Nonalcoholic SteatohepatitisPhase 2TEREPINSNCT01919294
Testosterone Replacement in Non-alcoholic Steatohepatitis (TEREPINS)
A Phase 2 study testing testosterone undecanoate in people with Nonalcoholic Steatohepatitis and Hypogonadism, run by Sheffield Teaching Hospitals NHS Foundation Trust at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years, men only
- Conditions the study is for
- Nonalcoholic Steatohepatitis, Hypogonadism
- What is being tested?
- testosterone undecanoate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Jul 2013to 30 Jan 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust
Sheffield, South Yorkshire, S10 2JF
About this study
Official title: Pilot Open Study of Testosterone Replacement in Non-alcoholic Steatohepatitis
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.
Read the 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.
- Conditions
- Nonalcoholic Steatohepatitis, Hypogonadism
- Being tested
- testosterone undecanoate
- Keywords
- nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypogonadism, testosterone replacement therapy
- Medical subject headings
- Non-alcoholic Fatty Liver Disease, Hypogonadism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
testosterone undecanoateDrug
Also called Nebido
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
| Study group | Role | What they receive |
|---|---|---|
| testosterone undecanoate | Experimental | 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. Receives: Drug: testosterone undecanoate |
What is being measured
The primary outcome is the main question the study is designed to answer.
steatosis histology
Proportion of patients in whom severity of steatohepatitis improves with testosterone replacement therapy, assessed by liver biopsy
Measured: baseline and 12 months
Secondary outcomes (7)
Proportion of patients in whom liver inflammation improves
Proportion of patients in whom liver inflammation improves
Measured: baseline and 12 months
Proportion of patients in whom liver ballooning improves
Proportion of patients in whom liver ballooning improves
Measured: baseline and 12 months
Proportion of patients in whom liver fibrosis improves
Proportion of patients in whom liver fibrosis improves
Measured: baseline and 12 months
Change in fat content of liver
Change in fat content of liver assessed by by MR spectroscopy and its correlation with steatosis on liver biopsy
Measured: baseline and 12 months
Change in HOMA index
measure of insulin sensitivity
Measured: baseline and 12 months
Change in serum liver enzymes
Measured: baseline and 12 months
Adverse events
Adverse events recorded over 12 month period
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Aug 2013 (estimated)
- Study startJul 2013
- Primary completion30 Jan 2017
- Study completion30 Jan 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Nonalcoholic SteatohepatitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sheffield Teaching Hospitals NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Collaborators
- Bayer
- Responsible party
- Sponsor
- Investigators
- Dermot Gleeson, MD, Principal investigator, Sheffield Teaching Hospitals NHS Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01919294
- Sponsor's protocol ID
- STH16037
- Other IDs
- 2012-002564-27
- Acronym
- TEREPINS
- Status last verified
- Apr 2017
- First submitted
- 6 Aug 2013
- Last updated
- 26 Apr 2017
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 26 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Open Study of Testosterone Replacement in Non-alcoholic Steatohepatitis
- ClinicalTrials.gov ID
- NCT01919294
- Acronym / sponsor ID
- TEREPINS / STH16037
- Conditions
- Nonalcoholic Steatohepatitis, Hypogonadism
- Keywords
- nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypogonadism, testosterone replacement therapy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 3 participants (actual)
- Lead sponsor
- Sheffield Teaching Hospitals NHS Foundation TrustUniversity, hospital or other
- Collaborators
- Bayer
- Study start
- Jul 2013
- Primary completion
- 30 Jan 2017 (actual)
- Study completion
- 30 Jan 2017 (actual)
- First posted
- 9 Aug 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| testosterone undecanoate | Experimental | Drug: testosterone undecanoateOpen 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. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (19 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| testosterone undecanoateAlso: NebidoPreparation: 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 | Drug | testosterone undecanoate |
Primary outcome
steatosis histology
Time frame: baseline and 12 months
Proportion of patients in whom severity of steatohepatitis improves with testosterone replacement therapy, assessed by liver biopsy
7 secondary outcomes
Proportion of patients in whom liver inflammation improves
Time frame: baseline and 12 months
Proportion of patients in whom liver ballooning improves
Time frame: baseline and 12 months
Proportion of patients in whom liver fibrosis improves
Time frame: baseline and 12 months
Change in fat content of liver
Time frame: baseline and 12 months
Change in HOMA index
Time frame: baseline and 12 months
Change in serum liver enzymes
Time frame: baseline and 12 months
Adverse events
Time frame: 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Apr 2017.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dermot Gleeson, MD principal investigator
Sheffield Teaching Hospitals NHS Foundation Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing testosterone undecanoate in people with Nonalcoholic Steatohepatitis and Hypogonadism, run by Sheffield Teaching Hospitals NHS Foundation Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
steatosis histology (time frame: baseline and 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Apr 2017.