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    Clinical Trial Results:
    Testosterone Replacement in Young Male cancer Survivors (TRYMS)

    Summary
    EudraCT number
    		 2011-000677-31
    Trial protocol
    		 GB  
    Global end of trial date
    06 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2019
    First version publication date
    21 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    STH15216
    Additional study identifiers
    ISRCTN number
    		 ISRCTN70274195
    US NCT number
    		 NCT99999999
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sheffield Teaching Hospitals NHS Foundation Trust
    Sponsor organisation address
    11 Broomfield Road, Sheffield, United Kingdom, S10 2SE
    Public contact
    Clinical Trials Research Unit (CTRU), University of Leeds, +44 01133431477, a.f.smith@leeds.ac.uk
    Scientific contact
    Clinical Trials Research Unit (CTRU), University of Leeds, +44 01133431477, a.f.smith@leeds.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principal research question is to find out whether testosterone replacement therapy can reduce body fat and improve quality of life in young male cancer survivors who have a borderline low level of testosterone. This question is split in to two principal research objectives which are: • To assess the effect of 26 weeks of testosterone treatment on levels of fat within the body • To assess the effect of 26 weeks of testosterone treatment on the participants' physical functioning. This information is collected using questionnaires that are completed by the participant.
    Protection of trial subjects
    Testosterone gel is a drug that is widely used and has a robust safety profile. It is accepted as being a low risk drug with serious side effects occurring very rarely. As such the risk to the participant of using a drug that they may not have otherwise received is believed to be very low. As all participants were expected to receive testosterone gel for at least 13 weeks all participants should receive some benefit to outweigh the minimal risk. Participants received 2 whole body scans called DXAs which involved a very low dose of radiation, about the same as you would get from the Earth’s atmosphere in a few days, and less than you would get from taking a flight to America. The Xray exposure in the study has been assessed and approved by a radiation expert. The Health Protection Agency Radiation Protection Division describes a few days natural background radiation as ‘negligible risk’ and participants are unlikely to experience any health problems from these scans. Throughout the study participants were asked to have 6 additional blood tests which were the same as normal blood tests that participants will have had them before during cancer treatment. As with any blood test, there was a small risk of bruising and discomfort, and very rarely infections. These tests were performed in hospitals by appropriately trained members of staff. Tostran gel may cause skin irritation such as a rash. Less commonly it can cause an increase in the participants' number of red blood cells, increased hair growth, enlargement of the male breast tissue, soft tissue swelling and an increase in PSA (Prostate Specific Antigen) levels. To minimise these risks red blood cell count and PSA were tested regularly during the study, and if the participants' doctor thought they were having significant side effects they could withdraw them from the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 May 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 136
    Worldwide total number of subjects
    136
    EEA total number of subjects
    136
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    136
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between May 2012 and March 2015, 1407 patients were screened for the TRYMS trial, of which 304 were registered and 136 were randomised to the TRYMS trial.

    Pre-assignment
    Screening details
    		 1407 patients screened. 1103 were not registered because: they did not want to participate (N=399), clinically ineligible (N=610), too ill to consent (N=2), Other (N=46), no reason given (N=46). 168 were registered but not randomised because: ineligible (N=152), other (N=16). 136 patients were randomised.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Treatment/placebo gels and canisters identical in appearance and identified by unique code assigned at random by Statistician to maintain the blind of patients and site staff (except in the case of emergency unblinding). All CTRU staff remained blind apart from key personnel incl. Statisticians and safety team for SUSAR reporting and independent endocrinologist for escalation of out-of-range testosterone levels after 2W. Testosterone samples taken at baseline and 26W analysed centrally.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tostran 2% Gel
    Arm description
    		 - One gram of gel contains 20mg testosterone. One press of the canister piston delivers 0.5g of gel containing 10mg testosterone. - Supplied by ProStrakan
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tostran 2% gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    3g gel (containing 60mg testosterone)/day applied cutaneously. At 2 weeks the dose may be adjusted based on the participants serum testosterone levels. If serum testosterone is lower than 11nmol/l the daily dose will be increased by 20mg, if serum testosterone is between 11 and 15nmol/l the daily dose will be increased by 10mg. If the testosterone level is greater than 15 but lower than 35 the daily dose will remain the same and if the level is between 35nmol and 40nmol/l then the daily dose will be reduced by 20mg. If the testosterone level is greater than 40nmol/l the unblinded endocrinologist will determine an appropriate dose.

    Arm title
    		 Placebo
    Arm description
    		 - Composition: Propylene glycol, ethanol anhydrous, isopropylalcohol, oleic acid, carbomer 1382, trolamine, butylhydroxytoluene (E321), water, purified and hydrochloric acid (for pH) adjustment - Supplied by ProStrakan
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    3g gel/day applied cutaneously for 2 weeks. At 2 weeks dosage adjusted at random in line with active arm dose titration. Treatment continues for a further 24 weeks.

    Number of subjects in period 1
    		Tostran 2% Gel Placebo
    Started
    68
    68
    Completed
    54
    56
    Not completed
    14
    12
         Consent withdrawn by subject
    3
    5
         Lost to follow-up
    11
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tostran 2% Gel
    Reporting group description
    		 - One gram of gel contains 20mg testosterone. One press of the canister piston delivers 0.5g of gel containing 10mg testosterone. - Supplied by ProStrakan

    Reporting group title
    Placebo
    Reporting group description
    		 - Composition: Propylene glycol, ethanol anhydrous, isopropylalcohol, oleic acid, carbomer 1382, trolamine, butylhydroxytoluene (E321), water, purified and hydrochloric acid (for pH) adjustment - Supplied by ProStrakan

    Reporting group values
    		 Tostran 2% Gel Placebo Total
    Number of subjects
    		 68 68 136
    Age categorical
    Patients were stratified by age group (25-37 and 38-50). No patients outside of the age range 25-50 were not eligible for the trial.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        25-37 years
    		 29 29 58
        38-50 years
    		 39 39 78
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.4 ( 6.4 ) 38 ( 6.4 ) -
    Gender categorical
    Patients were only eligible if they were male.
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 68 68 136
    Body Mass Index
    Units: Subjects
        <25 kg/m^2
    		 12 12 24
        25-29.9 kg/m^2
    		 41 41 82
        30-35 kg/m^2
    		 15 15 30
    Serum testosterone level
    Serum testosterone level measured locally for eligibility and randomisation
    Units: Subjects
        7-9.9 nmol/L
    		 40 41 81
        10-12 nmol/L
    		 28 27 55
    Type of previous cancer
    Units: Subjects
        Testicular cancer
    		 60 60 120
        Lymphoma
    		 6 7 13
        Leukaemia
    		 2 1 3
    time between end of curative anti-cancer treatment and study entry
    Units: Subjects
        12-30 months
    		 27 31 58
        31-60 months
    		 17 18 35
        61+ months
    		 24 19 43

    End points

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    End points reporting groups
    Reporting group title
    Tostran 2% Gel
    Reporting group description
    		 - One gram of gel contains 20mg testosterone. One press of the canister piston delivers 0.5g of gel containing 10mg testosterone. - Supplied by ProStrakan

    Reporting group title
    Placebo
    Reporting group description
    		 - Composition: Propylene glycol, ethanol anhydrous, isopropylalcohol, oleic acid, carbomer 1382, trolamine, butylhydroxytoluene (E321), water, purified and hydrochloric acid (for pH) adjustment - Supplied by ProStrakan

    Primary: Truncal fat mass at 26 weeks

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    End point title
    		 Truncal fat mass at 26 weeks
    End point description
    Summary statistics reported for absolute change at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo.
    End point type
    Primary
    End point timeframe
    collected at baseline and 26 weeks.
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [1]
    68 [2]
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    -0.864 ( 1.952 )
    0.028 ( 1.64 )
    Notes
    [1] - prior to multiple imputation 8 patients had missing data at 26 weeks
    [2] - Prior to multiple 8 patients had missing data at 26 weeks.
    Statistical analysis title
    		 Truncal fat mass primary endpoint
    Comparison groups
    Placebo v Tostran 2% Gel
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0073
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 -0.3

    Secondary: SF36™ physical functioning scale at 26 weeks

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    End point title
    		 SF36™ physical functioning scale at 26 weeks
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks on a categorical scale.
    End point type
    Secondary
    End point timeframe
    collected at baseline, 13 weeks and 26 weeks
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [3]
    68 [4]
    Units: unit
        median (inter-quartile range (Q1-Q3))
    0 (0 to 5)
    0 (0 to 5)
    Notes
    [3] - prior to multiple imputation 3&7 patients were missing abs change at 13&26 weeks respectively.
    [4] - Prior to multiple imputation 7&8 patients were missing abs change data at 13 &26 weeks respectively.
    Statistical analysis title
    		 SF36 Physical Functioning
    Statistical analysis description
    Repeated measures Logistic regression was used to model the binary endpoint of perfect physical functioning (score=100) vs non perfect physical functioning (score<100) because the data were strongly negatively skewed. Baseline measurement, stratification factors, treatment, time and treatment-time interaction were adjusted for as fixed effects. All missing Physical Functioning scores were assumed to be <100. point estimates are presented for the 26 week timepoint.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6105 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.788
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.313
         upper limit
    		 1.985
    Notes
    [5] - p-value for timepoint=0.8108 p-value for treatment-time interaction=0.9890

    Secondary: BMI (at 13 and 26 weeks)

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    End point title
    		 BMI (at 13 and 26 weeks)
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    measured at baseline, 13 weeks and 26 weeks.
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [6]
    68 [7]
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    -0.053 ( 1.258 )
    0.221 ( 1.052 )
    Notes
    [6] - Prior to multiple imputation 6&5 patients were missing data at 13&26 weeks respectively.
    [7] - Prior to multiple imputation 4&8 patients were missing data at 13&26 weeks respectively.
    Statistical analysis title
    		 BMI
    Statistical analysis description
    Repeated measures linear regression adjusting for baseline measurement, stratification factors, treatment, time and treatment-time interaction.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 0.22

    Secondary: Fasting insulin: glucose ratio (at 26 weeks)

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    End point title
    		 Fasting insulin: glucose ratio (at 26 weeks)
    End point description
    Summary statistics reported for untransformed values on the continuous scale at 26 weeks. Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    collected at baseline and 26 weeks.
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [8]
    68 [9]
    Units: pmol/L over mmol/L
        median (inter-quartile range (Q1-Q3))
    11.37 (5.8 to 16.25)
    11.96 (8.04 to 17.2)
    Notes
    [8] - Prior to multiple imputation 9 and 17 patients missing data at baseline and 26 weeks respectively.
    [9] - prior to multiple imputation 7 and 14 patients missing data at baseline and 26 weeks.
    Statistical analysis title
    		 ln(insulin:glucose ratio)
    Statistical analysis description
    linear regression of log transformed insulin:glucose ratio adjusting for log(baseline measurement), stratification factors and treatment.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.19

    Secondary: Total cholesterol

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    End point title
    		 Total cholesterol
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    baseline and 26 weeks
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [10]
    68 [11]
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.2 ( 0.7 )
    -0.1 ( 0.7 )
    Notes
    [10] - prior to multiple imputation 13 patients were missing abs change at 26 weeks
    [11] - prior to multiple imputation 7 were missing abs change at 26 weeks
    Statistical analysis title
    		 total cholesterol
    Statistical analysis description
    linear regression adjusting for baseline, stratification factors and treatment
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.21

    Secondary: LH levels (at 26 weeks)

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    End point title
    		 LH levels (at 26 weeks)
    End point description
    Summary statistics reported for absolute change in LH levels on the continuous scale at 26 weeks (from baseline). The subgroup analysis has been conducted using pre-defined normal and high levels of LH.
    End point type
    Secondary
    End point timeframe
    collected at baseline at 26 weeks
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    49
    56
    Units: IU/L
        arithmetic mean (standard deviation)
    -5.7 ( 4.9 )
    0.1 ( 2.2 )
    Statistical analysis title
    		 likelihood ratio test
    Statistical analysis description
    Likelihood ratio test to assess the statistical significance of baseline-LH and treatment interaction on truncal fat mass at 26 weeks.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7665 [12]
    Method
    		 LRT
    Confidence interval
    Notes
    [12] - corresponds to likelihood ratio test

    Secondary: Bone density (at 26 weeks)

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    End point title
    		 Bone density (at 26 weeks)
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    measured at baseline and 26 weeks.
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [13]
    68 [14]
    Units: g/squared cm
        arithmetic mean (standard deviation)
    0.005 ( 0.025 )
    0 ( 0.026 )
    Notes
    [13] - prior to multiple imputation 8 patients were missing their 26 week measurement.
    [14] - Prior to multiple imputation 8 patients were missing their 26 week measurement.
    Statistical analysis title
    		 Bone density
    Statistical analysis description
    Linear regression adjusting for baseline measurement, stratification factors and treatment as fixed effects.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.01

    Secondary: Physical Component summary from the SF36™

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    End point title
    		 Physical Component summary from the SF36™
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    Collected at baseline, 13 weeks and 26 weeks.
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [15]
    68 [16]
    Units: units
        arithmetic mean (standard deviation)
    0.61 ( 5.70 )
    1.04 ( 5.25 )
    Notes
    [15] - prior to multiple imputation 3&9 patients were missing their abs change at 13&26 weeks respectively.
    [16] - Prior to multiple imputation 7&8 patients were missing abs change at 13&26 weeks respectively.
    Statistical analysis title
    		 Physical component summary
    Statistical analysis description
    Repeated measures analysis adjusting for baseline measurement, stratification factors, treatment, time and treatment-time interaction.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.86
         upper limit
    		 0.9

    Secondary: Waist circumference (at 13 and 26 weeks)

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    End point title
    		 Waist circumference (at 13 and 26 weeks)
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    measured at baseline, 13 weeks and 26 weeks.
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [17]
    68 [18]
    Units: cm
        arithmetic mean (standard deviation)
    -0.52 ( 7.76 )
    -0.89 ( 3.85 )
    Notes
    [17] - prior to multiple imputation 6&8 patients were missing abs change at 13&26 weeks respectively.
    [18] - prior to multiple imputation 6&11 patients were missing abs change at 13&26 weeks respectively.
    Statistical analysis title
    		 waist circumference
    Statistical analysis description
    Repeated measures linear regression adjusting for baseline measurement, stratification factors, treatment, time, treatment-time interaction.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.81
         upper limit
    		 2.13

    Secondary: whole body fat mass

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    End point title
    		 whole body fat mass
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    Measured at baseline and 26 weeks
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [19]
    68 [20]
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    -1.63 ( 3.05 )
    0.1 ( 2.72 )
    Notes
    [19] - prior to multiple imputation 8 patients were missing their 26 week measurement
    [20] - prior to multiple imputation 8 patients were missing their 26 week measurement.
    Statistical analysis title
    		 Whole body fat mass
    Statistical analysis description
    linear regression adjusting for baseline measurement, stratification factors and treatment.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 -0.7

    Secondary: Lean body mass

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    End point title
    		 Lean body mass
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    measured at baseline and 26 weeks
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [21]
    68 [22]
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    1.8 ( 1.6 )
    0.2 ( 1.44 )
    Notes
    [21] - prior to multiple imputation 8 were missing values at 26 weeks
    [22] - prior to multiple imputation 8 were missing values at 26 weeks
    Statistical analysis title
    		 Lean body mass
    Statistical analysis description
    linear regression adjusting for baseline measurement, stratification factors and treatment.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 2.1

    Secondary: mental component summary from the SF36

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    End point title
    		 mental component summary from the SF36
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    collected at baseline, 13 weeks and 26 weeks.
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [23]
    68 [24]
    Units: units
        arithmetic mean (standard deviation)
    5.54 ( 14.22 )
    5.03 ( 9.45 )
    Notes
    [23] - prior to multiple imputation 3&9 patients were missing abs change at 13&26 weeks respectively.
    [24] - prior to multiple imputation 7&8 patients were missing abs change data at 13&26 weeks.
    Statistical analysis title
    		 Mental component summary
    Statistical analysis description
    Repeated measures linear regression adjusting for baseline measurement, stratification factors, treatment, time, treatment-time interaction.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.49
         upper limit
    		 3.82

    Secondary: Rosenberg Self-Esteem Scale

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    End point title
    		 Rosenberg Self-Esteem Scale
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    collected at baseline, 13 weeks and 26 weeks.
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [25]
    68 [26]
    Units: Units
        arithmetic mean (standard deviation)
    1.67 ( 4.79 )
    1.84 ( 4.49 )
    Notes
    [25] - prior to multiple imputation 6&11 patients missing abs change at 13&26 weeks
    [26] - prior to multiple imputation 9&13 patients missing abs change at 13&26 weeks.
    Statistical analysis title
    		 Rosenberg Self-Esteem Scale
    Statistical analysis description
    Repeated measures linear regression adjusting for baseline measurement, stratification factors, treatment, time and treatment-time interaction.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.99
         upper limit
    		 1.2

    Secondary: FACIT Fatigue

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    End point title
    		 FACIT Fatigue
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    collected at baseline, 13 weeks and 26 weeks.
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [27]
    68 [28]
    Units: units
        arithmetic mean (standard deviation)
    4.32 ( 10.65 )
    5.14 ( 7.12 )
    Notes
    [27] - Prior to multiple imputation, 3&8 patients were missing abs change at 13&26 weeks.
    [28] - prior to multiple imputation, 7&9 patients were missing data at 13&26 weeks.
    Statistical analysis title
    		 FACIT Fatigue
    Statistical analysis description
    Repeated measures linear regression adjusted for baseline score, stratification factors, treatment, time, treatment-time interaction.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 2.13

    Secondary: DISF-SR (II) M

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    End point title
    		 DISF-SR (II) M
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Note that a formal analysis has not been conducted on this endpoint because of large amounts of missing data. We were unable to ascertain reasons for missing data as they could be because the questions are not relevant (if they do not have a partner) or because they did not want to complete them (e.g. due to the sensitivity of the questions).
    End point type
    Secondary
    End point timeframe
    collected at baseline, 13 weeks and 26 weeks.
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    44 [29]
    40 [30]
    Units: units
        median (inter-quartile range (Q1-Q3))
    7.5 (-6.5 to 20.5)
    12 (-2 to 25.5)
    Notes
    [29] - 24 patients missing data at 26 weeks
    [30] - 28 patients missing data at 26 weeks
    No statistical analyses for this end point

    Secondary: high-density lipoprotein

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    End point title
    		 high-density lipoprotein
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    baseline and 26 weeks
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [31]
    68 [32]
    Units: mmol/L
        arithmetic mean (standard deviation)
    0.019 ( 0.508 )
    -0.098 ( 0.607 )
    Notes
    [31] - prior to multiple imputation 16 were missing abs change at 26 weeks
    [32] - prior to multiple imputation 10 were missing abs change at 26 weeks,
    Statistical analysis title
    		 high-density lipoprotein
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.18

    Secondary: low-density lipoprotein

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    End point title
    		 low-density lipoprotein
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    baseline and 26 weeks
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [33]
    68 [34]
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.116 ( 0.618 )
    -0.069 ( 0.569 )
    Notes
    [33] - prior to multiple imputation 24 were missing abs change at 26 weeks
    [34] - prior to multiple imputation 18 were missing abs change at 26 weeks
    Statistical analysis title
    		 low-density lipoprotein
    Statistical analysis description
    linear regression adjusting for baseline, stratification factors and treatment.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.17

    Secondary: triglycerides

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    End point title
    		 triglycerides
    End point description
    Summary statistics reported for absolute change on the continuous scale at 26 weeks (from baseline). Treatment effect estimates are reported for Active Tostran vs placebo at 26 weeks.
    End point type
    Secondary
    End point timeframe
    baseline and 26 weeks
    End point values
    		 Tostran 2% Gel Placebo
    Number of subjects analysed
    68 [35]
    68 [36]
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.15 ( 1.47 )
    0.03 ( 1.09 )
    Notes
    [35] - prior to multiple imputation 13 patients were missing abs change at 26 weeks
    [36] - prior to multiple imputation 9 patients were missing absolute change at 26 weeks
    Statistical analysis title
    		 ln(Triglycerides)
    Statistical analysis description
    linear regression of log transformed data adjusting for ln(baseline measurement), stratification factors and treatment.
    Comparison groups
    Tostran 2% Gel v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.15

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reports at 6, 13, 19 and 26 weeks after randomisation. A further follow-up phone call was made to the participant 30 days after finishing trial treatment.
    Adverse event reporting additional description
    Adverse events of specific interest (urinary symptoms or skin rash/irritation) and/or severity (CTCAE grade 3 and above) were recorded with relevant information recorded as volunteered by the participant, discovered by investigator questioning or detected through physical examination, lab test, or other investigation,.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Active
    Reporting group description
    		 Participants allocated to receive Tostran 2% gel (active treatment).

    Reporting group title
    Placebo
    Reporting group description
    		 Patients allocated to receive placebo gel

    Serious adverse events
    		 Active Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 68 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Active Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 68 (39.71%)
    26 / 68 (38.24%)
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    non-specific rash
         subjects affected / exposed
    25 / 68 (36.76%)
    21 / 68 (30.88%)
         occurrences all number
    41
    34
    Renal and urinary disorders
    Urinary symptoms
         subjects affected / exposed
    1 / 68 (1.47%)
    5 / 68 (7.35%)
         occurrences all number
    2
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2011
    Schedule of Events table in protocol updated to document SAE collection at baseline and during eligibility assessment. Additional withdrawal criterion added to include withdrawal of patients who suffer AE grade 3 or higher.
    15 May 2013
    Protocol updated to include statement that eligibility waivers are not permitted; addition of inclusion criteria to allow patients who are more than 12 months from end of glucocorticoid treatment following allogeneic bone marrow transplant; clarification that both oral & IV corticosteroid treatment are exclusions; addition of historical allergic reaction to Tostran as an exclusion; addition of active chronic graft vs host disease as an exclusion; addition of disease or current medication known to have effects on body fat mass added as an exclusion; addition of severe obstructive sleep apnoea as an exclusion; addition of active liver disease as an exclusion; addition of uncontrolled hypertension as an exclusion; exclusion criterion renal failure changed to renal impairment; deep vein thrombosis deleted as an exclusion criterion; clarification that patients may not be randomised more than once; additional information provided on how patients should be approached about participating in the trial; clarification that canister code lists will only be password protected when treatment allocation info is included on the list; addition of advice stating that IMP should be applied in the morning; various amendments to information given about the titration sample; amendment to state that for serum testosterone levels between 35nmol/l & 40nmol/l testosterone dose will be reduced by 20mg and if testosterone level is greater than 40nmol/l the independent endocrinologist will determine an appropriate dose between 20-40mg; deletion of significant changes to other hormone replacement therapy as a withdrawal criterion; deletion of treatment with oral corticosteroids for longer than a week as a withdrawal criterion; changes to timing of blood samples; inclusion of additional oestradiol measurement; changes to definition of end of trial, SAEs, SUSARs; amendment to state that the significance levels for the two primary endpoints have been adjusted to avoid an inflated type I error.
    25 Nov 2013
    Protocol amended to exclude participation of patients who are intending to conceive in the next 12 months (6 months of trial treatment + 6 months for sperm count to return to pre-trial levels).
    02 Apr 2014
    Protocol and patient information amended to allow addition of optional preliminary consent process to allow eligibility assessments to be performed prior to main consent; clarification regarding timing of testosterone samples clarification regarding the storage of serum samples; clarification that the measurement of fasting lipids is not time dependent.
    16 Oct 2014
    Major amendment to the protocol to change the trial design and sample size. For the primary endpoint the two baseline testosterone subgroups (7.0-9.9nmol/L: 10-12nmol/L) were combined and a minimum sample size of 112 participants introduced, with the treatment effect for each of the subgroups to be estimated in an exploratory manner. Protocol also amended to clarify that only deaths occurring after randomisation and within the trial period should be reported and that pregnancies in trial participants partners will be followed up until the outcome is know.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Please note that there was 1 patient in the placebo group who experienced an SAE but this was not related to treatment. Details have not been included in the database due to potential risk of identifiability.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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