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Preventive Effect of Enoxaparin, Pentoxifylline and Ursodeoxycholic Acid to Radiation Induced Liver Toxicity (ELDORADO)

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ClinicalTrials.gov Identifier: NCT01149304
Recruitment Status : Completed
First Posted : June 23, 2010
Last Update Posted : November 20, 2017
Sponsor:
Collaborator:
Sirtex Medical
Information provided by (Responsible Party):
Robert Damm, University of Magdeburg

Tracking Information
First Submitted Date  ICMJE June 4, 2010
First Posted Date  ICMJE June 23, 2010
Last Update Posted Date November 20, 2017
Study Start Date  ICMJE June 2009
Actual Primary Completion Date November 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 22, 2010)
  • HDR-brachytherapy isodose (measured in Gy) that corresponds to the metastases without enhancement of Gd-EOB-DTPA in MR imaging using an axial T1 THRIVE sequence. [ Time Frame: One day prior to brachytherapy. ]
    The primary variable is the HDR-brachytherapy isodose that encloses liver tissue with a diminished uptake of the hepatocyte selective contrast agent GD-EOB-DTPA. By identifying the damaged volume in every layer of the axial T1 THRIVE image, 3D data can be calculated and correlated to a specific isodose when merged with the 3D irradiation treatment plan. Prior to brachytherapy, the baseline volume of the metastases will be measured instead of the liver tissue damaged by irradiation.
  • HDR-brachytherapy isodose (measured in Gy) that corresponds to the irradiated liver tissue without enhancement of Gd-EOB-DTPA in MR imaging using an axial T1 THRIVE sequence. [ Time Frame: 3 days after brachytherapy. ]
    The primary variable is the HDR-brachytherapy isodose that encloses liver tissue with a diminished uptake of the hepatocyte selective contrast agent GD-EOB-DTPA. Liver tissue without enhancement of Gd-EOB-DTPA around the irradiated metastases is defined as damaged by irradiation. By identifying the irreversibly damaged volume in every layer of the axial T1 THRIVE image, 3D data can be calculated and correlated to a specific isodose when merged with the 3D irradiation treatment plan. Imaging up to 3 months after brachytherapy is mandatory for inclusion in the analysis.
  • HDR-brachytherapy isodose (measured in Gy) that corresponds to the irradiated liver tissue without enhancement of Gd-EOB-DTPA in MR imaging using an axial T1 THRIVE sequence. [ Time Frame: 6 weeks after brachytherapy. ]
    The primary variable is the HDR-brachytherapy isodose that encloses liver tissue with a diminished uptake of the hepatocyte selective contrast agent GD-EOB-DTPA. Liver tissue without enhancement of Gd-EOB-DTPA around the irradiated metastases is defined as damage by irradiation. By identifying the irreversibly damaged volume in every layer of the axial T1 THRIVE image, 3D data can be calculated and correlated to a specific isodose when merged with the 3D irradiation treatment plan. Imaging up to 3 months after brachytherapy is mandatory for inclusion in the analysis.
  • HDR-brachytherapy isodose (measured in Gy) that corresponds to the irradiated liver tissue without enhancement of Gd-EOB-DTPA in MR imaging using an axial T1 THRIVE sequence. [ Time Frame: 3 months after brachytherapy. ]
    The primary variable is the HDR-brachytherapy isodose that encloses liver tissue with a diminished uptake of the hepatocyte selective contrast agent GD-EOB-DTPA. Liver tissue without enhancement of Gd-EOB-DTPA around the irradiated metastases is defined as damage by irradiation. By identifying the irreversibly damaged volume in every layer of the axial T1 THRIVE image, 3D data can be calculated and correlated to a specific isodose when merged with the 3D irradiation treatment plan. Imaging up to 3 months after brachytherapy is mandatory for inclusion in the analysis.
  • HDR-brachytherapy isodose (measured in Gy) that corresponds to the irradiated liver tissue without enhancement of Gd-EOB-DTPA in MR imaging using an axial T1 THRIVE sequence. [ Time Frame: 6 months after brachytherapy. ]
    The primary variable is the HDR-brachytherapy isodose that encloses liver tissue with a diminished uptake of the hepatocyte selective contrast agent GD-EOB-DTPA. Liver tissue without enhancement of Gd-EOB-DTPA around the irradiated metastases is defined as damage by irradiation. By identifying the irreversibly damaged volume in every layer of the axial T1 THRIVE image, 3D data can be calculated and correlated to a specific isodose when merged with the 3D irradiation treatment plan. Imaging up to 3 months after brachytherapy is mandatory for inclusion in the analysis.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 22, 2010)
  • Correlation between the HDR brachytherapy isodose that corresponds to damaged live tissue as defined by missing Gd-EOB-DTPA enhancement in MR imaging and liver-specific laboratory values. [ Time Frame: One day prior to brachytherapy, 3 days, 6 weeks, 3 months and 6 months after brachytherapy. ]
    To evaluate the relation between hepatocyte dysfunction by irradiation as assessed in GD-EOB-DTPA-enhanced MRI and changes in liver-specific and inflammatory laboratory values. The following laboratory values are included:
    • bilirubin
    • ASAT/ALAT
    • albumin
    • ChE
    • gamma-GT
    • GLDH
    • INR
    • fibrinogen
    • fibrin monomer
    • factor VIII
    • IL 2 + 6
    • PAI
    • protein c + s
    • vWF
    • AT3
  • Quality of live. [ Time Frame: One day prior to brachytherapy, 3 days, 6 weeks, 3 months and 6 months after brachytherapy. ]
    To evaluate the quality of live comparing both patient groups using the EQ-5D questionnaire and ECOG performance status.
  • Safety of the study drugs. [ Time Frame: Up to 6 months after brachytherapy. ]
    To assess the safety of the combination regimen of pentoxifylline, low dose low molecular weight heparin, and ursodeoxycholic acid given after HDR brachytherapy.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Preventive Effect of Enoxaparin, Pentoxifylline and Ursodeoxycholic Acid to Radiation Induced Liver Toxicity
Official Title  ICMJE Evaluation of the Preventive Effect of Enoxaparin, Pentoxifylline and Ursodeoxycholic Acid to Radiation Induced Liver Toxicity After Brachytherapy of Liver Metastases From Colorectal Carcinoma, Assessed in a Prospective Randomised Trial
Brief Summary To evaluate whether a combination regimen of pentoxifylline, ursodeoxycholic acid and enoxaparin provides a protective effect on the liver parenchyma after high dose rate (HDR) brachytherapy.
Detailed Description

A preventive effect of pentoxifylline, ursodeoxycholic acid and low dose low molecular weight heparin on pathological processes in healthy tissue after irradiation is described in clinical studies on percutaneous liver irradiation and on bone marrow transplantation. However, data remains inconclusive.

This exploratory study aims at assessing whether a protective effect of the combination of pentoxifylline, ursodeoxycholic acid and enoxaparin can be demonstrated in a limited number of patients with liver metastases of colorectal cancer after HDR brachytherapy.

All patients receive a single fraction CT/MRI-guided HDR-brachytherapy of colorectal liver metastases using Iridium-192 as a standard therapy. The follow-up consists of 4 MRI controls of the abdomen using the hepatocyte-specific contrast agent Gd-EOB-DTPA (Primovist) after 3 days, 6 weeks, 3 months and 6 months as well as blood samples and a questionnaire taken the same time.Within the study, 22 patients are given low dose low molecular weight heparin, pentoxifylline and ursodeoxycholic acid for 8 weeks starting with the preinterventional day. Another 22 patient will receive the standard therapy without the medication. After completion of the follow-up, MRI volume data of the lesion will be acquired and compared to the dosimetric treatment plan. Blood samples are tested for liver-specific and inflammatory laboratory parameters.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Colorectal Cancer
  • Liver Metastases
  • Irradiation Damage
  • Radiation Induced Liver Disease
Intervention  ICMJE
  • Drug: Pentoxifylline
    Pentoxifylline is given for 8 weeks since the evening of the day of intervention with a dose of 400mg applied three times daily (morning, noon, evening).
    Other Name: Trental (CAS 6493-05-6, ATC C04AD03)
  • Drug: Ursodeoxycholic Acid
    Ursodeoxycholic acid is administered for 8 weeks since the evening of the day of intervention. Dosage is 250mg given three times daily (morning, noon, evening).
    Other Name: Ursofalk (CAS 128-13-2, ATC A05AA02)
  • Drug: Enoxaparin
    Enoxaparin with a dose of 40mg is injected subcutaneously once a day for 8 weeks since the evening of the day of intervention after the HDR-brachytherapy.
    Other Name: Clexane (CAS 9005-49-6, ATC B01AB05)
Study Arms  ICMJE
  • Experimental: Group A
    Medication group with patients receiving the study medication according to the study protocol for 8 weeks after HDR brachytherapy.
    Interventions:
    • Drug: Pentoxifylline
    • Drug: Ursodeoxycholic Acid
    • Drug: Enoxaparin
  • No Intervention: Group B
    Comparison group with patients receiving the standard therapy of HDR brachytherapy without the study specific medication.
Publications * Seidensticker M, Seidensticker R, Damm R, Mohnike K, Pech M, Sangro B, Hass P, Wust P, Kropf S, Gademann G, Ricke J. Prospective randomized trial of enoxaparin, pentoxifylline and ursodeoxycholic acid for prevention of radiation-induced liver toxicity. PLoS One. 2014 Nov 13;9(11):e112731. doi: 10.1371/journal.pone.0112731. eCollection 2014.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 16, 2017)
22
Original Estimated Enrollment  ICMJE
 (submitted: June 22, 2010)
44
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date November 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 18 to 80
  • If female, postmenopausal or surgically sterilized
  • Liver metastases from colorectal carcinoma scheduled for a CT/MRI-guided single-fraction interstitial HDR brachytherapy
  • Non-cirrhotic liver
  • Life expectancy longer than 6 months
  • willing and able to undergo all study procedures
  • Having voluntarily provided written and fully informed consent

Exclusion Criteria:

  • Women who are pregnant, lactating or who are of childbearing potential
  • Liver cirrhosis
  • Hepatitis B
  • Hepatitis C
  • Patients being clinically unstable
  • Uncooperative, in the investigator's opinion
  • Having been previously enrolled in this study
  • Participating in another therapy-modulating clinical trial
  • Contraindication for MRI
  • Contraindication or hypersensitivity to one or more components of Gd-EOB-DTPA, Enoxaparin, Ursodeoxycholic acid and/or Pentoxifylline
  • Any prior irradiation therapy of the liver
  • Close affiliation with the investigational site; e.g. a close relative of the investigator
  • Severe coronary artery disease
  • Autoimmune diseases
  • Acute bacterial endocarditis
  • Active major bleedings and high rish of uncontrolled haemorrhage
  • Patients with severe or moderate renal impairment (GFR below 60 mL/min/1.73 m2 according to the MDRD or Cockroft-Gault formula, calculated from a creatinine value obtained within 1 week before each planned Primovist-enhanced MR examination)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01149304
Other Study ID Numbers  ICMJE RAD052
2008-002985-70 ( EudraCT Number )
MD-R20080507 ( Other Identifier: Sponsor's protocol code number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Robert Damm, University of Magdeburg
Study Sponsor  ICMJE University of Magdeburg
Collaborators  ICMJE Sirtex Medical
Investigators  ICMJE
Investigator: Jens Ricke, MD University of Magdeburg, Faculty for Medicine
Principal Investigator: Robert Damm, MD University of Magdeburg, Faculty for Medicine
PRS Account University of Magdeburg
Verification Date November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP