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    Summary
    EudraCT Number:2012-002564-27
    Sponsor's Protocol Code Number:STH16037
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-01-04
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2012-002564-27
    A.3Full title of the trial
    Pilot open study of testosterone replacement in non-alcoholic steatohepatitis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Testosterone Replacement in men with liver disease
    A.3.2Name or abbreviated title of the trial where available
    TEREPINS: Testosterone Replacement in Non-alcoholic Steatohepatitis
    A.4.1Sponsor's protocol code numberSTH16037
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSheffield Teaching Hospitals NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBayer PLC
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSheffield Teaching Hospitals NHS Foundation Trust
    B.5.2Functional name of contact pointJim Lithgow
    B.5.3 Address:
    B.5.3.1Street AddressClinical Research Office, 11 Broomfield Rd
    B.5.3.2Town/ citySheffield
    B.5.3.3Post codeS10 2SE
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01142265424
    B.5.5Fax number01142265937
    B.5.6E-mailjim.lithgow@sth.nhs.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Nebido
    D.2.1.1.2Name of the Marketing Authorisation holderBayer PLC
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTestosterone Undecanoate (Nebido)
    D.3.2Product code not applicable
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTestosterone Undecanoate
    D.3.9.2Current sponsor code6232 6B 1658
    D.3.9.3Other descriptive name17 beta-hydroxyandrost-4-en-3-one
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInjection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Non alcoholic fatty liver disease (NAFLD) in men with low serum testosterone levels
    E.1.1.1Medical condition in easily understood language
    Men who have excess fat in their livers which has caused some liver damage and who also have low blood levels of testosterone (male hormone).
    E.1.1.2Therapeutic area Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    In hypogonadal men with non-alcoholic steatohepatitis (NASH), does Testosterone Replacement Therapy (TRT), given for 12 months, improve severity of steatosis assessed by liver biopsy?
    E.2.2Secondary objectives of the trial
    In hypogonadal men with non-alcoholic steatohepatitis (NASH), does Testosterone Replacement Therapy (TRT), given for 12 months,

    - 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.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Men will be recruited with hypogonadism and NAFLD based on all of:

    1. 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.
    2. Negative serological tests for hepatitis Bs ag and C antibody.
    3. 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 44.
    4. Liver biopsy, performed as part of clinical management within 6 months of recruitment, which shows all of: (a) steatosis (Kleiner grade 2 or 3)45; (b) NASH (combined intralobular inflammation and hepatocyte ballooning score of >1)45; (c) fibrosis Ishak stage <446; and (d) no evidence to suggest another major liver disease.
    5. Hypotestosteronaemia, defined by total serum testosterone <11 ng/L40 . We predict that this will include about 25% of men with NAFLD as defined above.
    E.4Principal exclusion criteria
    1. Inability to give informed consent.
    2. Age <18 or >75 years.
    3. Symptomatic sexual dysfunction.
    4. 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).
    5. Space occupying lesion on ultrasound with any suspicion of malignancy.
    6. Evidence of other chronic liver diseases pace occupying lesion on ultrasound with any suspicion of malignancy.
    7. Prostatic nodule or mass on PR examination unless full urological examination rules our prostate cancer
    8. Serum PSA or alpha feta protein above the age-specific normal range
    9. Carcinoma of male breast
    10. Taking medications (amiodarone, anti-retrovirals, sodium alproate, corticosteroids, tamoxifen) the previous 3 months (known to improve steatosis).
    11. 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.
    12. Severe or complicated obesity, likely requiring bariatric surgery in next 2 years.
    13. LH/FSH levels, raising the possibility of primary pituitary disease.
    14. Subject trying to or hoping to conceive within next 18 months.
    15. Haematocrit of >0.54
    16. 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.
    17. Severe co morbidity likely in the opinion of the investigators to reduce life expectancy to <10 years.
    18. Hypersensitivity to active agent or to any of the excipients.

    Patients in whom H-MRS is contraindicated (e.g. due to a pacemaker) will be eligible for the trial but H-MRS will not be performed with those participants.
    E.5 End points
    E.5.1Primary end point(s)
    Improvement in severity of steatosis on repeat liver biopsy after 52 weeks.
    E.5.1.1Timepoint(s) of evaluation of this end point
    This will he assessed by grading fat infiltration on repeat liver biopsy after 52 weeks of treatment with testosterone replacement therapy, which will be compared to baseline liver biopsy (performed for clinical diagnosis).
    E.5.2Secondary end point(s)
    1. Proportion of patients in whom liver inflammation, ballooning and fibrosis respectively improve
    2. Change in fat content of liver by MR spectroscopy and its correlation with steatosis on liver biopsy
    3. Change in HOMA index
    4. Change in serum liver enzymes
    5. Adverse events

    (B) Eligibility, recruitment and data completeness rates
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 months as per primary endpoint described above.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial is defined as the date of the last on-treatment clinic visit or trial investigation (liver biopsy, MRI scan) if performed on another day. Note that these investigations will be performed within 10 days of 52 weeks.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 7
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At the end of the study the patient will revert to standard clinical management (6 monthly clinic visits). If participants report benefits from the medication they will be offerred a referral to an Endocrine Clinic for consideration of continuing TRT.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-01-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-01-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-01-30
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