Trial document




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  DRKS00004858

Trial Description

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Title

Evaluation of the safety, tolerability, efficacy and immunological responses of the interleukin-2 analogue Aldesleukin (Proleukin®) in the treatment of systemic lupus erythematosus as prototypic autoimmune disease (PRO-IMMUN)

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Trial Acronym

PRO-IMMUN

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URL of the Trial

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Brief Summary in Lay Language

The pathogenesis of systemic lupus erythematosus (SLE) involves an acquired deficiency of the cytokine Interleukin-2, an essential growth and survival factor for regulatory T cells (Treg), which play an important role in the control of autoimmunity in SLE. Low-dose IL-2 therapy of SLE aims to compensate the pre-existing IL-2 deficiency and thus to restore a physiological state. We hypothesize a beneficial effect of exogenously supplemented low-dose IL-2 on numbers, percentages, function, and phenotype of Treg and consequently a reduction in the disease activity in patients with active disease. Due to the low-dose regimen, clinical and cellular benefits can be achieved without eliciting relevant side effects. The study population will consist of 12 patients with the diagnosis of SLE and increased disease activity despite treatment with at least two different standard immunosuppressive or immunomodulatory therapies.

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Brief Summary in Scientific Language

PRO-IMMUN is a combined phase I/IIa, interventional, prospective, open-label, uncontrolled, single-center and investigator-initiated trial addressing the safety, tolerability, efficacy and immunological responses of a subcutaneous low-dose regimen with the interleukin-2 analogue Aldesleukin (Proleukin®) in patients with SLE and increased disease activity refractory to standard treatments.
SLE is caused by a hyperactivity of the immune system at both a cellular
and a humoral level. As a consequence, immunosuppressive therapies are used with potential harmful side effects that have emerged nowadays as leading factors for morbidity and mortality in SLE.
Regulatory T cells (Treg) are natural barriers against autoimmunity by suppressing the activation and expansion of autoreactive T cells and other harmful cells.
The survival, growth and homeostatic maintenance of Treg fundamentally depend on the availability of the cytokine IL-2. IL-2 deficiency results in a severe systemic autoimmune disease resembling SLE in many aspects. With regard to this, defects in IL-2 expression and Treg biology have been described to be present in murine and human SLE. Our previous studies in murine models of SLE provided a causal linkage between an acquired IL-2 deficiency, defects in Treg biology and the development of SLE. In addition, we demonstrated that compensation of the IL-2 deficiency by low-dose IL-2 therapy selectively corrects these Treg defects and ameliorates already established disease in these mice. In SLE patients, we found that Treg display similar phenotypic abnormalities than Treg from lupus and IL-2 deficient mice, pointing to a relevant IL-2 deprivation of Treg also in human SLE patients. These findings in conjunction with recent publications demonstrating selective Treg expansion and clinical improvement by a low-dose IL-2 therapy in two different immune-mediated diseases provide strong rationales for an IL-2-based immunotherapy of SLE in order to restore Treg-mediated tolerance. In these diseases, IL-2 deficiency has not been described. It is therefore hypothesized that the effect of IL-2 therapy would be even more pronounced in SLE, where IL-2 deficiency plays an important role in disease pathogenesis.
High-dose IL-2 therapy is currently approved for the therapy of metastatic renal cell carcinoma and malignant melanoma with the rationale to broadly stimulate the anti-tumor activity of T and NK cells. In contrast to this, low-dose IL-2 therapy aims to selectively enhance Treg activity in order to re-establish endogenous mechanisms of tolerance that can counteract autoimmunity. Because Treg constitutively express the high-affinity IL-2-receptor, low-dose IL-2 therapy targets mainly the Treg population and therefore is suitable to selectively stimulate and expand the Treg population in vivo with little or no activation of other immune cells.
Here we aim to conduct a combined phase I/IIa, prospective, open-label single-center, investigator-initiated trial addressing the safety, tolerability, clinical efficacy and immunological responses of a low-dose IL-2 therapy in patients with active SLE and who are refractory to standard therapies. Primary endpoints are safety, tolerability and the cellular response of the Treg population defined by an increase in the percentage of CD25++ cells among CD3+CD4+Foxp3+CD127lo Treg by at least 100% at week 9 compared to baseline at week 1. Secondary and exploratory endpoints include clinical efficacy and other immunological and cellular response parameters. An advanced monitoring of the phenotype, frequency and function of cells of the immune system, including high-throughput sequencing of the TCR repertoire and gene expression profiling, will accompany the clinical study.
This study is focused on the implementation of a novel, innovative and selective therapeutic approach aiming to resurrect the natural barrier against autoimmunity in SLE. Compensation of the IL-2 deficiency and the related re-establishment of a functional Treg compartment represent a unique biological therapeutic approach, which directly interacts with pathophysiological mechanisms and which changes the therapeutic concept from broadly suppressing the hyperactivity of the immune system to an endogenous enrichment of cells which can counteract autoimmunity. In vivo expansion and modification of the Treg population by low-dose IL-2 could therefore provide a selective and physiological therapeutic strategy to control autoimmunity efficiently while avoiding side effects and morbidity that are associated with conventional immunosuppressive drugs. There are strong rationales coming from animal lupus models, from the careful examination of SLE patients, from studies with low-dose IL-2 in other human immune-mediated diseases without any known IL-2 deficiency, and finally from a pilot study with low-dose IL-2 in one SLE patient.
This proof-of-concept study will provide a basis for larger clinical trials and support its application for further indications.

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Organizational Data

  •   DRKS00004858
  •   2014/03/26
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  •   yes
  •   Approved
  •   13/0449 ZS-EK10, Ethik-Kommission des Landes Berlin
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Secondary IDs

  •   2013-001599-40 
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Health Condition or Problem studied

  •   M32.1 -  Systemic lupus erythematosus with organ or system involvement
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Interventions/Observational Groups

  •   The whole therapeutic regimen consists of four treatment cycles each with
    daily subcutaneous injections of the study medication for five consecutive
    days. In the 1st cycle, 1.5 million IU of Aldesleukin (Proleukin®) per day will
    be administered for five consecutive days (day 1-5, week 1). After a
    washout period of nine days, 3.0 million IU of Aldesleukin per day will be
    administered for five consecutive days in the 2nd cycle (day 15-19, week 3)
    followed by a 16-day washout period. In the 3rd and 4th cycle (week 6 and
    week 9), 4.5 million IU of Aldesleukin per day will be administered for five
    consecutive days with a washout period of 16 days in between. Dose adaptations will be conducted according
    to tolerability, incidence of adverse events, changes in laboratory
    parameters and according to the cellular response of the Treg population.
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   I-II
  •   Yes
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Primary Outcome

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

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Secondary Outcome

• Changes in serum antibody titers for anti-dsDNA-Abs determined by ELISA and by the Crithidia luciliae IFT, serum levels of the complement factors C3 and C4 and serum levels of circulating immune complexes at week 9 (Visit 9) compared to baseline at week 1 (Visit 2)
• Changes in serum antibody titers for ANA, ENA, anti-SmD1-Abs and other individually relevant serological markers, which were present at baseline or at previous examinations, at week 9 (Visit 9) compared to baseline at week 1 (Visit 2).
• Changes in the disease activity scores SELENA-SLEDAI and BILAG 2004, and changes in PGA and VAS at week 9 (Visit 9) compared to baseline at week 1 (Visit 2).
• Changes in health related Quality of Life (SF36®) one day after the 4th therapeutic cycle (Visit 9; week 9) compared to baseline values (Visit 2; week 1).
• Changes in organ specific parameters based on individual SLE manifestations either at week 9 (Visit 9) and/or during the follow-up period (weeks 12-18) compared to values obtained at the baseline visit (Visit 2; week 1) or during the screening period.
• Changes in SLE-associated organ damage by the SLICC/ACR Damage Index one day after the 4th cycle (visit 9; week 9) and at the termination visit (Visit 11; week 18) compared to values at screening visit (Visit 1).
• Assessment of the durability of clinical and serological responses in subjects who responded to the therapy by comparing values at the follow-up and termination visits (Visits 10 and 11; week 12 and 18) to values from week 9 (Visit 9) and to baseline values (Visit 2; week 1).
• Assessment of incidence, frequency and severity of SLE flares throughout the whole study.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2014/03/31
  •   12
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   75   Years
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Additional 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.

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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 <100.000/µl.
5. Leukocytopenia with WBC of <3.000/µl or neutropenia with a neutrophil count of <1.500/µl.
6. Anemia with hemoglobin of <9.0 g/dl.
7. History of thrombotic microangiopathy (TTP).
8. History of thrombosis or thrombotic event (including venous thrombosis, pulmonary embolism, cortical sinus thrombosis, stroke, or arterial embolism causing digital gangrene or tissue necrosis) within the last 6 month prior to the screening visit (Visit 1).
9. Infection requiring antibiotic therapy or infection requiring hospitalisation within the last 4 weeks prior to the baseline visit (Visit 2).
10. Long-term chronically active infectious disease, HIV infection (positive serum antibodies against HIV1/2), active or chronic hepatitis B infection (positive for HBs-Ag in serum), active or chronic hepatitis C infection (positive for serum antibodies against HCV), active tuberculosis.
11. Pleuritis with pleural effusion of clinical relevance (≥ grade 2 according to the CTCAE v4.03).
12. Pericarditis with pericardial effusion of clinical relevance (≥ grade 3 according to the CTCAE v4.03).
13. Chronic or acute renal impairment with an eGFR of < 30 ml/min/1.73 m2 (calculated GFR using the MDRD formula with modification for race) or oliguria.
14. Severe impairment of liver function with elevated plasma levels of bilirubin of ≥ 2 mg/dl or an INR of ≥ 1.7.
15. Patients with diagnosis of type-1 diabetes mellitus or of Crohn´s Disease.
16. Patients with inadequately controlled type-2 diabetes mellitus (HbA1c >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 visit (Visit 1) 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 (AV-Block >1°).
22. Valvular heart disease of clinical relevance (≥ grade 3 according to the CTCAE v4.03).
23. Patients with inadequately controlled permanently abnormal heart rate with <45 or >120 beats per minute in resting position.
24. Patients with inadequately controlled permanent hypotension with systolic blood pressure <100 mmHG or diastolic blood pressure <50 mmHG in resting position.
25. Patients with inadequately controlled permanent hypertension with systolic blood pressure >160 mmHG or diastolic blood pressure >100 mmHG in resting position.
26. History of orthostatic dysregulation, fainting, or blackouts within the last 3 month prior to the screening visit (Visit 1).
27. History of chronic organic psychosis or endogenous psychosis (schizophrenia, mania, bipolar disorder), except mild and transient forms of depression.
28. History of seizures within the last 6 month prior to the screening visit (Visit 1).
29. Treatment with Rituximab or any B cell depleting therapy within the last 6 months prior to the screening visit (Visit 1).
30. Treatment with calcineurin-inhibitors (ciclosporin A, sirolimus, tacrolimus), cyclophosphamide, methotrexate (MTX) or Belimumab within the last 4 weeks prior to the baseline visit (Visit 2).
31. Treatment with antiproliferative, cytostatic or cytotoxic agents within the last 4 weeks prior to the baseline visit (Visit 2) with the exception of permitted concomitant SLE-related medications.
32. Treatment with alpha and beta-interferons within the last 4 weeks prior to the baseline visit (Visit 2).
33. Experimental therapy or participation in another clinical study with investigational medicinal products within the last three month prior to the baseline visit (Visit 2).
34. Necessity for application of radiographic iodinated contrast media during and 2 weeks after the completion of the last (4th) treatment cycle.
35. Live vaccination within the last 4 weeks prior to the baseline visit (Visit 2), or plan to receive a live vaccine during study participation.
36. Major surgery within the last 4 weeks prior to the screening visit (Visit 1) or plan to have elective major surgery during study participation.
37. Pregnancy and lactating women.
38. Lack of ability or willingness to practice reliable methods of contraception during the study (female and male participants).
39. Abuse of alcohol or drugs.
40. Lack of willingness for storage and transmission of pseudonymized medical data obtained during the clinical study
41. Minors and subjects who are incapable to provide informed consent or who are considered to be incapable of adhering to the protocol and visit schedule and to be unable to comply with all study requirements according to the judgment of the investigator (according to AMG § 42(2) and (3)).
42. Subjects kept in detention due to judicial or official order (according to AMG § 40 (1) 4).

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Addresses

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    • Charité - Universitätsmedizin Berlin
    • Charitéplatz 1
    • 10117  Berlin
    • Germany
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    • Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Klinik für Rheumatologie
    • Mr.  Dr. med.  Jens  Humrich 
    • Ratzeburger Allee 160
    • 23538  Lübeck
    • Germany
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    • Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Klinik für Rheumatologie
    • Mr.  Dr. med.  Jens  Humrich 
    • Ratzeburger Allee 160
    • 23538  Lübeck
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung Dienstsitz Bonn
    • Heinemannstr. 2
    • 53175  Bonn
    • Germany
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    • Charité - Universitätsmedizin Berlin
    • Mr.  Prof. Dr.  Gerd-Rüdiger  Burmester 
    • Charitéplatz 1
    • 10117  Berlin
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2016/10/20
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Trial Publications, Results and other Documents

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