E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diffuse cutaneous systemic sclerosis according to the ACR/EULAR criteria |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
To evaluate (in both treatment arms) whether disease activity correlates with immunological parameters, including immunopathology of skin, immune reconstitution, and autoantibodies. We will also determine the cost-effectiveness of HSCT as first line treatment versus usual care and try to identify factors associated with response to treatment |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
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E.3 | Principal inclusion criteria |
1. Age between 18 and 65 years. 2. Fulfilling the 2013 ACR-EULAR classification criteria 3. Disease duration ≤ 2 years (from onset of first non-Raynaud’s symptoms) and - progressive skin involvement with a mRSS ≥ 15 (diffuse skin pattern) and/or - major organ involvement as defined by either: a) clinically significant respiratory involvement b) clinically significant renal involvement c) clinically significant cardiac involvement |
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E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study: 1. Pregnancy or unwillingness to use adequate contraception during study 2. Concomitant severe disease (respiratory, renal, cardiac, liver failure, psychiatric disorders including active drug or alcohol abuse, concurrent neoplasms or myelodysplasis, bone marrow insufficiency, uncontrolled hypertension, uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity, ZUBROD-ECOG-WHO Performance Status Scale > 2, known hypersensitivity to any of the study drug constituents) 3. Previous treatments with immunosuppressants > 6 months including mycophenolate mofetil, methotrexate, azathioprine, rituximab, tocilizumab, glucocorticosteroids. 4. Previous treatments with TLI, TBI or alkylating agents including cyclophosphamide. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is event-free survival. 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
Note 1. When major organ failure has occurred, its persistence is to be confirmed by repeated evaluation after 3 months.
Note 2. Cardiac MR is considered the gold standard for assessment of LVEF. LVEF measurements by cardiac echo (instead of cardiac MR) will be accepted when baseline and follow-up evaluations have been performed by the same experienced echocardiologist.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
3, 6, 9, 12, 15, 18, 21, 24 months after treatment |
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E.5.2 | Secondary end point(s) |
- Progression-free survival, defined as the time in days since the day of randomisation until any of the following relative changes from baseline 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. - Treatment related mortality is 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. - Treatment toxicity will be assessed using WHO toxicity parameters (adverse events =/> grade 3) in consecutive 3-month periods following randomisation until two years follow-up. - The area under the curve (AUC) of the CRISS over time, measuring the ‘predicted probability of being im-proved’ over 2 years.(22) This AUC is calculated based on 4 repeated measures (6, 12, 18 and 24 months) with back translation to the original scale between 0 and 1. - Change over years follow-up of the following parameters: • modified Rodnan skin score by independent assessor (appendix G) • Pulmonary involvement = diffusion capacity for carbon monoxide (DLCO and DLCO/VA), (forced)vital capacity ((F)VC), total lung capacity (TLC), residual volume (RV), mean pulmonary artery pressure by cardiac echo (or right heart catheterization), lung density measurement by thoracic CT • Renal involvement = urine portion: creatinin/ protein ratio Myocardial involvement= left ventricular function as measured by cardiac MR (at baseline and 12 months), ECG and cardiac echo (annually) and semiquantitative measurement of cardiac involvement with the cardiac score (based on the presence or absence of left axis deviation on ECG and moderate or large pericardial effusion on echo).(23) Quality-of-life (EuroQol (EQ-5D-5L)) (appendix H) Customized version (focussing on the important cost-drivers) of the iMCQ and iPCQ (appendix I) SHAQ incl visual analogue scales (VAS) for scleroderma-specific symptoms (appendix J) Gastrointestinal symptom scale (UCL-GIT 2.0) (appendix K) Sexual functioning (IIEF-5 and BMSFI (in men) and Sexual Function Questionnaire (SFQ-28)) (appendix L)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3, 6, 9, 12, 15, 18, 21, 24, 36, 48, 60 months after treatment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
autologous stem cell transplantation |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |