Testosterone Replacement in Non-alcoholic Steatohepatitis (TEREPINS)

• Status: Completed
• Trial end date: 2017-01-30
• Target enrollment: 0
• Participant gender: Male

Summary

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Sheffield Teaching Hospitals NHS Foundation Trust
• Collaborator: Bayer
• Treatments: Methyltestosterone; Testosterone; Testosterone 17 beta-cypionate; Testosterone enanthate; Testosterone undecanoate

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.