Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    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 Metformin in Subjects with Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    		 2012-001259-37
    Trial protocol
    		 CZ   HU   PL  
    Global end of trial date
    01 Oct 2013

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-259-0147
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01555164
    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
    01 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 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, multicenter study to determine the effect of ranolazine when added to metformin on glycemic control in adults with type 2 diabetes mellitus (T2DM) who were inadequately controlled despite current treatment with stable 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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jun 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: 5
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    United States: 149
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Russian Federation: 86
    Country: Number of subjects enrolled
    Ukraine: 64
    Country: Number of subjects enrolled
    India: 93
    Country: Number of subjects enrolled
    South Africa: 11
    Country: Number of subjects enrolled
    Israel: 3
    Worldwide total number of subjects
    442
    EEA total number of subjects
    22
    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)
    372
    From 65 to 84 years
    70
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled (during the Qualifying Period) at a total of 112 study sites in Canada, Europe, Asia, Mexico, South Africa, and the United States. The first participant was screened on 28 June 2012. The last participant observation occurred on 01 October 2013.

    Pre-assignment
    Screening details
    		 580 participants enrolled in the Qualifying Period prior to randomization.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo+Metformin
    Arm description
    		 Qualifying phase: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment phase. Treatment phase: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24. Participants were required to maintain their diet and exercise regimen.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin 1000 mg (2 x 500 mg tablets) administered twice daily

    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 administered twice daily

    Arm title
    		 Ranolazine+metformin
    Arm description
    		 Qualifying phase: Metformin 1000 mg + placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment phase. Treatment phase: Ranolazine 500 mg + metformin 500 mg + placebo to match metformin twice daily on Days 1 through 7, followed by ranolazine 1000 mg + metformin 500 mg + placebo to match metformin twice daily from Day 8 through Week 24. Participants were required to maintain their diet and exercise regimen.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin 1000 mg (2 x 500 mg tablets) administered twice daily

    Investigational medicinal product name
    Ranolazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ranolazine 500 mg administered twice daily on Days 1 through 7, followed by ranolazine 1000 mg administered twice daily from Day 8 through Week 24.

    Number of subjects in period 1
    		Placebo+Metformin Ranolazine+metformin
    Started
    222
    220
    Completed
    182
    185
    Not completed
    40
    35
         'Subject Withdrew Consent '
    6
    11
         Adverse event, non-fatal
    5
    7
         Protocol violation
    9
    5
         Hyperglycaemia
    -
    1
         Investigator's Discretion
    2
    2
         Subject Non-compliance
    14
    6
         Lost to follow-up
    4
    3

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Placebo+Metformin
    Reporting group description
    		 Qualifying phase: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment phase. Treatment phase: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24. Participants were required to maintain their diet and exercise regimen.

    Reporting group title
    Ranolazine+metformin
    Reporting group description
    		 Qualifying phase: Metformin 1000 mg + placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment phase. Treatment phase: Ranolazine 500 mg + metformin 500 mg + placebo to match metformin twice daily on Days 1 through 7, followed by ranolazine 1000 mg + metformin 500 mg + placebo to match metformin twice daily from Day 8 through Week 24. Participants were required to maintain their diet and exercise regimen.

    Reporting group values
    		 Placebo+Metformin Ranolazine+metformin Total
    Number of subjects
    		 222 220 442
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56 ± 8.9 56 ± 9.3 -
    Gender categorical
    Units: Subjects
        Female
    		 98 121 219
        Male
    		 124 99 223
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 53 37 90
        Not Hispanic or Latino
    		 166 181 347
        Unknown or Not Reported
    		 3 2 5
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 0 2
        Asian
    		 52 54 106
        Black or African American
    		 8 11 19
        White
    		 160 153 313
        Other
    		 0 2 2
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 31.2 ± 4.46 31.6 ± 4.95 -
    Estimated glomerular filtration rate (eGFR)
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    		 90.8 ± 20.01 89.9 ± 21.82 -
    Glycosylated hemoglobin (HbA1c)
    Units: % hemoglobin which is glycosylated
        arithmetic mean (standard deviation)
    		 8.09 ± 0.729 8.1 ± 0.692 -
    Fasting Serum Glucose (FSG)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 170 ± 35.97 168.8 ± 32.86 -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 6.7 ± 5.31 6.4 ± 5.37 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo+Metformin
    Reporting group description
    		 Qualifying phase: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment phase. Treatment phase: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24. Participants were required to maintain their diet and exercise regimen.

    Reporting group title
    Ranolazine+metformin
    Reporting group description
    		 Qualifying phase: Metformin 1000 mg + placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment phase. Treatment phase: Ranolazine 500 mg + metformin 500 mg + placebo to match metformin twice daily on Days 1 through 7, followed by ranolazine 1000 mg + metformin 500 mg + placebo to match metformin twice daily from Day 8 through Week 24. Participants were required to maintain their diet and exercise regimen.

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

    		 Close Top of page
    End point title
    		 Change From Baseline in 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 (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) with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Placebo+Metformin Ranolazine+metformin
    Number of subjects analysed
    174
    179
    Units: % hemoglobin which is glycosylated
    arithmetic mean (standard deviation)
        HbA1c at Week 24
    7.86 ± 1.003
    7.72 ± 1.069
        Change from baseline in HbA1c at Week 24
    -0.2 ± 0.949
    -0.37 ± 0.916
    Statistical analysis title
    		 Difference in change from baseline
    Comparison groups
    Placebo+Metformin v Ranolazine+metformin
    Number of subjects included in analysis
    353
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.306 [2]
    Method
    		 Mixed Effects Model Analysis
    Parameter type
    		 difference in least squares mean
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.1
    Notes
    [1] - 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 -0.4% (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.
    [2] - P-value from a mixed-effects model including terms for baseline HbA1c value, treatment group, visit week, and treatment by visit week interaction. Unstructured covariance matrix was used.

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

    		 Close Top of page
    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+Metformin Ranolazine+metformin
    Number of subjects analysed
    171
    176
    Units: mg/dL
        arithmetic mean (standard deviation)
    -3 ± 44.7
    3 ± 42.5
    No statistical analyses for this end point

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

    		 Close Top of page
    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. 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.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Placebo+Metformin Ranolazine+metformin
    Number of subjects analysed
    166
    173
    Units: mg/dL
        arithmetic mean (standard deviation)
    -4 ± 54
    7 ± 58.2
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Up to 24 weeks plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo+Metformin
    Reporting group description
    		 Qualifying period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening) and participants who were ≥ 80% compliant and meeting eligibility criteria continued to the treatment period. Treatment period: Metformin 1000 mg (2 x 500 mg tablets) twice daily plus placebo to match ranolazine twice daily through Week 24. Participants were required to maintain their diet and exercise regimen.

    Reporting group title
    Ranolazine+metformin
    Reporting group description
    		 Qualifying Period: Participants will receive metformin 1000 mg + placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening). Treatment Period: Participants will receive ranolazine 500 mg + metformin 500 mg + placebo to match metformin twice daily on Days 1 through 7, followed by ranolazine 1000 mg + metformin 500 mg + placebo to match metformin twice daily from Day 8 through Week 24. Participants are required to maintain their diet and exercise regimen.

    Serious adverse events
    		 Placebo+Metformin Ranolazine+metformin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 222 (0.90%)
    3 / 220 (1.36%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 220 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Impaired gastric emptying
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 220 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 220 (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
    Metabolic acidosis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 220 (0.45%)
         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+Metformin Ranolazine+metformin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 222 (6.31%)
    18 / 220 (8.18%)
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    14 / 222 (6.31%)
    18 / 220 (8.18%)
         occurrences all number
    19
    23

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Sep 2012
    Amendment 1: addition of a paragraph which describes the safety of ranolazine in subjects with mild, moderate and severe renal impairment; addition of bicarbonate to the standard safety panel at every study visit.

    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.
    Significantly lower metformin (MET) trough concentrations were observed in the ranolazine (RAN) 1000mg/MET 500mg group vs the placebo/MET 1000mg group-this may have contributed to the observed results with respect to the HbA1c and glucose endpoints.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Fri Apr 26 20:02:51 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA