To assess the clinical and biological activity of Deferasirox in patients with NASH and increased iron storage / disturbed distribution of iron on liver function and liver histology MedDRA version: 14.0 Level: LLT Classification code 10053219 Term: Non-alcoholic steatohepatitis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Trade Name: Exjade
Pharmaceutical Form: Tablet
INN or Proposed INN: DEFERASIROX
CAS Number: 201530-41-8
Current Sponsor code: ICL670
Concentration unit: mg milligram(s)
Concentration type: equal
Conce
Sponsors
CROLLL GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: -Patients with elevated liver enzymes: transaminases (ALAT or ASAT) and/or g-GT = 1.5 ULN, max. 5 ULN -Elevated serum ferritin: females > 300 ng/ml, males > 450 ng/ml -Liver Histology consistent with a diagnosis of NASH (NAS Score = 3), as evaluated by the NASH activity scoring system (NAS) according to Kleiner DE et al. Hepatology 2005 -Males and females of age = 18 years -Informed consent given Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: -Alcohol intake > 140 g/week -Established liver cirrhosis Child Pugh B or C -Copresence of other causes of chronic liver disease, such as HBV/HCV infection, PSC, PBC, AIH, overlap syndromes, Wilsons Disease, alpha-1 AT deficiency, Porphyrias -Anemia 5 ULN; bilirubin > 1.5 ULN; elevation of > 2.5 ULN for other liver enzymes -Serum creatinine > 1.4 mg/dl or Ccr < 60 ml/min -Hemochromatosis (defined as homozygous state for the C282Y mutation documented by molecular diagnostic testing) -Known allergy or contraindication to the administration of Deferasirox -Lack of ability to comply with all study-related procedures, medications, and evaluations -Sexually active pre-menopausal female patients who are unable to use double-barrier contraception, oral contraceptive plus barrier contraceptive. An exception is made for those who have undergone clinically documented total hysterectomy and/or oophorectomy, tubal ligation. Postmenopausal is defined by amenorrhea for at least 12 months. -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 (V1) -Desferal treatment within 1 month of the screening visit (V1) -Patients currently or previously treated with deferiprone or Deferasirox -Significant medical condition interfering with the ability to partake in this study -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 -Illicit drug use -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 (V1) -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). However, if any of these medications must be introduced or discontinued throughout the study for more than two weeks duration, the patient has to be excluded from final PP analysis. Changes in dose of preexisting medications (excluding insulin) will be registered and those patients will be further analysed in a subgroup analysis
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: For phase I: Safety and tolerability of deferasirox over 12 weeks of continued treatment in two dose escalating cohorts For phase II: Changes in liver histology at 48 weeks of treatment with Deferasirox: 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. Deferasirox will be regarded as active in NASH, if = 33% of patients will have a decrease in NAS of = 1 at week 48;Secondary Objective: Phase I: -changes in liver enzymes, serum ferritin, and hemoglobin levels -changes in serologically assessed parameters for NASH -changes in hepatic iron content and distribution (immunohistochemistry) -changes in histology based assessment of hepatic steatosis and fibrosis -changes in liver function (13C-breath testing) Phase II: -changes in liver enzymes -changes in serologically assessed parameters for NASH -changes in hepatic iron content and distribution (immunohistochemistry, MRI assessment) -changes in MRI and histology based assessment of hepatic steatosis and fibrosis -changes in liver function (13C-breath testing) -response association with initial HFE/HD63 gene status -changes in metabolic status -changes in body mass index, fat distribution -safety and tolerability of Deferasirox;Primary end point(s): For phase I: Safety and tolerability of deferasirox over 12 weeks of continued treatment in two dose escalating cohorts For phase II: Changes in liver histology at 48 weeks of treatment with Deferasirox: 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. Deferasirox will be regarded as active in NASH, if = 33% of patients will have a decrease in NAS of = 1 at week 48;Timepoint(s) of evaluation of this end point: For phase I: 12 weeks For phase II: 48 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase I: -changes in liver enzymes, serum ferritin, and hemoglobin levels -changes in serologically assessed parameters for NASH -changes in hepatic iron content and distribution (immunohistochemistry) -changes in US based assessments of hepatic steatosis and fibrosis (facultatively, where available) -changes in liver function (13C-breath testing) Phase II: additionally: -changes in hepatic iron content and distribution (MRI assessment) -changes in MRI based assessment of hepatic steatosis and fibrosis;Timepoint(s) of evaluation of this end point: For phase I: 12 weeks For phase II: 48 weeks | — |
Countries
Germany
Contacts
Public ContactCRO
CROLLL GmbH
Outcome results
None listed