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The Impact of Deferasirox on Non-Alcoholic-Steatohepatitis (DEFINE)

Primary Purpose

Non-alcoholic Steatohepatitis, Increased Iron Storage / Disturbed Distribution

Status
Completed
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
Exjade
Sponsored by
Crolll Gmbh
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-alcoholic Steatohepatitis focused on measuring Non-alcoholic steatohepatitis (NASH) and increased iron storage / disturbed distribution

Eligibility Criteria

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

Inclusion Criteria (shortened):

  • Patients with elevated liver enzymes
  • Elevated serum ferritin (females > 300 ng/ml, males > 450 ng/ml)
  • Liver Histology consistent with a diagnosis of NASH

Exclusion Criteria (shortened):

  • Alcohol intake > 140 g/week
  • Established liver cirrhosis Child Pugh B or C
  • Copresence of other causes of chronic liver disease
  • Anemia < 10 g/dl
  • Any elevation of liver enzymes > 5 ULN (ALAT, ASAT, g-GT), > 2.5 ULN (other), > 1.5 (Bilirubin)
  • Serum creatinine > 1.4 mg/dl or Ccr < 60 ml/min
  • Hemochromatosis
  • Known allergy or contraindication to the administration of Deferasirox
  • Sexually active pre-menopausal female patients who are unable to use a highly effective method of birth control. An exception is made for those who have undergone clinically documented total hysterectomy and/or oophorectomy, tubal ligation.
  • Patients with impaired coagulation
  • History of blood transfusion during the 6 months prior to study entry
  • Oral iron supplementation within the last 4 weeks of study entry
  • Treatment with phlebotomy within 2 weeks of screening visit
  • Desferal treatment within 1 month of the screening visit
  • Patients currently or previously treated with deferiprone or Deferasirox
  • Presence of a surgical or medical condition that might significantly alter the absorption, distribution, metabolism or excretion of any study drug
  • Positive HIV serology
  • Patients with active inflammatory diseases that may interfere with the accurate measurement of serum ferritin
  • Patients with a diagnosis of a clinically relevant cataract or a previous history of clinically relevant ocular toxicity related to iron chelation
  • Pregnant or breast feeding patients
  • Patients treated with systemic investigational drug within 4 weeks prior or with topical investigational drug within 7 days prior to the screening visit
  • Medications with proven or suspected influence on NASH such as glitazones, statins, or metformin are no exclusion criteria for study entry (insulin is not regarded to interfere with NASH).

Sites / Locations

  • Zollernalbklinikum
  • Charité, Virchow Klinikum
  • Klinikum der J. W. Goethe-Universität, Med. Klinik I
  • Universitätsklinikum Halle, Klinik & Poliklinik für Innere Medizin I
  • Universitätsklinikum des Saarlandes
  • Universitätsklinikum Magdeburg, Klinik für Gastroenterologie, Hepatologie und Infektiologie
  • Universitätsklinikum Mainz, I. Medizinische Klinik und Poliklinik
  • Universitätsklinikum Regensburg, Klinik und Poliklinik für Innere Med. I
  • Universitätsklinikum Tübingen, Medizinische Klinik IV

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Exjade

Arm Description

Outcomes

Primary Outcome Measures

Safety and tolerability of deferasirox in all patients (Phase I)
Safety and tolerability assessments will consist of evaluating (serious) adverse events, laboratory parameters including hematology, chemistry; vital signs and physical examinations according to CTC.
Changes in liver histology in all patients (Phase II)
A decrease in the NASH activity score (NAS) of ≥1 compared to baseline will be classified as response, an unchanged score or an increase in NAS will be judged as non-response.

Secondary Outcome Measures

Phase I: e.g. changes in liver enzymes, serum ferritin, and hemoglobin levels
Phase II: e.g. changes in MRI and histology based assessment of hepatic steatosis, fibrosis and iron content

Full Information

First Posted
January 14, 2011
Last Updated
July 19, 2012
Sponsor
Crolll Gmbh
Collaborators
Estimate, GmbH, University of Magdeburg
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1. Study Identification

Unique Protocol Identification Number
NCT01278056
Brief Title
The Impact of Deferasirox on Non-Alcoholic-Steatohepatitis
Acronym
DEFINE
Official Title
The Impact of Deferasirox on Non-Alcoholic-Steatohepatitis (NASH) - a Prospective Open Label Phase I/II Trial
Study Type
Interventional

2. Study Status

Record Verification Date
July 2012
Overall Recruitment Status
Completed
Study Start Date
March 2010 (undefined)
Primary Completion Date
March 2012 (Actual)
Study Completion Date
July 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Crolll Gmbh
Collaborators
Estimate, GmbH, University of Magdeburg

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase I/II open-label uncontrolled, prospective study to assess the clinical and biological effects of Deferasirox (ICL 670, Exjade®) in patients with NASH and increased iron storage / distribution of iron on liver function and liver histology. NASH is defined clinically and histologically by elevated liver enzymes, signs of hepatic steatosis on ultrasound and magnetic resonance imaging, impaired liver function as expressed by functional breath tests, and significantly altered liver histology. Patients will be treated in a phase I and phase II part for either 12 or 48 weeks. Both study parts have different endpoints: in phase I the side effect profile will be evaluated while in phase II the therapeutic response will be tested. Accordingly, measures will be different. Approximately 10 patients in phase I and 50 patients in phase II will be enrolled according to sample size calculations. The design is an "adaptive" Two-stage design, allowing to minimize the number of patients included into the trial as well as to introduce corrections for the second stage.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-alcoholic Steatohepatitis, Increased Iron Storage / Disturbed Distribution
Keywords
Non-alcoholic steatohepatitis (NASH) and increased iron storage / disturbed distribution

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Exjade
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Exjade
Other Intervention Name(s)
Deferasirox, ICL670
Intervention Description
Two dose escalating cohorts of oral administration in Phase I. Phase II: oral administration of the maximum tolerated dose.
Primary Outcome Measure Information:
Title
Safety and tolerability of deferasirox in all patients (Phase I)
Description
Safety and tolerability assessments will consist of evaluating (serious) adverse events, laboratory parameters including hematology, chemistry; vital signs and physical examinations according to CTC.
Time Frame
Phase I: 12 weeks of treatment
Title
Changes in liver histology in all patients (Phase II)
Description
A decrease in the NASH activity score (NAS) of ≥1 compared to baseline will be classified as response, an unchanged score or an increase in NAS will be judged as non-response.
Time Frame
Phase II: 48 weeks of treatment
Secondary Outcome Measure Information:
Title
Phase I: e.g. changes in liver enzymes, serum ferritin, and hemoglobin levels
Time Frame
Phase I: 12 weeks of treatment
Title
Phase II: e.g. changes in MRI and histology based assessment of hepatic steatosis, fibrosis and iron content
Time Frame
Phase II: 48 weeks of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria (shortened): Patients with elevated liver enzymes Elevated serum ferritin (females > 300 ng/ml, males > 450 ng/ml) Liver Histology consistent with a diagnosis of NASH Exclusion Criteria (shortened): Alcohol intake > 140 g/week Established liver cirrhosis Child Pugh B or C Copresence of other causes of chronic liver disease Anemia < 10 g/dl Any elevation of liver enzymes > 5 ULN (ALAT, ASAT, g-GT), > 2.5 ULN (other), > 1.5 (Bilirubin) Serum creatinine > 1.4 mg/dl or Ccr < 60 ml/min Hemochromatosis Known allergy or contraindication to the administration of Deferasirox Sexually active pre-menopausal female patients who are unable to use a highly effective method of birth control. An exception is made for those who have undergone clinically documented total hysterectomy and/or oophorectomy, tubal ligation. Patients with impaired coagulation History of blood transfusion during the 6 months prior to study entry Oral iron supplementation within the last 4 weeks of study entry Treatment with phlebotomy within 2 weeks of screening visit Desferal treatment within 1 month of the screening visit Patients currently or previously treated with deferiprone or Deferasirox Presence of a surgical or medical condition that might significantly alter the absorption, distribution, metabolism or excretion of any study drug Positive HIV serology Patients with active inflammatory diseases that may interfere with the accurate measurement of serum ferritin Patients with a diagnosis of a clinically relevant cataract or a previous history of clinically relevant ocular toxicity related to iron chelation Pregnant or breast feeding patients Patients treated with systemic investigational drug within 4 weeks prior or with topical investigational drug within 7 days prior to the screening visit Medications with proven or suspected influence on NASH such as glitazones, statins, or metformin are no exclusion criteria for study entry (insulin is not regarded to interfere with NASH).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gerhard Treiber, PD Dr. med.
Official's Role
Principal Investigator
Facility Information:
Facility Name
Zollernalbklinikum
City
Balingen/Hechingen
ZIP/Postal Code
72336
Country
Germany
Facility Name
Charité, Virchow Klinikum
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Klinikum der J. W. Goethe-Universität, Med. Klinik I
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Facility Name
Universitätsklinikum Halle, Klinik & Poliklinik für Innere Medizin I
City
Halle
ZIP/Postal Code
06097
Country
Germany
Facility Name
Universitätsklinikum des Saarlandes
City
Homburg/Saar
ZIP/Postal Code
66421
Country
Germany
Facility Name
Universitätsklinikum Magdeburg, Klinik für Gastroenterologie, Hepatologie und Infektiologie
City
Magdeburg
ZIP/Postal Code
39120
Country
Germany
Facility Name
Universitätsklinikum Mainz, I. Medizinische Klinik und Poliklinik
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Universitätsklinikum Regensburg, Klinik und Poliklinik für Innere Med. I
City
Regensburg
ZIP/Postal Code
93042
Country
Germany
Facility Name
Universitätsklinikum Tübingen, Medizinische Klinik IV
City
Tübingen
ZIP/Postal Code
72076
Country
Germany

12. IPD Sharing Statement

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The Impact of Deferasirox on Non-Alcoholic-Steatohepatitis

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