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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Ranolazine When Added to Glimepiride in Subjects with Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    		 2011-000997-77
    Trial protocol
    		 HU   CZ   PL   SK  
    Global end of trial date
    28 Aug 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-259-0110
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01494987
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd , ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.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
    Final
    Date of interim/final analysis
    28 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a randomized, double-blind, placebo-controlled, parallel-group, multi-center study to determine the effect of ranolazine when added to glimepiride on glycemic control in adults with type 2 diabetes mellitus (T2DM) who are inadequately controlled despite current treatment with stable sulfonylurea or metformin therapy in addition to diet and exercise.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride received glimepiride 2 mg once daily, and if tolerated the dose was increased on Day 8 (+ 2 days) to 4 mg once daily. Treatment period: participants received glimepiride 4 mg once daily for 24 weeks. Participants were required to maintain their diet and exercise regimen.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jan 2012
    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: 9
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Russian Federation: 203
    Country: Number of subjects enrolled
    Ukraine: 53
    Country: Number of subjects enrolled
    United States: 121
    Country: Number of subjects enrolled
    Romania: 20
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Serbia: 4
    Worldwide total number of subjects
    431
    EEA total number of subjects
    43
    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)
    314
    From 65 to 84 years
    117
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled (during the Qualifying Period) at a total of 103 study sites in Asia, Europe, South Africa, and the United States. The first participant was screened on 12 January 2012. The last participant observation occurred on 28 August 2013.

    Pre-assignment
    Screening details
    		 595 participants entered the qualifying period (355 required and completed the glimepiride stabilization period); 431 were randomized and treated (Safety Analysis Set). Of these, 14 were excluded due to major eligibility criteria protocol violation or had no baseline or ontreatment data; thus, 417 were included in the Full Analysis Set.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo+Glimepiride
    Arm description
    		 Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride at a dose of 4 mg once daily received glimepiride 2 mg once daily, and if tolerated the dose was increased on Day 8 (+ 2 days) to 4 mg once daily. Qualifying period: participants received placebo to match ranolazine twice daily in addition to glimepiride for 14 days (+ 2 days) and if ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: participants were randomized to receive placebo to match ranolazine plus glimepiride 4 mg once daily for 24 weeks. Participants were required to maintain their diet and exercise regimen.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match ranolazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match ranolazine tablet(s) for the duration of the study

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride tablets (2 mg or 4 mg) administered orally once daily with the morning dose of study drug or placebo. The target dosing regimen for glimepiride is 4 mg once daily.

    Arm title
    		 Ranolazine+Glimepiride
    Arm description
    		 Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride at a dose of 4 mg once daily received glimepiride 2 mg once daily, and if tolerated the dose was increased on Day 8 (+ 2 days) to 4 mg once daily. Qualifying period: participants received placebo to match ranolazine twice daily in addition to glimepiride for 14 days (+ 2 days) and if ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: participants were randomized to receive ranolazine (1 x 500 mg tablet) twice daily plus glimepiride 4 mg once daily on Days 1 through 7, followed by ranolazine 1000 mg (2 x 500 mg tablets) twice daily plus glimepiride 4 mg once daily from Day 8 (or by Day 16 if not well tolerated) through Week 24. Participants were required to maintain their diet and exercise regimen.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ranolazine
    Investigational medicinal product code
    Other name
    Ranexa®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ranolazine tablet(s) (1 or 2 x 500 mg) administered orally twice daily

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride tablets (2 mg or 4 mg) administered orally once daily with the morning dose of study drug or placebo. The target dosing regimen for glimepiride was 4 mg once daily.

    Number of subjects in period 1
    		Placebo+Glimepiride Ranolazine+Glimepiride
    Started
    216
    215
    Completed
    188
    187
    Not completed
    28
    28
         Subject Non-Compliance
    9
    10
         Subject Withdrew Consent
    2
    3
         Adverse event, non-fatal
    6
    5
         Investigator's Discretion
    1
    2
         Protocol Violation
    3
    3
         Lost to follow-up
    1
    1
         Hyperglycemia
    6
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo+Glimepiride
    Reporting group description
    		 Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride at a dose of 4 mg once daily received glimepiride 2 mg once daily, and if tolerated the dose was increased on Day 8 (+ 2 days) to 4 mg once daily. Qualifying period: participants received placebo to match ranolazine twice daily in addition to glimepiride for 14 days (+ 2 days) and if ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: participants were randomized to receive placebo to match ranolazine plus glimepiride 4 mg once daily for 24 weeks. Participants were required to maintain their diet and exercise regimen.

    Reporting group title
    Ranolazine+Glimepiride
    Reporting group description
    		 Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride at a dose of 4 mg once daily received glimepiride 2 mg once daily, and if tolerated the dose was increased on Day 8 (+ 2 days) to 4 mg once daily. Qualifying period: participants received placebo to match ranolazine twice daily in addition to glimepiride for 14 days (+ 2 days) and if ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: participants were randomized to receive ranolazine (1 x 500 mg tablet) twice daily plus glimepiride 4 mg once daily on Days 1 through 7, followed by ranolazine 1000 mg (2 x 500 mg tablets) twice daily plus glimepiride 4 mg once daily from Day 8 (or by Day 16 if not well tolerated) through Week 24. Participants were required to maintain their diet and exercise regimen.

    Reporting group values
    		 Placebo+Glimepiride Ranolazine+Glimepiride Total
    Number of subjects
    		 216 215 431
    Age categorical
    Units: Subjects
    Age continuous
    Baseline characteristics are reported for the Safety Analysis Set following randomization. The Safety Analysis Set includes randomized participants who received at least one dose of study treatment.
    Units: years
        arithmetic mean (standard deviation)
    		 59 ± 8.6 59 ± 8.8 -
    Gender categorical
    Safety Analysis Set
    Units: Subjects
        Female
    		 123 120 243
        Male
    		 93 95 188
    Race/Ethnicity
    Safety Analysis Set
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 4 3 7
        Black or African American
    		 10 3 13
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        White
    		 198 204 402
        Other
    		 2 5 7
    Body Mass Index
    Safety Analysis Set
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 32.8 ± 4.35 32.2 ± 3.88 -
    Glycosylated hemoglobin (HbA1c)
    Safety Analysis Set
    Units: percent glycosylated hemoglobin
        arithmetic mean (standard deviation)
    		 8.1 ± 0.746 8.07 ± 0.776 -
    Fasting Serum Glucose
    Safety Analysis Set
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 177.2 ± 34.27 177.4 ± 37.03 -
    Duration of Diabetes
    Participants in the Safety Analysis Set with available data were analyzed (n = 215 in both groups).
    Units: years
        arithmetic mean (standard deviation)
    		 7 ± 5.07 7.1 ± 4.92 -
    Estimated glomerular filtration rate (eGFR)
    Safety Analysis Set
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    		 83.2 ± 18.77 81.2 ± 20.85 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo+Glimepiride
    Reporting group description
    		 Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride at a dose of 4 mg once daily received glimepiride 2 mg once daily, and if tolerated the dose was increased on Day 8 (+ 2 days) to 4 mg once daily. Qualifying period: participants received placebo to match ranolazine twice daily in addition to glimepiride for 14 days (+ 2 days) and if ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: participants were randomized to receive placebo to match ranolazine plus glimepiride 4 mg once daily for 24 weeks. Participants were required to maintain their diet and exercise regimen.

    Reporting group title
    Ranolazine+Glimepiride
    Reporting group description
    		 Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride at a dose of 4 mg once daily received glimepiride 2 mg once daily, and if tolerated the dose was increased on Day 8 (+ 2 days) to 4 mg once daily. Qualifying period: participants received placebo to match ranolazine twice daily in addition to glimepiride for 14 days (+ 2 days) and if ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: participants were randomized to receive ranolazine (1 x 500 mg tablet) twice daily plus glimepiride 4 mg once daily on Days 1 through 7, followed by ranolazine 1000 mg (2 x 500 mg tablets) twice daily plus glimepiride 4 mg once daily from Day 8 (or by Day 16 if not well tolerated) through Week 24. Participants were required to maintain their diet and exercise regimen.

    Subject analysis set title
    Placebo+Glimepiride FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo+Glimepiride Full Analysis Set (FAS): randomized participants who received ≥ 1 dose of study treatment with a baseline and at least one postbaseline measurement of HbA1c, excluding participants with major eligibility violations and analyzed based on randomized treatment, regardless of actual treatment received.

    Subject analysis set title
    Ranolazine+Glimepiride FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ranolazine+Glimepiride Full Analysis Set: randomized participants who received ≥ 1 dose of study treatment with a baseline and at least one postbaseline measurement of HbA1c, excluding participants with major eligibility violations and analyzed based on randomized treatment, regardless of actual treatment received.

    Subject analysis set title
    Placebo+Glimepiride MMTT FAS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo+Glimepiride Mixed Meal Tolerance Test (MMTT) Full Analysis Set: randomized participants who received at least one dose of study treatment with a baseline and at least one postbaseline measurement of serum glucose at T=120 minutes during the MMTT, administered under fasting conditions, excluding participants with major eligibility protocol violations, analyzed based on the randomized treatment regardless of actual treatment received.

    Subject analysis set title
    Ranolazine+Glimepiride MMTT FAS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Ranolazine+Glimepiride MMTT Full Analysis Set: randomized participants who received at least one dose of study treatment with a baseline and at least one postbaseline measurement of serum glucose at T=120 minutes during the MMTT, administered under fasting conditions, excluding participants with major eligibility protocol violations, analyzed based on the randomized treatment regardless of actual treatment received.

    Primary: Change From Baseline in Percent Glycosylated Hemoglobin (HbA1c) at Week 24

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    End point title
    		 Change From Baseline in Percent Glycosylated Hemoglobin (HbA1c) at Week 24
    End point description
    The average (mean) change from baseline in HbA1c at Week 24 was analyzed. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Placebo+Glimepiride FAS Ranolazine+Glimepiride FAS
    Number of subjects analysed
    184
    188
    Units: percent glycosylated hemoglobin
    arithmetic mean (standard deviation)
        HbA1c at Week 24
    8.08 ± 1.07
    7.58 ± 1.089
        Change from baseline in HbA1c at Week 24
    0.03 ± 0.949
    -0.47 ± 0.971
    Statistical analysis title
    		 Placebo vs Ranolazine: Change in Percent HbA1c
    Statistical analysis description
    Assuming a common standard deviation of 1.2%, an effective sample size of 400 would provide at least 90% power to detect a statistically significant treatment difference of -0.5% (ranolazine vs. placebo) for the reduction of HbA1c from baseline at Week 24 based on a 2-sided alpha of 0.05 and 1:1 randomization.
    Comparison groups
    Placebo+Glimepiride FAS v Ranolazine+Glimepiride FAS
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.001 [2]
    Method
    		 Mixed Effects Model Analysis
    Parameter type
    		 difference in least squares mean (LSM)
    Point estimate
    -0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 -0.32
    Notes
    [1] - The primary analysis of the change from Baseline in HbA1c at Week 24 was performed using a mixed models repeated measures (MMRM) approach which accounts for correlations among observations within a subject, allows for baseline adjustment, and uses all available data. Effects include baseline HbA1c value, prior anti-hyperglycemic therapy, treatment group, visit week, and treatment group by visit week interaction term.
    [2] - P-value is from a mixed-effect model including terms for baseline HbA1c value, prior antihyperglycemia therapy, treatment group, visit week, and treatment by visit week interaction. Unstructured covariance matrix was used.

    Secondary: Change From Baseline in Incremental Change of 2-hour Postprandial Serum Glucose at Week 24

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    End point title
    		 Change From Baseline in Incremental Change of 2-hour Postprandial Serum Glucose at Week 24
    End point description
    The average (mean) change from baseline in incremental change of 2-hour postprandial serum glucose at Week 24 was analyzed. Participants in the Mixed Meal Tolerance Test (MMTT) Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Placebo+Glimepiride MMTT FAS Ranolazine+Glimepiride MMTT FAS
    Number of subjects analysed
    169
    168
    Units: mg/dL
        arithmetic mean (standard deviation)
    -2 ± 42.6
    1 ± 44.7
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fasting Serum Glucose at Week 24

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    End point title
    		 Change From Baseline in Fasting Serum Glucose at Week 24
    End point description
    The average (mean) change from baseline in fasting serum glucose at Week 24 was analyzed. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Placebo+Glimepiride FAS Ranolazine+Glimepiride FAS
    Number of subjects analysed
    181
    183
    Units: mg/dL
        arithmetic mean (standard deviation)
    8 ± 40.7
    2 ± 45.3
    No statistical analyses for this end point

    Secondary: Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24

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    End point title
    		 Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24
    End point description
    The average (mean) change from baseline in 2-hour postprandial serum glucose at Week 24 was analyzed. Participants in the MMTT Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Placebo+Glimepiride MMTT FAS Ranolazine+Glimepiride MMTT FAS
    Number of subjects analysed
    175
    172
    Units: mg/dL
        arithmetic mean (standard deviation)
    4 ± 58
    1 ± 59.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 24 weeks plus 30 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo+Glimepiride
    Reporting group description
    		 Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride at a dose of 4 mg once daily received glimepiride 2 mg once daily, and if tolerated the dose was increased on Day 8 (+ 2 days) to 4 mg once daily. Qualifying period: participants received placebo to match ranolazine twice daily in addition to glimepiride for 14 days (+ 2 days) and if ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: participants were randomized to receive placebo to match ranolazine plus glimepiride 4 mg once daily for 24 weeks. Participants were required to maintain their diet and exercise regimen.

    Reporting group title
    Ranolazine+Glimepiride
    Reporting group description
    		 Glimepiride stabilization period (up to 8 weeks): participants not on stable glimepiride at a dose of 4 mg once daily received glimepiride 2 mg once daily, and if tolerated the dose was increased on Day 8 (+ 2 days) to 4 mg once daily. Qualifying period: participants received placebo to match ranolazine twice daily in addition to glimepiride for 14 days (+ 2 days) and if ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: participants were randomized to receive ranolazine (1 x 500 mg tablet) twice daily plus glimepiride 4 mg once daily on Days 1 through 7, followed by ranolazine 1000 mg (2 x 500 mg tablets) twice daily plus glimepiride 4 mg once daily from Day 8 (or by Day 16 if not well tolerated) through Week 24. Participants were required to maintain their diet and exercise regimen.

    Serious adverse events
    		 Placebo+Glimepiride Ranolazine+Glimepiride
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 216 (1.85%)
    4 / 215 (1.86%)
         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)
    Breast cancer
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 215 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 215 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein thrombosis
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 215 (0.47%)
         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
    Pulmonary embolism
         subjects affected / exposed
    1 / 216 (0.46%)
    0 / 215 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 216 (0.00%)
    1 / 215 (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
    		 Placebo+Glimepiride Ranolazine+Glimepiride
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 216 (21.30%)
    42 / 215 (19.53%)
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 216 (3.24%)
    11 / 215 (5.12%)
         occurrences all number
    8
    11
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    32 / 216 (14.81%)
    21 / 215 (9.77%)
         occurrences all number
    37
    25
    Hypoglycaemia
         subjects affected / exposed
    10 / 216 (4.63%)
    13 / 215 (6.05%)
         occurrences all number
    11
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 May 2012
    Secondary efficacy endpoints were revised as follows: specified that the change from baseline in PPG through Week 24 was the incremental change of 2-hour PPG; and added the change from baseline in 2-hour PPG at Week 24 to the endpoint of change from baseline in FSG at Week 24.
    07 Sep 2012
    The exclusion criterion regarding participants undergoing dialysis treatments was modified to additionally exclude participants with severe renal impairment.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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