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    Clinical Trial Results:
    A single site, placebo controlled, double blind randomised clinical trial evaluating the effectiveness of metformin to prevent post-transplant diabetes in a cohort of patients undergoing renal transplantation.

    Summary
    EudraCT number
    		 2017-004880-11
    Trial protocol
    		 GB  
    Global end of trial date
    30 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jun 2023
    First version publication date
    18 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    012280
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05240274
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC: 18/LO/0958, IRAS: 203080
    Sponsors
    Sponsor organisation name
    Barts Health NHS Trust
    Sponsor organisation address
    Joint Research and Management Office, Dept. W, 69-89 Mile End Rd, London , London, United Kingdom, E1 4UJ
    Public contact
    Dr Kieran McCafferty, Barts Health NHS Trust , kieran.mccafferty4@nhs.net
    Scientific contact
    Dr Kieran McCafferty, Barts Health NHS Trust , kieran.mccafferty4@nhs.net
    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
    06 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether treating post-renal transplant patients with metformin as compared with placebo for 3 months lead to a long term reduction in post transplant diabetes mellitus, as defined by a positive 2 hour oral glucose tolerance test 1 year post transplant.
    Protection of trial subjects
    Participants were given a minimum 24 hours after being invited to take part in the clinical trial prior to being consented. They were encouraged to ask questions and were made aware that they could withdraw consent and stop participation in the trial at any time. Every effort was made to minimise any additional burden on the participants by synchronising trial visits with clinical visits and taking trial blood samples at the same time as clinical blood samples. Data protection and pseudonymisation were performed in line with recognised standards: the trial was performed in adherence to the principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), and all subsequent amendments of the clinical trial regulations, current UK Policy Framework for Health and Social Care Research, the World Medical Association Declaration of Helsinki (1996), GCP guidelines, the Sponsor’s SOPs, and other regulatory requirements as amended.
    Background therapy
    		 All participants received standard clinical care post-transplantation. This included triple immunosuppression (i.e. tacrolimus, mycophenolate mofetil and prednisolone). Clinicians were able to alter participants' medical therapies per clinical indication. If the IMP was thought to be responsible or contributing to an adverse event or serious adverse event, it could be held after discussion with the trial PI. If participants were thought to have developed hyperglycaemia, then their case should be discussed with the trial PI who would request an oral glucose tolerance test. Should it be found to be positive, the initiation of anti-diabetic medication would be determined on a case by case basis, with discussion between the PI and the clinical team.
    Evidence for comparator
    		 Kidney transplantation is widely held to be the optimal form of renal replacement therapy for patients with end-stage renal disease, leading to a longer survival and improved quality of life in patients receiving a renal transplant compared to those that remain on dialysis. However renal transplantation brings with it a new set of challenges for the clinician. One of the most important of these is post-transplant diabetes mellitus (PTDM). The prevalence of PTDM has increased over time and may occur in up to a third of all post-transplant patients making it a critical challenge for transplant physicians. PTDM tends to occur early post-transplant, with most patients developing PTDM within the first 3-6 months. A reason for this is the higher doses of immunosuppressive medication used during the early transplant period. Thus, the early post-transplant period represents a crucial window to intervene to reduce the incidence of PTDM. Recent evidence suggests that basal insulin may protect the pancreas from the pro-diabetogenic stimuli in the first months post-transplantation, thus preventing PTDM. However, insulin with its risks of hypoglycaemia and weight gain may not be the ideal therapy for this patient group. Metformin is a biguanide which leads to a reduction in hyperglycaemia by reducing the expression of gluconeogenesis genes, enhancing the uptake of glucose into cells and reducing free fatty acids which are the substrate for gluconeogenesis. It is recommended as the first line treatment for patients with type 2 diabetes. Our hypothesis is that treatment with metformin is safe and will significantly reduce the incidence of diabetes in a post renal transplant cohort of patients in a London Transplant unit.
    Actual start date of recruitment
    22 Jan 2019
    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: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    0
    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)
    56
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place at the Royal London Hospital from Jan 2019 to April 2021. There were two pauses to recruitment from March-July 2020 and from Dec 2020-March 2021 due to the COVID-19 pandemic: transplantation activity was halted and trial staff redeployed.

    Pre-assignment
    Screening details
    		 Eligible patients needed to be consented and have a negative OGTT and eGFR >/= 30ml/min within 10 days of transplant. Of 190 people approached: 39 declined, 30 did not meet criteria, already met target for 4; 30 screen-fail eGFR, 24 screen-fail OGTT; 2 screen-fail both; 1 started anti-diabetic drug; 60 enrolled and randomised.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject
    Blinding implementation details
    A spreadsheet of treatment codes (linked to either active substance or placebo) was created using an online generator using a block randomisation sequence and stored in the pharmacy dispensary. Each treatment code (for example A1, A2,…A60), was written on a card and sealed in an envelope. At randomisation, one envelope was chosen at random to associate study IDs with treatment codes. Only pharmacy and sponsor team had access to the treatment code matched to the treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Metformin
    Arm description
    		 Patients received 500mg OD metformin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg once daily

    Arm title
    		 Placebo
    Arm description
    		 Patients received placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo 500mg once daily

    Number of subjects in period 1
    		Metformin Placebo
    Started
    30
    30
    Completed
    30
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 Patients received 500mg OD metformin

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received placebo

    Reporting group values
    		 Metformin Placebo Total
    Number of subjects
    		 30 30 60
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    age of patients
    Units: years
        arithmetic mean (standard deviation)
    		 41.5 ± 12.6 46.6 ± 15.5 -
    Gender categorical
    Units: Subjects
        Female
    		 11 12 23
        Male
    		 19 18 37
    Patient ethnicity
    patient ethnicity
    Units: Subjects
        Asian
    		 10 4 14
        Black
    		 5 12 17
        White
    		 15 13 28
        Other
    		 0 1 1
    Family history of diabetes mellitus
    Family history of diabetes mellitus
    Units: Subjects
        Yes
    		 13 9 22
        No
    		 17 21 38
    Dialysis modality
    Type of renal replacement therapy prior to transplantation
    Units: Subjects
        Peritoneal dialysis
    		 6 9 15
        Haemodialysis
    		 17 14 31
        Pre-dialysis (pre-emptive transplant)
    		 7 7 14
    Cause of end-stage renal disease
    Cause of ESRF (broad categories)
    Units: Subjects
        Glomerular
    		 11 11 22
        Vascular
    		 5 12 17
        Tubulointerstitial
    		 0 0 0
        Polycystic kidney disease
    		 6 0 6
        Unknown
    		 6 3 9
        Other
    		 2 4 6
    Previous transplant
    History of previous transplant (no recipient had had more than one previous transplant)
    Units: Subjects
        No
    		 25 25 50
        Yes
    		 5 5 10
    Smoking status
    Smoking status
    Units: Subjects
        No
    		 29 30 59
        Yes
    		 1 0 1
    Type of transplant
    Type of renal transplant
    Units: Subjects
        DBD
    		 15 19 34
        DCD
    		 0 2 2
        live unrelated
    		 6 4 10
        live related
    		 9 5 14
    Extended criteria donor
    Extended criteria donor
    Units: Subjects
        No
    		 15 19 34
        Yes
    		 0 2 2
        Not applicable (live donor)
    		 15 9 24
    Donor cause of death
    Donor cause of death (broad categories)
    Units: Subjects
        Vascular
    		 9 11 20
        Trauma
    		 1 3 4
        Hypoxic
    		 5 4 9
        Infective
    		 0 1 1
        Other
    		 0 2 2
        Not available
    		 15 9 24
    Donor sex
    Donor sex
    Units: Subjects
        Female
    		 16 11 27
        Male
    		 14 19 33
    CMV serology match
    Donor to recipient CMV status
    Units: Subjects
        -/-
    		 5 6 11
        -/+
    		 8 8 16
        +/-
    		 2 3 5
        +/+
    		 15 13 28
    HLA mismatch (total)
    Number of HLA mismatches (total)
    Units: Subjects
        0 MM
    		 2 1 3
        1 MM
    		 3 3 6
        2 MM
    		 4 7 11
        3 MM
    		 12 11 23
        4 MM
    		 5 3 8
        5 MM
    		 3 5 8
        6 MM
    		 1 0 1
    Time on dialysis (vintage)
    number of days spent on dialysis
    Units: days
        median (inter-quartile range (Q1-Q3))
    		 662 (410 to 1992) 882 (515 to 1522) -
    Time on transplant waitlist
    number of days on transplant waiting list
    Units: days
        median (inter-quartile range (Q1-Q3))
    		 251.5 (51.3 to 421) 336.5 (161.5 to 800.5) -
    Height of patient
    patient height in metres
    Units: metre
        arithmetic mean (standard deviation)
    		 1.72 ± 0.10 1.70 ± 0.13 -
    Weight at screening
    patient weight in kg at screening visit
    Units: kilograms
        median (inter-quartile range (Q1-Q3))
    		 79.5 (68.6 to 87.3) 73.5 (62.2 to 81.9) -
    BMI at screening
    patient BMI at screening visit in kilograms per metres squared
    Units: kg/m2
        median (inter-quartile range (Q1-Q3))
    		 26.2 (23.9 to 29.1) 24.9 (22.1 to 27.3) -
    Donor age
    age of kidney donor
    Units: years
        arithmetic mean (standard deviation)
    		 43.5 ± 14.1 47.9 ± 16.5 -
    Transplant CIT
    cold ischaemia time of transplant in minutes
    Units: minutes
        median (inter-quartile range (Q1-Q3))
    		 404.5 (236 to 765) 588.5 (277.5 to 866.3) -
    Transplant WIT
    secondary warm ischaemia time of transplant in minutes
    Units: minutes
        median (inter-quartile range (Q1-Q3))
    		 31.5 (27.8 to 44.3) 32.5 (28.5 to 42.8) -
    Units of alcohol/week
    Units of alcohol consumed per week
    Units: units
        median (inter-quartile range (Q1-Q3))
    		 0 (0 to 0) 0 (0 to 0) -
    Systolic BP at screening
    Systolic BP at screening
    Units: mmHg
        arithmetic mean (standard deviation)
    		 147 ± 16.4 152 ± 21.8 -
    Diastolic BP at screening
    Diastolic BP at screening
    Units: mmHg
        arithmetic mean (standard deviation)
    		 89 ± 10.8 87 ± 10.1 -
    Hb at screening
    Haemoglobin at screening
    Units: g/L
        arithmetic mean (standard deviation)
    		 95.4 ± 15.2 89.5 ± 11.5 -
    WBC at screening
    White blood cell count at screening
    Units: x10^9
        median (inter-quartile range (Q1-Q3))
    		 6.9 (5.3 to 8.2) 7.4 (5.8 to 9.3) -
    Plts at screening
    Platelet count at screening
    Units: x10^9
        median (inter-quartile range (Q1-Q3))
    		 166 (132.8 to 195) 167 (138.3 to 235.3) -
    Na at screening
    Serum sodium at screening
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 139 (137 to 140) 139 (137 to 141) -
    K at screening
    Serum potassium at screening
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.4 ± 0.5 4.4 ± 0.4 -
    Bicarb at screening
    Serum bicarbonate at screening
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 23 ± 2.7 22 ± 2.9 -
    Urea at screening
    Serum urea at screening
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 8.0 (6.0 to 9.2) 8.9 (5.3 to 11.0) -
    Creatinine at screening
    Serum creatinine at screening
    Units: umol/L
        arithmetic mean (standard deviation)
    		 143 ± 40.8 156 ± 42.3 -
    eGFR at screening
    Estimated glomerular function rate at screening
    Units: ml/min
        median (inter-quartile range (Q1-Q3))
    		 42 (36 to 55) 35 (32 to 52) -
    ALT at screening
    Serum alanine transaminase at screening
    Units: unit/L
        median (inter-quartile range (Q1-Q3))
    		 25 (15.8 to 35) 28 (17 to 46.8) -
    ALP at screening
    Serum alkaline phosphatase at screening
    Units: unit/L
        median (inter-quartile range (Q1-Q3))
    		 60 (48 to 72) 61 (48.8 to 77.8) -
    cCa at screening
    Serum corrected calcium at screening
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.34 ± 0.2 2.29 ± 0.2 -
    PO4 at screening
    Serum phosphate at screening
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 0.63 (0.55 to 0.76) 0.82 (0.52 to 0.96) -
    CRP at screening
    Serum C-reactive protein at screening
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    		 7 (5 to 14.5) 11.5 (8 to 14) -
    Triglycerides at screening
    Serum triglycerides at screening
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 1.83 (1.33 to 2.25) 1.43 (1.11 to 1.69) -
    Mg at screening
    Serum magnesium at screening
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 0.8 (0.7 to 0.9) 0.9 (0.7 to 1.0) -
    Glucose at screening
    Serum glucose at screening
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 4.9 (4.5 to 5.4) 5.0 (4.6 to 5.5) -
    HbA1c at screening
    Glycated haemoglobin at screening (mmol/mol)
    Units: mmol/mol
        arithmetic mean (standard deviation)
    		 33 ± 4.4 33 ± 4.2 -
    UPCR at screening
    Urine protein:creatinine ratio at screening
    Units: mg/mmol
        median (inter-quartile range (Q1-Q3))
    		 46.6 (31.4 to 63.0) 57.1 (31.7 to 76.0) -
    C-peptide at screening
    Serum C-peptide at screening
    Units: pmol/L
        median (inter-quartile range (Q1-Q3))
    		 1136 (872 to 1379.5) 1143 (860.5 to 1444) -
    HOMA-IR at screening
    HOMA-IR (calculated measure of insulin resistance) at screening
    Units: units
        median (inter-quartile range (Q1-Q3))
    		 2.5 (1.86 to 2.94) 2.58 (1.80 to 3.23) -
    Tacrolimus level at screening
    Serum tacrolimus level at screening
    Units: mcg/L
        arithmetic mean (standard deviation)
    		 8.9 ± 4.0 7.6 ± 4.4 -
    OGTT time 0 at screening
    Glucose level at time 0 of oral glucose tolerance test at screening
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.7 ± 0.6 4.8 ± 0.6 -
    OGTT time 2 at screening
    Glucose level at time 2 (2 hours) of oral glucose tolerance test at screening
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 7.8 ± 1.7 8.5 ± 1.3 -
    CMV at screening
    Cytomegalovirus DNA viral load at screening
    Units: log units
        median (inter-quartile range (Q1-Q3))
    		 0 (0 to 0) 0 (0 to 0) -
    BKV at screening
    BK virus DNA viral load at screening
    Units: log units
        median (inter-quartile range (Q1-Q3))
    		 0 (0 to 0) 0 (0 to 0) -

    End points

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    End points reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 Patients received 500mg OD metformin

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received placebo

    Primary: Primary: Diagnosis of PTDM

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    End point title
    		 Primary: Diagnosis of PTDM
    End point description
    The primary end point is the diagnosis of diabetes following a 3 month course of metformin or placebo, defined as a positive 2-hour Oral Glucose tolerance (blood sugar greater than11.1mmol/l) test at 3, 6, or 12 months post-transplant, or following an OGTT due to suspected new diabetes at other routine clinical visits
    End point type
    Primary
    End point timeframe
    Between randomisation visit and month 12 visit
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    30 [1]
    30 [2]
    Units: proportion
        PTDM
    7
    5
        No PTDM
    23
    25
    Notes
    [1] - intention to treat
    [2] - intention to treat
    Statistical analysis title
    		 Kaplan-Meier survival
    Statistical analysis description
    Survival curve where event was defined as a diagnosis of PTDM by OGTT at any point between randomisation visit and 12 month visit
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Chi-square
    Statistical analysis description
    Diagnosis of PTDM as defined by positive OGTT at 3, 6 or 12 month visits
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 > 0.05
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [3] - Chi-square test

    Secondary: HOMA IR

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    End point title
    		 HOMA IR
    End point description
    The effect of 3/12 metformin on markers of pancreatic beta cell function using the HOMA-IR test (a calculation of insulin resistance) at 3,6, and 12 months
    End point type
    Secondary
    End point timeframe
    from randomisation visit to 12 month visit
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    30 [4]
    30 [5]
    Units: units
        arithmetic mean (standard deviation)
    2.74 ± 1.22
    1.83 ± 1.10
    Notes
    [4] - intention to treat
    [5] - intention to treat
    Statistical analysis title
    		 2-way repeated measure ANOVA
    Statistical analysis description
    2-way repeated measure ANOVA
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    P-value
    		 > 0.05 [7]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [6] - within subject = time; between subject = treatment allocation
    [7] - no significant difference caused by treatment allocation

    Secondary: HbA1c

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    End point title
    		 HbA1c
    End point description
    2 way repeated measure ANOVA on the effect of 3 months of metformin on HbA1c at 3, 6 and 12 months from baseline
    End point type
    Secondary
    End point timeframe
    from randomisation visit to month 12 visit
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    30
    30
    Units: mmol/mol
        arithmetic mean (standard deviation)
    39.4 ± 6.8
    36.4 ± 4.5
    Statistical analysis title
    		 2-way repeated measures ANOVA
    Comparison groups
    Placebo v Metformin
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05 [8]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [8] - change was significant over time but not by treatment allocation

    Secondary: IGTT

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    End point title
    		 IGTT
    End point description
    Chi-Square and Kaplan-Meier survival analysis on whether participants developed impaired glucose tolerance or post-transplant diabetes mellitus
    End point type
    Secondary
    End point timeframe
    from randomisation visit to 12 month visit
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    30
    30
    Units: proportion/patients
        No
    18
    16
        IGT or OGTT
    12
    14
    Statistical analysis title
    		 Kaplan-Meier
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Logrank
    Confidence interval

    Secondary: Renal function at 12 months

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    End point title
    		 Renal function at 12 months
    End point description
    renal function as measured by eGFR: difference between randomisation to 12 month (last eGFR carried forward if missing value)
    End point type
    Secondary
    End point timeframe
    from randomisation to month 12 visit
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    30 [9]
    30 [10]
    Units: ml/min
        arithmetic mean (standard deviation)
    56 ± 18.3
    51 ± 15.2
    Notes
    [9] - intention to treat
    [10] - intention to treat
    Statistical analysis title
    		 t-test
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Patient/graft survival

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    End point title
    		 Patient/graft survival
    End point description
    patient or graft survival over 12 months - all patients and grafts survived hence no further statistical analysis completed
    End point type
    Secondary
    End point timeframe
    from randomisation to month 12 visit
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    30 [11]
    30 [12]
    Units: proportion/participants
        Graft survived
    30
    30
        Patient survived
    30
    30
    Notes
    [11] - intention to treat
    [12] - intention to treat
    No statistical analyses for this end point

    Secondary: Episodes of acute rejection

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    End point title
    		 Episodes of acute rejection
    End point description
    episodes of acute rejection
    End point type
    Secondary
    End point timeframe
    from randomisation to month 12 visit
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    30
    30
    Units: proportion/participants
        Rejection
    2
    3
        No rejection
    28
    27
    Statistical analysis title
    		 Kaplan-Meier survival
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Logrank
    Confidence interval

    Secondary: AE events

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    End point title
    		 AE events
    End point description
    rate of AEs (inc SAEs) as per MedDRA system organ class - no adjustment for multiple events per subject
    End point type
    Secondary
    End point timeframe
    from screening visit to month 12 visit
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    30
    30
    Units: proportion/participants
        Blood & Lymphatic AE
    14
    19
        Cardiac AE
    2
    2
        ENT AE
    0
    2
        Endocrine AE
    1
    0
        Eye AE
    4
    3
        Gastro AE
    14
    22
        General Disorders AE
    20
    9
        Immune System AE
    2
    3
        Infections & Infestations AE
    27
    29
        Injury, Poisoning & Procedural AE
    18
    16
        Investigations AE
    25
    22
        Metabolism & Nutrition AE
    9
    8
        Musculoskeletal AE
    10
    15
        Neoplasms AE
    2
    3
        Nervous System AE
    17
    13
        Psych AE
    2
    5
        Renal & GU AE
    15
    20
        Reproductive & Breast AE
    5
    1
        Resp AE
    8
    6
        Skin AE
    10
    12
        Social AE
    1
    0
        Surgical & Medical Procedures AE
    1
    4
        Vascular AE
    24
    21
    Statistical analysis title
    		 Mann Whitney U
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from consent to 12 months after randomisation
    Adverse event reporting additional description
    AE collected at each study visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Metformin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 30 (23.33%)
    9 / 30 (30.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Post transplant lymphoproliferative disorder
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post-procedural urine leak
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arteriovenous fistula operation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia repair
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery stent placement
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Perinephric collection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jiroveci pneumonia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strongyloidiasis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Metformin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 30 (100.00%)
    30 / 30 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Vascular disorders
    Blood pressure fluctuation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    20 / 30 (66.67%)
    16 / 30 (53.33%)
         occurrences all number
    23
    17
    Hypotension
         subjects affected / exposed
    3 / 30 (10.00%)
    5 / 30 (16.67%)
         occurrences all number
    4
    5
    Intermittent claudication
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Lymphocele
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Lymphoedema
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Thrombophlebitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Thyroxine therapy
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Fatigue
         subjects affected / exposed
    7 / 30 (23.33%)
    2 / 30 (6.67%)
         occurrences all number
    7
    2
    Gait disturbance
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Oedema
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Peripheral swelling
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 30 (13.33%)
         occurrences all number
    3
    5
    Puncture site haemorrhage
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 30 (3.33%)
         occurrences all number
    5
    2
    Suprapubic pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Swelling
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Swelling face
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Social circumstances
    Social problem
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Heavy menstrual bleeding
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Painful erection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Penile pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Perineal pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Polycystic ovaries
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Prostatism
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Testicular swelling
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    2
    3
    Dyspnoea
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Increased bronchial secretion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Obstructive sleep apnoea syndrome
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Upper airway cough syndrome
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Irritability
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Paramnesia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Paranoia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    2 / 30 (6.67%)
    5 / 30 (16.67%)
         occurrences all number
    2
    5
    Blood calcium decreased
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Blood calcium increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    6 / 30 (20.00%)
    4 / 30 (13.33%)
         occurrences all number
    6
    4
    Blood magnesium decreased
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Blood parathyroid hormone increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood phosphorus decreased
         subjects affected / exposed
    11 / 30 (36.67%)
    4 / 30 (13.33%)
         occurrences all number
    11
    4
    Blood potassium decreased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood potassium increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Culture urine positive
         subjects affected / exposed
    15 / 30 (50.00%)
    12 / 30 (40.00%)
         occurrences all number
    22
    21
    Heart rate irregular
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    2 / 30 (6.67%)
    6 / 30 (20.00%)
         occurrences all number
    2
    6
    Staphylococcus test positive
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Streptococcus test positive
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Strongyloides test positive
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Weight decreased
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Weight increased
         subjects affected / exposed
    7 / 30 (23.33%)
    6 / 30 (20.00%)
         occurrences all number
    7
    6
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Arteriovenous fistula aneurysm
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Arteriovenous fistula site complication
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Complications of transplant surgery
         subjects affected / exposed
    7 / 30 (23.33%)
    5 / 30 (16.67%)
         occurrences all number
    7
    5
    Foot fracture
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Incisional hernia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Joint dislocation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Penile contusion
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Post procedural contusion
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Post procedural haematoma
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Post procedural urine leak
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Postoperative wound complication
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Procedural pain
         subjects affected / exposed
    2 / 30 (6.67%)
    4 / 30 (13.33%)
         occurrences all number
    2
    4
    Product dose omission in error
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Product use issue
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Road traffic accident
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Vascular access site haemorrhage
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Wound complication
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 30 (10.00%)
         occurrences all number
    2
    4
    Wound secretion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Wrist fracture
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Wrong dose
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Sinus node dysfunction
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Burning sensation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Cerebral venous thrombosis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Dizziness postural
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Formication
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    6 / 30 (20.00%)
    1 / 30 (3.33%)
         occurrences all number
    7
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Migraine
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Neuralgia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    10 / 30 (33.33%)
    9 / 30 (30.00%)
         occurrences all number
    11
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 30 (23.33%)
    11 / 30 (36.67%)
         occurrences all number
    7
    11
    Leukocytosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    6 / 30 (20.00%)
    5 / 30 (16.67%)
         occurrences all number
    6
    6
    Neutropenia
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Polycythaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Thrombocytosis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Eye disorders
    Eye swelling
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Periorbital swelling
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Photophobia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Visual impairment
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Vitreous floaters
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    0 / 30 (0.00%)
    5 / 30 (16.67%)
         occurrences all number
    0
    5
    Abdominal pain upper
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    3 / 30 (10.00%)
    6 / 30 (20.00%)
         occurrences all number
    3
    6
    Diarrhoea
         subjects affected / exposed
    7 / 30 (23.33%)
    9 / 30 (30.00%)
         occurrences all number
    11
    9
    Dyspepsia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Gastritis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 30 (13.33%)
         occurrences all number
    3
    4
    Inguinal hernia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Rectal bleeding
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 30 (10.00%)
         occurrences all number
    4
    3
    Skin and subcutaneous tissue disorders
    Acanthosis nigricans
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Acne
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    4
    3
    Alopecia
         subjects affected / exposed
    4 / 30 (13.33%)
    2 / 30 (6.67%)
         occurrences all number
    4
    2
    Hypertrophic scar
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Keloid scar
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Night sweats
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Palisaded neutrophilic granulomatous dermatitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    Rash papular
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Rash pruritic
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Scar pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Skin depigmentation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Dysuria
         subjects affected / exposed
    5 / 30 (16.67%)
    4 / 30 (13.33%)
         occurrences all number
    6
    5
    Haematuria
         subjects affected / exposed
    4 / 30 (13.33%)
    5 / 30 (16.67%)
         occurrences all number
    5
    5
    Nocturia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Perinephric collection
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Pollakiuria
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Polyuria
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Proteinuria
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Renal artery stenosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Renal haematoma
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Renal impairment
         subjects affected / exposed
    4 / 30 (13.33%)
    5 / 30 (16.67%)
         occurrences all number
    4
    5
    Renal mass
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Renal tubular necrosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Urethral pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Hydronephrosis
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 30 (10.00%)
         occurrences all number
    4
    4
    Arthritis reactive
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Flank pain
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Groin pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Joint swelling
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    Limb mass
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Muscle twitching
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Myalgia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 30 (13.33%)
         occurrences all number
    3
    4
    Infections and infestations
    Body tinea
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Cellulitis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    COVID-19
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Cystitis klebsiella
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Cytomegalovirus viraemia
         subjects affected / exposed
    7 / 30 (23.33%)
    7 / 30 (23.33%)
         occurrences all number
    8
    7
    Escherichia urinary tract infection
         subjects affected / exposed
    6 / 30 (20.00%)
    5 / 30 (16.67%)
         occurrences all number
    8
    5
    Fungal foot infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gastroenteritis Escherichia coli
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Genital candidiasis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Genital herpes
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Genital herpes simplex
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Herpes simplex
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Herpes simplex viraemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Oral candidiasis
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 30 (10.00%)
         occurrences all number
    4
    3
    Oral herpes
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Orchitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Polyomavirus viraemia
         subjects affected / exposed
    7 / 30 (23.33%)
    7 / 30 (23.33%)
         occurrences all number
    7
    7
    Polyomavirus-associated nephropathy
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Proteus infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Pustular rash
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Renal graft infection
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 30 (10.00%)
         occurrences all number
    2
    3
    Rhinitis
         subjects affected / exposed
    6 / 30 (20.00%)
    5 / 30 (16.67%)
         occurrences all number
    7
    5
    Rhinovirus infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Tinea versicolour
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 30 (6.67%)
    5 / 30 (16.67%)
         occurrences all number
    2
    6
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Wound infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gout
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    Hypervolaemia
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Increased appetite
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Iron deficiency
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Malnutrition
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jun 2020
    New secondary outcome to follow-up patients who screen-fail for positive OGTT: review of records at 1 year post-transplant. Updated contact details, updated SPC, updated SAP, updated schedule of visits table to more accurately reflect the text. Extension to screening period from 7 to 10 days (COVID-19), and leeway for 3 month visit extended to 2 weeks, leeway for month 6 and 12 visits extended to 1 month (COVID-19). Study forms part of sub-I's PhD; CI is academic supervisor.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Mar 2020
    Recruitment interrupted due to cessation of transplant programme March-July 2020 and redeployment of research staff in response to the COVID-19 pandemic
    13 Jul 2020
    21 Dec 2020
    Recruitment interrupted due to cessation of transplant programme Dec 2020-March 2021 and redeployment of research staff in response to the COVID-19 pandemic
    15 Mar 2021

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to COVID-19, follow-up visits were late/missing (immunosuppressed patients declined to attend): missing 29 OGTTs total. 6 patients did not return IMP so unable to verify compliance; 4 patients had <80% adherence on return of IMP.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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