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    Clinical Trial Results:
    TAILoR – (TelmisArtan and InsuLin Resistance in HIV): A Dose-Ranging Phase II Randomised Open-Labelled Trial of Telmisartan as a strategy for the Reduction of Insulin Resistance in HIV-Positive Individuals on Combination Antiretroviral Therapy (cART)

    Summary
    EudraCT number
    		 2012-000935-18
    Trial protocol
    		 GB  
    Global end of trial date
    20 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Aug 2018
    First version publication date
    05 Aug 2018
    Other versions
    Summary report(s)
    		 TAILOR additional data received after database lock

    Trial information

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    Trial identification
    Sponsor protocol code
    UoL000841
    Additional study identifiers
    ISRCTN number
    		 ISRCTN51069819
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Funder's Reference Number: 10/60/37, Co-sponsor's Reference Number: 4209, REC reference: 12/NW/0214
    Sponsors
    Sponsor organisation name
    University of Liverpool
    Sponsor organisation address
    Brownlow Hill, Liverpool, United Kingdom, L69 3BX
    Public contact
    Clinical Research Governance Manager, University of Liverpool, +44 0151 794 8722, lindsay.carter@liverpool.ac.uk
    Scientific contact
    Clinical Research Governance Manager, University of Liverpool, +44 0151 794 8722, lindsay.carter@liverpool.ac.uk
    Sponsor organisation name
    Royal Liverpool and Broadgreen Hospitals NHS Trust
    Sponsor organisation address
    Prescot street, Liverpool, United Kingdom, L7 8XP
    Public contact
    Research Governance Manager, Royal Liverpool and Broadgreen Hospitals NHS Trust, +44 0151 706 3702, Heather.Rogers@rlbuht.nhs.uk
    Scientific contact
    Research Governance Manager, Royal Liverpool and Broadgreen Hospitals NHS Trust, +44 0151 706 3702, Heather.Rogers@rlbuht.nhs.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
    08 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The trial will assess whether telmisartan can reduce insulin resistance (reduced response to insulin) in HIV-positive individuals being treated with combination antiretroviral therapy (cART). Primary objective: To determine the effect of telmisartan on insulin resistance in HIV-positive individuals on combination antiretroviral therapy using HOMA-IR (Homeostatic Model Assessment - Insulin Resistance) as a measurable, validated surrogate marker of insulin resistance.
    Protection of trial subjects
    TAILOR trial recruited competent adults in their usual clinical care setting. Where the protocol treatment regimen allowed, the trial visits and assessments were scheduled in line with usual clinical practice, with visit windows allowing as much flexibility as possible to fit with participant commitments. Travel expenses were paid for (up to) two dose titration visits and one other visit (generally the baseline visit) that took place outside of routine clinical appointments. TAILOR treatment was administered as a single daily dose as an oral tablet formulation, minimising the pill burden on the population as much as possible.
    Background therapy
    		 No additional interventions were provided.
    Evidence for comparator
    		 In Stage I of the trial, a quarter of the patients will be allocated to the non-intervention control arm. These patients will not receive any investigational drug and therefore do not get any direct benefit of the intervention, if any; however such a non-intervention comparator arm is necessary for the identification of a positive drug effect in the treatment arm(s). However, this does not have any impact on the control of HIV infection since the intended use of telmisartan in this patient population is only as an adjuvant drug and not as the primary drug. A percentage of the participants could also be on a treatment arm found to be less effective than control or other treatment arms during the interim analysis and hence, be dropped. Again, this does not have any impact on the control of HIV infection since the intended use of telmisartan in this patient population is only as an adjuvant drug and not as the primary drug.
    Actual start date of recruitment
    21 Feb 2013
    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: 377
    Worldwide total number of subjects
    377
    EEA total number of subjects
    377
    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)
    362
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in 19 UK Sexual Health Clinics and/or HIV treatment centres from February 2013 until July 2015. The target recruitment rate for the study was two to five patients per month per site, based on the original 8 sites recruiting and a target recruitment figure of 370.

    Pre-assignment
    Screening details
    		 In total, 1953 patients were screened at the participating centres over the duration of the trial. Of the 1121 patients meeting the eligibility criteria, 698 declined to participate, 44 consented but were not randomised and 379 were randomised initially but there were 2 post randomisation exclusions. Final total randomised was 377.

    Pre-assignment period milestones
    Number of subjects started
    		 1953 [1]
    Intermediate milestone: Number of subjects
    Eligible: 1121
    Intermediate milestone: Number of subjects
    Consent obtained: 423
    Intermediate milestone: Number of subjects
    Randomised: 379
    Number of subjects completed
    		 377

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Randomised the same patient in error: 1
    Reason: Number of subjects
    		 Patient was not present at randomisation: 1
    Reason: Number of subjects
    		 Not eligible: 832
    Reason: Number of subjects
    		 Consent not provided: 698
    Reason: Number of subjects
    		 Consented but not randomised: 44
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of patients who started the pre-assignment period (screened - 1953) is larger than the number who enrolled in the trial (randomised - 377).
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (Baseline)
    Arm description
    		 Arm A: Non-intervention (control)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Arm B (Baseline)
    Arm description
    		 Arm B: Telmisartan 20mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Telmisartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    24 weeks oral telmisartan 20 milligram (mg) dose, once daily

    Arm title
    		 Arm C (Baseline)
    Arm description
    		 Arm C: Telmisartan 40mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Telmisartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    24 weeks oral telmisartan 40 mg dose, once daily. The starting dose for patients in this arm will be 20 mg and dose titration to 40mg will be undertaken over a period of 2 weeks.

    Arm title
    		 Arm D (Baseline)
    Arm description
    		 Arm D: Telmisartan 80mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Telmisartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    24 weeks oral telmisartan 80 mg dose, once daily. The starting dose for patients in this arm will be 20 mg and dose titration to 80mg will be undertaken over a period of 4 weeks.

    Number of subjects in period 1
    		Arm A (Baseline) Arm B (Baseline) Arm C (Baseline) Arm D (Baseline)
    Started
    105
    84
    82
    106
    Completed
    105
    84
    82
    106
    Period 2
    Period 2 title
    Final Analysis
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (Final)
    Arm description
    		 Arm A: Non-intervention (control)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Arm D (Final)
    Arm description
    		 Arm D: Telmisartan 80mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Telmisartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    24 weeks oral telmisartan 80 mg dose, once daily. The starting dose for patients in this arm will be 20 mg and dose titration to 80mg will be undertaken over a period of 4 weeks.

    Number of subjects in period 2 [2]
    		Arm A (Final) Arm D (Final)
    Started
    105
    106
    Basline
    100
    100
    Week 24
    89
    82
    Included in Final analysis
    85
    78
    Completed
    85
    78
    Not completed
    20
    28
         Withdrew before 24 weeks
    11
    16
         Did not attend week 24
    4
    3
         Haemolysed samples collected 24 weeks
    -
    2
         Samples not collected/un-fasted baseline
    1
    2
         Haemolysed samples collected baseline
    3
    3
         Samples not collected/un-fasted 24 weeks
    1
    2
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Arms B and C were dropped following interim analysis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (Baseline)
    Reporting group description
    		 Arm A: Non-intervention (control)

    Reporting group title
    Arm B (Baseline)
    Reporting group description
    		 Arm B: Telmisartan 20mg

    Reporting group title
    Arm C (Baseline)
    Reporting group description
    		 Arm C: Telmisartan 40mg

    Reporting group title
    Arm D (Baseline)
    Reporting group description
    		 Arm D: Telmisartan 80mg

    Reporting group values
    		 Arm A (Baseline) Arm B (Baseline) Arm C (Baseline) Arm D (Baseline) Total
    Number of subjects
    		 105 84 82 106 377
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 99 79 80 104 362
        From 65-84 years
    		 6 5 2 2 15
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.2 ± 10.5 47.1 ± 10.1 47.9 ± 7.5 44.9 ± 9.2 -
    Gender categorical
    Units: Subjects
        Female
    		 20 15 13 17 65
        Male
    		 85 69 69 89 312
    Ethnicity
    Units: Subjects
        British
    		 71 52 56 70 249
        Irish
    		 3 1 0 4 8
        Any other white
    		 9 8 8 7 32
        White and black african
    		 1 1 0 0 2
        Any other mixed
    		 0 2 0 1 3
        Indian
    		 0 1 0 0 1
        Any other Asian
    		 0 1 2 0 3
        Caribbean
    		 8 8 9 7 32
        African
    		 10 7 4 9 30
        Any other black
    		 3 2 3 6 14
        Chinese
    		 0 1 0 1 2
        Any other ethnic group
    		 0 0 0 1 1
    Physical exam
    Was a physical exam carried out at this visit (yes/no)?
    Units: Subjects
        No
    		 15 16 12 22 65
        Yes
    		 90 68 69 84 311
        Missing
    		 0 0 1 0 1
    Hepatits C
    Has participant been tested for Hepatitis C within the last 6 months (yes/no)?
    Units: Subjects
        No
    		 23 22 25 28 98
        Yes
    		 82 62 57 78 279
    BMI
    Number of participants missing data for baseline characteristic: Arm A: 2, Arm B: 0, Arm C: 1, Arm D: 0
    Units: KG/m^2
        arithmetic mean (standard deviation)
    		 26.6 ± 5.2 27.1 ± 5.8 27.1 ± 4.8 26.0 ± 4.7 -
    Blood pressure Systolic
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 0, Arm C: 1, Arm D: 0
    Units: mmHg
        arithmetic mean (standard deviation)
    		 126.8 ± 13.9 124.4 ± 14.2 126.9 ± 14.3 124.8 ± 15.4 -
    Blood pressure diastolic
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 0, Arm C: 1, Arm D: 0
    Units: mmHg
        arithmetic mean (standard deviation)
    		 80.0 ± 10.7 78.2 ± 11.2 79.7 ± 9.9 78.6 ± 11.1 -
    Heat rate
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 2, Arm C: 2, Arm D: 0
    Units: Beats/min
        arithmetic mean (standard deviation)
    		 73.0 ± 11.5 72.5 ± 11.7 71.6 ± 13.1 72.8 ± 12.2 -
    Temperature
    Number of participants missing data for baseline characteristic: Arm A: 6, Arm B: 6, Arm C: 4, Arm D: 4
    Units: celsius temperature
        arithmetic mean (standard deviation)
    		 36.3 ± 0.5 36.3 ± 0.4 36.4 ± 0.3 36.3 ± 0.5 -
    Respiratory rate
    Number of participants missing data for baseline characteristic: Arm A: 3, Arm B: 1, Arm C: 6, Arm D: 3
    Units: breaths/min
        arithmetic mean (standard deviation)
    		 15.6 ± 2.9 15.9 ± 4.0 16.0 ± 4.2 16.5 ± 3.4 -
    Waist circumference
    Number of participants missing data for baseline characteristic: Arm A: 4, Arm B: 1, Arm C: 3, Arm D: 4
    Units: cm
        arithmetic mean (standard deviation)
    		 93.5 ± 11.8 94.6 ± 14.7 97.1 ± 12.2 93.0 ± 11.6 -
    Thigh circumference
    Number of participants missing data for baseline characteristic: Arm A: 4, Arm B: 2, Arm C: 5, Arm D: 4
    Units: cm
        arithmetic mean (standard deviation)
    		 50.8 ± 7.5 52.3 ± 7.7 51.8 ± 6.0 49.6 ± 8.5 -
    CD4 Cell count
    Number of participants missing data for baseline characteristic: Arm A: 3, Arm B: 1, Arm C: 4, Arm D: 5
    Units: cells/mm^3
        arithmetic mean (standard deviation)
    		 640.0 ± 231.1 619.2 ± 272.5 613.8 ± 248.4 617.0 ± 266.1 -
    CD4 Cell count & HIV viral load
    Number of participants missing data for baseline characteristic: Arm A: 3, Arm B: 0, Arm C: 1, Arm D: 0
    Units: percent
        arithmetic mean (standard deviation)
    		 32.1 ± 7.7 29.2 ± 8.6 30.1 ± 9.3 30.5 ± 7.9 -
    HIV Viral Load (continuous)
    Number of participants missing data for this continuous baseline characteristic: Arm A: 70, Arm B: 67, Arm C: 51, Arm D: 72 The missing data are presented in categorical form due to there being upper and lower limits of measurement: < 10 : Arm A: 2, Arm B: 1, Arm C: 2, Arm D: 1 < 20 : Arm A: 13, Arm B: 20, Arm C: 11, Arm D: 23 < 40 : Arm A: 50, Arm B: 38, Arm C: 35, Arm D: 43 < 45 : Arm A: 2, Arm B: 6, Arm C: 3, Arm D: 3 < 100 : Arm A: 0, Arm B: 1, Arm C: 0, Arm D: 0 Missing: Arm A: 3, Arm B: 1, Arm C: 0, Arm D: 2
    Units: copies/ml
        arithmetic mean (standard deviation)
    		 43.0 ± 96.4 21.6 ± 31.1 58.0 ± 119.4 25.1 ± 33.2 -
    Sodium
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 1, Arm C: 0, Arm D: 1
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 139.7 ± 2.2 140.1 ± 2.0 140.5 ± 2.3 140.1 ± 2.3 -
    Potassium
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 1, Arm C: 0, Arm D: 1
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 4.3 ± 0.3 4.3 ± 0.3 4.3 ± 0.4 4.3 ± 0.3 -
    Urea
    Number of participants missing data for baseline characteristic: Arm A: 15, Arm B: 12, Arm C: 5, Arm D: 16
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 5.0 ± 1.4 5.1 ± 1.4 5.2 ± 1.2 5.0 ± 1.3 -
    Bicarbonate
    Number of participants missing data for baseline characteristic: Arm A: 89, Arm B: 66, Arm C: 60, Arm D: 80
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 26.2 ± 3.5 26.8 ± 3.0 25.8 ± 3.1 26.2 ± 3.7 -
    Creatinine
    Number of participants missing data for baseline characteristic: Arm A: 2, Arm B: 0, Arm C: 0, Arm D: 2
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 78.7 ± 15.6 80.2 ± 14.9 82.6 ± 15.1 80.1 ± 15.1 -
    eGFR (continuous)
    Number of participants missing data for baseline characteristic: Arm A: 55, Arm B: 43, Arm C: 44, Arm D: 52 The missing data are presented in categorical form due to there being upper and lower limits of measurement: < 60 : Arm A: 0, Arm B: 0, Arm C: 0, Arm D: 1 < 90 : Arm A: 1, Arm B: 0, Arm C: 0, Arm D: 0 > 60 : Arm A: 24, Arm B: 23, Arm C: 25, Arm D: 22 > 90 : Arm A: 28, Arm B: 19, Arm C: 19, Arm D: 28 Missing: Arm A: 2, Arm B: 1, Arm C: 0, Arm D: 1
    Units: eGFR score
        arithmetic mean (standard deviation)
    		 79.8 ± 13.6 79.9 ± 10.8 77.9 ± 10.5 81.4 ± 14.5 -
    ALT
    Number of participants missing data for baseline characteristic: Arm A: 13, Arm B: 9, Arm C: 5, Arm D: 10
    Units: iu/l
        arithmetic mean (standard deviation)
    		 26.8 ± 13.5 29.4 ± 20.3 29.1 ± 12.8 32.2 ± 31.9 -
    AST
    Number of participants missing data for baseline characteristic: Arm A: 78, Arm B: 67, Arm C: 64, Arm D: 79
    Units: iu/l
        arithmetic mean (standard deviation)
    		 34.7 ± 50.7 27.3 ± 6.7 28.6 ± 8.3 28.8 ± 14.0 -
    ALP
    Number of participants missing data for baseline characteristic: Arm A: 4, Arm B: 4, Arm C: 10, Arm D: 9
    Units: iu/l
        arithmetic mean (standard deviation)
    		 96.5 ± 45.2 96.1 ± 46.9 83.7 ± 29.6 89.2 ± 40.4 -
    Albumin
    Number of participants missing data for baseline characteristic: Arm A: 3, Arm B: 1, Arm C: 1, Arm D: 3
    Units: g/l
        arithmetic mean (standard deviation)
    		 43.7 ± 4.1 44.3 ± 3.5 44.2 ± 3.2 44.7 ± 3.8 -
    Total protein
    Number of participants missing data for baseline characteristic: Arm A: 33, Arm B: 25, Arm C: 23, Arm D: 37
    Units: g/l
        arithmetic mean (standard deviation)
    		 74.5 ± 5.3 73.7 ± 4.0 74.2 ± 4.6 73.4 ± 3.9 -
    Bilirubin
    Number of participants missing data for baseline characteristic: Arm A: 5, Arm B: 6, Arm C: 6, Arm D: 8 Some data are presented in both continuous and categorical form due to there being upper and lower limits of measurement: < 2 : Arm A: 0, Arm B: 1, Arm C: 0, Arm D: 0 < 3 : Arm A: 3, Arm B: 2, Arm C: 2, Arm D: 2 < 15 : Arm A: 1, Arm B: 2, Arm C: 1, Arm D: 4
    Units: μmol/l
        arithmetic mean (standard deviation)
    		 11.1 ± 13.3 10.9 ± 14.1 14.6 ± 17.6 16.6 ± 15.1 -
    Haemoglobin
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 1, Arm C: 0, Arm D: 0
    Units: g/dl
        arithmetic mean (standard deviation)
    		 143.77 ± 12.28 144.16 ± 13.32 146.73 ± 12.15 145.72 ± 12.92 -
    Red blood cell count
    Number of participants missing data for baseline characteristic: Arm A: 7, Arm B: 5, Arm C: 5, Arm D: 9
    Units: 10^12/l
        arithmetic mean (standard deviation)
    		 4.55 ± 0.44 4.62 ± 0.44 4.69 ± 0.41 4.60 ± 0.44 -
    White blood cell count
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 0, Arm C: 0, Arm D: 1
    Units: 10^9/l
        arithmetic mean (standard deviation)
    		 6.43 ± 2.3 6.12 ± 1.99 5.92 ± 1.74 6.07 ± 2.14 -
    Platelets
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 0, Arm C: 0, Arm D: 0
    Units: 10^9/l
        arithmetic mean (standard deviation)
    		 243.07 ± 74.67 226.61 ± 55.48 226.16 ± 62.24 226.24 ± 55.37 -
    Mean cell volume
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 0, Arm C: 0, Arm D: 0
    Units: fl
        arithmetic mean (standard deviation)
    		 93.40 ± 5.65 92.87 ± 5.48 92.47 ± 5.48 94.37 ± 5.33 -
    Mean cell Haemoglobin
    Number of participants missing data for baseline characteristic: Arm A: 25, Arm B: 17, Arm C: 21, Arm D: 21
    Units: pg
        arithmetic mean (standard deviation)
    		 31.49 ± 3.92 31.35 ± 2.06 36.17 ± 37.78 31.35 ± 3.68 -
    Mean cell Haemoglobin
    Number of participants missing data for baseline characteristic: Arm A: 37, Arm B: 31, Arm C: 29, Arm D: 41
    Units: g/dl
        arithmetic mean (standard deviation)
    		 340.71 ± 11.83 335.28 ± 12.97 340.57 ± 13.03 336.55 ± 12.48 -
    Red cell distribution width
    Number of participants missing data for baseline characteristic: Arm A: 76, Arm B: 62, Arm C: 56, Arm D: 78
    Units: percent
        arithmetic mean (standard deviation)
    		 13.31 ± 0.98 13.36 ± 0.7 13.18 ± 0.65 13.61 ± 1.57 -
    Neutrophils
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 0, Arm C: 0, Arm D: 0
    Units: 10^9/l
        arithmetic mean (standard deviation)
    		 3.62 ± 1.95 3.27 ± 1.51 3.21 ± 1.43 3.29 ± 1.64 -
    Lymphocytes
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 0, Arm C: 0, Arm D: 0
    Units: 10^9/l
        arithmetic mean (standard deviation)
    		 2.10 ± 0.69 2.17 ± 0.72 2.05 ± 0.66 2.08 ± 0.68 -
    Eosinophils
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 2, Arm C: 0, Arm D: 0
    Units: 10^9/l
        arithmetic mean (standard deviation)
    		 0.17 ± 0.15 0.15 ± 0.12 0.15 ± 0.08 0.16 ± 0.12 -
    Basophils
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 0, Arm C: 0, Arm D: 0
    Units: 10^9/l
        arithmetic mean (standard deviation)
    		 0.03 ± 0.04 0.02 ± 0.04 0.02 ± 0.04 0.03 ± 0.04 -
    Monocytes
    Number of participants missing data for baseline characteristic: Arm A: 0, Arm B: 0, Arm C: 0, Arm D: 0
    Units: 10^9/l
        arithmetic mean (standard deviation)
    		 0.49 ± 0.20 0.46 ± 0.18 0.48 ± 0.16 0.49 ± 0.22 -
    Insulin
    Number of participants missing data for baseline characteristic: Arm A: 3, Arm B: 3, Arm C: 4, Arm D: 6
    Units: pmol/l
        arithmetic mean (standard deviation)
    		 72.26 ± 53.42 76.56 ± 58 81.29 ± 78.52 73 ± 72.74 -
    Glucose
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 1, Arm C: 2, Arm D: 2
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 5.2 ± 0.5 5.2 ± 0.58 5.29 ± 0.7 5.22 ± 0.54 -
    QUICKI
    Number of participants missing data for baseline characteristic: Arm A: 5, Arm B: 2, Arm C: 4, Arm D: 4
    Units: QUICKI score
        arithmetic mean (standard deviation)
    		 0.117 ± 0.009 0.116 ± 0.009 0.116 ± 0.010 0.118 ± 0.009 -
    Revised QUICKI
    Number of participants missing data for baseline characteristic: Arm A: 5, Arm B: 2, Arm C: 4, Arm D: 5
    Units: revised QUICKI score
        arithmetic mean (standard deviation)
    		 0.132 ± 0.017 0.134 ± 0.019 0.134 ± 0.019 0.133 ± 0.016 -
    HOMAIR
    Number of participants missing data for baseline characteristic: Arm A: 5, Arm B: 2, Arm C: 4, Arm D: 4
    Units: HOMA-IR Score
        arithmetic mean (standard deviation)
    		 2.494 ± 2.083 2.568 ± 1.923 2.820 ± 3.040 2.544 ± 2.794 -
    HDLc
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 2, Arm C: 3, Arm D: 3
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 1.19 ± 0.4 1.21 ± 0.39 1.14 ± 0.4 1.18 ± 0.38 -
    Cholesterol
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 2, Arm C: 3, Arm D: 3
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 5.01 ± 0.99 5 ± 1.11 4.83 ± 1.04 4.97 ± 1.04 -
    LDLc
    Number of participants missing data for baseline characteristic: Arm A: 2, Arm B: 3, Arm C: 4, Arm D: 4
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 3.1 ± 0.91 3.14 ± 0.97 2.97 ± 0.9 3.12 ± 0.91 -
    Adiponectin
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 2, Arm C: 4, Arm D: 5
    Units: microgram(s)/millilitre
        arithmetic mean (standard deviation)
    		 15.62 ± 7.81 17.89 ± 10.78 16.85 ± 10.97 15.9 ± 14.36 -
    Leptin
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 3, Arm C: 4, Arm D: 3
    Units: pg/ml
        arithmetic mean (standard deviation)
    		 12484 ± 18996 14046 ± 25894 11842 ± 20774 10995 ± 18246 -
    IL8
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 2, Arm C: 4, Arm D: 4
    Units: pg/ml
        arithmetic mean (standard deviation)
    		 33.46 ± 89.94 21.38 ± 25.19 22.3 ± 23.96 31.66 ± 46 -
    TNFalpha
    Number of participants missing data for baseline characteristic: Arm A: 2, Arm B: 2, Arm C: 4, Arm D: 5
    Units: pg/ml
        arithmetic mean (standard deviation)
    		 2.9 ± 1.99 2.3 ± 0.91 2.56 ± 1.29 3.35 ± 5.67 -
    Resistin
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 2, Arm C: 4, Arm D: 5
    Units: pg/ml
        arithmetic mean (standard deviation)
    		 6630.2 ± 4116.6 5779 ± 3196.8 5602.4 ± 2753.1 6510.5 ± 3120.9 -
    hsCRP
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 2, Arm C: 4, Arm D: 3
    Units: mg/ml
        arithmetic mean (standard deviation)
    		 4.94 ± 12.16 3.08 ± 3.64 4.1 ± 11.03 3.34 ± 6.02 -
    NEFA
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 1, Arm C: 3, Arm D: 2
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 0.459 ± 0.240 0.416 ± 0.229 0.396 ± 0.204 0.460 ± 0.240 -
    Chloride
    Number of participants missing data for baseline characteristic: Arm A: 82, Arm B: 69, Arm C: 59, Arm D: 86
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 103.0 ± 2.6 103.1 ± 3.0 102.7 ± 1.9 103.2 ± 2.3 -
    Haematocrit
    Number of participants missing data for baseline characteristic: Arm A: 35, Arm B: 35, Arm C: 32, Arm D: 41
    Units: percentage
        arithmetic mean (standard deviation)
    		 42.23 ± 3.29 42.16 ± 6.51 42.82 ± 3.18 42.46 ± 5.69 -
    Fasting glucose
    Number of participants missing data for baseline characteristic: Arm A: 75, Arm B: 66, Arm C: 59, Arm D: 81
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 5.05 ± 0.73 4.99 ± 0.48 4.97 ± 0.56 5.08 ± 0.64 -
    HBA1c
    Number of participants missing data for baseline characteristic: Arm A: 102, Arm B: 78, Arm C: 80, Arm D: 100
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 34.67 ± 1.15 36.00 ± 2.53 37.00 ± 4.24 37.17 ± 2.48 -
    HBA1c (%)
    Number of participants missing data for baseline characteristic: Arm A: 104, Arm B: 83, Arm C: 82, Arm D: 106 ***Please note for Arm C and Arm D there were no values to report but system requires that field not left blank so entered 0 in these cells. These are not genuine zeros.***
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 5.2 (5.2 to 5.2) 5.7 (5.7 to 5.7) 0 (0 to 0) 0 (0 to 0) -
    OGTT
    Number of participants missing data for baseline characteristic: Arm A: 104, Arm B: 84, Arm C: 81, Arm D: 106 ***Please note for Arm B and Arm D there were no values to report but system requires that field not left blank so entered 0 in these cells. These are not genuine zeros.***
    Units: mmol/l
        median (inter-quartile range (Q1-Q3))
    		 5.8 (5.8 to 5.8) 0 (0 to 0) 7.3 (7.3 to 7.3) 0 (0 to 0) -
    Random plasma glucose
    Number of participants missing data for baseline characteristic: Arm A: 27, Arm B: 18, Arm C: 25, Arm D: 25
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 5.03 ± 0.83 5.07 ± 0.80 5.12 ± 0.84 4.97 ± 0.83 -
    Triglycerides
    Number of participants missing data for baseline characteristic: Arm A: 1, Arm B: 2, Arm C: 3, Arm D: 3
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 1.61 ± 0.89 1.42 ± 0.75 1.56 ± 0.91 1.46 ± 0.88 -

    End points

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    End points reporting groups
    Reporting group title
    Arm A (Baseline)
    Reporting group description
    		 Arm A: Non-intervention (control)

    Reporting group title
    Arm B (Baseline)
    Reporting group description
    		 Arm B: Telmisartan 20mg

    Reporting group title
    Arm C (Baseline)
    Reporting group description
    		 Arm C: Telmisartan 40mg

    Reporting group title
    Arm D (Baseline)
    Reporting group description
    		 Arm D: Telmisartan 80mg
    Reporting group title
    Arm A (Final)
    Reporting group description
    		 Arm A: Non-intervention (control)

    Reporting group title
    Arm D (Final)
    Reporting group description
    		 Arm D: Telmisartan 80mg

    Primary: Reduction in insulin resistance measured by HOMA-IR (Final analysis)

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    End point title
    		 Reduction in insulin resistance measured by HOMA-IR (Final analysis)
    End point description
    insulin resistance measured by HOMA-IR. HOMA-IR was calculated by HOMA-IR = (fasting insulin (µU/ml) × fasting glucose (mmol/l))/22.5 The conversion factor for fasting insulin to convert from pmol/L to μU/mL is 0.144.
    End point type
    Primary
    End point timeframe
    Change in 24 week HOMA-IR score compared to baseline
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    85 [1]
    78 [2]
    Units: HOMA-IR
    arithmetic mean (standard deviation)
        Baseline
    2.5 ± 2.08
    2.5 ± 2.79
        Week 24
    3.0 ± 3.25
    3.4 ± 6.89
    Attachments
    		 Untitled (Filename: Primary efficacy data.pdf)
    Notes
    [1] - 100 baseline, 89 week 24, 85 have both baseline and week 24 measurements so included in analysis
    [2] - 100 baseline, 82 week 24, 78 have both baseline and week 24 measurements so included in analysis
    Statistical analysis title
    		 ANCOVA HOMA-IR(Final)
    Statistical analysis description
    An ANCOVA model is used by fitting the regression model HOMAIR_24 = HOMAIR_0 + treatment + stratification factor (Black/Non-Black). where HOMAIR_0 is the HOMAIR value at the baseline prior to randomisation and HOMAIR_24 is the HOMA-IR value at 24 weeks. The treatment variable is categorical with control (arm A) as the reference level. The test statistic is given by the t – values. The test statistic will be compared to the final critical value (-2.086).
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 > 0.05 [4]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - The test statistic is 0.065 and compared to the critical value of -2.086. As 0.065 is not smaller than the critical value we fail to reject the null hypothesis – i.e. no difference between Arm D and Arm A.
    [4] - This was a one sided test with an overall type I error of 5%. The treatment effect (slope) from the ANCOVA model was 0.007 and the standard error of the mean was 0.106.
    Statistical analysis title
    		 HOMAIR sensitivity analysis 1 (Final)
    Statistical analysis description
    Fit the same ANCOVA model by imputing values for missing HOMA-IR values at baseline and 24 weeks using the MICE algorithm. The MICE algorithm imputed missing HOMA-IR values conditional on available HOMA-IR values at baseline, 12 weeks and 24 weeks, treatment allocation (Arm D/Control) and stratification factor (black/non-black).
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 > 0.05 [6]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [5] - Sensitivity analysis comparing arm D to arm A. The test statistic is 0.172 and compared to the critical value of -2.086. As 0.172 is not smaller than the critical value we fail to reject the null hypothesis – i.e. no difference between Arm D and Arm A.
    [6] - This was a two sided test with an overall type I error of 5%. The treatment effect (slope) from the ANCOVA model was 0.02 and the standard error of the mean was 0.116.
    Statistical analysis title
    		 HOMA-IR sensitivity analysis 3 (Final)
    Statistical analysis description
    A compliance-adjusted primary outcome analysis is undertaken using instrumental variable (IV) regression, in order to estimate the effect of actual dose on outcome. The model includes patients from arm A (assumed to have received dose of 0mg) and patients from arm D who provided compliance data from both the treatment diary and pill count. Dose is based on average between two measures of compliance (treatment diary and pill count).
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2885 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.028
         upper limit
    		 0.008
    Notes
    [7] - p-value 0.2885 > 0.05 implies that there is no effect of telmisartan after adjusting for dose.

    Secondary: Change in insulin resistance measured by QUICKI (Final)

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    End point title
    		 Change in insulin resistance measured by QUICKI (Final)
    End point description
    Two alternative measures of insulin resistance, QUICKI and revised QUICKI, to further investigate the effect of telmisartan. QUICKI= 1/(log G + log I), where G is fasting glucose (mg/dl) anf I is fasting insulin (μU/mL). Fasting glucose is recorded in mmol/l for the primary analysis, and the conversion factor for fasting glucose to convert from mmol/l to mg/dl is 18 (1 mmol/l = 18 mg/dl)
    End point type
    Secondary
    End point timeframe
    Change in QUICKI in telmisartan treated (arm D) after 24 weeks of treatment in comparison with control (arm A)
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    85 [8]
    78 [9]
    Units: QUICKI
    arithmetic mean (standard deviation)
        Baseline
    0.117 ± 0.0092
    0.118 ± 0.0091
        Week 24
    0.115 ± 0.0093
    0.116 ± 0.0105
    Attachments
    		 Untitled (Filename: QUICKI and revised QUICKI.pdf)
    Notes
    [8] - 100 baseline, 89 week 24, 85 have both baseline and week 24 measurements so included in analysis
    [9] - 100 baseline, 82 week 24, 78 have both baseline and week 24 measurements so included in analysis
    Statistical analysis title
    		 ANCOVA QUICKI (Final)
    Statistical analysis description
    The same ANCOVA model as the primary HOMAIR analysis is fitted (with QUICK in place of HOMAIR).
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 > 0.05 [11]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [10] - Comparing arm A to arm D. The test statistic is 0.0813 and compared to the critical value of 2.086. As 0.0813 is not larger than the critical value we fail to reject the null hypothesis, i.e. no difference between Arm D and Arm A.
    [11] - This was a two sided test with an overall type I error of 5%. The treatment effect (slope) from the ANCOVA model was 0.00011 and the standard error of the mean was 0.00133.

    Secondary: Change in insulin resistance measured by Revised QUICKI (Final)

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    End point title
    		 Change in insulin resistance measured by Revised QUICKI (Final)
    End point description
    Two alternative measures of insulin resistance, QUICKI and revised QUICKI, to further investigate the effect of telmisartan. Revised QUICKI = 1/(log G + log I + log NEFA), where G is fasting glucose (mg/dl), I is fasting insulin (μU/mL), and NEFA is plasma non esterified fatty acids concentration (mmol/l). Fasting glucose is recorded in mmol/l for the primary analysis, and the conversion factor for fasting glucose to convert from mmol/l to mg/dl is 18 (1 mmol/l = 18 mg/dl).
    End point type
    Secondary
    End point timeframe
    Change in Revised-QUICKI in telmisartan arm (arm D) after 24 weeks of treatment in comparison with control (arm A)
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    84 [12]
    78 [13]
    Units: Revised QUICKI
    arithmetic mean (standard deviation)
        Baseline
    0.132 ± 0.0168
    0.133 ± 0.0156
        Week 24
    0.132 ± 0.0176
    0.133 ± 0.0178
    Attachments
    		 Untitled (Filename: QUICKI and revised QUICKI.pdf)
    Notes
    [12] - 100 baseline, 88 week 24, 84 have both baseline and week 24 measurements so included in analysis
    [13] - 99 baseline, 82 week 24, 78 have both baseline and week 24 measurements so included in analysis
    Statistical analysis title
    		 ANCOVA Revised-QUICKI (Final)
    Statistical analysis description
    The same ANCOVA model as the primary HOMAIR analysis is fitted (with Revised-QUICK in place of HOMAIR).
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 > 0.05 [15]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [14] - The test statistic is 0.4418 and compared to the critical value of 2.086. As 0.4418 is not larger than the critical value we fail to reject the null hypothesis, i.e. no difference between Arm D and Arm A.
    [15] - This was a two sided test with an overall type I error of 5%. The treatment effect (slope) from the ANCOVA model was 0.0011 and the standard error of the mean was 0.00249.

    Secondary: HOMA-IR longitudinal (Final)

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    End point title
    		 HOMA-IR longitudinal (Final)
    End point description
    insulin resistance measured by HOMA-IR. HOMA-IR was calculated by HOMA-IR = (fasting insulin (µU/ml) × fasting glucose (mmol/l))/22.5 The conversion factor for fasting insulin to convert from pmol/L to μU/mL is 0.144.
    End point type
    Secondary
    End point timeframe
    Change in HOMA-IR at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    91
    87
    Units: Number of patients
    91
    87
    Attachments
    		 Untitled (Filename: Longitudinal HOMAIR.pdf)
    Statistical analysis title
    		 Longitudinal analysis HOMA-IR (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t = 48(had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2753
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.096
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.265
         upper limit
    		 0.066

    Secondary: QUICKI longitudinal (Final)

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    End point title
    		 QUICKI longitudinal (Final)
    End point description
    Two alternative measures of insulin resistance, QUICKI and revised QUICKI, to further investigate the effect of telmisartan. QUICKI= 1/(log G + log I), where G is fasting glucose (mg/dl) anf I is fasting insulin (μU/mL). Fasting glucose is recorded in mmol/l for the primary analysis, and the conversion factor for fasting glucose to convert from mmol/l to mg/dl is 18 (1 mmol/l = 18 mg/dl)
    End point type
    Secondary
    End point timeframe
    Change in QUICKI at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    91
    87
    Units: Number of patients
    91
    87
    Attachments
    		 Untitled (Filename: Longitudinal QUICKI.pdf)
    Statistical analysis title
    		 Longitudinal analysis QUICKI (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4671
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.008
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.013
         upper limit
    		 0.03

    Secondary: Revised-QUICKI longitudinal (Final)

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    End point title
    		 Revised-QUICKI longitudinal (Final)
    End point description
    Two alternative measures of insulin resistance, QUICKI and revised QUICKI, to further investigate the effect of telmisartan. Revised QUICKI = 1/(log G + log I + log NEFA), where G is fasting glucose (mg/dl), I is fasting insulin (μU/mL), and NEFA is plasma non esterified fatty acids concentration (mmol/l). Fasting glucose is recorded in mmol/l for the primary analysis, and the conversion factor for fasting glucose to convert from mmol/l to mg/dl is 18 (1 mmol/l = 18 mg/dl).
    End point type
    Secondary
    End point timeframe
    Change in revised-QUICKI at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    91
    86
    Units: Number of patients
    91
    86
    Attachments
    		 Untitled (Filename: Longitudinal Revised QUICKI.pdf)
    Statistical analysis title
    		 Longitudinal analysis revised-QUICKI (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0295
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 0.068

    Secondary: HDL-c longitudinal (Final)

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    End point title
    		 HDL-c longitudinal (Final)
    End point description
    Increase in HDL-c is a marker for a change in lipid profile
    End point type
    Secondary
    End point timeframe
    increase in HDL-c at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    94
    90
    Units: Number of patients
    94
    90
    Attachments
    		 Untitled (Filename: Longitudinal HDLc.pdf)
    Statistical analysis title
    		 Longitudinal analysis HDL-c (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6004
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.036
         upper limit
    		 0.05

    Secondary: Cholesterol longitudinal (Final)

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    End point title
    		 Cholesterol longitudinal (Final)
    End point description
    Reduction in total cholesterol is a marker for a change in lipid profile
    End point type
    Secondary
    End point timeframe
    Reduction in total cholesterol at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    94
    90
    Units: Number of patients
    94
    90
    Attachments
    		 Untitled (Filename: Longitudinal Cholesterol.pdf)
    Statistical analysis title
    		 Longitudinal analysis cholesterol (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8375
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.016
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.156

    Secondary: Triglycerides longitudinal (Final)

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    End point title
    		 Triglycerides longitudinal (Final)
    End point description
    Reduction in Triglycerides profile is a marker for a change in lipid profile
    End point type
    Secondary
    End point timeframe
    Reduction in Triglycerides profile at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    94
    90
    Units: Number of patients
    94
    90
    Attachments
    		 Untitled (Filename: Longitudinal Triglycerides.pdf)
    Statistical analysis title
    		 Longitudinal analysis Triglycerides (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4997
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.056
         upper limit
    		 0.106

    Secondary: LDL-c longitudinal (Final)

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    End point title
    		 LDL-c longitudinal (Final)
    End point description
    Reduction in LDL-c profile is a marker for a change in lipid profile
    End point type
    Secondary
    End point timeframe
    Reduction in LDL-c profile at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    93
    89
    Units: Number of patients
    93
    89
    Attachments
    		 Untitled (Filename: Longitudinal LDLc.pdf)
    Statistical analysis title
    		 Longitudinal analysis LDL-c (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9643
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.131
         upper limit
    		 0.11

    Secondary: Adiponectin longitudinal (Final)

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    End point title
    		 Adiponectin longitudinal (Final)
    End point description
    Change in Adiponectin is a biomarker of Change in plasma concentration
    End point type
    Secondary
    End point timeframe
    Change in adiponectin at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    93
    87
    Units: Number of patients
    93
    87
    Attachments
    		 Untitled (Filename: Longitudinal Adiponectin.pdf)
    Statistical analysis title
    		 Longitudinal analysis Adiponectin (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4172
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.043
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.072
         upper limit
    		 0.143

    Secondary: Leptin longitudinal (Final)

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    End point title
    		 Leptin longitudinal (Final)
    End point description
    Change in Leptin is a biomarker of Change in plasma concentration
    End point type
    Secondary
    End point timeframe
    Change in Leptin at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    94
    89
    Units: Number of patients
    94
    89
    Attachments
    		 Untitled (Filename: Longitudinal Leptin.pdf)
    Statistical analysis title
    		 Longitudinal analysis Leptin (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6467
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.097
         upper limit
    		 0.192

    Secondary: IL8 longitudinal (Final)

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    End point title
    		 IL8 longitudinal (Final)
    End point description
    Change in IL8 is a biomarker of change in plasma concentration
    End point type
    Secondary
    End point timeframe
    Change in IL8 at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    94
    89
    Units: Number of patients
    94
    89
    Attachments
    		 Untitled (Filename: Longitudinal IL8.pdf)
    Statistical analysis title
    		 Longitudinal analysis IL8 (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4712
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.049
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.082
         upper limit
    		 0.17

    Secondary: TNF-α longitudinal (Final)

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    End point title
    		 TNF-α longitudinal (Final)
    End point description
    Change in TNF-α is a biomarker of change in plasma concentration
    End point type
    Secondary
    End point timeframe
    Change in TNF-α at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    93
    88
    Units: Number of patients
    93
    88
    Attachments
    		 Untitled (Filename: Longitudinal TNFalpha.pdf)
    Statistical analysis title
    		 Longitudinal analysis TNF-α (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7026
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.077

    Secondary: Resistin longitudinal (Final)

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    End point title
    		 Resistin longitudinal (Final)
    End point description
    Change in Resistin is a biomarker of change in plasma concentration
    End point type
    Secondary
    End point timeframe
    Change in Resistin at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    94
    88
    Units: Number of patients
    94
    88
    Attachments
    		 Untitled (Filename: Longitudinal Resistin.pdf)
    Statistical analysis title
    		 Longitudinal analysis Resistin (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1308
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.068
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.153
         upper limit
    		 0.024

    Secondary: hs-CRP longitudinal (Final)

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    End point title
    		 hs-CRP longitudinal (Final)
    End point description
    Change in hs-CRP is a biomarker of change in plasma concentration
    End point type
    Secondary
    End point timeframe
    Change in hs-CRP at T+12, T+24 and T+48 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    94
    90
    Units: Number of patients
    94
    90
    Attachments
    		 Untitled (Filename: Longitudinal hsCRP.pdf)
    Statistical analysis title
    		 Longitudinal analysis hs-CRP (Final)
    Statistical analysis description
    To identifying change in the expression of the markers in arm D in comparison to arm A, a joint model of the longitudinal marker will be fitted adjusting for the dropout from the study. Patients who had a missing marker were considered as ‘dropouts’ and the first time point (t = 12, 24, or 48) at which marker is missing is taken as the time of dropout. Those who did not dropout from the study before t =48 (had complete record of biomarker) were censored at 48 weeks.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0289
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.236
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.475
         upper limit
    		 -0.062

    Secondary: Internal visceral fat (MRI/ MRS Substudy)

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    End point title
    		 Internal visceral fat (MRI/ MRS Substudy)
    End point description
    Reduction in visceral fat at T+24 weeks between telmisartan treated arms and control arm
    End point type
    Secondary
    End point timeframe
    Change in body fat redistribution as measured by MRI/MRS at T+24 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    8 [16]
    8 [17]
    Units: dm^3
    arithmetic mean (standard deviation)
        Baseline
    3.53 ± 1.08
    4.10 ± 2.71
        Week 24
    3.74 ± 1.43
    4.74 ± 2.59
    Attachments
    		 Untitled (Filename: Sub study data.pdf)
    Notes
    [16] - 8 baseline, 8 week 24, 8 have both baseline and week 24 measurements so included in analysis
    [17] - 8 baseline, 8 week 24, 8 have both baseline and week 24 measurements so included in analysis
    Statistical analysis title
    		 Internal visceral fat (MRI/MRS sub-study)
    Statistical analysis description
    Multiple linear regression models will be fitted to explore the differences in outcomes between treatment arms with control as the reference level while accounting for potential confounders. Model : Internal visceral fat at 24 weeks will be the outcome variable. A multiple linear regression model will be fitted. The relative change of total external fat (=(value at 24 weeks - value at baseline)/value at baseline) will be added in the model to account for this potential confounder.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.879
    Method
    		 Regression, Linear
    Parameter type
    		 Slope
    Point estimate
    0.043
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.563
         upper limit
    		 0.65

    Secondary: Expected/unexpected SAEs

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    End point title
    		 Expected/unexpected SAEs
    End point description
    Difference in expected and unexpected SAEs between Telmisartan treated arms(s) and the control arm.
    End point type
    Secondary
    End point timeframe
    Adverse event reporting will occur from the point that the participant provides informed consent and throughout the trial treatment period up until seven days after the patient has taken the final dose of investigational medicinal product.
    End point values
    		 Arm A (Baseline) Arm B (Baseline) Arm C (Baseline) Arm D (Baseline)
    Number of subjects analysed
    105 [18]
    84 [19]
    82 [20]
    106 [21]
    Units: Number of patients
    5
    3
    4
    7
    Notes
    [18] - Number of events 6
    [19] - Number of events 3
    [20] - Number of events 4
    [21] - Number of events 8
    Statistical analysis title
    		 Expected/ Unexpected SAEs
    Statistical analysis description
    Difference in expected and unexpected SAEs between telmisartan treated arm(s) and the control arm.
    Comparison groups
    Arm B (Baseline) v Arm C (Baseline) v Arm D (Baseline) v Arm A (Baseline)
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8152
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Intrahepatic fat (MRI/ MRS Substudy)

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    End point title
    		 Intrahepatic fat (MRI/ MRS Substudy)
    End point description
    Change in intrahepatic fat as measured by MRI/MRS at T+24 weeks between telmisartan treated arms and control arm
    End point type
    Secondary
    End point timeframe
    Change in intrahepatic fat as measured by MRI/MRS at T+24 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    8 [22]
    8 [23]
    Units: CH2/H20 (%)
    arithmetic mean (standard deviation)
        Baseline
    8.21 ± 18.23
    2.24 ± 4.17
        Week 24
    3.01 ± 4.07
    1.60 ± 2.26
    Attachments
    		 Untitled (Filename: Primary efficacy data.pdf)
    Notes
    [22] - 12 baseline, 8 week 24, 8 have both baseline and week 24 measurements so included in analysis
    [23] - 10 baseline, 8 week 24, 8 have both baseline and week 24 measurements so included in analysis
    Statistical analysis title
    		 Intrahepatic fat (MRI/MRS sub-study)
    Statistical analysis description
    Multiple linear regression models will be fitted to explore the differences in outcomes between treatment arms with control as the reference level while accounting for potential confounders. Model : Intrahepatic triglyceride content in liver at 24 weeks will be the outcome variable. A multiple linear regression model will be fitted.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0688
    Method
    		 Regression, Linear
    Parameter type
    		 Slope
    Point estimate
    -1.309
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.734
         upper limit
    		 0.116

    Secondary: Lower leg muscle (MRI/ MRS Substudy)

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    End point title
    		 Lower leg muscle (MRI/ MRS Substudy)
    End point description
    Change in lower leg muscle fat at T+24 weeks between telmisartan treated arms and control arm
    End point type
    Secondary
    End point timeframe
    Change in lower leg muscle fat at T+24 weeks between telmisartan treated arm (arm D) and the control arm (arm A).
    End point values
    		 Arm A (Final) Arm D (Final)
    Number of subjects analysed
    8 [24]
    8 [25]
    Units: CH2/creatine
    arithmetic mean (standard deviation)
        Soleus Baseline
    19.50 ± 10.78
    17.29 ± 11.77
        Soleus Week 24
    19.45 ± 13.25
    16.63 ± 8.97
        Tibialis Baseline
    6.25 ± 3.10
    7.82 ± 2.79
        Tibialis Week 24
    8.10 ± 4.97
    7.41 ± 2.73
    Attachments
    		 Untitled (Filename: Sub study data.pdf)
    Notes
    [24] - Soleus: 12 baseline, 8 week 24, 8 analysed. Tibialis: 11 baseline, 8 week 24, 8 analysed.
    [25] - Soleus: 10 baseline, 8 week 24, 8 analysed. Tibialis: 9 baseline, 8 week 24, 8 analysed.
    Statistical analysis title
    		 lower leg muscle: bi-dimensional (substudy)
    Statistical analysis description
    Multiple linear regression models will be fitted to explore the differences in outcomes between treatment arms with control as the reference level while accounting for potential confounders. Model: Intramyocellular triglyceride content in the soleus and tibialis anterior at 24 weeks will be treated as a bi-dimensional outcome. A multivariate multiple regression model will be fitted.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7839
    Method
    		 Regression, Linear
    Confidence interval
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Lower leg muscle: Soleus (MRI/ MRS Substudy)
    Statistical analysis description
    Multiple linear regression models will be fitted to explore the differences in outcomes between treatment arms with control as the reference level while accounting for potential confounders. Model: Intramyocellular triglyceride content in the soleus at 24 weeks will be the outcome variable. A multiple linear regression model will be fitted.
    Comparison groups
    Arm A (Final) v Arm D (Final)
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.245
    Method
    		 Regression, Linear
    Parameter type
    		 Slope
    Point estimate
    -2.977
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.278
         upper limit
    		 2.324
    Statistical analysis title
    		 Lower leg muscle: Tibialis (MRI/ MRS Substudy)
    Statistical analysis description
    Multiple linear regression models will be fitted to explore the differences in outcomes between treatment arms with control as the reference level while accounting for potential confounders. Model: Intramyocellular triglyceride content in the Tibialis at 24 weeks will be the outcome variable. A multiple linear regression model will be fitted.
    Comparison groups
    Arm D (Final) v Arm A (Final)
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8539
    Method
    		 Regression, Linear
    Parameter type
    		 Slope
    Point estimate
    -0.442
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.557
         upper limit
    		 4.673

    Secondary: Urinary biomarker (sub-study)

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    End point title
    		 Urinary biomarker (sub-study)
    End point description
    Change in urinary biomarker levels (creatine, urea, total protein, novel biomarkers such as KIM-1, NGAL, and RBP) at T+12, T+24 and T+48 weeks between telmisartan treated arm(s) and the control arm.The assessment of renal safety biomarkers was not planned to take place as part of the main study assessments, and will not be included in the final report to the TAILoR funder however this analysis has since been conducted and have been included for completion. See attached pdf for details.
    End point type
    Secondary
    End point timeframe
    Change in urinary biomarker levels (creatine, urea, total protein, novel biomarkers such as KIM-1, NGAL, and RBP) at T+12, T+24 and T+48 weeks between telmisartan treated arm(s) and the control arm.
    End point values
    		 Arm A (Baseline) Arm B (Baseline) Arm C (Baseline) Arm D (Baseline)
    Number of subjects analysed
    105 [26]
    84 [27]
    82 [28]
    106 [29]
    Units: Number randomised
    105
    84
    82
    106
    Attachments
    		 Untitled (Filename: Urine Sub study data.pdf)
    Notes
    [26] - Number analysed not specified in final report. 105 is the number randomised - see pdf for analysis.
    [27] - Number analysed not specified in final report. 84 is the number randomised - see pdf for analysis.
    [28] - Number analysed not specified in final report. 82 is the number randomised - see pdf for analysis.
    [29] - Number analysed not specified in final report. 106 is the number randomised - see pdf for analysis.
    No statistical analyses for this end point

    Other pre-specified: Reduction in insulin resistance measured by HOMA-IR (Interim analysis)

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    End point title
    		 Reduction in insulin resistance measured by HOMA-IR (Interim analysis)
    End point description
    The interim analysis was scheduled to take place once the 24 week change in HOMA-IR score was available for at least 42 patients in each arm. The sample standard deviation pooled across all four arms was used to construct test statistics expressing the advantage of each of the three active treatments over the control arm. There were 48/49/47/45 patients who were randomised to arms A/B/C/D respectively, with a total of 189 patients available for analysis. However, only 154 patients had a complete set of baseline and 24 week HOMA-IR data and were therefore included in the analysis. There were 39 in A, 45 in B, 35 in C and 35 in D included in the analysis. 31 patients were unavailable for analysis due to withdrawal from the study, visit not attended and loss to follow-up. There were 7 in A, 4 in B, 11 in C and 9 in D who were unavailable. There were 4 patients who were missing data at either baseline or week 24 and were excluded from the analysis, 2 in A, 0 in B, 1 in C and 1 in D.
    End point type
    Other pre-specified
    End point timeframe
    24 week change in HOMA-IR from baseline. The database requires a p-value or a confidence interval to be reported, however this information was unavailable - see attached pdf for full analysis results for this outcome.
    End point values
    		 Arm A (Baseline) Arm B (Baseline) Arm C (Baseline) Arm D (Baseline)
    Number of subjects analysed
    39 [30]
    45 [31]
    35 [32]
    35 [33]
    Units: HOMA-IR
    arithmetic mean (standard deviation)
        Baseline
    2.4 ± 2
    2.3 ± 1.6
    2.8 ± 3.9
    2.6 ± 2.7
        Week 24
    2.5 ± 1.9
    2.7 ± 1.9
    3.4 ± 4.4
    2.5 ± 1.7
    Attachments
    		 Untitled (Filename: Interim.pdf)
    Notes
    [30] - Interim analysis: 48 randomised, 7 Withdrew, did not attend wk24 or loss to followup, 2 missing data
    [31] - Interim analysis: 49 randomised, 4 Withdrew, did not attend wk24 or loss to followup, 0 missing data
    [32] - Interim analysis: 47 randomised, 11 Withdrew, didn't attend wk24 or loss to followup, 1 missing data
    [33] - Interim analysis: 45 randomised, 9 Withdrew, did not attend wk24 or loss to followup, 1 missing data
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event reporting will occur from the point that the participant provides informed consent and throughout the trial treatment period up until seven days after the patient has taken the final of investigational medicinal product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Control arm, no exposure to treatment but still included for reporting of serious adverse events.

    Reporting group title
    Arm B
    Reporting group description
    		 Telmisartan (20mg daily)

    Reporting group title
    Arm C
    Reporting group description
    		 Telmisartan (40mg daily)

    Reporting group title
    Arm D
    Reporting group description
    		 Telmisartan (80mg daily)

    Serious adverse events
    		 Arm A Arm B Arm C Arm D
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 105 (4.76%)
    3 / 84 (3.57%)
    4 / 82 (4.88%)
    7 / 106 (6.60%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasmablastic lymphoma
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected bite
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis cryptococcal
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A Arm B Arm C Arm D
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 105 (0.00%)
    28 / 84 (33.33%)
    28 / 82 (34.15%)
    49 / 106 (46.23%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    1 / 82 (1.22%)
    1 / 106 (0.94%)
         occurrences all number
    0
    1
    2
    1
    Orthostatic hypotension
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    2 / 82 (2.44%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    3
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    1
    1
    Fatigue
         subjects affected / exposed
    0 / 105 (0.00%)
    4 / 84 (4.76%)
    4 / 82 (4.88%)
    6 / 106 (5.66%)
         occurrences all number
    0
    5
    4
    6
    Feeling cold
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Feeling hot
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    Ejaculation failure
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    2 / 106 (1.89%)
         occurrences all number
    0
    0
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    1
    1
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    3 / 82 (3.66%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    3
    1
    Confusional state
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Depressed mood
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    3 / 106 (2.83%)
         occurrences all number
    0
    1
    0
    3
    Morbid thoughts
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Congenital, familial and genetic disorders
    Double ureter
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    3 / 106 (2.83%)
         occurrences all number
    0
    0
    0
    3
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Amnesia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Burning sensation
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 105 (0.00%)
    6 / 84 (7.14%)
    6 / 82 (7.32%)
    16 / 106 (15.09%)
         occurrences all number
    0
    6
    7
    17
    Dysgeusia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    0 / 105 (0.00%)
    6 / 84 (7.14%)
    7 / 82 (8.54%)
    9 / 106 (8.49%)
         occurrences all number
    0
    6
    7
    11
    Loss of consciousness
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    2 / 106 (1.89%)
         occurrences all number
    0
    0
    0
    2
    Somnolence
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tension headache
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    2
    Lacrimation increased
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    1 / 82 (1.22%)
    2 / 106 (1.89%)
         occurrences all number
    0
    1
    1
    2
    Visual impairment
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    3 / 82 (3.66%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    3
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    2 / 82 (2.44%)
    6 / 106 (5.66%)
         occurrences all number
    0
    1
    3
    6
    Dry mouth
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 105 (0.00%)
    2 / 84 (2.38%)
    1 / 82 (1.22%)
    1 / 106 (0.94%)
         occurrences all number
    0
    2
    1
    1
    Faeces soft
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    2 / 106 (1.89%)
         occurrences all number
    0
    0
    0
    2
    Nausea
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    2 / 82 (2.44%)
    1 / 106 (0.94%)
         occurrences all number
    0
    1
    3
    2
    Tongue coated
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    2 / 82 (2.44%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    2
    1
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 105 (0.00%)
    2 / 84 (2.38%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 105 (0.00%)
    4 / 84 (4.76%)
    1 / 82 (1.22%)
    3 / 106 (2.83%)
         occurrences all number
    0
    4
    1
    3
    Rash
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    1 / 82 (1.22%)
    4 / 106 (3.77%)
         occurrences all number
    0
    1
    1
    4
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal impairment
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Back pain
         subjects affected / exposed
    0 / 105 (0.00%)
    2 / 84 (2.38%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    2
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    2 / 106 (1.89%)
         occurrences all number
    0
    0
    0
    2
    Neck pain
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Osteopenia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Pain in jaw
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 105 (0.00%)
    2 / 84 (2.38%)
    1 / 82 (1.22%)
    4 / 106 (3.77%)
         occurrences all number
    0
    2
    1
    4
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    2 / 106 (1.89%)
         occurrences all number
    0
    0
    1
    2
    Onychomycosis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    0 / 82 (0.00%)
    1 / 106 (0.94%)
         occurrences all number
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 84 (1.19%)
    0 / 82 (0.00%)
    0 / 106 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 84 (0.00%)
    1 / 82 (1.22%)
    0 / 106 (0.00%)
         occurrences all number
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jun 2012
    Exclusion criteria amended in Page 18. An additional criterion was added: ‘Patients with cholestasis, biliary obstructive disorders or severe hepatic impairment’
    28 Sep 2012
    Section 14 - Indemnity statement amended to show that UoL holds Clinical Trial insurance Section 8.5 – Body fat redistribution amended to reflect that participants are free to withdraw from the sub study and remain in the main study, if they so wish Cover Page – the ISRCTN reference number has been added and the UoL sponsorreference number has been corrected Contact details – Clinical laboratory changed from RLH to UHA, CTRC Sherrington addressadded Section 1 – exclusion criteria number 12 ‘non hormonal contraception’ replaced with ‘reliable contraception’ Section 1 – point 7 added to ‘secondary objectives’ Section 1 – mention of ‘serum’ removed Section 2.1 – paragraph on possible renoprotective effects of Telmisartan added Section 2.3 point 7 added to secondary objectives Section 2.4.1 – paragraph on renal artery stenosis has been added Section 4.2 – point 6 added to secondary outcomes Section 5.2 – exclusion criteria number 12 ‘non hormonal contraception’ replaced with ‘reliable contraception’ Section 5.3.2 – point b – spelling mistake corrected Section 5.3.2 – Inserted j – it is discovered that the patient is pregnant Section 6.3 – point 7 – changed number of blood samples from 2 to 3 Section 6.3 – point 8 collection of urine sample added Section 7.2.2 – changed packaging description Section 7.3 – replaced phrase ‘treatment pack’ with ‘trial treatment’ Section 7.7.3 – amended to state the female patients discovering they are pregnant should let the research team know immediately Section 8.1 – table 1 – removed ‘collection of blood sample 1’ and collection of blood sample 2’ replaced with ‘collection of 3 blood samples for bioanalysis’ Section 8.1 – table 1 – inserted collection of urine sample Section 8.2.1 – replaced mention of Department of Clinical Biochemistry, Royal Liverpool Hospital, with ClinicalClinical Laboratories, University Hospital Aintree Section 8.2.1 – replaced ‘radioimmunoassay’ with enzymatic immunoassay’
    28 Sep 2012
    Section 8.4.1– replaced mention of Department of Clinical Biochemistry, Royal Liverpool Hospital, with Clinical Laboratories, University Hospital Aintree Section 8.4.2 – replaced mention of Department of Clinical Biochemistry, Royal Liverpool Hospital, with Clinical Laboratories, University Hospital Aintree Section 8.4.4 – section inserted to describe assessment of renal biomarkers Section 9.2 – Changed stratification details and added a sentence on ethnicity Contact details: Institutions– Clinical Laboratory changed from Department of Clinical Biochemistry, Royal Liverpool Hospital, to Clinical Laboratories, University Hospital Aintree Section 10.8– altered to reflect that adverse reactions and all serious events are to be recorded Section 10.8.1– Altered to reflect Telmisartan related ARs only Section 10.9 (– amended to read ‘all ARs that are observed or reported.....The investigator is also responsible for reporting all SAEs’ Section 10.9 i)– inserted ‘if a control (Arm A) patient has experienced an SAE the event does not need to be assessed for expectedness or relationship to study treatment, although the event should still be reported’ Section 10.9 ii)– amended phone number Section 10.9 iii)– amended fax number
    03 Sep 2013
    Contact details – these have been removed Section 1 – point 2 clarified Section 1 – point 6 clarified Section 1 – point 9 addition of extra drug group due to changes in Summary of Product Characteristics Section 4.2 – point 6 clarified Section 5.2 – point 2 clarified Section 5.2 – point 6 clarified Section 5.2 – point 9 further drug group/class added due to change in Summary of Product Characteristics Section 6.3 – point 3 further clarification of medical history Section 6.4 – added trial coordinator to contacts if a problem with the randomisation system arises and removed helpdesk Section 7.1 – statement inserted to clarify that treatment is not stopped between stage I and II Section 7.3.1 – added statement of time windows for visits Section 7.3.1.2 – clarification on time windows Section 7.3.1.2 – change to dispensing guidelines to minimise drug wastage Section 7.3.1.3 – clarification on time windows Section 7.3.1.3 – change to dispensing guidelines to minimise drug wastage Section 7.3.1.4 – clarification on time windows Section 7.3.1.4 – change to dispensing guidelines to minimise drug wastage Section 7.2 – clarification of ‘acceptable period of time Section 8.1 – clarification on time windows Section 8.1, table 1 – clarification on Medical History Section 10.4 – removal of fax number Section 10.9 – removal of fax number Section 10.10 – insertion of table 3 @SAE Evaluator Contacts Section 11.1.5 – insertion of statement on patient travel expenses Section 15.1 – insertion of statement on travel expenses
    24 Jan 2014
    Section 1 and section 5.2 – The units for the HbA1C value in exclusion criterion 1 have been Corrected Section 7 – removal of all mentions of ‘Micardis’ – a brand name of telmisartan Section 7.2.1 – insertion of a statement on dispensing of telmisartan if a high dose is unavailable Section 7.2.1 – insertion of statements on reference safety information and bioequivalence Section 7.2.3 – insertion of word manufacturers
    16 Jun 2014
    Section 1 and section 5.2 – the included and excluded drugs have been clarified Section 6.3 – insertion of the phrase ‘by a medically qualified person’ to the verification of eligibility criteria Section 7.3.3 – removal of the phrase ‘in the morning’ from the administration instructions Table 1 – Insertion of ‘by a medically qualified person’ to assessment of eligibility criteria Section 10.8.2 – Insertion of ‘All events that meet the serious criteria need to be reported (regardless of causality)’
    13 May 2015
    Glossary – Addition of abbreviation for Liverpool Clinical Laboratories Glossary – Deletion of University Hospitals Aintree Section 1 – change to the number of participants to be enrolled Section 8.2.1, 8.4.1, and 8.4.2 – replaced Clinical laboratories, University Hospitals Aintree with Liverpool Clinical Laboratories Section 8.4.5 and 8.5.4 – insertion of statement(s) on the reporting of any clinically significant results Section 9.4 – insertion of statement on what happens ‘post interim analysis’ Section 9.5 – insertion of statement that after interim analysis randomisation will continue in an equal ratio
    20 Jun 2016
    ***This protocol amendment occurred on 28/07/2016 which was after the global end of trial date 20/06/2016 (defined as last patient last visit). However the EudraCT database gives an error as it does not allow the date of amendment to be input later than the global end of trial date. To get round this error the date was entered was entered as the global end of trial date (20/06/2016) rather than the actual amendment date (28/07/2016).*** Cover page – insertion of trial statistician signature Protocol Summary – insertion of a further secondary objective Section 2.2 – insertion of a statement on alternative surrogate indices of insulin sensitivity Section 2.3 – insertion of a further secondary objective Section 4.2 – insertion of a further secondary outcome Section 8.4.3 – change to novel biomarkers Section 8.4.3 – removal of assessment of renal biomarkers Section 8.4.4 – addition of section on alternate measures of insulin resistance Section 8.5 – changed to sub-study 1 Section 8.6 – Insertion of sub-study 2 (assessment of renal biomarkers) Section 9.4.1 – changed to sub study 1 Section 9.4.2 – insertion of statement on sample size for sub study 2 (renal biomarkers) Section 9.6.2.1 – removal of assessment by structural equation models Section 9.6.2.3- insertion of statement on evaluation of alternate measures of insulin resistance Section 9.6.2.4 – insertion of statement on renal biomarkers References – addition of reference 57

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Apr 2015
    The decision was made as follows: • If the largest of these statistics exceeds a critical value (equal to 2.782), this would mean that one active dose group shows a substantially higher mean reduction of 24 week HOMA-IR score than the control group, and therefore the study will be stopped and the corresponding dose will be recommended for further testing. • If any active dose shows no improvement over control (i.e. has a negative measure of advantage) that active dose will be dropped from the second stage. • If all three active doses satisfy this criterion, then the study will be stopped and no significant improvement over control will be claimed for any of the active doses. • If some improvement over control is detected for at least one of the doses (i.e. if at least one test statistic is between 0 and 2.782), the study will progress to the second stage and the patients will be randomised between these dose(s) and control. Interim decision: • Drop arms B (20mg) and C (40mg). • Progress to the second stage of the study. Randomise patients between dose arm D (80mg) and control.
    10 Apr 2015

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    N/A
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