Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    NCT04464434
Previous Study | Return to List | Next Study

Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis (UPSIDE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04464434
Recruitment Status : Recruiting
First Posted : July 9, 2020
Last Update Posted : April 8, 2021
Sponsor:
Collaborators:
ZonMw: The Netherlands Organisation for Health Research and Development
Boehringer Ingelheim
Miltenyi Biotec, Inc.
Information provided by (Responsible Party):
Jacob M van Laar, UMC Utrecht

Brief Summary:

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).


Condition or disease Intervention/treatment Phase
Systemic Sclerosis Systemic Scleroses, Diffuse Scleroderma Scleroderma, Diffuse Autologous Stem Cell Transplantation Cyclophosphamide Mycophenolate Mofetil Treatment Strategy Procedure: Upfront autologous HSCT Phase 3

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
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.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 17, 2020
Estimated Primary Completion Date : September 17, 2025
Estimated Study Completion Date : February 1, 2026


Arm Intervention/treatment
Experimental: Upfront autologous HSCT Procedure: Upfront autologous HSCT

HSCT comprises the following consecutive steps:

  1. 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).
  2. 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.
  3. 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.

  4. Peripheral stem cell infusion The number of CD34+ cells to be reinfused should be ≥ 2.0 x 10^6/kg.

Active Comparator: Immunosuppressive therapy

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.

Procedure: Upfront autologous HSCT

HSCT comprises the following consecutive steps:

  1. 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).
  2. 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.
  3. 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.

  4. Peripheral stem cell infusion The number of CD34+ cells to be reinfused should be ≥ 2.0 x 10^6/kg.




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

    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


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

    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.

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

  3. Number of patient alive after 24 months (Overall mortality) [ Time Frame: 24 months ]
    Any death, regardless of relationship to treatment, between randomization and 24 months post-randomization

  4. Number of CTCAE toxicity advserse events [ Time Frame: 24 months ]
    Number of CTCAE v5.0 toxicity advserse events =/> grade 3 that occur in consecutive 3-month periods following randomisation until 24 months follow-up.

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

    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.


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

  7. Changes in cardiac function(Left Ventricular Ejection Fraction) [ Time Frame: 12 and 24 months ]
    LVEF is measured by cardiac echo and at baseline and 12 months with cardiac MRI.

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

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

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

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

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

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

  14. Changes in self-assessed skin thickness (PASTUL_) [ Time Frame: 60 months ]
    Patients will assess their skin thickness using the validate PASTUL questionnaire every 3 months.

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

  16. Changes in sexual functioning [ Time Frame: 12 and 24 months ]
    We will use the validated IIEF-5 and SFQ-28

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

  18. Changes in ability to work, measured by the customized Productivity Cost Questionnaire (iPCQ) [ Time Frame: 12 and 24 months ]
    The customized iPCQ is a selection of 5 questions derived from the full iPCQ

  19. Changes in fatigue measured with the FACIT questionnaire [ Time Frame: 12 and 24 months ]
    The FACIT questionnaire is a validated questionnaire for evaluating fatigue

  20. Changes in handmobility [ Time Frame: 24 months ]
    assessment done using the mHAMIS



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

      1. 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.

      2. 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.
      3. 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:

  1. Pregnancy or unwillingness to use adequate contraception during study
  2. Concomitant severe disease =

    1. respiratory: resting mean pulmonary artery pressure (mPAP) > 20 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 > 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04464434


Contacts
Layout table for location contacts
Contact: Julia Spierings, MD +31641888582 J.Spierings@umcutrecht.nl
Contact: Anne Karien Marijnissen, PhD A.C.A.Marijnissen@umcutrecht.nl

Locations
Layout table for location information
Belgium
University Hospital Ghent Not yet recruiting
Ghent, Belgium
Contact: Vanessa Smith         
University Hospital Leuven Not yet recruiting
Leuven, Belgium
Contact: Ellen De Langhe         
Croatia
University Hospital Zagreb Not yet recruiting
Zagreb, Croatia
Contact: Miro Mayer         
Germany
Ruhr University Bochum Not yet recruiting
Bochum, Germany
Contact: Roland Schroers         
University Hospital Freiburg Not yet recruiting
Freiburg, Germany
Contact: Reinhard Voll         
Universitats Klinikum Tuebingen Not yet recruiting
Tuebingen, Germany
Contact: Joerg Henes         
Universitats Klinikum Wurzburg Not yet recruiting
Würzburg, Germany
Contact: Marc Schmalzing         
Italy
ASST Pini-CTO Not yet recruiting
Milan, Italy
Contact: Nicoletta Del Papa         
Netherlands
Amsterdam Rheumatology Centre Recruiting
Amsterdam, Netherlands
Contact: Alexandre Voskuyl         
University Medical Centre Leiden Recruiting
Leiden, Netherlands
Contact: Jeska de Vries-Bouwstra         
Radboudumc Nijmegen Not yet recruiting
Nijmegen, Netherlands
Contact: Madelon Vonk         
University Medical Centre Utrecht Recruiting
Utrecht, Netherlands
Contact: Julia Spierings         
Contact: Anne Karien Marijnissen         
Sweden
Skåne University Hospital Lund Not yet recruiting
Lund, Sweden
Contact: Roger Hesselstrand         
Sub-Investigator: Dirk Wuttge         
Switzerland
University Hospital Basel Not yet recruiting
Basel, Switzerland
Contact: Ulrich Walker         
Sponsors and Collaborators
UMC Utrecht
ZonMw: The Netherlands Organisation for Health Research and Development
Boehringer Ingelheim
Miltenyi Biotec, Inc.
Investigators
Layout table for investigator information
Principal Investigator: Jacob M van Laar, MD PhD UMC Utrecht
Study Director: Julia Spierings UMC Utrecht
Additional Information:
Publications:
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, Kötter 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, Quéré I, Rich É, Westhovens R, Griffiths B, Saccardi R, van den Hoogen FH, Fibbe WE, Socié 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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Jacob M van Laar, Principal Investigator, Clinical professor, UMC Utrecht
ClinicalTrials.gov Identifier: NCT04464434    
Other Study ID Numbers: NL72607.041.20
First Posted: July 9, 2020    Key Record Dates
Last Update Posted: April 8, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is not a plan to make IPD available.

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Jacob M van Laar, UMC Utrecht:
Randomized controlled trial
Autologous stem cell transplantation
Systemic Sclerosis
Cyclophosphamide
Mycophenolate Mofetil
Upfront
Treatment strategy
Event Free survival
Additional relevant MeSH terms:
Layout table for MeSH terms
Scleroderma, Systemic
Scleroderma, Diffuse
Scleroderma, Localized
Sclerosis
Pathologic Processes
Connective Tissue Diseases
Skin Diseases