monthly i.v. pulses CYC (750 mg/m2), followed by at least 12 months of oral MMF (max 3
      grams daily) at one year after start of treatment. Rescue therapy may be considered in both
      arms in case of insufficient response or clinically relevant flare, but preferably not within
      the first 3 months after randomisation. For patients from Arm A methotrexate, mycophenolate
      mofetil or mycophenolic acid, or rituximab can be (re)instituted, according to local
      preference. Based on earlier studies, the clinical benefits of i.v. pulse cyclophosphamide
      may take between 6-12 months. Therefore it is recommended to then switch patients from arm B
      to HSCT only in case of rapidly progressive disease, which is arbitrarily defined as ≥30%
      increase in mRSS or ≥20% relative decline in FVC, TLC, or DLCO predicted.

      Main study parameters/endpoints: The main study parameter is event-free survival after
      randomisation/treatment start.

      Secondary efficacy endpoints: Overall Survival (OS), progression-free survival, number of
      participants that need rescue therapy (i.e. the alternative treatment) due to treatment
      failure. Treatment related mortality, treatment toxicity, and changes in mRSS, FVC, TLC and
      DLCO, nailfold microscopy, immunological markers in skin and blood, cardiac MR and 18FDG-PET.
      The CRISS at 12 months. Safety and tolerability outcomes according to CTC-criteria (CTCAE
      v5.0). Patient reported outcomes at 12 and 24 months include: Quality of life (EQ-5D), SHAQ,
      Gastrointestinal complaints (UCLA SCTC GIT 2.0), sexual functioning.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: 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.
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients who survive without major events (event free survival)
time frame: 24 months
description: 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 < 30% by cardiac MR (or cardiac echo)
Lungs: respiratory failure = resting arterial oxygen tension (PaO2) < 8 kPa (< 60 mmHg) and/or resting arterial carbon dioxide tension (PaCO2) > 6.7 kPa (> 50 mmHg) without oxygen supply
Kidney: need for renal replacement therapy
measure: Number of patients who survive without disease progression (Progression-free survival)
time frame: 24 months
description: Defined as the time in days since the day of randomisation until any of the following relative changes from base-line 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.
measure: Number of patients who die due to complications related to the treatment (Treatment related mortality)
time frame: 24 months
description: 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.
measure: Number of patient alive after 24 months (Overall mortality)
time frame: 24 months
description: Any death, regardless of relationship to treatment, between randomization and 24 months post-randomization
measure: Number of CTCAE toxicity advserse events
time frame: 24 months
description: Number of CTCAE v5.0 toxicity advserse events =/> grade 3 that occur in consecutive 3-month periods following randomisation until 24 months follow-up.
measure: The area under the curve (AUC) of the CRISS over time
time frame: 24 months
description: The American College of Rheumatology Composite Response Index in Diffuse Cutaneous Systemic Sclerosis (ACR CRISS) was developed using expert consensus and data driven approaches for use in clinical trials (Khanna et al, 2016).
The exponential algorithm determines the predicted probability of improvement from baseline, incorporating change in the mRSS, FVC percent predicted, physician and patient global assessments, and HAQ-DI. The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). A higher score indicates greater improvement. Subjects are not considered improved (ACR CRISS score = 0) if they develop new: 1) renal crisis; 2) decline in FVC% predicted by 15% (relative) from baseline and confirmed after 1 month; or 3) left ventricular failure (systolic ejection fraction < 45%); or 4) new pulmonary artery hypertension on right heart catheterization requiring treatment.
measure: Changes in skin involvement (modified Rodnan Skin Score)
time frame: 24 months
description: Modified Rodnan Skin Score (mRSS) The MRSS is a validated physical examination method for estimating skin induration. It is correlated with biopsy measures of skin thickness and reflects prognosis and visceral involvement, especially in early disease2, 4. It is scored on a 0 (normal) to 3+ (severe induration) ordinal scales over 17 body areas, with a maximum score of 51 and is used to categorize severity of SSc. Minimally clinically significant difference in MRSS is 3-5 points (Amjadi et al., American College of Rheumatology; Aug 2009; 2493-2494) It has been extensively used as primary/ secondary outcome in RCT with Scleroderma. This will be collected at every study visit.
measure: Changes in cardiac function(Left Ventricular Ejection Fraction)
time frame: 12 and 24 months
description: LVEF is measured by cardiac echo and at baseline and 12 months with cardiac MRI.
measure: Changes in pulmonary function
time frame: 12 and 24 months
description: Diffusion in liters of carbon monoxide (DLCO) is a measure of lung function. Predicted values for DLCO were computed using the Crapo Morris equations and adjusted per the Cotes formula for anemia, if a participant's hemoglobin was <13 or >17 gm/dL, and altitude (Calgary site only). Forced Vital Capacity (FVC) is the amount of air that can be forcibly exhaled after a full breath and is a measure of lung function. Predicted FVC was based on institutional standards.
measure: Changes in health related quality of life EQ-5D-5L index
time frame: 24 months
description: HR-QoL will be assessed using the validated EuroQol (EQ-5D-5L), the calculated index ranges from 0 (worse HR-QoL) to 1 (best HR-QoL).
measure: Changes in nailfold capillaroscopy
time frame: 12 and 24 months
description: Nailfold capillaroscopy (NFS) will be obtained by the local capillaroscopist pre- and post-ASCT (at baseline, at 6, 12 24 months and yearly after). The evaluation of the images will be done centrally. The NFS-findings will be described standardly according to the consensus of the EULAR study group on microcirculation in rheumatic diseases. As such, the images will be evaluated in a quantitative (density, di-mension, morphology and presence of haemorrhages) and a qualitative way (normal, aspecific abnormalities, early/active/late scleroderma pattern). As we will analyse 16 NFS-images per subject, an overall qualitative as-sessment per subject will be assigned, based on the most prevalent pattern per subject.
measure: Changes in 18F FDG-PET scan from the thorax
time frame: 12 months
description: Validation of semi-quantitative analysis method with respiratory gated and non-gated 18F FDG-PET prospec-tively and comparison of 18F FDG-PET with routine HR-CT thorax, pulmonary lung function and clinical symptoms, will be done at baseline and at 12 months follow-up.
measure: Changes in gastrointestinal complaints (UCLA SCTC GIT 2.0)
time frame: 12 and 24 months
description: The UCLA SCTC GIT 2.0 is a standardized set of outcome measures developed through literature review, patient focus groups and cognitive debriefing among patients with a variety of gastrointestinal disorders including irritable bowel syndrome, inflammatory bowel disease, other common gastrointestinal disorders, SSc, and a census-based US general population control sample (Khanna et al, 2009). The scale consists of eight domains relating to gastroesophageal reflux (13 items), disrupted swallowing (7 items), diarrhea (5 items), bowel incontinence/soilage (4 items), nausea and vomiting (4 items), constipation (9 items), belly pain (6 items), and gas/bloat/flatulence (12 items). The scales correlated significantly with both generic and disease-targeted legacy instruments, and demonstrate evidence of reliability.
measure: Changes in several subsets of the immune system
time frame: 12 months
description: We will evaluate antibody repertoire pre- and post-treatment at dedicated timepoints and assess correlations to clinical disease course characteristics. Also, B cells will be characterized in terms of frequency, phenotype and functional capacities before and after treatment. Additionally, transcriptomics analysis on the immune cell (sub-)populations isolated will be done.
measure: Changes in self-assessed skin thickness (PASTUL_)
time frame: 60 months
description: Patients will assess their skin thickness using the validate PASTUL questionnaire every 3 months.
measure: Inflammatory and fibrotic characteristics and changes of the skin and composition of the microbiome of the skin
time frame: 12 months
description: Skin biopsies from affected skin will be used to investigate the inflammatory and fibrotic changes and the skin microbiome. Before taking the skin biopsies the skin will be anesthetized with lidocaine 1%. The biopsy used for analysis of the inflammatory and fibrotic characteristics, using immunohistochemistry, will be frozen in liquid nitrogen. 6S rRNA gene sequencing will be done to obtain the microbial profiles of the skin biopsies.
measure: Changes in sexual functioning
time frame: 12 and 24 months
description: We will use the validated IIEF-5 and SFQ-28
measure: Changes in daily functioning
time frame: 12 and 24 months
description: SHAQ-DI The SHAQ-DI is a disease-targeted, musculoskeletal-targeted measure intended for assessing functional ability in scleroderma. It is a self-administered 20-question instrument that assesses a patient's level of functional ability and includes questions that involve both upper and lower extremities. The SHAQ-DI score ranges from 0 (no disability) to 3 (severe disability). It has a 7 day recall period and has been extensively used in SSc. Five visual analog scales are included in the scleroderma-HAQ assessing burden of digital ulcers, Raynaud's, gastrointestinal involvement, breathing, and overall disease.
measure: Changes in ability to work, measured by the customized Productivity Cost Questionnaire (iPCQ)
time frame: 12 and 24 months
description: The customized iPCQ is a selection of 5 questions derived from the full iPCQ
measure: Changes in fatigue measured with the FACIT questionnaire
time frame: 12 and 24 months
description: The FACIT questionnaire is a validated questionnaire for evaluating fatigue
measure: Changes in handmobility
time frame: 24 months
description: assessment done using the mHAMIS
arm group label: Upfront autologous HSCT
arm group type: Experimental
arm group label: Immunosuppressive therapy
arm group type: Active Comparator
description: 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.
intervention type: Procedure
intervention name: Upfront autologous HSCT
description: HSCT comprises the following consecutive steps:
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).
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.
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.
Peripheral stem cell infusion The number of CD34+ cells to be reinfused should be ≥ 2.0 x 10^6/kg.
arm group label: Immunosuppressive therapy
arm group label: Upfront autologous HSCT
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Jacob M van Laar, MD PhD
role: Principal Investigator
affiliation: UMC Utrecht
last name: Julia Spierings
role: Study Director
affiliation: UMC Utrecht
last name: Julia Spierings, MD
phone: +31641888582
email: J.Spierings@umcutrecht.nl
last name: Anne Karien Marijnissen, PhD
email: A.C.A.Marijnissen@umcutrecht.nl
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
country: Italy
country: Netherlands
country: Sweden
country: Switzerland
country: United Kingdom
country: Belgium
country: Croatia
country: Germany
url: http://upsidetrial.com/
description: official trial website
citation: 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
citation: 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
citation: 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
citation: 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
responsible party type: Principal Investigator
investigator affiliation: UMC Utrecht
investigator full name: Jacob M van Laar
investigator title: Principal Investigator, Clinical professor
mesh term: Scleroderma, Systemic
mesh term: Scleroderma, Diffuse
mesh term: Scleroderma, Localized
mesh term: Sclerosis
sharing ipd: No
ipd description: There is not a plan to make IPD available.