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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Active-controlled Study to Evaluate the Effects of Bexagliflozin versus Glimepiride in Subjects with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control by Metformin

    Summary
    EudraCT number
    		 2016-002013-21
    Trial protocol
    		 ES   PL  
    Global end of trial date
    19 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Sep 2021
    First version publication date
    09 Sep 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    THR-1442-C-480
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02769481
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Theracos Sub, LLC
    Sponsor organisation address
    225 Cedar Hill Road, Suite 200, Marlborough, United States, 01752
    Public contact
    Geoffrey Walford, M.D., Theracos Sub, LLC, 001 6176434986, gwalford@partners.org
    Scientific contact
    Geoffrey Walford, M.D., Theracos Sub, LLC, 001 6176434986, gwalford@partners.org
    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
    19 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy objective is to demonstrate that bexagliflozin is non-inferior to glimepiride by evaluating the treatment effect on hemoglobin A1c (HbA1c) reduction at week 60 in subjects whose type 2 diabetes mellitus (T2DM) is inadequately controlled by metformin.
    Protection of trial subjects
    Subjects were advised to continue daily, fasting SMBG measurements and contact the clinic if any fasting SMBG is >= 270 mg/dL from baseline to Week 6, >= 240 mg/dL after Week 6 to Week 12, or >=200 mg/dL after Week 12. Hyperglycemia were monitored by FPG at scheduled visits. Hyperglycemia was managed first with diet and exercise counseling. If this failed, medical therapy was intesified at the investigator's discretion for the well-being of the subject, including up-titration of glimepiride dose and addition of rescue medication. The investigator had the ability to provide rescue treatment with any approved medication for diabetes that is not otherwise contraindicated, with the exception of SGLT2 inhibitor, sulfonylurea and metformin. The study drug could be discontinued at the discretion of the investigator if symptomatic hypoglycemia occurs in subjects not prescribed rescue medication. Other safety monitoring activities included assessments of vital signs, 12-lead ECG, physical examinations, urinalysis, blood chemistry, hematology, adverse events and concomitant medication use. An independent Data and Safety Monitoring Board (DSMB) will monitor overall safety information during the bexagliflozin development program. An independent adjudication committee was established to review all potential cardiovascular events and all potential diabetic ketoacidosis events.
    Background therapy
    		 The study will enroll T2DM patients who are treated with only metformin or who are treated with metformin and one additional oral hypoglycemic agent. All subjects must have taken metformin at a stable dose of >= 1500 mg/day for >= 8 weeks prior to screening. Study subjects will continue receiving open-labeled metformin background medication during the entire study at a stable dose and frequency.
    Evidence for comparator
    		 Metformin is the most commonly prescribed oral hypoglycemic agent and is recommended as the first-line therapy for the treatment for T2DM. Subjects with T2DM often require multiple anti-diabetic medications for glycemic control. Sulfonylureas are often prescribed with metformin as a combination therapy for treating T2DM. Sulfonylureas can reduce the risk of long-term microvascular complications via effective glycemic control. Common side effects of sulfonylureas include weight gain and increased risk of hypoglycemia. Glimepiride is one of the most commonly prescribed second-generation sulfonylureas. Therefore, it is an appropriate active comparator in the subject population studied during the treatment period (96 weeks).
    Actual start date of recruitment
    10 Aug 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
    Poland: 153
    Country: Number of subjects enrolled
    Spain: 88
    Country: Number of subjects enrolled
    Germany: 57
    Country: Number of subjects enrolled
    United States: 128
    Worldwide total number of subjects
    426
    EEA total number of subjects
    298
    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)
    296
    From 65 to 84 years
    128
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study population included ~420 subjects whose T2DM was inadequately controlled by metformin and who met all of the inclusion criteria and none of the exclusion criteria. Clinical sites in the North America and Europe participated and recruited subjects. Clinical sites in other continents were also allowed to participate in the trial.

    Pre-assignment
    Screening details
    		 Subjects who were treated with metformin + OHA will undergo a 6-week wash-out of the non-metformin OHA to exclude the potential influence of other OHAs on the study outcomes. Subjects continued to take metformin at the same dose and frequency. Subjects in the glimepiride arm started at 2 mg daily and underwent dose up-titration.

    Pre-assignment period milestones
    Number of subjects started
    		 812 [1]
    Intermediate milestone: Number of subjects
    Entered Run-In: 539
    Intermediate milestone: Number of subjects
    Randomized: 427
    Number of subjects completed
    		 426

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen fails prior to Run-In: 273
    Reason: Number of subjects
    		 Screen fails prior to randomization: 112
    Reason: Number of subjects
    		 Excluded due to duplicate enrollment: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects (812) who started the pre-assignment period included those who signed the informed consent form. However, only 426 subjects were included in the intention-to-treat analysis set. Others were excluded due to screen fails prior to Run-in and screen fails prior to randomization. The worldwide number enrolled in the trial (426) included all those who were successfully randomized, except for one randomized subject who was excluded due to duplicate enrollment.
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bexagliflozin
    Arm description
    		 Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Glimepiride capsules are inactive and their appearance are made to match the active comparator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bexagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bexagliflozin tablet, 20 mg, is to be administered once daily to subjects in the active arm.

    Arm title
    		 Glimepiride
    Arm description
    		 Subjects received a glimepiride capsule at different dose of 2, 4 or 6 mg, once daily for the duration of the study. Subjects continued to take metformin and receive placebo for bexagliflozin for the duration of the study. The placebo tablets are inactive and their appearances are made to match the active comparator.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride capsules, 2, 4, or 6 mg or placebo, were taken once daily with the first meal. Subjects will receive the starting dose of glimepiride at 2 mg or placebo at week 0 (V6). At weeks 2, 4, and 6, subjects will return to the clinic for the assessment of glimepiride dose up-titration and safety evaluation. If a subject had >= 50% of documented fasting SMBG measurements > 110 mg/dL and no severe or documented symptomatic hypoglycemia events in the preceding 2 weeks, glimepiride dose was increased to the next level. During weeks 0 to 6, each up-titration visit was conducted no more than 2 weeks after the prior visit. If subjects did not meet up-titration glycemic criteria, subjects continued glimepiride at the same dose prescribed to them at the previous visit. Subjects assigned to receive placebo glimepiride received mock titrations at Week 2, 4, and 6. No dose changes in glimepiride occurred after 6 weeks of treatment.

    Number of subjects in period 1
    		Bexagliflozin Glimepiride
    Started
    213
    213
    Study complete at Week 60
    193
    192
    Completed
    180
    177
    Not completed
    33
    36
         Consent withdrawn by subject
    14
    16
         Physician decision
    -
    1
         Adverse event, non-fatal
    3
    6
         Death
    -
    1
         Terminated by sponsor
    1
    -
         Undefined
    4
    1
         Lost to follow-up
    9
    9
         Entry criteria not met
    1
    2
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bexagliflozin
    Reporting group description
    		 Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Glimepiride capsules are inactive and their appearance are made to match the active comparator.

    Reporting group title
    Glimepiride
    Reporting group description
    		 Subjects received a glimepiride capsule at different dose of 2, 4 or 6 mg, once daily for the duration of the study. Subjects continued to take metformin and receive placebo for bexagliflozin for the duration of the study. The placebo tablets are inactive and their appearances are made to match the active comparator.

    Reporting group values
    		 Bexagliflozin Glimepiride Total
    Number of subjects
    		 213 213 426
    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
    Units: years
        arithmetic mean (standard deviation)
    		 59.5 ± 9.06 59.7 ± 10.35 -
    Gender categorical
    Units: Subjects
        Female
    		 95 83 178
        Male
    		 118 130 248
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 46 47 93
        Not Hispanic or Latino
    		 167 166 333
        Unknown or Not Reported
    		 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 9 4 13
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 5 4 9
        White
    		 198 204 402
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 1 1
    Region of Enrollment
    Units: Subjects
        United States
    		 65 63 128
        Poland
    		 74 79 153
        Germany
    		 28 29 57
        Spain
    		 46 42 88
    Systolic Blood Pressure Categories
    Units: Subjects
        < 140 mm Hg
    		 135 138 273
        > 140 mm Hg
    		 78 75 153
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 166.7 ± 11.13 167.1 ± 9.53 -
    Body Weight at Baseline
    Units: kg
        arithmetic mean (standard deviation)
    		 87.95 ± 19.122 90.23 ± 17.616 -
    BMI
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 31.45 ± 4.861 32.22 ± 5.155 -
    Systolic Blood Pressure at Baseline
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 133.3 ± 14.88 134.2 ± 14.37 -

    End points

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    End points reporting groups
    Reporting group title
    Bexagliflozin
    Reporting group description
    		 Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for glimepiride for the duration of the study. Glimepiride capsules are inactive and their appearance are made to match the active comparator.

    Reporting group title
    Glimepiride
    Reporting group description
    		 Subjects received a glimepiride capsule at different dose of 2, 4 or 6 mg, once daily for the duration of the study. Subjects continued to take metformin and receive placebo for bexagliflozin for the duration of the study. The placebo tablets are inactive and their appearances are made to match the active comparator.

    Primary: Change from Baseline in HbA1c at Week 60

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    End point title
    		 Change from Baseline in HbA1c at Week 60
    End point description
    The primary objective is to demonstrate that bexagliflozin is non-inferior to glimepiride by evaluating the treatment effect on HbA1c reduction at week 60 in subjects whose T2DM is inadequately controlled by metformin. The least square mean (LSM) change from baseline to Week 60 was analyzed using a mixed model repeated measures (MMRM) analysis of covariance model (ANCOVA).
    End point type
    Primary
    End point timeframe
    Baseline to Week 60
    End point values
    		 Bexagliflozin Glimepiride
    Number of subjects analysed
    193
    191
    Units: Percentage of glycated hemoglobin
        least squares mean (standard error)
    -0.70 ± 0.058
    -0.66 ± 0.058
    Statistical analysis title
    		 Comparing bexagliflozin to glimepiride
    Statistical analysis description
    The primary objective is to demonstrate that bexagliflozin is non-inferior to glimepiride by evaluating the treatment effect on HbA1c reduction at week 60 in subjects whose T2DM is inadequately controlled by metformin. The least square mean (LSM) change from baseline to Week 60 was analyzed using a mixed model repeated measures (MMRM) analysis of covariance model (ANCOVA).
    Comparison groups
    Bexagliflozin v Glimepiride
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.11
    Notes
    [1] - The null hypothesis for the primary endpoint was that the change in HbA1c from baseline to week 60 in the bexagliflozin arm would be greater than change in the glimepiride arm by greater than 0.35%. A 95% CI was calculated to estimate the range of values in which the treatment difference was likely to lie. If the 95% CI fell below the specified non inferiority margin of 0.35%, the non inferiority of bexagliflozin to glimepiride would be demonstrated and the null hypothesis would be rejected.

    Secondary: Change from Baseline in Body Weight at Week 60 for Subjects with Baseline BMI ≥ 25 kg/m2

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    End point title
    		 Change from Baseline in Body Weight at Week 60 for Subjects with Baseline BMI ≥ 25 kg/m2
    End point description
    Least squares (LS) mean treatment difference between the bexagliflozin group and placebo group in the change of body weight in subjects with baseline BMI ≥ 25 kg/m2 at week 60 is analyzed using ANCOVA.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 60
    End point values
    		 Bexagliflozin Glimepiride
    Number of subjects analysed
    182
    182
    Units: kg
        least squares mean (standard error)
    -3.71 ± 0.285
    0.59 ± 0.284
    Statistical analysis title
    		 Comparing bexagliflozin to glimepiride
    Statistical analysis description
    Least squares (LS) mean treatment difference between the bexagliflozin group and placebo group in the change of body weight in subjects with baseline BMI ≥ 25 kg/m^2 at week 60 is analyzed using ANCOVA.
    Comparison groups
    Bexagliflozin v Glimepiride
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed-effects repeated measures
    Parameter type
    		 Difference of LS Means
    Point estimate
    -4.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 -3.52
    Notes
    [2] - P-value is based on one sided statistical tests using a 0.025 level of significance.

    Secondary: Change From Baseline in Systolic Blood Pressure (SBP) at Week 60 for Subjects With Baseline SBP ≥ 140 mmHg

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    End point title
    		 Change From Baseline in Systolic Blood Pressure (SBP) at Week 60 for Subjects With Baseline SBP ≥ 140 mmHg
    End point description
    Least squares (LS) mean treatment difference between the bexagliflozin group and placebo group in the change of SBP in subjects with baseline SBP ≥ 140 mmHg at week 60 is analyzed using ANCOVA.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 60
    End point values
    		 Bexagliflozin Glimepiride
    Number of subjects analysed
    74
    68
    Units: mm Hg
        least squares mean (standard error)
    -13.48 ± 1.404
    -6.95 ± 1.460
    Statistical analysis title
    		 Comparing bexagliflozin to glimepiride
    Statistical analysis description
    Least squares (LS) mean treatment difference between the bexagliflozin group and placebo group in the change of SBP in subjects with baseline SBP ≥ 140 mmHg at week 60 is analyzed using ANCOVA.
    Comparison groups
    Bexagliflozin v Glimepiride
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008 [3]
    Method
    		 Mixed-effects repeated measures
    Parameter type
    		 Difference of LS Means
    Point estimate
    -6.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.56
         upper limit
    		 -2.51
    Notes
    [3] - P-value is based on one sided statistical tests using a 0.025 level of significance.

    Secondary: Difference in Proportion of Subjects With ≥ 1 Severe or Documented Symptomatic Hypoglycemia Events Over 96 Weeks

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    End point title
    		 Difference in Proportion of Subjects With ≥ 1 Severe or Documented Symptomatic Hypoglycemia Events Over 96 Weeks
    End point description
    The difference in proportion of subjects with ≥ 1 severe or documented symptomatic hypoglycemia events in the bexagliflozin group compared with glimepiride group over 96 weeks is analyzed using a logistic regression model. The full model included region, baseline HbA1c value, background treatment status (metformin or metformin + OHA), eGFR at baseline ≥ 90 or < 90 mL min 1 per 1.73 m^2), treatment as a fixed effect covariate.
    End point type
    Secondary
    End point timeframe
    During the 96 week treatment period
    End point values
    		 Bexagliflozin Glimepiride
    Number of subjects analysed
    213
    212
    Units: Proportion of participants
        number (confidence interval 95%)
    0.02 (0.01 to 0.05)
    0.15 (0.10 to 0.22)
    Statistical analysis title
    		 Comparing bexagliflozin to glimepiride
    Statistical analysis description
    The difference in proportion of subjects with ≥ 1 severe or documented symptomatic hypoglycemia events in the bexagliflozin group compared with glimepiride group over 96 weeks is analyzed using a logistic regression model. The full model included region, baseline HbA1c value, background treatment status (metformin or metformin + OHA), eGFR at baseline ≥ 90 or < 90 mL min 1 per 1.73 m^2), treatment as a fixed effect covariate.
    Comparison groups
    Bexagliflozin v Glimepiride
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.28
    Notes
    [4] - P-value is based on one sided statistical tests using a 0.025 level of significance.

    Secondary: Superiority of Bexagliflozin Over Glimepiride in HbA1c Reduction at Week 60

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    End point title
    		 Superiority of Bexagliflozin Over Glimepiride in HbA1c Reduction at Week 60
    End point description
    Superiority of bexagliflozin over glimepiride in HbA1c reduction from baseline to week 60 will be declared if the upper bound of 95% CI is less than 0.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 60
    End point values
    		 Bexagliflozin Glimepiride
    Number of subjects analysed
    193
    191
    Units: Percentage of glycated hemoglobin
        least squares mean (standard error)
    -0.70 ± 0.058
    -0.66 ± 0.058
    Statistical analysis title
    		 Comparing bexagliflozin to glimepiride
    Statistical analysis description
    Superiority of bexagliflozin over glimepiride in HbA1c reduction from baseline to week 60 will be declared if the upper bound of 95% CI is less than 0.
    Comparison groups
    Bexagliflozin v Glimepiride
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference of LS Means
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.11

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data was collected from Week -8 (V2, wash-out) to Week 98 (V18, follow-up).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Bexagliflozin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Bexagliflozin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 213 (11.74%)
    26 / 213 (12.21%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial occlusive disease
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Genital hemorrhage
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 213 (0.94%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischemia
         subjects affected / exposed
    1 / 213 (0.47%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 213 (0.47%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitation
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischemic attack
         subjects affected / exposed
    1 / 213 (0.47%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischemic stroke
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Ectropion
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Entropion
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Faecaloma
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 213 (0.47%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ecchymosis
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 213 (0.00%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder disorder
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 213 (0.47%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 213 (0.94%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 213 (0.47%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatremia
         subjects affected / exposed
    0 / 213 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bexagliflozin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    98 / 213 (46.01%)
    112 / 213 (52.58%)
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 213 (2.82%)
    16 / 213 (7.51%)
         occurrences all number
    6
    16
    Arthralgia
         subjects affected / exposed
    13 / 213 (6.10%)
    4 / 213 (1.88%)
         occurrences all number
    13
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    29 / 213 (13.62%)
    29 / 213 (13.62%)
         occurrences all number
    29
    29
    Urinary Tract Infection
         subjects affected / exposed
    25 / 213 (11.74%)
    10 / 213 (4.69%)
         occurrences all number
    25
    10
    Bronchitis
         subjects affected / exposed
    14 / 213 (6.57%)
    16 / 213 (7.51%)
         occurrences all number
    14
    16
    Metabolism and nutrition disorders
    Hypoglycemia
         subjects affected / exposed
    36 / 213 (16.90%)
    71 / 213 (33.33%)
         occurrences all number
    36
    71
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 213 (0.47%)
    17 / 213 (7.98%)
         occurrences all number
    1
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Oct 2016
    1. The Sponsor Contact and Medical Monitor were changed. 2. Language regarding persistent hyperglycemia and up-titration visits was updated to include all scheduled visits instead of only V8 and V9. 3. Amputation was added to the list of AESI following a potential safety issue of amputation identified from another SGLT2 inhibitor canagliflozin in 2016. 4. Language regarding OHAs was revised to prevent confusion regarding the number of oral medications that were allowed to be taken. 5. Metformin was included in the safe use of OHAs to ensure subject safety as subjects were required to be on a stable background of metformin to participate in the study. 6. Correction of error in protocol to maintain consistency with synopsis inclusion criteria: adhere to the investigational product administration requirements evidenced by missing no more than 2 doses of run-in medications. 7. Modification to exclusion criteria to include metformin to ensure subject safety as subjects are required to be on a stable background of metformin to participate in the study. 8. Modification to include any increase in LFTs >= 3 times the ULN be automatically considered as a laboratory AE unless diagnosed otherwise by the investigator. Any increase in LFTs that are < 3 times could also be considered as an AE if the change was determined to be clinically significant by investigators. 9. Languages regarding any amputation and related adverse events and procedures were added in Section 6.14.14. Investigators were reminded to counsel appropriate foot care to avoid cuts or sores and to treat even minor cuts/sores to prevent infection and ulceration. Special attention to be paid for patients who were also receiving thiazide diuretics as these have been shown to increase the risk of amputation in diabetes.

    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
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