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    Clinical Trial Results:
    TriMaster: Randomised Double-Blind Crossover study of a DPP4 inhibitor, SGLT2 inhibitor and thiazolidinedione as third line therapy in patients with type 2 diabetes who have suboptimal glycaemic control on dual therapy with metformin and a sulphonylurea

    Summary
    EudraCT number
    		 2015-002790-38
    Trial protocol
    		 GB  
    Global end of trial date
    14 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Dec 2022
    First version publication date
    17 Dec 2022
    Other versions
    Summary report(s)
    		 TriMaster Patient Stratification Paper - final author accepted version

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1603221
    Additional study identifiers
    ISRCTN number
    		 ISRCTN12039221
    US NCT number
    		 NCT02653209
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC: 16/SC/0147, IRAS: 183044
    Sponsors
    Sponsor organisation name
    Royal Devon University Healthcare NHS Foundation Trust
    Sponsor organisation address
    Barrack Road, Exeter, United Kingdom, EX2 DW
    Public contact
    Chief Investigator, University of Exeter Medical School, 0044 1392408260, a.t.hattersley@exeter.ac.uk
    Scientific contact
    Chief Investigator, University of Exeter Medical School, 0044 1392408260, a.t.hattersley@exeter.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study aims to test 2 hypotheses of how well or poorly different subgroups of patients respond to particular drugs based on particular clinical characteristics such as their weight or blood test results. Hypothesis 1: Patients with insulin resistance (characterised by a raised BMI >30 kg/m2), compared to non-obese patients (BMI ≤30) will: a) respond well to pioglitazone b) respond less well to sitagliptin Hypothesis 2: Patients with modestly reduced renal function, compared to those with normal renal function will: a) respond poorly to canagliflozin b) respond well to sitagliptin Therefore the study’s primary research question: a) Do obese patients (BMI >30kgm-2), compared to non-obese patients, achieve a lower HbA1c when given pioglitazone rather than sitagliptin? b) Do patients with an eGFR <90 mls/min/1.73m2 achieve a lower HbA1c, compared to patients with an eGFR>90 mls/min/1.73m2, when givena sitagliptin rather than canagliflozin.
    Protection of trial subjects
    This study used established existing medications within their licensed indications to determine predictors of treatment response. SmPC updates related to drug safety were reviewed on a monthly basis by the CI/host centre via the https://www.medicines.org.uk/emc website. All required urgent safety measures were communicated to all PIs and research teams via email and the study database. Where necessary, participant information sheets were updated with new drug information. All study data was stored in link-anonymised format by unique participant ID in locked offices within research facilities. Where medical notes were required to confirm eligibility these were stored in line with NHS data protection guidelines. Electronic data was held on password protected computers, and databases hosted on University of Exeter secure severs requiring unique log-in access for each individual involved in research. Blood samples and meal tests were undertaken by fully qualified clinical staff. Participants were provided with contact information for local research staff, in case of side effects including hypoglycaemia and/or adverse events. This information was restated before each new drug period. An emergency unblinding service was provided by NIHR Exeter Clinical Research Facility, where following a detailed protocol staff were able to unblind study medication 24/7 for the duration of the study.
    Background therapy
    		 Metformin alone, or metformin and a sulphonylurea
    Evidence for comparator
    		 The three drugs used in the study were those oral-therapy classes recommended by the UK's NICE as standard care for those patients with type 2 diabetes who required a second or third intensification of drug treatment to maintain glucose levels. At the time of study design and set up these were thiazolidindione (pioglitazone), DPP4-i (sitagliptin) and SGLT2-i (canagliflozin).
    Actual start date of recruitment
    22 Nov 2016
    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: 525
    Worldwide total number of subjects
    525
    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)
    303
    From 65 to 84 years
    222
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 742 patients were screened for eligibility between 22 November 2016 and 24 January 2020, at 24 UK centres. Of these, 210 patients did not meet eligibility criteria, and seven withdrew before being randomized. 525 participants were randomized to one of the six sequences of drug allocations.

    Pre-assignment
    Screening details
    		 742 patients were identified in primary care/ research cohorts and screened for eligibility. Those eligible were invited to participate, provided with information sheets and attended a screening appointment. Written informed consent was given before screening data, including samples collected to confirm eligibility. Those eligible were randomised.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Randomisation was carried out at the baseline visit as described in the study protocol and statistical analysis plan. The three therapies were allocated in random order according to six possible treatment orders: ABC, ACB, BAC, BCA, CAB, CBA. Drugs were blinded by over-encapsulation

    Arms
    Arm title
    		 All subjects
    Arm description
    		 All subjects - ABC, ACB, BAC, BCA, CAB, CBA
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pioglitazone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (30mg) once daily

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (100mg) once daily

    Investigational medicinal product name
    Canagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (100mg) once daily

    Number of subjects in period 1
    		All subjects
    Started
    525
    Completed
    503
    Not completed
    22
         Ineligible
    2
         Consent withdrawn by subject
    10
         Adverse event, non-fatal
    4
         Lost to follow-up
    4
         Protocol deviation
    2
    Period 2
    Period 2 title
    Period 1
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    The three therapies were allocated in random order according to six possible treatment orders: ABC, ACB, BAC, BCA, CAB, CBA. Drugs were blinded by over-encapsulation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pioglitazone
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pioglitazone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (30mg) once daily

    Arm title
    		 Sitagliptin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (100mg) once daily

    Arm title
    		 Canagliflozin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Canagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (100mg) once daily

    Number of subjects in period 2
    		Pioglitazone Sitagliptin Canagliflozin
    Started
    168
    168
    167
    Completed
    165
    162
    163
    Not completed
    3
    6
    4
         Consent withdrawn by subject
    1
    5
    1
         Physician decision
    -
    1
    -
         Adverse event, non-fatal
    2
    -
    1
         Lost to follow-up
    -
    -
    1
         Protocol deviation
    -
    -
    1
    Period 3
    Period 3 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    The three therapies were allocated in random order according to six possible treatment orders: ABC, ACB, BAC, BCA, CAB, CBA. Drugs were blinded by over-encapsulation

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pioglitazone
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pioglitazone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (30mg) once daily

    Arm title
    		 Sitagliptin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (100mg) once daily

    Arm title
    		 Canagliflozin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Canagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (100mg) once daily

    Number of subjects in period 3
    		Pioglitazone Sitagliptin Canagliflozin
    Started
    164
    160
    166
    Completed
    152
    154
    163
    Not completed
    12
    6
    3
         Adverse event, serious fatal
    2
    1
    -
         Consent withdrawn by subject
    3
    4
    2
         Physician decision
    1
    1
    -
         Adverse event, non-fatal
    5
    -
    -
         Protocol deviation
    1
    -
    1
    Period 4
    Period 4 title
    Period 3
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    The three therapies were allocated in random order according to six possible treatment orders: ABC, ACB, BAC, BCA, CAB, CBA. Drugs were blinded by over-encapsulation

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pioglitazone
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pioglitazone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (30mg) once daily

    Arm title
    		 Sitagliptin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (100mg) once daily

    Arm title
    		 Canagliflozin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Canagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1x capsule (100mg) once daily

    Number of subjects in period 4
    		Pioglitazone Sitagliptin Canagliflozin
    Started
    155
    161
    153
    Completed
    152
    158
    148
    Not completed
    3
    3
    5
         Consent withdrawn by subject
    1
    -
    2
         Adverse event, non-fatal
    2
    1
    2
         Diagnosis of T1DM
    -
    1
    -
         Lost to follow-up
    -
    -
    1
         Protocol deviation
    -
    1
    -
    Period 5
    Period 5 title
    Period 4 - final visit
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Blinding to the allocation order remained until study end but there were no study drugs in period 4.

    Arms
    Arm title
    		 All subjects
    Arm description
    		 All subjects, ABC, ACB, BAC, BCA, CAB, CBA
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 5
    		All subjects
    Started
    458
    Completed
    457
    Not completed
    1
         Did not provide data
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Baseline = 525

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 525 525
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 303 303
        From 65-84 years
    		 222 222
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.9 ± 9.5 -
    Gender categorical
    Units: Subjects
        Female
    		 142 142
        Male
    		 383 383
    Subject analysis sets

    Subject analysis set title
    BMI >30 - Sitagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 1 - BMI strata >30 Sitagliptin

    Subject analysis set title
    BMI >30 - Pioglitazone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 1 - BMI strata >30 Pioglitazone

    Subject analysis set title
    BMI <30 - Sitagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 1 - BMI strata <30 Sitagliptin

    Subject analysis set title
    BMI <30 - Pioglitazone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 1 - BMI strata <30 Pioglitazone

    Subject analysis set title
    eGFR <90 - Sitagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 2 - eGFR strata <90 - Sitagliptin

    Subject analysis set title
    eGFR >90 - Sitagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 2 - eGFR strata >90 - Sitagliptin

    Subject analysis set title
    eGFR <90 - Canagliflozin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 2 - eGFR strata <90 - Canagliflozin

    Subject analysis set title
    eGFR >90 - Canagliflozin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 2 - eGFR strata >90 - Canagliflozin

    Subject analysis sets values
    		 BMI >30 - Sitagliptin BMI >30 - Pioglitazone BMI <30 - Sitagliptin BMI <30 - Pioglitazone eGFR <90 - Sitagliptin eGFR >90 - Sitagliptin eGFR <90 - Canagliflozin eGFR >90 - Canagliflozin
    Number of subjects
    215
    215
    141
    141
    163
    179
    163
    179
    Age categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.5 ± 9.2
    61.5 ± 9.2
    64.2 ± 8.7
    64.2 ± 8.7
    67.2 ± 7.4
    57.8 ± 8.7
    67.2 ± 7.4
    57.8 ± 8.7
    Gender categorical
    Units: Subjects
        Female
    58
    58
    37
    37
    36
    54
    36
    54
        Male
    157
    157
    104
    104
    127
    179
    127
    179

    End points

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    End points reporting groups
    Reporting group title
    All subjects
    Reporting group description
    		 All subjects - ABC, ACB, BAC, BCA, CAB, CBA
    Reporting group title
    Pioglitazone
    Reporting group description
    		 -

    Reporting group title
    Sitagliptin
    Reporting group description
    		 -

    Reporting group title
    Canagliflozin
    Reporting group description
    		 -
    Reporting group title
    Pioglitazone
    Reporting group description
    		 -

    Reporting group title
    Sitagliptin
    Reporting group description
    		 -

    Reporting group title
    Canagliflozin
    Reporting group description
    		 -
    Reporting group title
    Pioglitazone
    Reporting group description
    		 -

    Reporting group title
    Sitagliptin
    Reporting group description
    		 -

    Reporting group title
    Canagliflozin
    Reporting group description
    		 -
    Reporting group title
    All subjects
    Reporting group description
    		 All subjects, ABC, ACB, BAC, BCA, CAB, CBA

    Subject analysis set title
    BMI >30 - Sitagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 1 - BMI strata >30 Sitagliptin

    Subject analysis set title
    BMI >30 - Pioglitazone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 1 - BMI strata >30 Pioglitazone

    Subject analysis set title
    BMI <30 - Sitagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 1 - BMI strata <30 Sitagliptin

    Subject analysis set title
    BMI <30 - Pioglitazone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 1 - BMI strata <30 Pioglitazone

    Subject analysis set title
    eGFR <90 - Sitagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 2 - eGFR strata <90 - Sitagliptin

    Subject analysis set title
    eGFR >90 - Sitagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 2 - eGFR strata >90 - Sitagliptin

    Subject analysis set title
    eGFR <90 - Canagliflozin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 2 - eGFR strata <90 - Canagliflozin

    Subject analysis set title
    eGFR >90 - Canagliflozin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Hypothesis 2 - eGFR strata >90 - Canagliflozin

    Primary: HbA1c value achieved after each treatment period

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    End point title
    		 HbA1c value achieved after each treatment period
    End point description
    End point type
    Primary
    End point timeframe
    16 weeks on treatment (12-18weeks)
    End point values
    		 BMI >30 - Sitagliptin BMI >30 - Pioglitazone BMI <30 - Sitagliptin BMI <30 - Pioglitazone eGFR <90 - Sitagliptin eGFR >90 - Sitagliptin eGFR <90 - Canagliflozin eGFR >90 - Canagliflozin
    Number of subjects analysed
    100
    100
    100
    100
    100
    100
    100
    100
    Units: mmol/mol
        arithmetic mean (standard deviation)
    60.5 ± 11.5
    59.0 ± 11.5
    58.3 ± 8.6
    59.7 ± 10.4
    59.0 ± 9.6
    60.6 ± 11.7
    60.7 ± 8.7
    59.6 ± 9.4
    Statistical analysis title
    		 Hypothesis 1
    Comparison groups
    BMI >30 - Sitagliptin v BMI >30 - Pioglitazone v BMI <30 - Sitagliptin v BMI <30 - Pioglitazone
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0003
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 4.85
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Hypothesis 2
    Comparison groups
    eGFR <90 - Sitagliptin v eGFR >90 - Sitagliptin v eGFR <90 - Canagliflozin v eGFR >90 - Canagliflozin
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 4.61
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from consent to study end, including of-treatment period between visits 4 and 5.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    		 -

    Serious adverse events
    		 All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    41 / 503 (8.15%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowel cancer
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Hernia repair
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip surgery
         subjects affected / exposed
    2 / 503 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Physiotherapy
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostatectomy
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal operation
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Social circumstances
    Alcohol use
         subjects affected / exposed
    2 / 503 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract infection
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung Infection
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    COPD
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 503 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Nervous breakdown
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Cardiac ventriculogram
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Eye injury
         subjects affected / exposed
    4 / 503 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute chest syndrome
         subjects affected / exposed
    41 / 503 (8.15%)
         occurrences causally related to treatment / all
    0 / 45
         deaths causally related to treatment / all
    0 / 3
    Atrial fibrillation
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    3 / 503 (0.60%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Angina unstable
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Vertigo
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bleeding
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Flank pain
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    406 / 503 (80.72%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign and malignant combined
         subjects affected / exposed
    3 / 503 (0.60%)
         occurrences all number
    3
    Vascular disorders
    Vascular disorders combined
         subjects affected / exposed
    22 / 503 (4.37%)
         occurrences all number
    24
    Surgical and medical procedures
    Surgical and medical procedures combined
         subjects affected / exposed
    22 / 503 (4.37%)
         occurrences all number
    32
    General disorders and administration site conditions
    General disorders and administration site conditions combined
         subjects affected / exposed
    123 / 503 (24.45%)
         occurrences all number
    165
    Immune system disorders
    Immune system disorders combined
         subjects affected / exposed
    3 / 503 (0.60%)
         occurrences all number
    3
    Reproductive system and breast disorders
    Reproductive system and breast disorders combined
         subjects affected / exposed
    124 / 503 (24.65%)
         occurrences all number
    176
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders combined
         subjects affected / exposed
    90 / 503 (17.89%)
         occurrences all number
    112
    Psychiatric disorders
    Psychiatric disorders combined
         subjects affected / exposed
    26 / 503 (5.17%)
         occurrences all number
    31
    Investigations
    Investigations combined
         subjects affected / exposed
    24 / 503 (4.77%)
         occurrences all number
    31
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural combined
         subjects affected / exposed
    26 / 503 (5.17%)
         occurrences all number
    34
    Cardiac disorders
    Cardiac disorders combined
         subjects affected / exposed
    16 / 503 (3.18%)
         occurrences all number
    20
    Nervous system disorders
    Nervous system disorders combined
         subjects affected / exposed
    118 / 503 (23.46%)
         occurrences all number
    163
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    14 / 503 (2.78%)
         occurrences all number
    14
    Ear and labyrinth disorders
    Ear and labyrinth disorders combined
         subjects affected / exposed
    12 / 503 (2.39%)
         occurrences all number
    12
    Eye disorders
    Eye disorders combined
         subjects affected / exposed
    34 / 503 (6.76%)
         occurrences all number
    35
    Gastrointestinal disorders
    Gastrointestinal disorders combined
         subjects affected / exposed
    200 / 503 (39.76%)
         occurrences all number
    373
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders combined
         subjects affected / exposed
    95 / 503 (18.89%)
         occurrences all number
    131
    Renal and urinary disorders
    Renal and urinary disorders combined
         subjects affected / exposed
    149 / 503 (29.62%)
         occurrences all number
    201
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 503 (0.20%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders combined
         subjects affected / exposed
    131 / 503 (26.04%)
         occurrences all number
    174
    Infections and infestations
    Infections combined
         subjects affected / exposed
    14 / 503 (2.78%)
         occurrences all number
    14
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders combined
         subjects affected / exposed
    187 / 503 (37.18%)
         occurrences all number
    351

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Sep 2016
    Amendment to randomisation process to allocate individual bottles rather than ‘packs’ of 3 bottles to allow for shorter expiry dates, and clarification of safety reporting procedures
    25 May 2017
    Amendment to exclusion criteria to allow patients who have previously tried the study drugs to be included, as long as this has not been in the previous 3 months. The original criteria was unnecessarily strict and did not reflect real-world prescribing habits. The amendment also removed the blanket exclusion for patients in concurrent clinical trials, providing sufficient washout period between IMPs.
    07 Sep 2017
    Amendment to eligibility criteria to include patients taking metformin-only, or metformin and a sulfonylurea. This was adjusted due to the change in guidelines and prescribing trends leading to decline in use of sulfonylureas. At the time of study design sulfonylureas were the most commonly prescribed second line therapy in the UK. Subsequent decline in their use in favour of DPP4-inhibitors and SGLT2 inhibitors 22, resulted in the inclusion of patients currently treated with either metformin and sulfonylureas or metformin only. We will perform a sensitivity analysis to determine if the difference in study “epoch” (before/after this amendment) has any impact on the main study outcomes. Altered exclusion criteria also added ‘limb ischaemia’ due to updated safety information for Canagliflozin, and an upper limit of HbA1c >110mmol/mol.
    06 Jul 2018
    Amendment to sample size due to over-cautious sample calculations (alpha changed to 0.05), extension to recruitment period due to delays in regulatory approvals at study set-up and slow early recruitment, and additional secondary analysis included on the advice of the Data Monitoring Committee.
    13 Jun 2019
    Amendment to study analysis plan. Following advice from the Trial Steering Committee statistician, the protocol was amended to analyse only those completing at least 12 weeks on therapy, as this will determine whether the strata result in differences in response (we cannot adequately measure glycaemic response by HbA1c if the patient has been on the drug for less than 12 weeks). A separate analysis will be performed to determine whether the strata influence tolerability by assessing whether the proportion completing at least 12 weeks on therapy differs by drug and strata.
    30 Apr 2020
    Amendment to ensure ongoing participant safety and study integrity during Covid-19 pandemic. Urgent safety measures included (i) extension of visit windows to 14-18 weeks to allow greater flexibility for participants who are unwell/isolating, (ii) provision for remote visits with sample collection outside the usual research setting, (iii) ensuring participants remained on study therapy when only a remote visit is possible, by allowing an additional ‘continuation’ bottle of the same IMP to be issued, or when no other option, transfer to the next IMP without collection of blood samples.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33371044
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