Low-dose Interleukin-2 for Treatment of Systemic Lupus Erythematosus

Open-label, Monocentric, Phase II, Investigator-initiated Clinical Trial on Unbiased Characterization of Immunological Parameters in Interleukin-2-treated Systemic Lupus Erythematosus

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.

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.

Exclusion Criteria:

• Contraindication to IL-2, e.g. known hypersensitivity or allergy.

• Solid organ transplant (allograft) recipient.

• Exposure to any new additional immunosuppressive medication within 4 weeks prior to enrollment.

• Exposure to rituximab 3 months prior to enrollment.

• Exposure to cyclophosphamide 3 months prior to enrollment.

• Following concomitant medications above the indicated maximal dose (given orally unless otherwise stated):

  g) Hydroxychloroquine, >400 mg/day h) Prednisone, >20 mg/day (or equivalent) i) Azathioprine, >2.5 mg/kg/day j) Mycophenolate-mofetil, >3 g/day k) Methotrexate, injected subcutaneously, >20 mg applied once weekly l) Belimumab, given intravenously, after induction >10 mg/kg every 4 weeks (only 4 participants with Belimumab treatment will be recruited, after this recruitment goal is achieved, Belimumab at any dose becomes an exclusion criteria)

• Simultaneous use of Sirolimus and Tacrolimus at the same time. Either agent alone is allowed. (Risk of thrombotic microangiopathy in chronic graft-versus-host disease patients)

• Participation in another study with investigational drug within 100 days preceding and during the present study.

• History of thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome or thrombotic microangiopathy.

• Any active uncontrolled infection.

• Women who are pregnant or breast feeding.

• Intention to become pregnant during the course of the study.

• Lack of safe contraception, defined as:

Female participants of childbearing potential, not using, not willing to use, and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices in addition to the use of condoms. Note that female participants who are surgically sterilized / hysterectomized or post-menopausal for longer than 2 years are not considered as being of childbearing potential.

Male participants are obliged to use condoms as well to inform their partner about the participation in this trial. In addition, the partner must use a save method of contraception as described above.

• Other clinically significant concomitant disease states (e.g. renal failure, hepatic dysfunction, cardiovascular disease, etc.).

• Known or suspected non-compliance, drug or alcohol abuse.

• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders or dementia of the participant.

• Previous enrolment in the current study.

• Enrolment of the investigator, his/her family members, employees and other dependent persons.

• Chronic infections:

  • HIV-positive individuals (increased risk of severe infections).
  • Patients suffering from active hepatitis B or C are ineligible.
  • Patients suffering from active tuberculosis are ineligible. Patients with latent tuberculosis may be eligible if patient received adequate tuberculostatic treatment.

• Any reason at the discretion of the treating physician where treatment with the investigational drug could indicate a risk for the patient.