Lupus Erythematosus, Systemic
Conditions
Keywords
Lupus Erythematosus, Systemic, SLE, Interleukin-2, IL-2, T-Lymphocytes, Regulatory, Treg
Brief summary
Systemic lupus erythematosus (SLE) is an autoimmune disease with multifactorial genesis. Recent research suggests a numerical and functional deficit of regulatory T (Treg) cells as an important contributing factor to the pathology seen in SLE. Treg cells play important roles in dampening overt stimulation of effector cells, as seen in many autoimmune diseases. As Treg cells are highly dependent on interleukin-2 (IL-2), application of low doses of IL-2 leads to markedly increased numbers and improved functionality of Treg cells in mice and humans. Several clinical trials investigated the safety of low-dose IL-2 treatment in different autoimmune diseases, including SLE. The trials conducted so far mainly focused on an increase in Treg cells after IL-2 treatment, not evaluating in detail the effects on other immune cells, presumably also playing important roles in the pathogenesis of SLE. For this reason, the investigators of this trial aim to conduct a complete phenotyping of cellular and soluble components in the blood of SLE patients treated with low-dose IL-2. Furthermore, the investigators want to offer this promising treatment to SLE patients in a controlled framework of an investigator initiated clinical trial.
Interventions
DRUGLow-dose Aldesleukin (Proleukin®)
Subcutaneous injection of 1.5 million international units (MIU) of Aldesleukin (Proleukin®, Interleukin-2) once daily in 5-day courses every three weeks for a total of 4 cycles.
Sponsors
Onur Boyman, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Informed consent forms as documented by signature. * Diagnosis of SLE according to the criteria issued by the American College of Rheumatology. * Female and male patients older than 18 years. * Corticosteroids given at a stable dose for at least 4 weeks prior to enrollment. * Immunosuppressive medication must be unchanged for at least 4 weeks prior to enrollment (e.g. mycophenolate-mofetil and/or methotrexate, see
Exclusion criteria
). * Participants must present with the following organ functions as defined below: * Cardiac: No myocardial infarction prior to enrollment. No symptoms of heart failure New York Heart Association (NYHA) Class II or higher. No severe uncontrolled ventricular arrhythmias. No clinical signs of angina pectoris. No acute ischemia or active conduction system abnormalities additionally documented by an electrocardiogram prior to study enrollment. * Pulmonary: forced expiratory volume 1 (FEV1) ≥50% (CTCAE grade 3 or lower) or diffusing capacity of the lungs for carbon monoxide (DLCO) ≥40% of predicted values. * Renal: Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2. * Hepatic: Adequate hepatic function (aspartate aminotransferase \[AST, also termed GOT\] and alanine aminotransferase \[ALT, also termed GPT\] ≤2-fold upper limit of normal; total bilirubin \<2.0 mg/dl, except for Gilbert-Meulengracht syndrome. * The life expectancy of the patients should be greater than 12 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of increase in percentage of Treg cells | Comparison between baseline (visit 2, day 0) and week 9 (visit 9, day 68). | The primary outcome of this study is an increase in percentage of Treg cells of total CD4+ T cells between visit 2 (baseline) and week 9 (visit 9) measured in the blood of SLE patients not receiving Belimumab treatment. Treg cells are defined as CD3+CD4+CD127loCD25hiFoxp3+ and total CD4+ T cells are defined as CD3+CD4+. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Exploratory assessment of cellular immune cell subsets in the blood of SLE patients. | Comparison between baseline (visit 2, day 0), visit 3 (day 5), visit 4 (day 21), visit 5 (day 26), visit 6 (day 42), visit 7 (day 47), visit 8 (day 63), visit 9 (day 68), visit 10 (day 96) and visit 11 (day 124). | Different immune cell subsets isolated from whole blood will be quantified. Immune cells of interest will include: T cell subsets, including effector and regulatory CD4 and CD8 T cells, B cells, natural killer cells, innate lymphoid cells, dendritic cells, monocytes/macrophages, as well as eosinophil, basophil and neutrophil granulocytes and their respective subtypes including premature stages. |
| Exploratory assessment of soluble cytokines in the blood of SLE patients. | Comparison between baseline (visit 2, day 0), visit 3 (day 5), visit 4 (day 21), visit 5 (day 26), visit 6 (day 42), visit 7 (day 47), visit 8 (day 63), visit 9 (day 68), visit 10 (day 96) and visit 11 (day 124). | Quantification of cytokines in the blood will include: common gamma chain cytokines, pro-inflammatory cytokines and anti-inflammatory cytokines. |
| Exploratory assessment of soluble CD25 in the blood of SLE patients. | Comparison between baseline (visit 2, day 0), visit 3 (day 5), visit 4 (day 21), visit 5 (day 26), visit 6 (day 42), visit 7 (day 47), visit 8 (day 63), visit 9 (day 68), visit 10 (day 96) and visit 11 (day 124). | Soluble CD25 will be quantified in the serum of SLE patients. |
| Exploratory assessment of antibodies in the blood of SLE patients. | Comparison between baseline (visit 2, day 0), visit 3 (day 5), visit 4 (day 21), visit 5 (day 26), visit 6 (day 42), visit 7 (day 47), visit 8 (day 63), visit 9 (day 68), visit 10 (day 96) and visit 11 (day 124). | Specific and unspecific antibodies will be quantified. This measurement will include Immunglobulin subclasses (IgA, IgG, IgD, IgM and IgE), anti-dsDNA, antinuclear, anti-Sm and anti-C1q antibodies. |
| Exploratory assessment of complement activity in SLE patients. | Comparison between baseline (visit 2, day 0), visit 3 (day 5), visit 4 (day 21), visit 5 (day 26), visit 6 (day 42), visit 7 (day 47), visit 8 (day 63), visit 9 (day 68), visit 10 (day 96) and visit 11 (day 124). | Activity of complete and classical complement pathways will be determined. |
| Clinical response measured by the SELENA-SLEDAI score. | Comparison between baseline (visit 2, day 0), visit 5 (day 26), visit 9 (day 68) and visit 11 (day 124). | — |
| Clinical response measured by the BILAG-2004 score. | Comparison between baseline (visit 2, day 0), visit 5 (day 26), visit 9 (day 68) and visit 11 (day 124). | — |
| Clinical response measured by the Physician's Global Assessment (PGA) score. | Comparison between baseline (visit 2, day 0), visit 5 (day 26), visit 9 (day 68) and visit 11 (day 124). | — |
| Clinical response measured by the SLE Responder Index (SRI). | Comparison between baseline (visit 2, day 0), visit 5 (day 26), visit 9 (day 68) and visit 11 (day 124). | — |
| Reduction in dosing of concomitant medication. | Comparison between baseline (visit 2, day 0), visit 3 (day 5), visit 4 (day 21), visit 5 (day 26), visit 6 (day 42), visit 7 (day 47), visit 8 (day 63), visit 9 (day 68), visit 10 (day 96) and visit 11 (day 124). | — |
| Assessment of immune cells with immunohistochemistry and immunofluorescence in skin biopsies (optional outcome) | Comparison between baseline (visit 2, day 0) and week 9 (visit 9, day 68). | Skin biopsies will be optional and only taken from patients signing a separate consent form. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events (safety and tolerability) | Visit 2 (day 0), visit 3 (day 5), visit 4 (day 21), visit 5 (day 26), visit 6 (day 42), visit 7 (day 47), visit 8 (day 63), visit 9 (day 68), visit 10 (day 96) and visit 11 (day 124). | Assessment of safety will be conducted by reporting adverse events. Frequency, severity and relation to IL-2 treatment will be evaluated and thoroughly described in the final report. Reporting will follow the Common Terminology Criteria for Adverse Events (CTCAE). |
Countries
Switzerland
Outcome results
None listed