Trial document





This trial has been registered retrospectively.
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  DRKS00004658

Trial Description

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Title

Therapy of polycythemia vera with pegylated interferon

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Trial Acronym

PV-PegIntron-Study

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URL of the Trial

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Brief Summary in Lay Language

Polycythemia vera (PV) is a disorder of the hematopoietic stem cell (“mother cell of hematopoiesis”). Main treatment aims besides the decrease of the red blood cell mass are the reduction of the occlusion rate of arterial and venous vessels (thromboembolic occlusions). Further aims are to avoid the development of myelofibrosis (increased fiber content of the bone marrow) and of acute leukemia in later stages of PV. In the majority of patients, plebotomies alone cannot control the increased values of blood cells and the splenomegaly sufficiently. One part of the drugs, which inhibit the cell growth (cytostatics) can induce a transition to acute leukemia or the development of secondary malignant diseases. Concerning hydroxyurea, which is commonly used as standard therapy of PV, leukemogenic (leukemia-causing) effects are also not certainly excluded.
Interferon-alpha (IFN) has a complex mode of action, thereby suppressing the affected hematopoiesis and allowing recovery of the normal hematopoiesis, which may be associated with a normalization of blood counts. Furthermore, it might be possible, that this is further followed by a delay of the late sequela of the disease (leukemia, myelofibrosis). The high rate of withdrawal of the drug of more than 20% due to side effects or lack of compliance represents the main problem of therapy with IFN. IFN is not officially approved for the therapy of PV.
In contrast to the frequent applications of the conventional non-pegylated IFN (several times per week or daily), the application of the pegylated formulation is required only once per week (pegylated: special formulation of IFN associated with long activity in the body). This might improve the tolerance and acceptance of the therapy. In an exactly defined treatment plan (phase II study) with pegylated IFN alpha 2b (PegIntron®), the positive and the adverse effects of the drug will be evaluated using a dosing schedule, which is adapted to the individual effectiveness and tolerance of the drug.

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Brief Summary in Scientific Language

IFN is the only substance so far, which can suppress the clonal hematopoiesis directly and long-lasting, as shown by the reduction of the parameters of myeloproliferation and by long-lasting remissions after termination of IFN.
In this prospective single-arm phase II trial with, pegylated IFN (pegylated Interferon-alpa 2b; PegIntron®), the effects on the parameters of myeloproliferation and on the profile of side effects are to be evaluated using a detailed treatment plan. The possible dose escalation or dose reduction is adapted to response and tolerability of PegIntron. Response to therapy mostly begins after a few weeks. Until development of maximum response it may need more than one year. Therefore, for definitive assessment of the effectiveness a treatment period of two years is scheduled. Relevant side effects of IFN are flu-like symptoms, fatigue, weakness, depression, neurotoxicity, disturbances of liver function, autoimmune thyreoiditis and myelosuppression leading to treatment termination in over 20% of patients.
Therapy starts with 50 µg PegIntron/week (dose level 1). During the phase of dose escalation and up to three months after starting of the individually maximum dose or of the maximum study dose of 150µg/week, respectively, evaluations in 6-weeks intervals are performed. In dependence on the results, the dose will be increased or continued unchanged or the therapy will be terminated.
Procedure on dose level 1 (50 µg PegIntron/week): if no complete remission (CR) after 6 weeks and no organ toxicity greater/equal WHO grade II und platelet count greater/equal 100000/µl and neutrophils greater/equal 1500/µl, dose increase to dose level 2 (100 µg PegIntron/week).
In the case of CR and no of organ toxicity greater/equal WHO grade II und platelet count 50000 to 100000/µl and neutrophil count 750 to 1500/µl, continuation on dose level 1. In the case of organ toxicity greater/equal WHO grade II und platelet count below 50000 or neutrophil count below 750/µl or intolerable side effects, PegIntron is to be terminated.
Procedure on dose levels 2 resp. 3 (100 µg bzw. 150 µg PegIntron/week): the increase to the next dose level is performed according to the same criteria as on dose level one. Instead of termination of PegIntron stepwise reduction to the previous lower dose level is performed.
In addition to PegIntron phlebotomies are performed to decrease the hematocrit below 45%.

Definition of response:
Complete remission (CR): No need of phebotomy and reduction of platelet count below 400 000/µl and normalization of spleen size (normal value by ultrasound: 11x5x7 cm). Good partial remission (PR 1): Reduction of the cumulative volume of phlebotomies by at least 50% and or reduction of platelet count by at least 50% and spleen size reduced or unchanged. Bad partial remission (PR2): Reduction of the cumulative volume of phlebotomies by at least 25% and or reduction of platelet count by at least 25% and spleen size reduced or unchanged. Minimal response (MR): Reduction of the cumulative volume of phlebotomies less than 25% and or reduction of platelet count less than 25% and spleen size reduced or unchanged. No change (NC): cumulative volume of phlebotomies and platelet count and spleen size unchanged. Progressive disease (PD): Worsening of at least of one parameter during therapy.

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Organizational Data

  •   DRKS00004658
  •   2013/01/28
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  •   yes
  •   Approved
  •   0197.2, Medizinische Ethik-Kommission II Medizinische Fakultät Mannheim der Universität Heidelberg
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Secondary IDs

  •   4019836 
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Health Condition or Problem studied

  •   D45 -  Polycythaemia vera
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Interventions/Observational Groups

  •   The treatment duration with IFN is planned for two years. Treatment with is performed continuously without interruptions.

    Therapy starts with 50 µg PegIntron/week (dose level 1) (subcutaneous application). During the phase of dose escalation and up to three months after starting of the individually maximum dose or of the maximum study dose of 150µg/week, respectively, evaluations in 6-weeks intervals are performed. In dependence on the results, the dose will be increased or continued unchanged or the therapy will be terminated.
    Procedure on dose level 1 (50 µg PegIntron/week): if no complete remission (CR) after 6 weeks and no organ toxicity greater/equal WHO grade II und platelet count greater/equal 100000/µl and neutrophils greater/equal 1500/µl, dose increase to dose level 2 (100 µg PegIntron/week).
    In the case of CR and no of organ toxicity greater/equal WHO grade II und platelet count 50000 to 100000/µl and neutrophil count 750 to 1500/µl, continuation on dose level 1. In the case of organ toxicity greater/equal WHO grade II und platelet count below 50000 or neutrophil count below 750/µl or intolerable side effects, PegIntron is to be terminated.
    Procedure on dose levels 2 resp. 3 (100 µg resp. 150 µg PegIntron/week): the increase to the next dose level is performed according to the same criteria as on dose level one. Instead of termination of PegIntron stepwise reduction to the previous lower dose level is performed.
    In addition to PegIntron phlebotomies are performed to decrease the hematocrit below 45%.
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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)
  •   II
  •   Yes
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Primary Outcome

Evaluation of the antiproliferative effects of PegIntron on the main parameters of the increased myeloproliferation (frequency of phlebotomies, platelet count, spleen size) after two years of therapy. These effects will be assessed using the response criteria outlined in the summary of the study.

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Secondary Outcome

Rate of side effects and rate of termination of therapy due to non-acceptable toxicity insufficient response or intolerance.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
  • Doctor's Practice 
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Recruitment

  •   Actual
  •   2003/03/03
  •   50
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   80   Years
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Additional Inclusion Criteria

Diagnosis PV according to the WHO criteria,
age 18 years or older without upper age limit,
no cytoreductive pretreatment or pretreatment with at most one cytoreductive drug,
persistent need of phlebotomies during previous therapy
no preteatment with non-pegylated interferon alpha,
written informed consent.

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Exclusion Criteria

Cytoreductive pretreatment with more than one drug,
pretreatment with non-pegylated interferon alpha
postpolycythemic myelofibrosis,
splenectomy,
secondary malignancy, if requiring therapy
severe comorbidity,
pregnancy and breast feeding,
diseases of CNS
psychiatric disorders,
paticipation in an other cliniocal study,
no consent of the patient.

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Addresses

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    • III. Medizinische Universitätsklinik Universitätsmedizin Mannheim
    • Ms.  PD Dr.  Eva  Lengfelder 
    • Theodor-Kutzer-Ufer 1-3
    • 68167  Mannheim
    • Germany
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    • III. Medizinische Klinik Universitätsmedizin Mannheim
    • Ms.  PD Dr.  Eva  Lengfelder 
    • Theodor-Kutzer-Ufer 1-3
    • 68167  Mannheim
    • Germany
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    • III. Medizinische Universitätsklinik Universitätsmedizin Mannheim
    • Ms.  PD Dr.  Eva  Lengfelder 
    • Theodor-Kutzer-Ufer 1-3
    • 68163  Manheim
    • Germany
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Sources of Monetary or Material Support

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    • III. Medizinische Klinik Universitätsmedizin Mannheim
    • Ms.  PD Dr.  Eva  Lengfelder 
    • Theodor-Kutzer-Ufer 1-3
    • 68167  Mannheim
    • Germany
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    • Essex Pharma GmbH
    • 81737  München
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2006/10/31
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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.