Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis (UPSIDE)
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|ClinicalTrials.gov Identifier: NCT04464434|
Recruitment Status : Recruiting
First Posted : July 9, 2020
Last Update Posted : December 8, 2021
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|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||120 participants|
|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)|
|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|
|Experimental: Upfront autologous HSCT||
Procedure: Upfront autologous HSCT
HSCT comprises the following consecutive steps:
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:
- 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
- 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:
- ≥ 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.
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Changes in sexual functioning [ Time Frame: 12 and 24 months ]We will use the validated IIEF-5 and SFQ-28
- 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.
- 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
- Changes in fatigue measured with the FACIT questionnaire [ Time Frame: 12 and 24 months ]The FACIT questionnaire is a validated questionnaire for evaluating fatigue
- Changes in handmobility [ Time Frame: 24 months ]assessment done using the mHAMIS
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
|Contact: Julia Spierings, MD||+31641888582||J.Spierings@umcutrecht.nl|
|Contact: Anne Karien Marijnissen, PhD||A.C.A.Marijnissen@umcutrecht.nl|
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|Contact: Miro Mayer|
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|Contact: Madelon Vonk|
|University Medical Centre Utrecht||Recruiting|
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|Contact: Anne Karien Marijnissen|
|Skåne University Hospital Lund||Recruiting|
|Contact: Dirk Wuttge firstname.lastname@example.org|
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|Contact: Ulrich Walker|
|Principal Investigator:||Jacob M van Laar, MD PhD||UMC Utrecht|
|Study Director:||Julia Spierings||UMC Utrecht|