Upfront Autologous Hematopoietic Stem Cell Transplantation Versus Immunosuppressive Medication in Early Diffuse Cutaneous Systemic Sclerosis: an International Multicentre, Open-label, Randomized Con-trolled Trial
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- UMC Utrecht
- 入组人数
- 60
- 试验地点
- 8
- 主要终点
- Global Rank Composite Score (GRCS)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age between 18 and 65 years.
- •Fulfilling the 2013 ACR-EULAR classification criteria for SSc
- •Either: 3.1 or 3.2 3.
- •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)
- •- 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
- •persistent urinalysis abnormalities (proteinuria, haematuria, casts), AND/OR
- •microangiopathic haemolytic anaemia AND/OR
- •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
- •Disease duration ≤ 1 year (from onset of first non-Raynaud's symptoms) and diffuse cutaneous disease with mRSS ≥ 10 and
- •High risk ANA for organ based disease: ATA or ARA positivity and/ or
- •Acute phase response (ESR > 25 mm/h and/or CRP > 10.0 mg/L )
- •4. Written Informed consent
排除标准
- •Pregnancy or unwillingness to use adequate contraception during study
- •Concomitant severe disease =
- •respiratory: resting mean pulmonary artery pressure (mPAP) > 25 mmHg (by right heart catheterisation), DLCO < 40% predicted, respiratory failure as defined by the primary endpoint
- •renal: creatinine clearance < 40 ml/min (measured or estimated)
- •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
- •liver failure as defined by a sustained 3-fold increase in serum transaminase or bilirubin, or a Child-Pugh score C
- •psychiatric disorders including active drug or alcohol abuse
- •concurrent neoplasms or myelodysplasia
- •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
- •uncontrolled hypertension
- •uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity
- •ZUBROD-ECOG-WHO Performance Status Scale > 2
- •Previous treatments with immunosuppressants > 12 months including MMF, methotrexate, azathioprine, rituximab, tocilizumab, glucocorticosteroids.
- •Previous treatments with TLI, TBI or alkylating agents including CYC.
- •Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica;
- •eosinophilic myalgia syndrome; eosinophilic fasciitis.
- •Poor compliance of the patient as assessed by the referring physicians.
研究组 & 干预措施
Upfront autologous HSCT
干预措施: Upfront autologous HSCT (Procedure)
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.
干预措施: Upfront autologous HSCT (Procedure)
结局指标
主要结局
Global Rank Composite Score (GRCS)
时间窗: 24 months
The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. For this endpoint, seveal endpoints will be used: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of \>30% in DLCO % predicted or \>20% in FVC % predicted ), renal failure (chronic dialysis \> 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction \<30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).
次要结局
- Number of CTCAE toxicity advserse events(24 months)
- Number of patients who survive without disease progression (Progression-free survival)(24 months)
- Number of patients who die due to complications related to the treatment (Treatment related mortality)(24 months)
- Number of patient alive after 24 months (Overall mortality)(24 months)
- Changes in skin involvement (modified Rodnan Skin Score)(24 months)
- The area under the curve (AUC) of the CRISS over time(24 months)
- Changes in cardiac function(Left Ventricular Ejection Fraction)(12 and 24 months)
- Changes in sexual functioning(12 and 24 months)
- Changes in daily functioning(12 and 24 months)
- Changes in handmobility(24 months)
- Changes in pulmonary function(12 and 24 months)
- Changes in health related quality of life EQ-5D-5L index(24 months)
- Inflammatory and fibrotic characteristics and changes of the skin and composition of the microbiome of the skin(12 months)
- Changes in ability to work, measured by the customized Productivity Cost Questionnaire (iPCQ)(12 and 24 months)
- Changes in fatigue measured with the FACIT questionnaire(12 and 24 months)
- Changes in nailfold capillaroscopy(12 and 24 months)
- Changes in 18F FDG-PET scan from the thorax(12 months)
- Changes in gastrointestinal complaints (UCLA SCTC GIT 2.0)(12 and 24 months)
- Changes in several subsets of the immune system(12 months)
- Changes in self-assessed skin thickness (PASTUL_)(60 months)
- Number of patients who survive without major events (event free survival)(24 months)
研究者
Jacob M van Laar
Principal Investigator, Clinical professor
UMC Utrecht