Testosterone Replacement in Non-alcoholic Steatohepatitis (TEREPINS)
The main research questions are: In hypogonadal men with non-alcoholic steatohepatitis (NASH), does Testosterone Replacement Therapy (TRT), given for 12 months
- improve severity of steatosis on liver biopsy (Primary Question)?
- improve severity of associated steatohepatitis on liver biopsy?
- reduce liver fat content as assessed by proton Magnetic Resonance Spectroscopy (1H-MRS)?
The work proposed here is an open pilot study of 10 patients, the main aim of which is to assess the effect size of TRT in regard to these end points (regarding which there are no published data), thereby allowing power calculations for a more definitive phase II trial. Other aims would be assessing recruitment and consent rates, which would also inform the design of the larger study.
Drug: testosterone undecanoate
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Pilot Open Study of Testosterone Replacement in Non-alcoholic Steatohepatitis|
- steatosis histology [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]Proportion of patients in whom severity of steatohepatitis improves with testosterone replacement therapy, assessed by liver biopsy
- Proportion of patients in whom liver inflammation improves [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]Proportion of patients in whom liver inflammation improves
- Proportion of patients in whom liver ballooning improves [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]Proportion of patients in whom liver ballooning improves
- Proportion of patients in whom liver fibrosis improves [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]Proportion of patients in whom liver fibrosis improves
- Change in fat content of liver [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]Change in fat content of liver assessed by by MR spectroscopy and its correlation with steatosis on liver biopsy
- Change in HOMA index [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]measure of insulin sensitivity
- Change in serum liver enzymes [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]
- Adverse events [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]Adverse events recorded over 12 month period
- Study recruitment rate [ Time Frame: 24 months ] [ Designated as safety issue: No ]With regard to this being a pilot feasibility study, the recruitment rate and level of data completeness achieved during the study will be assessed.
|Study Start Date:||July 2013|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||September 2015 (Final data collection date for primary outcome measure)|
Experimental: testosterone undecanoate
Open label testosterone injection. Testosterone Undecanoate (1 g in 4 ml oily base) will be given as slow (2 minute) intramuscular injections (Nebido, manufactured by Bayer-Schering). These will be administered by the study investigator or designated research nurse at time zero (baseline visit 2) and after 6, 18, 30 and 42 weeks.
Drug: testosterone undecanoate
Preparation: 1 gram in 4 ml of oily base. Requires no special storage conditions. Proposed regime: 1 mg as a single intramuscular injection at 0, 6, 18, 30 and 42 weeks
Other Name: Nebido
20-35% of adults have non-alcoholic fatty liver disease (NAFLD), which often leads to liver inflammation and damage and sometimes to cirrhosis, liver failure and liver cancer; it is now a common indication for liver transplantation in the UK. No medical treatment has been shown to be effective in preventing its progression.
Some men with NAFLD have low serum levels of testosterone (male hormone). Often, levels are only slightly low and do not cause symptoms. However there are several reasons to think that these low levels may be aggravating the liver disease. NAFLD is thought to be caused by resistance of tissues to the actions of the hormone insulin (Insulin Resistance or IR). Low testosterone levels may cause IR. Treatments for prostatic cancer which lower testosterone levels result in both IR and in NAFLD. Mice who cannot produce testosterone also develop NAFLD and this is reversed by testosterone replacement.
The investigators therefore speculate that testosterone replacement in men with NAFLD and low blood testosterone levels will reduce liver fat. Investigators will study 10 men with NAFLD and some inflammation or scarring (proven on liver biopsy performed for clinical diagnosis) and who have mildly reduced testosterone levels. Investigators will see if giving a 12 month course of Testosterone Replacement Therapy (TRT) to these men will lessen the severity of their liver damage.
Consented patients will be seen after 6, 18, 30, 42 and 52 weeks. Patients will undergo a baseline clinical assessment, blood tests, an ultra sound scan, magnetic resonance scanning of the liver (to estimate liver fat), and a repeat liver biopsy to end the study.
Patients will complete questionnaires, and undergo clinical assessment, blood tests, an ultrasound scan, and magnetic resonance (MR) scanning of the liver (to estimate liver fat) at baseline. Patients will have clinical assessments and blood tests at 6-weekly intervals for 12 months. At 12 months patients will have a repeat liver biopsy, ultrasound and MR scan.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01919294
|Contact: Dermot Gleeson, MD||0114 firstname.lastname@example.org|
|Contact: Jim Lithgow, PhD||0114 email@example.com|
|Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust||Recruiting|
|Sheffield, South Yorkshire, United Kingdom, S10 2JF|
|Principal Investigator: Dermot Gleeson, MD|
|Principal Investigator:||Dermot Gleeson, MD||Sheffield Teaching Hospitals NHS Foundation Trust|