Testosterone Replacement in Non-alcoholic Steatohepatitis (TEREPINS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Sheffield Teaching Hospitals NHS Foundation Trust
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
Sheffield Teaching Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier:
NCT01919294
First received: August 6, 2013
Last updated: March 27, 2014
Last verified: March 2014
  Purpose

The main research questions are: In hypogonadal men with non-alcoholic steatohepatitis (NASH), does Testosterone Replacement Therapy (TRT), given for 12 months

  1. improve severity of steatosis on liver biopsy (Primary Question)?
  2. improve severity of associated steatohepatitis on liver biopsy?
  3. 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.


Condition Intervention Phase
Nonalcoholic Steatohepatitis
Hypogonadism
Drug: testosterone undecanoate
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Sheffield Teaching Hospitals NHS Foundation Trust:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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


Other Outcome Measures:
  • 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.


Estimated Enrollment: 10
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)
Arms Assigned Interventions
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Abnormal serum ALT on >2 occasions over at least 3 months, despite standard lifestyle advice when appropriate, in regard to moderation of alcohol intake, weight reduction and exercise.
  • Negative serological tests for hepatitis Bs ag and C antibody.
  • Alcohol consumption >21 units per week for no more than 2 week in the last year and for no more than 3 months of the past 5 years, assessed using a lifetime alcohol consumption questionnaire.
  • Liver biopsy, performed as part of clinical management within 6 months of recruitment, which shows all of: (a) steatosis (Kleiner grade 2 or 3); (b) NASH (combined intralobular inflammation and hepatocyte ballooning score of >1); (c) fibrosis Ishak stage <4; and (d) no evidence to suggest another major liver disease.
  • Hypotestosteronaemia, defined by total serum testosterone <11 nmol/L . Investigators predict that this will include about 25% of men with NAFLD as defined above.

Exclusion Criteria:

  • Inability to give informed consent.
  • Age <18 or >75 years.
  • Symptomatic sexual dysfunction.
  • Cirrhosis either on baseline liver biopsy (Ishak score 5-6) or suggested by presence of varices, by ultrasound (small shrunken liver, ascites, splenomegaly) or by liver decompensation (encephalopathy, abnormal serum direct bilirubin, albumin or prothrombin time).
  • Space occupying lesion on ultrasound with any suspicion of malignancy.
  • Evidence of other chronic liver diseases pace occupying lesion on ultrasound with any suspicion of malignancy.
  • Prostatic nodule or mass on PR examination unless full urological examination rules our prostate cancer
  • Serum PSA or alpha feta protein above the age-specific normal range
  • Carcinoma of male breast
  • Taking medications (amiodarone, anti-retrovirals, sodium alproate, corticosteroids, tamoxifen) the previous 3 months (known to improve steatosis).
  • Diabetes or hyperlipidaemia, where therapy has been changed within the last 12 months or with suboptimal control anticipating the need for change in therapy during the study.
  • Severe or complicated obesity, likely requiring bariatric surgery in next 2 years.
  • LH/FSH levels, raising the possibility of primary pituitary disease.
  • Subject trying to or hoping to conceive within next 18 months.
  • Haematocrit of >0.54
  • History of any of the following: Sleep apnoea, breast or prostate or liver cancer, congestive heart failure, chronic renal failure (serum creatinine >150), severe chronic obstructive airways disease, uncontrolled hypertension epilepsy depression or migraine.
  • Severe co morbidity likely in the opinion of the investigators to reduce life expectancy to <10 years.
  • Hypersensitivity to active agent or to any of the excipients.
  • On long-term warfarin or heparin-based anticoagulant therapy. Treatment with antiplatelet agents will not be an exclusion criterion, however, these will be omitted at the time of liver biopsies, as per normal clinical practice.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01919294

Contacts
Contact: Dermot Gleeson, MD 0114 2713264 dermot.gleeson@sth.nhs.uk
Contact: Jim Lithgow, PhD 0114 2265424 jim.lithgow@sth.nhs.uk

Locations
United Kingdom
Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust Recruiting
Sheffield, South Yorkshire, United Kingdom, S10 2JF
Principal Investigator: Dermot Gleeson, MD         
Sponsors and Collaborators
Sheffield Teaching Hospitals NHS Foundation Trust
Bayer
Investigators
Principal Investigator: Dermot Gleeson, MD Sheffield Teaching Hospitals NHS Foundation Trust
  More Information

No publications provided

Responsible Party: Sheffield Teaching Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT01919294     History of Changes
Other Study ID Numbers: STH16037, 2012-002564-27
Study First Received: August 6, 2013
Last Updated: March 27, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
UK: National Research Ethics Service (Health Research Authority)

Keywords provided by Sheffield Teaching Hospitals NHS Foundation Trust:
nonalcoholic fatty liver disease
nonalcoholic steatohepatitis
hypogonadism
testosterone replacement therapy

Additional relevant MeSH terms:
Hypogonadism
Fatty Liver
Gonadal Disorders
Endocrine System Diseases
Liver Diseases
Digestive System Diseases
Testosterone
Testosterone enanthate
Testosterone undecanoate
Testosterone 17 beta-cypionate
Methyltestosterone
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Anabolic Agents

ClinicalTrials.gov processed this record on August 28, 2014