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    Clinical Trial Results:
    A Prospective Randomized Placebo Controlled Study to Evaluate the Effect of Celecoxib on the Efficacy and Safety of Amlodipine on Renal and Vascular Function in Subjects with Existing Hypertension Requiring Antihypertensive Therapy

    Summary
    EudraCT number
    		 2016-002214-47
    Trial protocol
    		 GB  
    Global end of trial date
    21 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Oct 2018
    First version publication date
    10 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KIT-302-03-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02979197
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kitov Pharma Ltd
    Sponsor organisation address
    One Azrieli Center, Round Tower, Floor 19, 132 Menachem Begin Road , Tel Aviv, Israel, 6701101
    Public contact
    Chief Medical Officer/US Agent, Kitov Pharma Ltd, 001 2029652215, paul@kitovpharma.com
    Scientific contact
    Chief Medical Officer/US Agent, Kitov Pharma Ltd, 001 2029652215, paul@kitovpharma.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
    21 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the mean reduction in average daytime (9:00 to 21:00) ambulatory systolic blood pressure (SBPday) after oral administration of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together once a day (qd) for 14 days in adult subjects with existing hypertension is no less than half the mean reduction in SBPday after oral administration of amlodipine tablets (10 mg) given alone (i.e., with matched celecoxib placebo) qd for 14 days in the same population.
    Protection of trial subjects
    This study was in compliance with the ethical principles derived from the principles of Good Clinical Practice (GCP) [current International Conference of Harmonization (ICH) guidelines], and the Declaration of Helsinki (1964) including all amendments up to and including the October 2013 revision. All local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. The safety assessments included clinical laboratory tests (hematology, serum chemistry and urinalysis), Electrocardiogram, Physical examination findings, Orthostatic Hypotension measurements and Vital signs. Adverse events were monitored throughout the study.
    Background therapy
    		 None
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Nov 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 105
    Worldwide total number of subjects
    105
    EEA total number of subjects
    105
    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)
    89
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted across 9 sites in the United Kingdom. The first patient first visit was on the 3rd November 2016. The last patient last visit was on the 21st July 2017.

    Pre-assignment
    Screening details
    		 Subjects underwent assessments to determine eligibility at the Initial Screening Visit (Day -14 to -10; 255 subjects), Final Screening Visit (Day -1; 159 subjects), and the morning prior to randomization (Study Day 0; 154 subjects). A total of 150 subjects were screen failures and the remaining 105 were randomized.

    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, Data analyst, Assessor
    Blinding implementation details
    Blinding of the subject and Investigational staff to treatment was achieved by using over-encapsulated (OE) formulations and matched placebo capsules. The appearance of the OE amlodipine tablets and matched placebo capsules were identical. Similarly, the appearance of the OE celecoxib capsules and matched placebo capsules were identical. Each patient kit, and the 2 bottles of study drug within the kit, were labeled in a manner to maintain blinding of the subject and Investigational staff.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Amlodipine+Celecoxib
    Arm description
    		 Over-encapsulated 10 mg amlodipine besylate tablet + over-encapsulated 200 mg celecoxib capsule once a day for two weeks Over-encapsulated 10 mg amlodipine besylate tablet: Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks Over-encapsulated 200 mg celecoxib capsule: Over-encapsulated 200 mg celecoxib capsule once a day for two weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    OE 10mg amlodipine besylate tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks

    Investigational medicinal product name
    OE 200mg celecoxib capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Over-encapsulated 200 mg celecoxib capsule once a day for two weeks

    Arm title
    		 Amlodipine+Placebo
    Arm description
    		 Over-encapsulated 10 mg amlodipine besylate tablet + matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Over-encapsulated 10 mg amlodipine besylate tablet: Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks Matched placebo capsule for over-encapsulated celecoxib capsule: Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    OE 10mg amlodipine besylate tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks

    Investigational medicinal product name
    Matched placebo capsule for OE celecoxib capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks

    Arm title
    		 Placebo+Placebo
    Arm description
    		 Matched placebo capsule for over-encapsulated amlodipine besylate tablet + matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Matched placebo capsule for over-encapsulated celecoxib capsule: Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Matched placebo capsule for over-encapsulated amlodipine besylate tablet: Matched placebo capsule for over-encapsulated amlodipine besylate tablet once a day for two weeks
    Arm type
    		 Sham comparator

    Investigational medicinal product name
    Matched placebo capsule for OE celecoxib capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks

    Investigational medicinal product name
    Matched placebo capsule for OE amlodipine tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matched placebo capsule for over-encapsulated amlodipine besylate tablet once a day for two weeks

    Number of subjects in period 1
    		Amlodipine+Celecoxib Amlodipine+Placebo Placebo+Placebo
    Started
    48
    49
    8
    Completed
    44
    45
    8
    Not completed
    4
    4
    0
         Subject unable to commit to study dates
    -
    1
    -
         Adverse event, non-fatal
    4
    2
    -
         Protocol deviation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Amlodipine+Celecoxib
    Reporting group description
    		 Over-encapsulated 10 mg amlodipine besylate tablet + over-encapsulated 200 mg celecoxib capsule once a day for two weeks Over-encapsulated 10 mg amlodipine besylate tablet: Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks Over-encapsulated 200 mg celecoxib capsule: Over-encapsulated 200 mg celecoxib capsule once a day for two weeks

    Reporting group title
    Amlodipine+Placebo
    Reporting group description
    		 Over-encapsulated 10 mg amlodipine besylate tablet + matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Over-encapsulated 10 mg amlodipine besylate tablet: Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks Matched placebo capsule for over-encapsulated celecoxib capsule: Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks

    Reporting group title
    Placebo+Placebo
    Reporting group description
    		 Matched placebo capsule for over-encapsulated amlodipine besylate tablet + matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Matched placebo capsule for over-encapsulated celecoxib capsule: Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Matched placebo capsule for over-encapsulated amlodipine besylate tablet: Matched placebo capsule for over-encapsulated amlodipine besylate tablet once a day for two weeks

    Reporting group values
    		 Amlodipine+Celecoxib Amlodipine+Placebo Placebo+Placebo Total
    Number of subjects
    		 48 49 8 105
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 42 39 8 89
        From 65-84 years
    		 6 10 0 16
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.5 ( 7.13 ) 56.7 ( 7.43 ) 52.5 ( 7.84 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 18 4 39
        Male
    		 31 31 4 66
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 1 1 2
        Black or African American
    		 1 0 0 1
        White
    		 46 47 7 100
        More than one race
    		 1 1 0 2
        Unkown or not reported
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
    Region of Enrollment
    Units: Subjects
        United Kingdom
    		 48 49 8 105
    Average daytime (9:00 to 21:00) ambulatory systolic blood pressure measured at Day -1
    Units: mmHg
        arithmetic mean (standard deviation)
    		 148.0 ( 7.95 ) 150.0 ( 8.25 ) 151.5 ( 10.91 ) -

    End points

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    End points reporting groups
    Reporting group title
    Amlodipine+Celecoxib
    Reporting group description
    		 Over-encapsulated 10 mg amlodipine besylate tablet + over-encapsulated 200 mg celecoxib capsule once a day for two weeks Over-encapsulated 10 mg amlodipine besylate tablet: Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks Over-encapsulated 200 mg celecoxib capsule: Over-encapsulated 200 mg celecoxib capsule once a day for two weeks

    Reporting group title
    Amlodipine+Placebo
    Reporting group description
    		 Over-encapsulated 10 mg amlodipine besylate tablet + matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Over-encapsulated 10 mg amlodipine besylate tablet: Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks Matched placebo capsule for over-encapsulated celecoxib capsule: Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks

    Reporting group title
    Placebo+Placebo
    Reporting group description
    		 Matched placebo capsule for over-encapsulated amlodipine besylate tablet + matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Matched placebo capsule for over-encapsulated celecoxib capsule: Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Matched placebo capsule for over-encapsulated amlodipine besylate tablet: Matched placebo capsule for over-encapsulated amlodipine besylate tablet once a day for two weeks

    Primary: Mean Reduction in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday)

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    End point title
    		 Mean Reduction in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday) [1]
    End point description
    Intent-to-treat (ITT) population = all randomized subjects with a valid Baseline (Day -1 to Day 0) ambulatory blood pressure monitor (ABPM) measurement. For efficacy analyses, the validity of ABPM measurements was based on valid daytime measurements.
    End point type
    Primary
    End point timeframe
    Baseline and 14 days
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the primary endpoint was the difference in the mean reduction in SBPday from baseline to final measurement between the Amlodipine+Celecoxib and Amlodipine+Placebo arms. A comparison with the Placebo+Placebo arm was not part of the primary endpoint and therefore is not included.
    End point values
    		 Amlodipine+Celecoxib Amlodipine+Placebo
    Number of subjects analysed
    48
    48
    Units: mmHg
        arithmetic mean (standard deviation)
    -8.0 ( 8.24 )
    -9.8 ( 8.89 )
    Statistical analysis title
    		 StatsAnalysis1 Mean Reduction in Average SBPday
    Statistical analysis description
    Last observation carried forward (LOCF) method was used. Primary efficacy analysis was based on the difference between the Amlodipine+Celecoxib and Amlodipine+Placebo (arms 1 and 2, respectively) in the mean reduction in SBPday from baseline (Day -1) to final (Day 13), where a subject completed the 14-day treatment plan, or to Day 6, where a subject was withdrawn from treatment before the Day 13 dose but after the Day 6 dose, or to baseline, where a subject was withdrawn before the Day 6 dose.
    Comparison groups
    Amlodipine+Celecoxib v Amlodipine+Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.024
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - A two-sample t-test was used to test the one-sided hypothesis that treatment with Amlodipine+Celecoxib (arm 1) was non-inferior to half of the effect achieved with Amlodipine+Placebo (arm 2). The primary efficacy endpoint was considered met if the lower limits of the 97.5% one-side confidence interval (CI) for the difference in SBPday reduction in arm 1 and 50% of the mean reduction in arm 2 was less than 0.

    Secondary: Mean Change in Body Weight

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    End point title
    		 Mean Change in Body Weight
    End point description
    ITT population as described for primary outcome
    End point type
    Secondary
    End point timeframe
    Baseline and 14 days
    End point values
    		 Amlodipine+Celecoxib Amlodipine+Placebo Placebo+Placebo
    Number of subjects analysed
    48
    48
    8
    Units: Kg
        arithmetic mean (standard deviation)
    0.3 ( 1.02 )
    -0.3 ( 1.03 )
    -1.5 ( 3.95 )
    Statistical analysis title
    		 StatsAnalysis1 Mean Change in Body Weight
    Statistical analysis description
    A serial gatekeeping strategy was used for the secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary efficacy endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate the secondary efficacy endpoints and was only to proceed from one secondary efficacy endpoint to the next if the alpha was met for the prior analyses. Mean change in body weight was the 1st of the four secondary efficacy endpoints. LOCF technique was used.
    Comparison groups
    Amlodipine+Celecoxib v Amlodipine+Placebo v Placebo+Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.006 [4]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [3] - Analysis of variance (ANOVA) was used to compare the mean changes in body weight from baseline to end of treatment among the three treatment arms. The omni-bus test was to conclude if any differences existed, with post-hoc comparisons identifying specific differences between treatment arms. Any statistically significant differences would be sufficient to pass this gate in the study-wide gate keeping strategy.
    [4] - While the ANOVA showed a statistically significant difference between the three treatment arms (p=0.006), the pairwise comparisons of the treatment arms did not show any clinically meaningful differences.

    Secondary: Mean Reduction in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h)

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    End point title
    		 Mean Reduction in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h) [5]
    End point description
    ITT population as described for primary outcome
    End point type
    Secondary
    End point timeframe
    Baseline and 14 days
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the secondary endpoint related to SBP24hr was the difference in the mean reduction in SBP24hr from baseline to final measurement between the Amlodipine+Celecoxib and Amlodipine+Placebo arms. A comparison with the Placebo+Placebo arm was not part of this secondary endpoint and therefore is not included.
    End point values
    		 Amlodipine+Celecoxib Amlodipine+Placebo
    Number of subjects analysed
    48
    48
    Units: mmHg
        arithmetic mean (standard deviation)
    -8.2 ( 7.80 )
    -8.5 ( 8.47 )
    Statistical analysis title
    		 StatsAnalysis1 Mean Reduction in Average SBP24h
    Statistical analysis description
    A serial gatekeeping strategy was used for the secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary efficacy endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate the secondary efficacy endpoints and was only to proceed from one secondary efficacy endpoint to the next if the alpha was met for the prior analyses. Mean reduction in SBP24h was the 2nd of the four secondary efficacy endpoints. LOCF technique was used.
    Comparison groups
    Amlodipine+Celecoxib v Amlodipine+Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.826
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [6] - A two-sample t-test for superiority was used to test the one-sided hypothesis that treatment with Amlodipine+Celecoxib lowered SBP24h to a greater degree than Amlodipine+Placebo.

    Secondary: Mean Reduction in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h)

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    End point title
    		 Mean Reduction in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h) [7]
    End point description
    ITT population as described for primary outcome
    End point type
    Secondary
    End point timeframe
    Baseline and 14 days
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the secondary endpoint related to DBP24hr was the difference in the mean reduction in DBP24hr from baseline to final measurement between the Amlodipine+Celecoxib and Amlodipine+Placebo arms. A comparison with the Placebo+Placebo arm was not part of this secondary endpoint and therefore is not included.
    End point values
    		 Amlodipine+Celecoxib Amlodipine+Placebo
    Number of subjects analysed
    48
    48
    Units: mmHg
        arithmetic mean (standard deviation)
    -4.4 ( 4.68 )
    -3.8 ( 5.27 )
    Statistical analysis title
    		 StatsAnalysis1 Mean Reduction in Average DBP24h
    Statistical analysis description
    A serial gatekeeping strategy was used for the secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary efficacy endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate the secondary efficacy endpoints and was only to proceed from one secondary efficacy endpoint to the next if the alpha was met for the prior analyses. Mean reduction in DBP24h was the 3rd of the four secondary efficacy endpoints. LOCF technique was used.
    Comparison groups
    Amlodipine+Celecoxib v Amlodipine+Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.5
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [8] - A two-sample t-test for superiority was used to test the one-sided hypothesis that treatment with Amlodipine+Celecoxib lowered DBP24h to a greater degree than Amlodipine+Placebo. Note, although the alpha was not met for the SBP24h efficacy endpoint of the serial gate-keeping strategy, DBP24h was still evaluated for informational purposes and the results are presented here.

    Secondary: Mean Change in Creatinine Clearance

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    End point title
    		 Mean Change in Creatinine Clearance [9]
    End point description
    ITT population as described for primary outcome
    End point type
    Secondary
    End point timeframe
    Baseline and 14 days
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Renal function was analyzed by evaluating the decreases in mean serum creatinine from baseline to Day 14 WITHIN EACH TREATMENT ARM, as well as BETWEEN TREATMENT ARMS. The within arm comparisons (i.e., mean decrease from baseline to Day 14) were conducted as three separate analyses, one for each of the three treatment arms. The between treatment arm comparisons (i.e., mean decrease from baseline to Day 14 between arms) were conducted as three separate PAIRWISE comparisons.
    End point values
    		 Amlodipine+Celecoxib Amlodipine+Placebo
    Number of subjects analysed
    48
    48
    Units: mL/min
        arithmetic mean (standard deviation)
    4.9 ( 10.62 )
    3.4 ( 20.96 )
    Statistical analysis title
    		 StatsAnalysis1 Mean Change in Creatinine Clearance
    Statistical analysis description
    A serial gatekeeping strategy was used for the secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary efficacy endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate the secondary efficacy endpoints and was only to proceed from one secondary efficacy endpoint to the next if the alpha was met for the prior analyses. Mean change in creatinine clearance was the 4th of the 4 secondary efficacy endpoints. LOCF technique was used.
    Comparison groups
    Amlodipine+Celecoxib v Amlodipine+Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.668 [11]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [10] - A two-sample t-test for superiority was used to test the one-sided hypothesis that treatment with Amlodipine+Celecoxib improved creatinine clearance to a greater degree than Amlodipine+Placebo. Note, although the alpha was not met for the DBP24h efficacy endpoint of the serial gate-keeping strategy, creatinine clearance was still evaluated for informational purposes and the results are presented here.
    [11] - Creatinine clearance increased from baseline to end of study in both arms; however, the superiority of Amlodipine+Celecoxib over Amlodipine+Placebo was not demonstrated. See further evaluation of renal function under serum creatinine outcome.

    Secondary: Incidence of Treatment Emergent Adverse Events

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    End point title
    		 Incidence of Treatment Emergent Adverse Events
    End point description
    Treatment emergent adverse events (TEAEs) included any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs.
    End point type
    Secondary
    End point timeframe
    1 month
    End point values
    		 Amlodipine+Celecoxib Amlodipine+Placebo Placebo+Placebo
    Number of subjects analysed
    48
    49
    8
    Units: Subjects
        number (not applicable)
    35
    32
    6
    Statistical analysis title
    		 StatsAnalysis1 Incidence of Treatment Emergent AEs
    Comparison groups
    Amlodipine+Celecoxib v Amlodipine+Placebo v Placebo+Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.675
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [12] - Differences in the incidence of TEAEs between treatment arms were evaluated using Chi-square test.
    Statistical analysis title
    		 StatsAnalysis2 Incidence of Treatment Emergent AEs
    Comparison groups
    Amlodipine+Celecoxib v Amlodipine+Placebo
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.555
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [13] - Amlodipine+Celecoxib and Amlodipine+Placebo arms were compared by logistic regression, where TEAE (1=at least one TEAE occurred for the subject; 0=otherwise) as dependent variable and treatment as fixed effect.

    Secondary: Non-transformed Plasma Concentration of Amlodipine

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    End point title
    		 Non-transformed Plasma Concentration of Amlodipine [14]
    End point description
    Pharmacokinetic (PK) population = all subjects enrolled at an Investigational Site with ultraviolet- (UV-) shielded lights who had blood drawn on Day 14, 24 hours ± 1 hour after receiving the final dose of study drugs for the measurement of plasma amlodipine concentration; only treatment arms that included amlodipine were included in the analyses.
    End point type
    Secondary
    End point timeframe
    24 hours post-dose on Day 14
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, no “amlodipine” PK statistical analyses were performed for the PK subjects in the placebo + placebo arms (i.e., the arms that did not receive amlodipine). No subjects in these arms had detectable levels of amlodine in their plasma, and as such, PK analysis was not possible for these subjects.
    End point values
    		 Amlodipine+Celecoxib Amlodipine+Placebo
    Number of subjects analysed
    23
    20
    Units: ng/mL
        arithmetic mean (standard deviation)
    15.9 ( 5.72 )
    18.3 ( 7.21 )
    Statistical analysis title
    		 Nontransformed PlasmaConcentration of Amlodipine
    Statistical analysis description
    For this analysis, all values below the limit of quantification were treated as 0.
    Comparison groups
    Amlodipine+Celecoxib v Amlodipine+Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.226
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Log-transformed Plasma Concentration of Amlodipine

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    End point title
    		 Log-transformed Plasma Concentration of Amlodipine [15]
    End point description
    PK population = all subjects enrolled at an Investigational Site with ultraviolet- (UV-) shielded lights who had blood drawn on Day 14, 24 hours ± 1 hour after receiving the final dose of study drugs for the measurement of plasma amlodipine concentration; only treatment arms that included amlodipine were included in the analyses.
    End point type
    Secondary
    End point timeframe
    24 hours post-dose on Day 14
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, no “amlodipine” PK statistical analyses were performed for the PK subjects in the placebo + placebo arms (i.e., the arms that did not receive amlodipine). No subjects in these arms had detectable levels of amlodine in their plasma, and as such, PK analysis was not possible for these subjects.
    End point values
    		 Amlodipine+Celecoxib Amlodipine+Placebo
    Number of subjects analysed
    23
    20
    Units: ng/mL
        arithmetic mean (standard deviation)
    2.7 ( 0.44 )
    2.8 ( 0.36 )
    Statistical analysis title
    		 Log-transformed Plasma Concentration of Amlodipine
    Statistical analysis description
    For this analysis, all values below the limit of quantification (BLQ) were treated as 0.04 ng/mL. Assignment of BLQ values to a nonzero number allowed computation of the log transformation. The selection of 0.04 ng/mL was based on the lower limit of quantification of the validated bioanalytical method (0.05 ng/mL) and selecting the next lowest number at the hundredth decimal place.
    Comparison groups
    Amlodipine+Celecoxib v Amlodipine+Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.215
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs.
    Adverse event reporting additional description
    Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, ECG, hematology, serum chemistry, and urinalysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Amlodipine+Celecoxib
    Reporting group description
    		 Over-encapsulated 10 mg amlodipine besylate tablet + over-encapsulated 200 mg celecoxib capsule once a day for two weeks Over-encapsulated 10 mg amlodipine besylate tablet: Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks Over-encapsulated 200 mg celecoxib capsule: Over-encapsulated 200 mg celecoxib capsule once a day for two weeks

    Reporting group title
    Amlodipine+Placebo
    Reporting group description
    		 Over-encapsulated 10 mg amlodipine besylate tablet + matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Over-encapsulated 10 mg amlodipine besylate tablet: Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks Matched placebo capsule for over-encapsulated celecoxib capsule: Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks

    Reporting group title
    Placebo+Placebo
    Reporting group description
    		 Matched placebo capsule for over-encapsulated amlodipine besylate tablet + matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Matched placebo capsule for over-encapsulated celecoxib capsule: Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks Matched placebo capsule for over-encapsulated amlodipine besylate tablet: Matched placebo capsule for over-encapsulated amlodipine besylate tablet once a day for two weeks

    Serious adverse events
    		 Amlodipine+Celecoxib Amlodipine+Placebo Placebo+Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 49 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Amlodipine+Celecoxib Amlodipine+Placebo Placebo+Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 48 (52.08%)
    23 / 49 (46.94%)
    6 / 8 (75.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 49 (4.08%)
    2 / 8 (25.00%)
         occurrences all number
    2
    2
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 48 (10.42%)
    9 / 49 (18.37%)
    2 / 8 (25.00%)
         occurrences all number
    10
    10
    3
    Dizziness
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 49 (2.04%)
    0 / 8 (0.00%)
         occurrences all number
    4
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 49 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    7 / 48 (14.58%)
    4 / 49 (8.16%)
    0 / 8 (0.00%)
         occurrences all number
    7
    5
    0
    Chest discomfort
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 49 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 49 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    1
    Feeling cold
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 49 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Feeling hot
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 49 (6.12%)
    0 / 8 (0.00%)
         occurrences all number
    1
    6
    0
    Pain
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    2
    Eye disorders
    Eye swelling
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 49 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 49 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Flatulence
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 49 (4.08%)
    1 / 8 (12.50%)
         occurrences all number
    1
    2
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 49 (4.08%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    1
    Rash
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 49 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    10 / 48 (20.83%)
    9 / 49 (18.37%)
    1 / 8 (12.50%)
         occurrences all number
    12
    13
    1
    Arthralgia
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 49 (6.12%)
    0 / 8 (0.00%)
         occurrences all number
    0
    8
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 49 (2.04%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Sinusitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 49 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 49 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    No limitations
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