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

    Summary
    EudraCT number
    		 2017-000420-95
    Trial protocol
    		 HU   CZ   ES  
    Global end of trial date
    18 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Sep 2021
    First version publication date
    05 Sep 2021
    Other versions
    Summary report(s)
    		 THR-1442-C-423 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    THR-1442-C-423
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03115112
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 EMA: UPI number 498543
    Sponsors
    Sponsor organisation name
    Theracos
    Sponsor organisation address
    225 Cedar Hill St., Marlborough, MA, United States, 01752
    Public contact
    Clinical Trial Project Management, Translational Medicine Group - MGH, 001 6177264236, info@theracos.com
    Scientific contact
    Clinical Trial Project Management, Translational Medicine Group - MGH, 001 6177264236, info@theracos.com
    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
    Interim
    Date of interim/final analysis
    31 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy objective of this trial is to demonstrate that bexagliflozin is non-inferior to sitagliptin by evaluating the treatment effect on HbA1c reduction at week 24 in subjects with inadequately controlled T2DM on metformin.
    Protection of trial subjects
    General safety assessments included treatment emergent AE (TEAE), 12-lead electrocardiograms parameters, physical examinations, vital signs including orthostatic blood pressure, urinalysis, blood chemistry, hematology, estimated glomerular filtration rate (eGFR) and use of concomitant medications. During placebo run-in period, subjects were instructed to measure self-monitored blood glucose (SMBG) in fasted state. During the treatment period, study subjects were instructed to measure the fasting SMBG daily. Any approved medication for diabetes that was not contraindicated was permissible to be used as a rescue medication for hyperglycemia, if it continued after diet and exercise counseling. If hypoglycemia occurred in any subjects, either metformin or rescue medication was to be reduced. If recurrent symptomatic hypoglycemia continued, the study drug was to be discontinued and the subject to be withdrawn from the study.
    Background therapy
    		 At the time of screening, all subjects were on metformin at a stable dose of ≥ 1500 mg per day for ≥ 8 weeks and have received diet and exercise counseling. Study subjects continued to receive open-labeled metformin during the entire study at a stable dose and frequency.
    Evidence for comparator
    		 The comparator, sitagliptin, is a DPP-4 inhibitor, which prevents the degradation of incretin. Incretin increases insulin production and reduces hepatic glucose production, leading to better glucose metabolism. DDP-4 inhibitors are considered second-line therapy for T2DM in clinical practice and are often prescribed with metformin as a combination therapy for treating T2DM. DDP-4 inhibitors can reduce the risk of long-term microvascular complications via effective glycemic control and do not have weight gain or increased hypoglycemic risk compared with placebo.
    Actual start date of recruitment
    12 Oct 2017
    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: 114
    Country: Number of subjects enrolled
    Spain: 75
    Country: Number of subjects enrolled
    Czech Republic: 41
    Country: Number of subjects enrolled
    Hungary: 56
    Country: Number of subjects enrolled
    United States: 36
    Country: Number of subjects enrolled
    Japan: 62
    Worldwide total number of subjects
    384
    EEA total number of subjects
    286
    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)
    259
    From 65 to 84 years
    125
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 384 eligible subjects were enrolled in the study. Subjects were recruited from Czech Republic, Hungary, Poland, Spain, USA and Japan.

    Pre-assignment
    Screening details
    		 Subjects with inadequately controlled T2DM with HbA1c between 7.0% and 11%, while taking metformin at ≥ 1500 mg per day were enrolled. All eligible subjects had 1 week run-in period. A change in treatment for hypertension or dyslipidemia during the run-in period was considered as screen failure.

    Pre-assignment period milestones
    Number of subjects started
    		 563 [1]
    Intermediate milestone: Number of subjects
    Entered Run-in: 395
    Intermediate milestone: Number of subjects
    Randomized: 386
    Number of subjects completed
    		 384

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Failure at screening: 168
    Reason: Number of subjects
    		 Failure during run-in: 9
    Reason: Number of subjects
    		 Excluded due to site closure for GCP violation: 2
    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 who started the pre-assignment period included those who signed the informed consent form. The worldwide number enrolled in the trial included all those who were successfully randomized, except for two subjects where the clinical sites were closed due to GCP violation.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Bexagliflozin tablets, 20 mg, and placebo were blue caplet-shaped, film-coated tablets. Sitagliptin tablets, 100 mg, and placebo were beige, round, film-coated tablets with "277" on one side. The results of urinary glucose testing were not available to any study personnel or subjects.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bexagliflozin
    Arm description
    		 The subjects received Bexagliflozin tablets, 20 mg, once daily and Sitagliptin placebo tablets, once daily, for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bexagliflozin tablets, 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The subjects received Bexagliflozin tablets, 20 mg, once daily orally.

    Investigational medicinal product name
    Sitagliptin tablets, placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The subjects received Sitagliptin tablets, placebo, once daily orally.

    Arm title
    		 Sitagliptin
    Arm description
    		 The subjects received Sitagliptin tablets, 100 mg, once daily and Bexagliflozin placebo tablets, once daily, for 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sitagliptin tablets, 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin 100 mg, orally, once daily

    Investigational medicinal product name
    Bexagliflozin tablets, placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The subjects received Bexagliflozin tablets, placebo, once daily orally.

    Number of subjects in period 1
    		Bexagliflozin Sitagliptin
    Started
    191
    193
    Completed
    180
    189
    Not completed
    11
    4
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    4
    2
         Adverse event, non-fatal
    5
    1
         Pregnancy
    1
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bexagliflozin
    Reporting group description
    		 The subjects received Bexagliflozin tablets, 20 mg, once daily and Sitagliptin placebo tablets, once daily, for 24 weeks.

    Reporting group title
    Sitagliptin
    Reporting group description
    		 The subjects received Sitagliptin tablets, 100 mg, once daily and Bexagliflozin placebo tablets, once daily, for 24 weeks.

    Reporting group values
    		 Bexagliflozin Sitagliptin Total
    Number of subjects
    		 191 193 384
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 130 129 259
        From 65-84 years
    		 61 64 125
    Age continuous
    Age is the age at informed consent, automatically computed in case report form.
    Units: years
        arithmetic mean (standard deviation)
    		 59.3 ( 9.69 ) 59.6 ( 9.76 ) -
    Gender categorical
    Units: Subjects
        Female
    		 71 67 138
        Male
    		 120 126 246
    Race
    Units: Subjects
        White
    		 158 156 314
        Black or African-American
    		 6 2 8
        Asian
    		 27 35 62
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 7 10
        Not Hispanic or Latino
    		 188 186 374
    Country of Investigational Site
    Units: Subjects
        Czech Republic
    		 16 25 41
        Hungary
    		 33 23 56
        Poland
    		 70 44 114
        Spain
    		 30 45 75
        USA
    		 15 21 36
        Japan
    		 27 35 62
    Region of Investigational Site
    Units: Subjects
        North America
    		 15 21 36
        Europe
    		 149 137 286
        Asia
    		 27 35 62
    BMI Categories
    Units: Subjects
        BMI < 25
    		 22 19 41
        BMI ≥ 25
    		 169 174 343
    Body Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 90.27 ( 20.736 ) 89.44 ( 19.235 ) -
    HbA1c at Baseline
    Units: Percentage
        arithmetic mean (standard deviation)
    		 7.94 ( 0.808 ) 8.03 ( 0.921 ) -
    FPG at Baseline
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 9.77 ( 2.323 ) 10.02 ( 2.578 ) -
    SBP at Baseline
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 135 ( 12.17 ) 135.7 ( 14.32 ) -
    eGFR at Baseline
    For Japanese subjects, eGFR = 194 × (Scr)^(-1.094) × (Age)^(-0.287) × (0.739 if female). For other non-Japanese subjects, eGFR = 175 × (Scr)^(-1.154) × (Age)^(-0.203) × (0.742 if female) × (1.212 if African American). Scr = Serum creatinine, ^ denotes raised to the indicated power.
    Units: mL min-1 per 1.73 m2
        arithmetic mean (standard deviation)
    		 88.7 ( 17.349 ) 87.15 ( 18.332 ) -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 8.22 ( 5.702 ) 9.36 ( 5.657 ) -
    BMI
    Units: kg m-2
        arithmetic mean (standard deviation)
    		 32.06 ( 6.052 ) 31.39 ( 5.294 ) -
    Subject analysis sets

    Subject analysis set title
    Bexagliflozin
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The subjects received Bexagliflozin tablets, 20 mg, once daily and Sitagliptin placebo tablets, once daily, for 24 weeks.

    Subject analysis set title
    Sitagliptin
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The subjects received Sitagliptin tablets, 100 mg, once daily and Bexagliflozin placebo tablets, once daily, for 24 weeks.

    Subject analysis sets values
    		 Bexagliflozin Sitagliptin
    Number of subjects
    191
    193
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    130
    129
        From 65-84 years
    61
    64
    Age continuous
    Age is the age at informed consent, automatically computed in case report form.
    Units: years
        arithmetic mean (standard deviation)
    59.3 ( 9.69 )
    59.6 ( 9.76 )
    Gender categorical
    Units: Subjects
        Female
    71
    67
        Male
    120
    126
    Race
    Units: Subjects
        White
    158
    156
        Black or African-American
    6
    2
        Asian
    27
    35
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    3
    7
        Not Hispanic or Latino
    188
    186
    Country of Investigational Site
    Units: Subjects
        Czech Republic
    16
    25
        Hungary
    33
    23
        Poland
    70
    44
        Spain
    30
    45
        USA
    15
    21
        Japan
    27
    35
    Region of Investigational Site
    Units: Subjects
        North America
    15
    21
        Europe
    149
    137
        Asia
    27
    35
    BMI Categories
    Units: Subjects
        BMI < 25
    22
    19
        BMI ≥ 25
    169
    174
    Body Weight
    Units: kg
        arithmetic mean (standard deviation)
    90.27 ( 20.736 )
    89.44 ( 19.235 )
    HbA1c at Baseline
    Units: Percentage
        arithmetic mean (standard deviation)
    7.94 ( 0.808 )
    8.03 ( 0.921 )
    FPG at Baseline
    Units: mmol/L
        arithmetic mean (standard deviation)
    9.77 ( 2.323 )
    10.02 ( 2.578 )
    SBP at Baseline
    Units: mm Hg
        arithmetic mean (standard deviation)
    135 ( 12.17 )
    135.7 ( 14.32 )
    eGFR at Baseline
    For Japanese subjects, eGFR = 194 × (Scr)^(-1.094) × (Age)^(-0.287) × (0.739 if female). For other non-Japanese subjects, eGFR = 175 × (Scr)^(-1.154) × (Age)^(-0.203) × (0.742 if female) × (1.212 if African American). Scr = Serum creatinine, ^ denotes raised to the indicated power.
    Units: mL min-1 per 1.73 m2
        arithmetic mean (standard deviation)
    88.7 ( 17.349 )
    87.15 ( 18.332 )
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    8.22 ( 5.702 )
    9.36 ( 5.657 )
    BMI
    Units: kg m-2
        arithmetic mean (standard deviation)
    32.06 ( 6.052 )
    31.39 ( 5.294 )

    End points

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    End points reporting groups
    Reporting group title
    Bexagliflozin
    Reporting group description
    		 The subjects received Bexagliflozin tablets, 20 mg, once daily and Sitagliptin placebo tablets, once daily, for 24 weeks.

    Reporting group title
    Sitagliptin
    Reporting group description
    		 The subjects received Sitagliptin tablets, 100 mg, once daily and Bexagliflozin placebo tablets, once daily, for 24 weeks.

    Subject analysis set title
    Bexagliflozin
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The subjects received Bexagliflozin tablets, 20 mg, once daily and Sitagliptin placebo tablets, once daily, for 24 weeks.

    Subject analysis set title
    Sitagliptin
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The subjects received Sitagliptin tablets, 100 mg, once daily and Bexagliflozin placebo tablets, once daily, for 24 weeks.

    Primary: Change in HbA1c from Baseline at Week 24

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    End point title
    		 Change in HbA1c from Baseline at Week 24
    End point description
    The primary effectiveness objective was to demonstrate that bexagliflozin was non-inferior to sitagliptin by evaluating the treatment effect on HbA1c reduction at week 24 in subjects with T2DM inadequately controlled by metformin.
    End point type
    Primary
    End point timeframe
    HbA1c was measured at weeks -3, 0, 6, 12, 18, 24 and 26 (Follow up).
    End point values
    		 Bexagliflozin Sitagliptin
    Number of subjects analysed
    180 [1]
    190 [2]
    Units: Percentage
        least squares mean (confidence interval 95%)
    -0.74 (-0.86 to -0.62)
    -0.82 (-0.93 to -0.71)
    Notes
    [1] - 11 subjects in the bexagliflozin arm had missing values for the primary endpoint.
    [2] - 3 subjects in the sitagliptin arm had missing values for the primary endpoint.
    Statistical analysis title
    		 Difference of LS Means from Sitaglitpin 100 mg
    Statistical analysis description
    The statistical method to estimate the treatment effect was based on the ITT analysis set using all the observed data and a mixed model repeated measures (MMRM) approach. The full model is a mixed-effects repeated measures analysis that includes region, treatment, visit, treatment-by-visit interaction and the baseline HbA1c value as fixed effect covariates. As unstructured covariance matrix was assumed.
    Comparison groups
    Bexagliflozin v Sitagliptin
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference of LS Means
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.22
    Notes
    [3] - If the 95% confidence interval was below the specified non-inferiority margin 0.35%, the results would have led to a conclusion of non-inferiority of bexagliflozin treatment compared to sitagliptin treatment. The non-inferiority margin of 0.35% was determined based on a reference clinical trial that demonstrated the effectiveness of sitagliptin, 100 mg, compared to placebo on HbA1c reduction in subjects with T2DM.

    Secondary: Change in FPG from Baseline at Week 24

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    End point title
    		 Change in FPG from Baseline at Week 24
    End point description
    To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in FPG at week 24.
    End point type
    Secondary
    End point timeframe
    Fasting plasma glucose (FPG) was measured at weeks -3, 0, 6, 12, 18, 24 and 26 (follow-up).
    End point values
    		 Bexagliflozin Sitagliptin
    Number of subjects analysed
    180 [4]
    190 [5]
    Units: mmol/L
        least squares mean (confidence interval 95%)
    -1.82 (-2.09 to -1.55)
    -1.45 (-1.70 to -1.19)
    Notes
    [4] - 11 subjects in the bexagliflozin arm with missing values were excluded.
    [5] - 3 subjects in the sitagliptin arm with missing values were excluded.
    Statistical analysis title
    		 Difference of LS Means from Sitaglitpin 100 mg
    Statistical analysis description
    The statistical method to estimate the treatment effect was based on the ITT analysis set using all the observed data and a mixed model repeated measures (MMRM) approach. The full model is a mixed-effects repeated measures analysis that includes region, treatment, visit, treatment-by-visit interaction and the baseline HbA1c value as fixed effect covariates. As unstructured covariance matrix was assumed.
    Comparison groups
    Bexagliflozin v Sitagliptin
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0123 [6]
    Method
    		 Mixed-model repeated measures
    Parameter type
    		 Difference of LS Means
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.05
    Notes
    [6] - P-value was presented based on one sided statistical tests using a 0.025 level of significance.

    Secondary: Change in Body Weight from Baseline in Subjects with a BMI ≥ 25 kg m2 at Week 24

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    End point title
    		 Change in Body Weight from Baseline in Subjects with a BMI ≥ 25 kg m2 at Week 24
    End point description
    To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in body weight in subjects with baseline body mass index (BMI) ≥ 25 kg m2 at Week 24.
    End point type
    Secondary
    End point timeframe
    Body weight was measured at weeks -3, 0, 6, 12, 18, 24 and 26 (follow up).
    End point values
    		 Bexagliflozin Sitagliptin
    Number of subjects analysed
    158 [7]
    171 [8]
    Units: kg
        least squares mean (confidence interval 95%)
    -3.35 (-3.85 to -2.84)
    -0.81 (-1.29 to -0.32)
    Notes
    [7] - Only included subjects with a value at baseline and at the specific visit.
    [8] - Only included subjects with a value at baseline and at the specific visit.
    Statistical analysis title
    		 Difference of LS Means from Sitaglitpin 100 mg
    Statistical analysis description
    The full model was a mixed-effects repeated measures analysis that included region, treatment, visit, treatment-by-visit interaction and the baseline body weight value as a fixed effect covariate. An unstructured covariance matrix was assumed. Data from Weeks 6, 12, 18 and 24 were used in the model.
    Comparison groups
    Bexagliflozin v Sitagliptin
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed-model repeated measures
    Parameter type
    		 Difference of LS Means
    Point estimate
    -2.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.15
         upper limit
    		 -1.92
    Notes
    [9] - P-value was presented based on one sided statistical tests using a 0.025 level of significance.

    Secondary: Change in SBP from Baseline to Week 24

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    End point title
    		 Change in SBP from Baseline to Week 24
    End point description
    To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in systolic blood pressure (SBP) in subjects at week 24.
    End point type
    Secondary
    End point timeframe
    SBP was measured at weeks -3, 0, 6, 12, 18, 24 and 26 (follow up)
    End point values
    		 Bexagliflozin Sitagliptin
    Number of subjects analysed
    180 [10]
    190 [11]
    Units: mm Hg
        least squares mean (confidence interval 95%)
    -4.23 (-6.18 to -2.28)
    -1.90 (-3.75 to -0.06)
    Notes
    [10] - 11 subjects in the bexagliflozin arm with missing values were excluded.
    [11] - 3 subjects in the sitagliptin arm with missing values were excluded.
    Statistical analysis title
    		 Difference of LS Means from Sitaglitpin 100 mg
    Statistical analysis description
    The full model was a mixed-effects repeated measures analysis that included region, treatment, visit, treatment-by-visit interaction and the baseline SBP value as a fixed effect covariate. An unstructured covariance matrix was assumed. Data from Weeks 6, 12, 18 and 24 were used in the model.
    Comparison groups
    Sitagliptin v Bexagliflozin
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0276 [12]
    Method
    		 Mixed-model repeated measures
    Parameter type
    		 Difference of LS Means
    Point estimate
    -2.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 0.05
    Notes
    [12] - P-value was presented based on one sided statistical tests using a 0.025 level of significance.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from Week -1 (run-in period) to Week 26 (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
    Sitagliptin
    Reporting group description
    		 -

    Serious adverse events
    		 Bexagliflozin Sitagliptin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 191 (3.66%)
    4 / 193 (2.07%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microvascular coronary artery disease
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial aneurysm
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 193 (0.52%)
         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
    Anaemia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gallstone ileus
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 193 (0.52%)
         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
    2 / 191 (1.05%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 193 (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
    		 Bexagliflozin Sitagliptin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 191 (14.66%)
    47 / 193 (24.35%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    15 / 191 (7.85%)
    25 / 193 (12.95%)
         occurrences all number
    15
    29
    influenza
         subjects affected / exposed
    3 / 191 (1.57%)
    10 / 193 (5.18%)
         occurrences all number
    3
    10
    Urinary tract infection
         subjects affected / exposed
    7 / 191 (3.66%)
    4 / 193 (2.07%)
         occurrences all number
    9
    4
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    6 / 191 (3.14%)
    10 / 193 (5.18%)
         occurrences all number
    12
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Apr 2017
    Sponsor contact changed. Storage guideline for bexagliflozin and sitagliptin tablets was changed. Study procedure modified to include body weight measurement at every visit except Visit 2. Drug accountability added to ensure adequate adherence and record keeping. Study activities modified to include body weight measurement at every visit except Visit 2. Drug accountability check is added to V3, V4, V5, V6 and V7. The investigators and study administrative structure is amended to include guidelines which ensure all qualified persons involved with trial-related duties to have proof of qualification and proof of adequate training on the protocol and assigned tasks. Appendix 1 is amended to match the changes in study activities.
    26 Oct 2017
    The current sponsor study contact was updated. The current Theracos Medical Monitor was updated.

    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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