Clinical trial NCT04464434: Upfront Autologous HSCT Versus Immunosuppression in Early Diffuse Cutaneous Systemic Sclerosis
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Systemic Sclerosis
Systemic Scleroses, Diffuse
Scleroderma
Scleroderma, Diffuse
Autologous Stem Cell Transplantation
Cyclophosphamide
Mycophenolate Mofetil
Treatment Strategy
Keywords: Randomized controlled trial
Autologous stem cell transplantation
Systemic Sclerosis
Cyclophosphamide
Mycophenolate Mofetil
Upfront
Treatment strategy
Event Free survival
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Boehringer Ingelheim
name: Miltenyi Biotec, Inc.
First posted: 2020-07-09
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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

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).

Detailed description: 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: Global Rank Composit score at 24 months follow-up.

Secondary efficacy endpoints: Event-free survival after randomisation/treatment, 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.

Eligibility criteria: Inclusion Criteria:

1. Age between 18 and 65 years.
2. Fulfilling the 2013 ACR-EULAR classification criteria for SSc

   Either: 3.1 or 3.2 3.1. Disease duration ≤ 3 years (from onset of first non-Raynaud's symptoms) and diffuse cutaneous disease with

   - progressive skin involvement with a mRSS ≥ 15 (in a diffuse pattern: involvement of skin on the upper limbs, chest and/or abdomen)

   and/or

   - major organ involvement as defined by either:

   a. clinically significant respiratory involvement = i. DLCO and/or (F)VC ≤ 85% (of predicted) and evidence of interstitial lung disease on HR-CT scan with clinically relevant obstructive disease and emphysema excluded. ii. Patients with a DCLO and/or FVC \> 85%, but with a progressive course of lung disease: defined as rela-tive decline of \>10% in FVC predicted and/or TLC predicted, or \>15% in DLCO predicted and evidence of interstitial lung disease on HR-CT scan with clinically relevant obstructive disease and emphysema ex-cluded, within 12 months. Intercurrent infections excluded.

   b. clinically significant renal involvement = i. new renal insufficiency (serum creatinine \> upper limit of normal) AND
   1. persistent urinalysis abnormalities (proteinuria, haematuria, casts), AND/OR
   2. microangiopathic haemolytic anaemia AND/OR
   3. hypertension (two successive BP readings of either systolic ≥ 160 mm Hg or diastolic \> 110 mm Hg, at least 12 hours apart), ; non-scleroderma related causes (e.g. medication, infection etc.) must be reasonably excluded.

   c. clinically significant cardiac involvement = any of the following criteria: i. reversible congestive heart failure, ii. atrial or ventricular rhythm disturbances such as atrial fibrillation or flutter, atrial paroxysmal tachycar-dia or ventricular tachycardia, 2nd or 3rd degree AV block, iii. pericardial effusion (not leading to hemodynamic problems), myocarditis; non-scleroderma related causes must have been reasonably excluded

   3.2. Disease duration ≤ 1 year (from onset of first non-Raynaud's symptoms) and diffuse cutaneous disease with mRSS ≥ 10 and
   1. High risk ANA for organ based disease: ATA or ARA positivity and/ or
   2. Acute phase response (ESR \> 25 mm/h and/or CRP \> 10.0 mg/L )

4. Written Informed consent

Exclusion Criteria:

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

   1. respiratory: resting mean pulmonary artery pressure (mPAP) \> 25 mmHg (by right heart catheterisation), DLCO \< 40% predicted, respiratory failure as defined by the primary endpoint
   2. renal: creatinine clearance \< 40 ml/min (measured or estimated)
   3. cardiac: clinical evidence of refractory congestive heart failure; LVEF \< 45% by cardiac echo or cardiac MR; chronic atrial fibrillation necessitating oral anticoagulation; uncontrolled ventricular arrhythmia; pericardial effusion with hemodynamic consequences
   4. liver failure as defined by a sustained 3-fold increase in serum transaminase or bilirubin, or a Child-Pugh score C
   5. psychiatric disorders including active drug or alcohol abuse
   6. concurrent neoplasms or myelodysplasia
   7. bone marrow insufficiency defined as leukocytopenia \< 4.0 x 109/L, thrombocytopenia \< 50x 10\^9/L, anaemia \< 8 gr/dL, CD4+ T lymphopenia \< 200 x 106/L
   8. uncontrolled hypertension
   9. uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity
   10. ZUBROD-ECOG-WHO Performance Status Scale \> 2
3. Previous treatments with immunosuppressants \> 12 months including MMF, methotrexate, azathioprine, rituximab, tocilizumab, glucocorticosteroids.
4. Previous treatments with TLI, TBI or alkylating agents including CYC.
5. Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica;
6. eosinophilic myalgia syndrome; eosinophilic fasciitis.
7. Poor compliance of the patient as assessed by the referring physicians.

Primary outcomes:
measure: Global Rank Composite Score (GRCS)
timeFrame: 24 months
Secondary outcomes:
measure: Number of patients who survive without disease progression (Progression-free survival)
timeFrame: 24 months
measure: Number of patients who die due to complications related to the treatment (Treatment related mortality)
timeFrame: 24 months
measure: Number of patient alive after 24 months (Overall mortality)
timeFrame: 24 months
measure: Number of CTCAE toxicity advserse events
timeFrame: 24 months
measure: The area under the curve (AUC) of the CRISS over time
timeFrame: 24 months
measure: Changes in skin involvement (modified Rodnan Skin Score)
timeFrame: 24 months
measure: Changes in cardiac function(Left Ventricular Ejection Fraction)
timeFrame: 12 and 24 months
measure: Changes in pulmonary function
timeFrame: 12 and 24 months
measure: Changes in health related quality of life EQ-5D-5L index
timeFrame: 24 months
measure: Changes in nailfold capillaroscopy
timeFrame: 12 and 24 months
measure: Changes in 18F FDG-PET scan from the thorax
timeFrame: 12 months
measure: Changes in gastrointestinal complaints (UCLA SCTC GIT 2.0)
timeFrame: 12 and 24 months
measure: Changes in several subsets of the immune system
timeFrame: 12 months
measure: Changes in self-assessed skin thickness (PASTUL_)
timeFrame: 60 months
measure: Inflammatory and fibrotic characteristics and changes of the skin and composition of the microbiome of the skin
timeFrame: 12 months
measure: Changes in sexual functioning
timeFrame: 12 and 24 months
measure: Changes in daily functioning
timeFrame: 12 and 24 months
measure: Changes in ability to work, measured by the customized Productivity Cost Questionnaire (iPCQ)
timeFrame: 12 and 24 months
measure: Changes in fatigue measured with the FACIT questionnaire
timeFrame: 12 and 24 months
measure: Changes in handmobility
timeFrame: 24 months
measure: Number of patients who survive without major events (event free survival)
timeFrame: 24 months
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Gaetano Pini-CTO
city: Milan
country: Italy
facility: Ospedale San Raffaele
city: Roma
country: Italy
facility: University Hospital Rome
city: Amsterdam
country: Netherlands
facility: Amsterdam Rheumatology Centre
city: Leiden
country: Netherlands
facility: University Medical Centre Leiden
city: Nijmegen
country: Netherlands
facility: Radboudumc Nijmegen
city: Utrecht
country: Netherlands
facility: University Medical Centre Utrecht
city: Lund
country: Sweden
facility: Skåne University Hospital Lund
city: Stockholm
country: Sweden
facility: Karolinska Institute/Karolinska University Hospital Solna
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bern
country: Switzerland
facility: Inselspital, Universitätsspital Bern
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
Study officials:
affiliation: UMC Utrecht
name: Jacob M van Laar, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UMC Utrecht
name: Julia Spierings
role: STUDY_DIRECTOR
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