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

Primary Purpose

Colorectal Cancer, Liver Metastases, Irradiation Damage

Status

Completed

Phase

Phase 2

Locations

Germany

Study Type

Interventional

Intervention

Pentoxifylline

Ursodeoxycholic Acid

Enoxaparin

About this trial

This is an interventional prevention trial for Colorectal Cancer focused on measuring brachytherapy, liver metastases, irradiation, radiation induced liver disease, dosimetry

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Clinic for Radiology and Nuclear Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Group A

Group B

Arm Description

Medication group with patients receiving the study medication according to the study protocol for 8 weeks after HDR brachytherapy.

Comparison group with patients receiving the standard therapy of HDR brachytherapy without the study specific medication.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

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.

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.

To evaluate the quality of live comparing both patient groups using the EQ-5D questionnaire and ECOG performance status.

Safety of the study drugs.

To assess the safety of the combination regimen of pentoxifylline, low dose low molecular weight heparin, and ursodeoxycholic acid given after HDR brachytherapy.

Full Information

NCT ID

NCT01149304

First Posted

June 4, 2010

Last Updated

November 16, 2017

Sponsor

University of Magdeburg

Collaborators

Sirtex Medical

1. Study Identification

Unique Protocol Identification Number

NCT01149304

Brief Title

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

Acronym

ELDORADO

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2017

Overall Recruitment Status

Completed

Study Start Date

June 2009 (undefined)

Primary Completion Date

November 15, 2017 (Actual)

Study Completion Date

undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Magdeburg

Collaborators

Sirtex Medical

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Cancer, Liver Metastases, Irradiation Damage, Radiation Induced Liver Disease

Keywords

brachytherapy, liver metastases, irradiation, radiation induced liver disease, dosimetry

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

22 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group A

Arm Type

Experimental

Arm Description

Medication group with patients receiving the study medication according to the study protocol for 8 weeks after HDR brachytherapy.

Arm Title

Group B

Arm Type

No Intervention

Arm Description

Comparison group with patients receiving the standard therapy of HDR brachytherapy without the study specific medication.

Intervention Type

Drug

Intervention Name(s)

Pentoxifylline

Other Intervention Name(s)

Trental (CAS 6493-05-6, ATC C04AD03)

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

Ursodeoxycholic Acid

Other Intervention Name(s)

Ursofalk (CAS 128-13-2, ATC A05AA02)

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

Enoxaparin

Other Intervention Name(s)

Clexane (CAS 9005-49-6, ATC B01AB05)

Intervention Description

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.

Primary Outcome Measure Information:

Title

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.

Description

Time Frame

One day prior to brachytherapy.

Title

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.

Description

Time Frame

3 days after brachytherapy.

Title

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.

Description

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.

Time Frame

6 weeks after brachytherapy.

Title

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.

Description

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.

Time Frame

3 months after brachytherapy.

Title

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.

Description

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.

Time Frame

6 months after brachytherapy.

Secondary Outcome Measure Information:

Title

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.

Description

Time Frame

One day prior to brachytherapy, 3 days, 6 weeks, 3 months and 6 months after brachytherapy.

Title

Quality of live.

Description

To evaluate the quality of live comparing both patient groups using the EQ-5D questionnaire and ECOG performance status.

Time Frame

One day prior to brachytherapy, 3 days, 6 weeks, 3 months and 6 months after brachytherapy.

Title

Safety of the study drugs.

Description

To assess the safety of the combination regimen of pentoxifylline, low dose low molecular weight heparin, and ursodeoxycholic acid given after HDR brachytherapy.

Time Frame

Up to 6 months after brachytherapy.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jens Ricke, MD

Organizational Affiliation

University of Magdeburg, Faculty for Medicine

First Name & Middle Initial & Last Name & Degree

Robert Damm, MD

Organizational Affiliation

University of Magdeburg, Faculty for Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Clinic for Radiology and Nuclear Medicine

City

Magdeburg

State/Province

Sachsen-Anhalt

ZIP/Postal Code

39120

Country

Germany

12. IPD Sharing Statement

Citations:

PubMed Identifier

25393877

Citation

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.

Results Reference

result

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

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