Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00007939

Trial Description

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Title

Multicentre Phase 2 Trial to Evaluate the Efficacy of Ruxolitinib in Steroid-refractory Acute Multicenter, Randomized Phase 2 Trial to Determine the Response Rate of Ruxolitinib and Best Available Treatment (BAT) Versus BAT in Steroid-refractory Acute Graft-versus-Host Disease (aGvHD)

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Trial Acronym

RIG

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URL of the Trial

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Brief Summary in Lay Language

The preliminary data demonstrate potent activity of Ruxolitinib in steroid-refractory aGvHD.
In this phase 2 trial the efficacy of Ruxolitinib and best available treatment (BAT) versus
BAT in steroid-refractory acute GvHD in approximately 12 transplantation centers in Germany
will be compared. The response by monitoring the clinical GvHD grade, requirement of
alternative GvHD active agents and serum levels of pro-inflammatory cytokines will be
determined.

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Brief Summary in Scientific Language

The pathophysiological hallmark of GvHD after allo-HCT is an allogeneic donor T cell
re-sponse against recipient antigens. This process is aggravated by increased processing and
presentation of host antigens by donor APCs following conditioning treatment. The
al-logeneic T cell response leads to inflammation, tissue damage and fibrosis and is
mediated by extensive production of inflammatory cytokines such as IL-1, IL-2R, IL-6 and
TNF. The signal transmission of inflammatory cytokines in effector cells requires activation
of specialized kinases from the family of the Janus kinases. These kinases, JAK1, 2 and 3
are linked to cytokine receptors, and are activated upon binding of the cytokine to the
receptor of the inflammatory effector. The JAK1/2 kinase inhibitor Ruxolitinib (INC424) is
approved for myelofibrosis. In advanced myelofibrosis, Ruxolitinib lead to sustained
clinical remissions with regard to constitutional symptoms, weight loss and spleen size in
the majority of treated patients. Of note, clinical responses correlated with a marked
reduction in inflammatory plasma cytokines.

Importantly, cytokines down-regulated by Ruxolitinib in patients with myelofibrosis
correspond to inflammatory effectors that mediate tissue damage and inflammation in GvHD.
These are mainly the cytokines IL- 1, IL -6, TNF and IFN-gamma. Since Ruxolitinib suppresses
the JAK1 / 2 cytokine response, we hypothesized that Ruxolitinib might attenuate the
cytokine mediated inflammatory tissue damage in GVHD and thus might favourably affect the
severity and course of GvHD after allo-HCT.

In vitro, we demonstrated in an allogeneic system (major mismatch mixed-lymphocyte
reactions) that co-incubation with Ruxolitinib strongly suppressed both the proliferation of
alloge-neic T cells and the production of inflammatory cytokines. Using a very aggressive
major mismatch mouse model of acute GvHD Ruxolitinib treatment signifi-cantly prolonged
survival of animals (see Figure 1A). In addition, in these animals showed a reduced weight
loss, significantly reduced histopathological GvHD severity, suppression of inflammatory
cytokines in the serum and a reduction of donor T cells in GvHD target organs such as the
intestines.

Sole suppression of cytokine production or cytokine receptor activity by Ruxolitinib would
be very similar to already established drugs for GvHD and no major conceptual advance.
However we observed that Ruxolitinib did not only suppress cytokine production but also led
to increased frequencies of FoxP3+ regulatory T cells. This cell type was previ-ously shown
to lead to long-lasting tolerance as compared to the short-term immunosuppression achieved
by conventional medication for GvHD.

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Organizational Data

  •   DRKS00007939
  •   2015/03/26
  •   2015/03/10
  •   yes
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Secondary IDs

  •   2014-004267-20 
  •   NCT02396628  (ClinicalTrials.gov)
  •   RIG-P000814  (Prof. Dr. Nikolas von Bubnoff)
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Health Condition or Problem studied

  •   Graft vs Host Disease
  •   T86.0 -  Bone-marrow transplant rejection
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Interventions/Observational Groups

  •   Drug: Experimental intervention
  •   Drug: Standard treatment
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Treatment
  •   Single (group)
  •   II
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Primary Outcome

- efficacy of Ruxolitinib and BAT as compared to BAT alone at day 28 after treatment start; time frame: at day 28 after treatment start; To evaluate efficacy of Ruxolitinib and BAT as compared to BAT alone at day 28 after treatment start in steroid-refractory acute GvHD, measured as response rate

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Secondary Outcome

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

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  •   2017/06/30
  •   148
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

1. Acute skin, intestinal or liver GvHD > grade 1 according to standard criteria

2. Histological confirmation in case of acute intestinal GvHD

3. Age ≥18 years

4. Failure of previous treatment, defined as presence of at least one of the following
criteria:

1. Treatment with prednisone/prednisolone/methylprednisolone in a dose of at least
2 mg/kg and lack of response after at least 7 days treatment

2. Treatment with prednisone/prednisolone/methylprednisolone in a dose of at least
2 mg/kg and progression after at least 3 days of treatment

3. Failure to taper the prednisone/prednisolone dose to 0.6 mg/kg/day or
methylpredniso-lone dose to <0.5 mg/kg/day

5. Written informed consent

6. Ability to understand the nature of the study and the study related procedures and to
comply with them

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Exclusion Criteria

1. Uncontrolled underlying disease

2. Active bleeding

3. Absence of clinical signs of acute GvHD

4. Diagnostic or distinctive clinical signs of chronic GvHD

5. Uncontrolled bacterial, viral or fungal infection

6. Any previous JAK2 inhibitor treatment prior to study enrolment, except Ruxolitinib
given prior to the allogeneic stem cell transplantati

7. Known Hypersensitivity to Ruxolitinib or any of the excipients

8. Known positivity for HIV, Hepatitis B or Hepatitis C at the time of screening.

9. Female patients who are pregnant or breast feeding

10. Concomitant use of any other investigational drug within the last thirty days before
the start of this study

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Addresses

  • start of 1:1-Block address primary-sponsor
    • Prof. Dr. Nikolas von Bubnoff
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    • Clinical Trials Unit Freiburg
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  • start of 1:1-Block address scientific-contact
    • Nikolas von Bubnoff, Professor 
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    • Nikolas von Bubnoff, Professor 
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Sources of Monetary or Material Support

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    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   4
  •   2017/05/10
* This entry means the parameter is not applicable or has not been set.