High dose immunoablation and autologous hematopoietic stem cell transplantation versus monthly intravenous pulse therapy cyclophosphamide in severe systemic sclerosis ( ‘ASTIS’-TRIAL: Autologous Stem Cell Transplantation International Scleroderma Trial) - ASTIS

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2006-004598-83-GB
• Date of registration: 24/10/2008
• Prospective Registration: No
• Primary sponsor: EBMT (European group for Blood and Marrow Transplantation)
• Public title: High dose immunoablation and autologous hematopoietic stem cell transplantation versus monthly intravenous pulse therapy cyclophosphamide in severe systemic sclerosis ( ‘ASTIS’-TRIAL: Autologous Stem Cell Transplantation International Scleroderma Trial) - ASTIS
• Scientific title: High dose immunoablation and autologous hematopoietic stem cell transplantation versus monthly intravenous pulse therapy cyclophosphamide in severe systemic sclerosis ( ‘ASTIS’-TRIAL: Autologous Stem Cell Transplantation International Scleroderma Trial) - ASTIS
• Date of first enrolment: 22/10/2008
• Target sample size: 150
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-004598-83
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Age between 18 and 65 years.

2. Established diagnosis of systemic sclerosis according to ARA-criteria.

3. Diffuse scleroderma with disease duration either: a. less than or equal 2 years since development of first sign of skin thickening, plus modified Rodnan skin score greater than or equal 20, plus involvement of trunk plus ESR > 25 mm/1st hour and/or Hb < 11 g/dL, not explained by other causes than active scleroderma,
or b.
less than or equal 4 years since development of first sign of skin thickening, plus modified Rodnan skin score greater than or equal 15, plus major organ involvement (with documented evidence of onset or clinically significant worsening in the previous 6 months) as defined by either:

a) Respiratory involvement = DLCO and/or (F)VC less than or equal 80% (of predicted) and evidence of interstitial lung disease (chest X-ray and/or HR-CT scan and/or bronchoalveolar lavage and/or biopsy of the lungs) with clinically relevant obstructive disease and emphysema excluded.

b) Renal involvement = any of the following criteria: hypertension (two successive BP readings of either systolic greater than or equal 160 mm Hg or diastolic > 110 mm Hg, at least 12 hours apart), persistent urinalysis abnormalities (proteinuria, hematuria, casts), microangiopathic hemolytic anemia, new renal insufficiency (serum creatinine > upper limit of normal); non-scleroderma related causes (e.g. medication, infection etc.) must be reasonably excluded.

c) Cardiac involvement = any of the following criteria: reversible congestive heart failure, atrial or ventricular rhythm disturbances such as recurrent episodes of atrial fibrillation or flutter, recurrent atrial paroxysmal tachycardia or ventricular tachycardia, 2nd or 3rd degree AV-block, pericardial effusion; non-scleroderma related causes must have been reasonably excluded by an experienced cardiologist.

4. Written informed consent

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Pregnancy or unwillingness to use adequate contraception during study

2. Concomitant severe disease =

2.1 respiratory: mean PAP > 50 mmHg (by cardiac echo or right heart catheterization), DLCO < 40% predicted, respiratory failure as defined by the primary endpoint

2.2 renal: creatinine clearance < 40 ml/min (measured or estimated)

2.3 cardiac: clinical evidence of refractory congestive heart failure; LVEF < 45% by multigated radionuclide angiography (MUGA) or cardiac echo; chronic atrial fibrillation necessitating oral anticoagulation; uncontrolled ventricular arrhythmia; pericardial effusion with hemodynamic consequences as evaluated by an experienced echocardiographist

2.4 liver failure as defined by a sustained 3-fold increase in serum transaminase or bilirubin

2.5 psychiatric disorders including active drug or alcohol abuse

2.6 concurrent neoplasms or myelodysplasia

2.7 bone marrow insufficiency defined as leucocytopenia < 4.0 x 109/L, thrombocytopenia < 50 x 109/L, anemia < 8 gr/dL, CD4+ T lymphopenia < 200 x 106/L

2.8 uncontrolled hypertension

2.9 uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity

3. Previous treatments with TLI, TBI or alkylating agents including cyclophosphamide
(> 5 g i.v. cumulative, or > 3 months oral up to 2 mg/kg b.wt).

4. Significant exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica; eosinophilic myalgia syndrome; eosinophilic fasciitis.

5. Poor compliance of the patient as assessed by the referring physicians.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Severe systemic sclerosis
MedDRA version: 9.1 Level: LLT Classification code 10042953 Term: Systemic sclerosis

Intervention(s)

Trade Name: Cyclophosphamide
Product Name: Cyclophosphamide
Pharmaceutical Form: Intravenous infusion
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50180
Current Sponsor code: Cyclophosphamide
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 28-

Trade Name: Neupogen
Product Name: Filgrastim
Pharmaceutical Form: Injection*
INN or Proposed INN: FILGRASTIM
CAS Number: 121181531
Concentration unit: µg/kg microgram(s)/kilogram
Concentration type: equal
Concentration number: 10-

Trade Name: Thymoglobuline
Product Name: Thymoglobuline
Product Code: rbATG
Pharmaceutical Form: Intravenous infusion
INN or Proposed INN: Anti-Thymocyte Globulin, Rabbit
Other descriptive name: ANTI-HUMAN T-LYMPHOCYTE IMMUNOGLOBULIN FROM RABBITS
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 2.5-

Trade Name: Solu-Medrone
Product Name: Methylprednisolone
Pharmaceutical Form: Intravenous infusion
INN or Proposed INN: METHYLPREDNISOLONE
CAS Number: 83432
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 1-

Trade Name: Cyclophosphamide
Product Name: Cyclophosphamide
Pharmaceutical Form: Intravenous infusion
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50180
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: equal
Concentration number: 750-

Trade Name: Mesna
Product Name: Mesna
Pharmaceutical Form: Solution for injection
INN or Proposed INN: MESNA
CAS Number: 19767454
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 400-

Trade Name: Mesna
Product Name: Mesna
Pharmaceutical Form: Solution for injection
INN or Proposed INN: MESNA
CAS Number: 19767454
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 400-

Primary Outcome(s)

Main Objective: To evaluate the potential clinical benefit of high dose immunoablation and autologous stem cell transplantation in comparison to intravenous pulse therapy cyclophosphamide, with respect to:

- Survival and prevention of major organ failure (‘event-free survival’)

- Safety

- Impact on skin thickening, visceral involvement, functional status, and quality of life

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 randomization until the occurrence of death due to any cause or the development of persistent1 major organ failure (heart, lung, kidney) defined as follows:

• Heart: left ventricular ejection fraction < 30% by MUGA (or cardiac echo2)

• 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 Objective: 1. To evaluate (in both treatment arms) whether disease activity correlates with immunological parameters, including immunopathology of skin, immune reconstitution, and autoantibodies.

2. To search for predictive factors (clinical and immunological) of response.

Secondary ID(s)

54371254