Clinical trial NCT00750971: Autologous Stem Cell Transplantation for Refractory Systemic Lupus Erythematosus (ASSIST)
Official title: An Open-Label, Phase II Multicenter Cohort Study of Immunoablation With Cyclophosphamide and Antithymocyte-Globulin and Transplantation of Autologous Cd34-Enriched Hemapoietic Stem Cells Versus Currently Available Immunosuppressive/Immunomodulatory Therapy for Treatment of Refractory Systemic Lupus Erythematosus
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Keywords: ASSIST
SLE
Stem Cell Transplantation
Tolerance
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
First posted: 2008-09-11
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: While glucocorticoids and immunosuppressants ameliorate manifestations of SLE in many patients, current therapies are insufficient to control the disease in a subset of patients, and their clinical prognosis remains poor due to the development of vital organ failure, cumulative drug toxicity and to the increased risk of cardiovascular disease and malignancy. Immunoablative chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) has recently emerged as a promising experimental therapy for severely affected patients, providing them the potential to achieve treatment-free, long-term remission. The investigators postulate that immunoablative therapy eliminates or effectively reduces the level of autoreactive T and B lymphocytes and then regeneration of de novo immunity resets the autoreactive immune system into a self-tolerant, protective immune system resulting in prolonged and treatment-free remission.


Eligibility criteria: Inclusion Criteria:

1. Diagnosis of SLE according to American College of Rheumatology (ACR) classification criteria
2. Age between 18 and 60 years, inclusive
3. Provision of informed consent
4. Active disease, refractory to standard immunosuppressive therapy defined as:

   * BILAG level A and a SLEDAI-score of at least 10, despite treatment with high-dose corticosteroids and pulse intravenous CYC at doses of 500-1000mg/m2 for at least 6 months or mycophenolate mofetil (MMF) at doses of at least 2g -
   * Lupus nephritis with renal biopsy performed within one year prior to screening showing glomerulonephritis WHO class III or IV
   * Parenchymal disease of heart or lung
   * Neuropsychiatric lupus
   * Autoimmune cytopenia OR
   * recurrence of disease activity (defined as BILAG level A and a SLEDAI of at least 10) within one year after successful induction therapy with cyclophosphamide or MMF in the presence of an adequate maintenance therapy with either cyclophosphamide (at least 500mg/m2 monthly), mycophenolate mofetil (at least 2g daily), azathioprine (at least 1.5mg/kg/d), methotrexate (at least 15mg weekly), cyclosporine (at least 3mg/kg/d) in patients with persistent anti-dsDNA antibodies

Exclusion Criteria:

1. Severe concomitant disease or organ damage

   * renal: renal insufficiency with glomerular filtration rate below 40ml/min
   * cardiac: congestive heart failure, LVEF \< 40% determined by echocardiogram, uncontrolled arrhythmia
   * pulmonary: mean pulmonary arterial pressure \>50mmHg, DLCO \< 40 % predicted
   * gastrointestinal: liver cirrhosis; SGOT, SGPT greater than 2 x the upper limit of normal, unless due to active lupus
2. Ongoing cancer or history of malignancy within 5 years of screening
3. Women who are pregnant or breastfeeding or use non-reliable methods of contraception
4. Subjects with active systemic infection
5. Subjects with history of active viral infection within 6 months prior to screening, known HIV-infection or chronic Hepatitis B or Hepatitis C
6. History of allergic reaction to cyclophosphamide, G-CSF or ATG
7. Use of immunosuppressive agents for indications other than SLE
8. Any comorbidity that in the opinion of the investigator would jeopardize the ability of the subject to tolerate therapy

Primary outcomes:
measure: SLEDAI
timeFrame: 48 months
Secondary outcomes:
measure: Serologic response (autoantibodies)
timeFrame: 48 months
measure: Immune Reconstitution
timeFrame: 48 months
measure: Organ-specific response parameters
timeFrame: 48 months
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Universitätsmedizin Charité
city: Düsseldorf
country: Germany
facility: Universitätsklinik Düsseldorf
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Heidelberg
country: Germany
facility: Universitätsklinik Heidelberg
city: Köln
country: Germany
facility: Universitätsklinik Köln
city: Mainz
country: Germany
facility: Universitäsklinik Mainz
city: Tübingen
country: Germany
facility: Universitätsklinik Tübingen
city: Würzburg
country: Germany
facility: Universitätsklinik Würzburg
Study officials:
affiliation: Universitätsmedizin Charité
name: Falk Hiepe, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: Thiel A, Alexander T, Schmidt CA, Przybylski GK, Kimmig S, Kohler S, Radtke H, Gromnica-Ihle E, Massenkeil G, Radbruch A, Arnold R, Hiepe F. Direct assessment of thymic reactivation after autologous stem cell transplantation. Acta Haematol. 2008;119(1):22-7. doi: 10.1159/000117824. Epub 2008 Feb 22.
citation: Jayne D, Passweg J, Marmont A, Farge D, Zhao X, Arnold R, Hiepe F, Lisukov I, Musso M, Ou-Yang J, Marsh J, Wulffraat N, Besalduch J, Bingham SJ, Emery P, Brune M, Fassas A, Faulkner L, Ferster A, Fiehn C, Fouillard L, Geromin A, Greinix H, Rabusin M, Saccardi R, Schneider P, Zintl F, Gratwohl A, Tyndall A; European Group for Blood and Marrow Transplantation; European League Against Rheumatism Registry. Autologous stem cell transplantation for systemic lupus erythematosus. Lupus. 2004;13(3):168-76. doi: 10.1191/0961203304lu525oa.
citation: Rosen O, Thiel A, Massenkeil G, Hiepe F, Haupl T, Radtke H, Burmester GR, Gromnica-Ihle E, Radbruch A, Arnold R. Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells. Arthritis Res. 2000;2(4):327-36. doi: 10.1186/ar107. Epub 2000 Jun 8.
citation: Alexander T, Thiel A, Rosen O, Massenkeil G, Sattler A, Kohler S, Mei H, Radtke H, Gromnica-Ihle E, Burmester GR, Arnold R, Radbruch A, Hiepe F. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood. 2009 Jan 1;113(1):214-23. doi: 10.1182/blood-2008-07-168286. Epub 2008 Sep 29.