Trial document

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Trial Description

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A Phase I-IIa trial on low-dose IL-2 (Aldesleukin) treatment for immunological dysregulation in common variable immunodeficiency (CVID)

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Trial Acronym

REGAIN: REGulatory T cells and Aldesleukin for Immunodeficiency- associated eNteropathy

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URL of the Trial


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Brief Summary in Lay Language

The hallmark of CVID ( "common variable immunodeficiency") is susceptibility to infections. Approximately 1/3 of the patients have additional reactions of the immune system against their own body (so-called autoimmune phenomena). One of these autoimmune phenomena may be the so-called autoimmune enteropathy, which manifests in patients with recurrent diarrhea and weight loss. The standard treatment for autoimmune enteropathy is a suppression of the immune system (immunosuppression) with steroids. Unfortunately, many patients suffer a relapse during tapering of steroids. A standard second-line treatment is not established. Cyclosporin A or methotrexate is frequently used. However, the immunosuppressive effect of these drugs is unfortunately in some patients heaping infections.
The aim of the present study is to test a therapy that promises a therapeutic effect without the immunosuppressive side effects. Low-dose IL-2 (aldesleukin) may have an immunomodulatory function caused by the expansion of so-called regulatory T cells (Treg). This was already shown for patients with graft-versus-host disease after blood stem cell transplantation (GVHD) and hepatitis C virus vasculitis and Type 1 diabetes.
Whether such a treatment is safe and feasible in CVID patients, is to be tested in the present study.

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Brief Summary in Scientific Language

Common variable immunodeficiency (CVID) represents a heterogeneous group of disease entities characterized by primary antibody deficiency resulting in susceptibility to infections, typically bacterial infections of the respiratory tract. Additionally 25% of patients suffer from manifestations of complex immune dysregulation such as autoimmune cytopenia, interstitial lung disease or enteropathy (reviewed in (Warnatz and Voll 2012)). These complications do not only indicate a more complex form of immunodeficiency but have turned out to be the major factors of morbidity and mortality (Chapel et al. 2012; Resnick et al. 2012). Specific therapy for these complications is challenging as immunosuppressive drugs have to be given on top of the preexisting immunodeficiency increasing the risk for infection. Most experts use glucocorticoid treatment as the first choice (Charlotte Cunningham-Rundles 2010; Malamut et al. 2010), but due to severe side effects of long-term steroid therapy and treatment failure in some patients, secondary treatment options are needed. However, CVID specific guidelines or published controlled trials for secondary treatment options do not exist and a variety of different treatment options is used reflecting experience and preferences of the treating physician. The use of T cell targeted immunosuppression in CVID is associated with an increased risk of opportunistic infections (Agarwal and Mayer 2009). Stem cell transplantation is a potential treatment option for some of these patients but is still associated with a high mortality (Wehr et al. 2015).
Low-dose IL-2 treatment predominantly expands regulatory T cells (Treg) as they are more sensitive towards the IL-2 effect than other T cells (Klatzmann and Abbas 2015). In CVID both serum IL-2 levels and Treg have been reported to be low (Arandi et al. 2013; Hel et al. 2014). Tregs have been shown to play a major role in PID associated enteropathy as is highlighted by IPEX patients who completely lack Tregs. We hypothesize that selective expansion of Tregs in CVID patients can positively influence immune dysregulation. Considering the side effects of conventional immunosuppression in this specific patient population and the lack of controlled studies in CVID patients suffering from AIE, the controlled evaluation of an immune modulatory treatment regimen - like low-dose IL-2 - promoting the reconstitution of a well-regulated immune system without interfering with the immune defense against pathogens is warranted.

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Organizational Data

  •   DRKS00010424
  •   2016/07/25
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  •   yes
  •   Approved
  •   240/16, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

  •   2015-003369-27 
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Health Condition or Problem studied

  •   D83 -  Common variable immunodeficiency
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Interventions/Observational Groups

  •   Induction:
    1.0 million IU/day for 5 days, wash-out period 9 days (optional increase to max. 2.0 million IU/day in non-responders). Duration of induction phase: 1(-2) cycle(s): 2(-4) week(s).

    1.0 Mio IU/day every two weeks (optional dose reduction or increase, range 0.5-2.5 Mio IU/day). Duration of maintenance:
    11 cycles (5.5 months).

    Follow-up: no treatment. Duration of follow-up: 1 month

    Total intervention per patient: 6 months

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  •   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

To assess the safety:
Adverse events will be recorded according to GCP guidelines during the treatment and follow-up phase at every site visit (every two weeks).
Autoantibodies will be measured before and after the therapy.
Differential blood count (eosinophil counts), lymphocyte subsets as well as liver enzymes, creatinine and coagulation parameters will be measured every two weeks.

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Secondary Outcome

To assess the optimal dose for expansion of Treg cells:
- % of Tregs will be measured before each cycle and on day 4 of every cycle and on day 6 of the induction cycle(s).

To assess the impact of low-dose Aldesleukin on chronic diarrhoea:
- Disease activity will be assessed with a self-administered questionnaire (IBDQ) and a stool diary filled in by patients.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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  •   Actual
  •   2017/02/23
  •   6
  •   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.Patient with a diagnosis of CVID according to the ESID/PAGID criteria
2.Sufficient IgG replacement therapy for at least 6 months with IgG trough levels above 6g/l.
3.Diagnosis of autoimmune enteropathy of the upper gastrointestinal tract proven by histology. Last biopsy <6 months before study inclusion.
4.Clinical activity of enteropathy within the last month before inclusion defined as ≥ 3 loose stools per day on more than half of the days.
5.Report of negative culture for pathogenic intestinal bacteria within one month before study inclusion.
6.Failure of topic or systemic steroid treatment or contraindications for steroid therapy or unacceptable side effects of steroid treatment.
7.Daily dose of glucocorticosteroids ≤ 20mg prednisolone (or equivalent) at the day of baseline visit.

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Exclusion Criteria

1.Need for a scheduled application of contrast agent during the trial.
2.Patients with malignant neoplasm within the last 5 years prior to visit 1 (except adequately treated basal cell carcinoma or squamous cell carcinoma of the skin and carcinoma in situ of the uterine cervix).
3.Patients with an ECOG ≥ 2.
4.Patients with a history of or current severe cardiac or pulmonary disease or uncontrolled pericardial or pleural effusion.
5.Patients with thrombosis or thromboembolic event < 6 months before study inclusion.
6.Patients with active CNS involvement (e.g. intracranial granulomata, multiple sclerosis, vasculitis or other autoinflammatory CNS disease) or recurrent seizures.
7.Uncontrolled chronic infectious disease (including HIV, EBV, CMV, HCV, HBV, tuberculosis) or conditions which represent a high risk for infection (i.e. severe bronchiectasis) which might interfere with the study at the discretion of the investigator.
8. Major infection requiring antibiotic therapy or infection requiring hospitalization within the last 4 weeks prior to the baseline visit.
9.Treatment with any immunosuppressive, cytotoxic drug within the last 4 weeks prior to visit 1 (except prednisolone ≤ 20mg or equivalent).
10.Patients with allogenic organ transplants.
11.Active autoimmue manifestation requiring treatment (except autoimmune enteropathy).
12.Clinically relevant chronic or acute renal (creatinine >1.25 ULN), hepatic (AST > 3 ULN, bilirubin > 1.5 x ULN) or other severe organ impairment.
13.Preexisting cytopenia (hematocrit <30%, thrombocytes <100.000/μl, leukocytes <3.000/μl or neutrophils <1.500/μl or CD4 cell counts <100/ μl.

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    • Universitätsklinikum Freiburg
    • Hugstetter Strasse 49
    • 79095  Freiburg
    • Germany
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    • Universitätsklinikum FreiburgCentrum für Chronische Immundefizienz – CCI
    • Mr.  Prof. Dr. med.  Klaus  Warnatz 
    • Breisacher Straße 115
    • 79106  Freiburg
    • Germany
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    • Universitätsklinikum FreiburgCentrum für Chronische Immundefizienz – CCI
    • Ms.  Dr. med.  Claudia  Wehr 
    • Breisacher Straße 115
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung Dienstsitz Berlin
    • Friedrichstraße 130 B
    • 10117  Berlin
    • Germany
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    • Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
    • Hebelstr 29
    • 79104  Freiburg
    • Germany
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  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.