ASTIL: Autologous Stem Cell Transplantation: International Lupus Trial

Sponsor

European Society for Blood and Marrow Transplantation (Other)

Overall Status

Withdrawn

CT.gov ID

NCT05063513

Collaborator

EULAR (Other)

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate remission induction therapy for refractory Lupus Erythematosus with autologous hematopoietic stem cell transplantation (AHSCT) versus Rituximab (anti CD20) followed by maintenance therapy with mycophenolate mofetil (MMF).

Condition or Disease	Intervention/Treatment	Phase
REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS	Biological: Autologous Hematopoietic Stem Cell Transplantation Drug: Rituximab	Phase 2/Phase 3

Detailed Description

To compare the efficacy of Autologous Hematopoietic Stem Cell Transplantation (experimental arm) versus rituximab (control arm), followed by maintenance therapy with Mycophenolate Mofetil for patients with severe Systemic Lupus Erythematosus refractory to treatment with Cyclophosphamide and/or MMF alone plus steroids.

Secondary Objectives

To evaluate the safety of AHSCT therapy versus rituximab (anti CD20) (control arm) with maintenance therapy by Mycophenolate Mofetil according to treatment related mortality and toxicity up to two years after randomization
To evaluate the long term efficacy in the study arms according to repeated measures of Disease Activity and Damage scores, Quality of Life, the presence of other co morbidities, the daily dose of steroids rated quarterly up to two years after randomization.
To evaluate in the study arms whether remission and disease activity correlates with immunological parameters, including immune reconstitution and auto antibodies

Trial Design:

Based on the existing European (28) and North American experience (29-31) of AHSCT in SLE, it is logical to suggest the following phase IIb trial designed in patients with severe refractory SLE after at least 6 months of best standard local therapy using either alone or successively according to current international clinical consensus as follows:

the short term Eurolupus protocol low dose CY regimen of 6 x 500 mg iv cyclophosphamide at 2 weeks interval or
the conventional treatment with 0.75 g/m2/month x 6 iv cyclophosphamide or
mycophenolate mofetil at 2 g/daily for 3 to 6 months plus oral steroids above 0.5 mg/kg/day and unable to decrease below 20 mg/day.

All patients will be randomised at time of inclusion in one of two groups:

Group A (experimental arm) will undergo mobilisation with CY 4 g/m2 (in two divided doses), followed by Autologous Hematopoietic Stem Cell Transplantation using CY (200 mg/kg body weight given in 4 daily doses) plus ATG and unmanipulated autologous graft and maintenance by Mycophenolate Mofetil (2 g/day) starting 3 months after randomization.
Group B (control arm) will receive 4 successive weekly infusions of rituximab (antiCD20) 375 mg/m2 body surface area for four weeks and maintenance by Mycophenolate Mofetil (2 g/day) starting 3 months after randomization.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Remission Induction Therapy for Refractory Systemic Lupus Erythematosus With Autologous Hematopoietic Stem Cell Transplantation (AHSCT) Versus Rituximab (antiCD20) Followed by Maintenance Therapy With Mycophenolate Mofetil (MMF)

Study Start Date :

Jul 1, 2009

Actual Primary Completion Date :

Jul 1, 2013

Actual Study Completion Date :

Jul 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Transplant arm Experimental arm will undergo mobilisation with cyclophosphamide (CY) 4 g/m2 (in two divided doses), followed by Autologous Hematopoietic Stem Cell Transplantation using CY (200 mg/kg body weight given in 4 daily doses) plus ATG and unmanipulated autologous graft and maintenance by Mycophenolate Mofetil (2 g/day) starting 3 months after randomization.	Biological: Autologous Hematopoietic Stem Cell Transplantation Experimental arm will undergo mobilisation with CY 4 g/m2 (in two divided doses), followed by Autologous Hematopoietic Stem Cell Transplantation using CY (200 mg/kg body weight given in 4 daily doses) plus ATG and unmanipulated autologous graft and maintenance by Mycophenolate Mofetil (2 g/day) starting 3 months after randomization. Other Names: Cellcept for Mycophenolate Mofetil
Active Comparator: Rituximab arm Control arm will receive 4 successive weekly infusions of rituximab (antiCD20) 375 mg/m2 body surface area for four weeks and maintenance by Mycophenolate Mofetil (2 g/day) starting 3 months after randomization.	Drug: Rituximab Control arm will receive 4 successive weekly infusions of rituximab (antiCD20) 375 mg/m2 body surface area for four weeks and maintenance by Mycophenolate Mofetil (2 g/day) starting 3 months after randomization. Other Names: MabThera for Rituximab Cellcept for Mycophenolate Mofetil

Arm

Intervention/Treatment

Experimental: Transplant arm

Experimental arm will undergo mobilisation with cyclophosphamide (CY) 4 g/m2 (in two divided doses), followed by Autologous Hematopoietic Stem Cell Transplantation using CY (200 mg/kg body weight given in 4 daily doses) plus ATG and unmanipulated autologous graft and maintenance by Mycophenolate Mofetil (2 g/day) starting 3 months after randomization.

Biological: Autologous Hematopoietic Stem Cell Transplantation

Experimental arm will undergo mobilisation with CY 4 g/m2 (in two divided doses), followed by Autologous Hematopoietic Stem Cell Transplantation using CY (200 mg/kg body weight given in 4 daily doses) plus ATG and unmanipulated autologous graft and maintenance by Mycophenolate Mofetil (2 g/day) starting 3 months after randomization.

Other Names:

Cellcept for Mycophenolate Mofetil

Active Comparator: Rituximab arm

Control arm will receive 4 successive weekly infusions of rituximab (antiCD20) 375 mg/m2 body surface area for four weeks and maintenance by Mycophenolate Mofetil (2 g/day) starting 3 months after randomization.

Drug: Rituximab

Other Names:

MabThera for Rituximab

Cellcept for Mycophenolate Mofetil

Outcome Measures

Primary Outcome Measures

To compare the efficacy of Autologous Hematopoietic Stem Cell Transplantation (study arm) versus rituximab (control arm), followed by maintenance therapy with Mycophenolate Mofetil for patients with severe Systemic Lupus Erythematosus [2 years]

Secondary Outcome Measures

To evaluate the safety of AHSCT therapy (study arm) versus rituximab (anti CD20) (control arm) with maintenance therapy by Mycophenolate Mofetil according to treatment related mortality and toxicity up to two years after randomization [2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age between 16 and 60 years.
Diagnosis of systemic lupus erythematosus (SLE) according to ACR-criteria with antinuclear antibodies positive (ANA) on at least 2 successive tests at 3 months interval plus disease duration of more than 5 years since the diagnosis or first time of intensive immunosuppressive drugs.
Sustained or relapsed active BILAG A SLE with documented evidence of at least one visceral involvement or refractory SLE as defined by either:

kidney involvement: with the criteria for lupus renal BILAG A and a creatinine clearance > 30 ml/min/m2, not explained by other causes than SLE activity with a renal biopsy of less than 12 months showing a class III or IV lupus nephritis
Any other type of vital organ involvement except mesenteric vasculitis with BILAG neurologic category A, cardiovascular or pulmonary category A, vasculitis category A
Auto-immune cytopenias (hemolytic anemia and/or thrombo-cytopenia) defined as BILAG hematologic category A and confirmed by a bone marrow aspirate
Secondary antiphospholipid syndrome (SAPL) active despite full (INR > 3) anticoagulation after at least 6 months of the best standard local therapy using

CY or MMF either alone or successively according to:

the short term Eurolupus protocol low dose CY regimen of 6 x 500 mg iv CY at 2 weeks interval or
the conventional treatment with 0.75 g/m2/month x 6 iv cyclophosphamide or
MMF at 2 g daily for 3 to 6 months plus oral steroids above 0.5 mg/kg/day and be corticosteroids dependent and unable to decrease below 20 mg/day.

Negative pregnancy test for women of child bearing age.
Written informed consent.

Exclusion Criteria:

Pregnancy, breast feeding or unwillingness to use adequate contraception methods during study (see 7.5).
Severe concomitant disease:

Respiratory: mean PAP > 50 mmHg (by cardiac echo or right heart catheterization), DLCO < 40% predicted, respiratory failure as defined by a resting arterial oxygen tension (PaO2) < 70 mmHg) and/or resting arterial carbon dioxide tension (PaCO2)> 50 mmHg) without oxygen supply
Renal: creatinine clearance < 30 ml/min
Cardiac: clinical evidence of congestive heart failure; LVEF < 40% (cardiac echo or multigated radionuclide angiography (MUGA)); > 1 cm pericardial effusion on cardiac echography; uncontrolled ventricular arrhythmia.

Liver failure defined as a transaminases levels (ASAT, ALAT > 2 normal) unless related to activity of the disease.
Severe psychiatric disorders, including severe psychosis related to SLE disease that may prevent the ability to sign informed consent or undergo the procedure.
Concurrent neoplasms or myelodysplasia except for localized basal cell carcinoma or squamous skin cancer or in situ cervical carcinoma of the uterus.
Bone marrow insufficiency defined as neutropenia < 0.5 x 109/l, thrombo- cytopenia < 30 x 109/l, anaemia < 8 g/dl, CD4+ T lymphopenia < 200 x 106/l.
Uncontrolled acute or chronic infection, including HIV, HTLV-1, 2 positivity, Hepatitis B surface Ag positive, hepatitis C PCR positive.
Previous treatments with TLI, TBI or alkylating agents including cyclophosphamide > 15 g cumulative.
Intracranial hematoma or previous bleeding documented within 30 days of the screening visit.
Mesenteric vasculitis or ongoing gastrointestinal bleeding.
Poor compliance of the patient as assessed by the referring physicians.