Patients with systemic lupus erythematosus (SLE) and increased disease activity refractory to standard therapies. MedDRA version: 18.0 Level: PT Classification code 10042945 Term: Systemic lupus erythematosus System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders MedDRA version: 18.0 Level: PT Classification code 10067657 Term: Systemic lupus erythematosus disease activity index increased System Organ Class: 10022891 - Investigations
Conditions
Interventions
Trade Name: Proleukin
Product Name: Proleukin
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: Aldesleukin
CAS Number: 110942-02-4
Other descriptive name: ALDESLEUKIN
Sponsors
Charité - Universitätsmedizin Berlin
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients with diagnosis of SLE made and documented by the investigator according to the revised ACR criteria fulfilling = 4 criteria with at least one autoantibody level abnormal (ANA, anti-dsDNA-abs, anti-Sm-abs, anti-Phospholipid-abs). 2. Active SLE patients with a SELENA-SLEDAI = 6 despite previous treatment with at least two different standard immunosuppressive or immunomodulatory therapies. 3. An EC approved written informed consent form signed and dated by the patient must be obtained prior to the performance of any protocol procedures and prior to the administration of the study medication (according to AMG §40 (1) 3b). 4. Stable dosage of standard immunosuppressive or immunomodulatory treatments for at least 4 weeks prior to the first administration of the study medication. 5. Daily dose of glucocorticosteroids must be = 30mg prednisolone (or equivalent) at the day of baseline visit (Visit 2). 6. Age of patients >18 years and = 75 years. 7. Willingness to perform blood analyses and to discontinue therapies which potentially interfere with the study medication. 8. Female patients of childbearing potential must have a negative serological pregnancy test at the screening visit (Visit 1) 9. Female patients of childbearing potential must use at least two reliable methods of birth control (1 of which is a barrier method) during study participation and up to 3 months after completion of the last (4th) treatment cycle. 10. Male patients must agree to use a contraceptive barrier method (eg, condom) with adjunct spermicide during sexual intercourse from the time of the administration of the study medication until at least 3 month after completion of the last (4th) treatment cycle. 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 12 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 12
Exclusion criteria
Exclusion criteria: 1. Hypersensibility to Aldesleukin or its excipients. 2. Patients with a reduced general condition of 2 or more according to the ECOG (Eastern Cooperative Oncology Group) Performance Status. 3. Severe impairment of vital organ or life-threatening disease. 4. Thrombocytopenia with platelet count of 9%) or patients with type-2 diabetes mellitus and history of recurrent hyperglycemia or hypoglycemia of clinical relevance (= grade 3 according to the CTCAE v4.03). 17. Patients who received allogeneic solid organ transplants, except patients who underwent an autologous or allogeneic hematopoetic stem-cell transplantation (HSCT) more than two years prior to the screening and who did not develop graft-versus-host disease (GvHD). 18. Patients with diagnosis of malignant neoplasm or treatment for malignant neoplasm within the last 5 years prior to the screening visit (Visit 1), except adequately treated basal cell carcinoma or squamous cell carcinoma of the skin and carcinoma in situ of the uterine cervix. 19. Patients with severe impairment of pulmonary function: severe restrictive lung disease with FVC of <50% of predicted value or obstructive lung disease with FEV1 of <50% of predicted value or O2-saturation of <90% determined by a pulse oxymeter under room air and in resting position. 20. Severe cardiomyopathy or chronic heart failure with an ejection fraction of <30% or of = grade 3 according to the CTCAE v4.03; instable angina pectoris; coronary heart disease with previous stent implantation within the last 3 month prior to the screening visit (Visit 1) or with three-vessel involvement; cardiac intervention or myocardial infarction within the last 12 month prior to the screening visit (Visit1); history of cardiac arrest. 21. Cardiac arrhythmias of clinical relevance or requiring permanent treatment (= grade 2 according to the CTCAE v4.03); persistent or permanent atrial fibrillation; disturbance of transmission of impulses of clinical relevance
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of PRO-IMMUN is to evaluate the safety, tolerability and the cellular response of the regulatory T cell (Treg) population of a repetitive and cyclic subcutaneous low-dose regimen with the interleukin-2 analogue Aldesleukin (Proleukin®) in SLE patients with increased disease activity refractory to standard therapies.;Secondary Objective: The secondary objectives of PRO-IMMUN are to evaluate the clinical efficacy by assessment of the following serological and clinical response parameters: • Serum antibody titers for anti-dsDNA-Abs, ANA, ENA, anti-SmD1-Abs, serum levels of the complement factors C3 and C4, serum levels of circulating immune complexes and other individually relevant serological markers. • SLE Disease activity scores SELENA-SLEDAI, BILAG 2004, PGA and VAS. • Health related Quality of Life (SF36®). • Organ specific parameters based on individual SLE manifestations. • SLICC/ACR Damage Index. • Durability of clinical and serological responses in subjects who responded to the therapy. • Incidence and severity of SLE flares. Exploratory objectives: The exploratory objectives of PRO-IMMUN are to evaluate a broad variety of immunological and cellular responses. ;Primary end point(s): The primary endpoint is defined by the increase in the percentage of CD25++ cells among CD3+CD4+Foxp3+CD127lo Treg cells by at least 100% (2-fold) at week 9 (Visit 9; after the 4th treatment cycle) compared to baseline at week 1 (Visit 2; before the 1st treatment cycle). Safety and tolerability will be evaluated descriptively by assessment of the incidence, frequency, duration, severity and causal relationship to the study medication of any adverse event (clinical and laboratory testings) at every scheduled visit after the screening visit and at every unscheduled visit.;Timepoint(s) of evaluation of this end point: Week 9 (Visit 9; after the 4th treatment cycle) compared to baseline values (Visit 2; week 1). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Endpoints: • Changes in serum antibody titers for anti-dsDNA-Abs, ANA, ENA, anti-SmD1-Abs, serum levels of the complement factors C3 and C4, serum levels of circulating immune complexes and other individually relevant serological markers. • Changes in SLE Disease activity scores SELENA-SLEDAI, BILAG 2004 and changes in PGA and VAS. • Changes in health related Quality of Life (SF36®). • Changes in organ specific parameters based on individual SLE manifestations. • Changes in SLICC/ACR Damage Index. • Assessment of the durability of clinical and serological responses in subjects who responded to the therapy. • Assessment of incidence and severity of SLE flares. Exploratory endpoints: • Changes in the percentage of CD3+CD4+Foxp3+CD127loCD25++ Treg cells among CD3+CD4+ T cells and changes in the percentage of CD25++ cells among CD3+CD4+Foxp3+CD127lo Treg. • Changes in the absolute numbers of CD3+CD4+Foxp3+CD127lo Treg and of CD3+CD4+Foxp3+CD127lo CD25++ Treg. • Changes in the differential blood count and in the absolute numbers, phenotype, activation, proliferation and survival of different immune cells (Treg cells, Tcon, NK cells, NKT cells, CD8+ T cells, B cells, plasma cells, granulocytes, monocytes). • Changes in the ratios of Treg and Tcon subsets. • Changes in the IL-2-induced phosphorylation of the intracellular signalling molecule STAT-5 in different cell types. • Changes in the expression of the IFN-a induced signature marker SIGLEG-1 on monocytes. • Changes in the numbers, composition and phenotype of immune cells in the urine of patients with proven renal involvement. • Changes in the serum levels of IL-2 and of other cytokines (IL-6, IL-10, IFN-g, IL-17). • Changes in the global gene expression by transcriptome analysis of PBMC. • Changes in the methylation status of the Foxp3 gene (TSDR) in IL-2 expanded Treg. • Changes in the TCR repertoire of Treg and Tcon. • Changes in the suppressive function of IL- | — |
Countries
Germany
Contacts
Public ContactRheumatologie, CC12
Charité - Universitätsmedizin Berlin
Outcome results
None listed