Evaluation of Celecoxib Effects on Amlodipine in Subjects... | NCT02979197

ID	Type	Description	Link
2016-002214-47	EudraCT Number

Description Module

Brief Summary

The purpose of this study was to evaluate the effect of celecoxib on the efficacy and safety of amlodipine besylate on renal and vascular function in subjects with existing hypertension requiring antihypertensive therapy.

Kitov Pharma Ltd. (Kitov) is developing KIT-302, an oral fixed combination drug product (FCDP) consisting of the calcium channel blocker amlodipine besylate and the nonsteroidal anti-inflammatory drug (NSAID) celecoxib, as a "convenience reformulation" FCDP to facilitate and improve patient compliance with the once a day (qd) administration of its individual components, amlodipine and celecoxib.

The formulation of KIT-302 consists of amlodipine besylate and celecoxib co-formulated in a single immediate release tablet. However, for this study (KIT-302-03-02), commercial celecoxib capsules (Celebrex®) and commercial amlodipine besylate tablets (Norvasc®) were separately over-encapsulated (OE) and matched placebos were used to allow for blinding.

Kitov completed a phase 3 pivotal trial in subjects with newly diagnosed hypertension (KIT-302-03-01) demonstrating that the amlodipine + celecoxib combination was statistically non-inferior to amlodipine monotherapy with regard to reduction of blood pressure. Further, trends towards superior blood pressure lowering effects and improved renal function were observed for the combination. This study (KIT-302-03-02) was conducted to quantify the beneficial renovascular effects noted in the prior study in subjects with existing hypertension requiring antihypertensive therapy.

On May 31, 2018, the United States (US) Food and Drug Administration (FDA) approved KIT-302, under the brand name Consensi® (amlodipine and celecoxib) tablets [New Drug Application (NDA) 210045] for the following indication: "patients for whom treatment with amlodipine for hypertension and celecoxib for osteoarthritis are appropriate. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions."

Label	Type	Description	Intervention Names
Amlodipine+Celecoxib	Experimental	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Drug: OE 10 mg amlodipine besylate tablet Drug: OE 200 mg celecoxib capsule
Amlodipine+Placebo	Active Comparator	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Drug: OE 10 mg amlodipine besylate tablet Drug: Matched placebo for OE celecoxib capsule
Placebo+Placebo	Sham Comparator	Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Drug: Matched placebo for OE amlodipine besylate tablet Drug: Matched placebo for OE celecoxib capsule

Name	Type	Description	Arm Group Labels	Other Names
OE 10 mg amlodipine besylate tablet	Drug		Amlodipine+Celecoxib Amlodipine+Placebo	OE 10 mg Norvasc tablet

Measure	Description	Time Frame
Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday)	An ambulatory blood pressure monitor (ABPM) fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, & Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBPday was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first & last study measurements of the period that fell between 9:00 and 21:00; measurements during the first hour (white-coat window) were not included. Change in SBPday was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used [last observation carried forward (LOCF) method]. A negative value for change in SBPday indicates a decrease in systolic blood pressure and a positive value indicates an increase.	Baseline and 14 days

Measure	Description	Time Frame
Change in Body Weight	Body weight was measured at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. The measurements were made using a calibrated scale with the subject wearing underwear and a light gown. Change in body weight was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in body weight indicates a decrease in body weight and a positive value indicates an increase.

Measure	Description	Time Frame
Change in Serum Creatinine	Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Change in serum creatinine was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). A negative value for change in serum creatinine indicates a decrease in creatinine and a positive value indicates an increase.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Adult 40 to 75 years of age
Existing hypertension that is being treated using pharmacological therapy with a single agent that is not a calcium channel blocker
SBPday > 135 and ≤ 169 mmHg and average daytime (9:00 to 21:00) ambulatory diastolic blood pressure (DBPday) ≤ 110 mmHg at Day 0 (after the 10- to 14-day washout from prior blood pressure medication)
Body Mass Index of 18.5 to 34.9 kg/m2
Healthy (other than hypertension) as determined by the Investigator based on medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory tests
A negative pregnancy test at initial screening visit
If woman of childbearing potential, agree to use a highly effective form of birth control while on study (from Screening through final study visit)
Able to comprehend and sign an informed consent form.

Exclusion Criteria:

Resting SBP > 169 mmHg or a resting DBP > 110 mmHg at initial screening visit while on their standard antihypertensive therapy (where resting is defined as supine for at least 10 minutes with minimal interaction)
Weight < 55 kg
Fragile health
Evidence of clinically significant findings on screening evaluations (clinical, laboratory, and ECG) which, in the opinion of the Investigator would pose a safety risk or interfere with appropriate interpretation of safety data
Current or recent history (within four weeks prior to initial screening visit) of a clinically significant bacterial, fungal, or mycobacterial infection
Current clinically significant viral infection
History of malignancy, with the exception of cured basal cell or squamous cell carcinoma of the skin
Major surgery within four weeks prior to initial screening visit
Presence of a malabsorption syndrome possibly affecting drug absorption (e.g., Crohn's disease or chronic pancreatitis)
Active peptic ulceration or history of gastrointestinal bleeding
History of myocardial infarction, congestive heart failure, or stroke
Any current cardiovascular disease (other than hypertension)
History of psychotic disorder
History of alcoholism or drug addiction or current alcohol or drug use that, in the opinion of the Investigator, will interfere with the subject's ability to comply with the dosing schedule and study evaluations
History of any illicit drug use within one year prior to initial screening visit
Positive drug screen at initial screening visit. A positive drug screen for opiates only (with all other drug tests negative) will not be a basis for exclusion if the subject took over-the-counter narcotics as indicated on the product label within 24 hours prior to the drug screen
Current treatment or treatment within 30 days prior to first dose of study drugs with another investigational drug or current enrollment in another clinical trial
Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
Known hypersensitivity to amlodipine or celecoxib
Known hypersensitivity to the inactive ingredients in the over-encapsulated (OE) study drugs
Asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic type reactions after taking acetylsalicylic acid or NSAIDs including cyclooxygenase-2 inhibitors
Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with the dosing schedule and study evaluations
Pregnant or lactating
Unable to correctly use ambulatory blood pressure monitor after instruction on its use
Subjects with Child-Pugh Class B or C cirrhosis
Subjects currently taking a calcium channel blocker or any NSAID for any reason will be excluded. Subjects will not be withdrawn from these drugs to be enrolled in the trial
Subjects that took a calcium channel blocker in the past for any indication
Creatinine clearance < 50 ml/min as estimated by the Cockroft-Gault equation
Known cytochrome P450 2C9 poor metabolizer
Subjects with allergy or hypersensitivity to sulfonamides

Name	Affiliation	Role
J. Paul Waymack, MD, PhD	Kitov Pharma Ltd	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Oldfield Surgery		Bath		BA2 3HT	United Kingdom
Celerion

ID	Title	Description
FG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
FG001	Amlodipine+Placebo	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Dec 16, 2016	Sep 10, 2018

ID	Title	Description
BG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
BG001	Amlodipine+Placebo	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
BG002	Placebo+Placebo	Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
BG003	Total	Total of all reporting groups

Units	Counts
Participants	BG00048 BG00149 BG0028 BG003105

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday)

An ambulatory blood pressure monitor (ABPM) fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, & Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBPday was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first & last study measurements of the period that fell between 9:00 and 21:00; measurements during the first hour (white-coat window) were not included. Change in SBPday was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used [last observation carried forward (LOCF) method]. A negative value for change in SBPday indicates a decrease in systolic blood pressure and a positive value indicates an increase.

Intent-to-treat (ITT) population = all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement. The primary endpoint of this trial was a comparison of the mean change in SBPday between the amlodipine+celecoxib and amlodipine+placebo arms (non-inferiority trial). Comparison to placebo+placebo was not part of primary endpoint.

Posted

Mean

Standard Deviation

mmHg

Baseline and 14 days

ID	Title	Description
OG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
OG001	Amlodipine+Placebo	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days

Units	Counts
Participants	OG00048 OG00148

Title

Denominators

Categories

Title	Measurements
	OG000-8.0± 8.24 OG001-9.8± 8.89

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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 change in SBPday from Baseline 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.	t-test, 2 sided		0.024														Non-Inferiority	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 change in arm 1 and 50% of the mean change in arm 2 was less than 0.

Secondary

Change in Body Weight

Body weight was measured at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. The measurements were made using a calibrated scale with the subject wearing underwear and a light gown. Change in body weight was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in body weight indicates a decrease in body weight and a positive value indicates an increase.

ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was a comparison of the mean change in body weight between all three treatment arms [analysis of variance (ANOVA) F test]. Thus, mean values for all three arms are presented.

Posted

Mean

Standard Deviation

Baseline and 14 days

ID	Title	Description
OG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
OG001	Amlodipine+Placebo	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
OG002	Placebo+Placebo

Secondary

Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h)

An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, & Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBP24h was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first & last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in SBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in SBP24h indicates a decrease in systolic blood pressure and a positive value indicates an increase.

ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was the comparison of the mean change in SBP24h between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.

Posted

Mean

Standard Deviation

mmHg

Baseline and 14 days

ID	Title	Description
OG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
OG001	Amlodipine+Placebo

Secondary

Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h)

An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, & Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. DBP24h was calculated by averaging all of the diastolic blood pressure measurements between the protocol-defined first & last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in DBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in DBP24h indicates a decrease in diastolic blood pressure and a positive value indicates an increase.

ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was the comparison of the mean change in DBP24h between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.

Posted

Mean

Standard Deviation

mmHg

Baseline and 14 days

ID	Title	Description
OG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
OG001	Amlodipine+Placebo

Secondary

Change in Creatinine Clearance

Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Estimated creatinine clearance was calculated using Cockcroft-Gault equation: (140 - age) X body weight (kg)/72 X serum creatinine concentration (mg/dL); multiplied by 0.85 for women. Change in creatinine clearance was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in creatinine clearance indicates a decrease in creatinine clearance and a positive value indicates an increase.

ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was the comparison of the mean change in creatinine clearance between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.

Posted

Mean

Standard Deviation

mL/min

Baseline and 14 days

ID	Title	Description
OG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
OG001	Amlodipine+Placebo	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days

Secondary

Occurrence of Treatment Emergent Adverse Events

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.

Safety population = all randomized subjects who received at least one dose of study drug. The occurrence of TEAEs was compared between all three arms (Chi-square test), as well as between the amlodipine+celecoxib and amlodipine+placebo arms (exact logistic regression model). Comparison to placebo+placebo was not part of this latter analysis.

Posted

Count of Participants

Participants

1 month

ID	Title	Description
OG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
OG001	Amlodipine+Placebo	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
OG002	Placebo+Placebo	Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days

Secondary

Non-transformed Plasma Concentration of Amlodipine

A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The resulting concentrations, without logarithmic transformation, were used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean non-transformed plasma concentrations of amlodipine.

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.

Posted

Mean

Standard Deviation

ng/mL

24 hours post-dose on Day 14

ID	Title	Description
OG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
OG001	Amlodipine+Placebo	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days

Secondary

Log-transformed Plasma Concentration of Amlodipine

A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated LC-MS/MS method. The concentrations were logarithmically transformed and used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean log-transformed plasma concentrations of amlodipine.

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.

Posted

Mean

Standard Deviation

ng/mL

24 hours post-dose on Day 14

ID	Title	Description
OG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
OG001	Amlodipine+Placebo	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days

Units	Counts

Other Pre-specified

Change in Serum Creatinine

Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Change in serum creatinine was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). A negative value for change in serum creatinine indicates a decrease in creatinine and a positive value indicates an increase.

Safety population = all randomized subjects who received at least one dose of study drug

Posted

Mean

Standard Deviation

μmol/L

Baseline and 14 Days

ID	Title	Description
OG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
OG001	Amlodipine+Placebo	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
OG002	Placebo+Placebo	Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Eye swelling	Eye disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected49 at risk EG0021 events1 affected8 at risk
Vision blurred	Eye disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected49 at risk EG0021 events1 affected8 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0011 events1 affected49 at risk EG0021 events1 affected8 at risk
Flatulence	Gastrointestinal disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected49 at risk EG0021 events1 affected8 at risk
Chest discomfort	General disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected49 at risk EG0021 events1 affected8 at risk
Fatigue	General disorders	MedDRA 19.1	Systematic Assessment	EG0002 events2 affected48 at risk EG0010 events0 affected49 at risk EG0021 events1 affected8 at risk
Feeling cold	General disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected49 at risk EG0021 events1 affected8 at risk
Feeling hot	General disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0016 events3 affected49 at risk EG0020 events0 affected8 at risk
Oedema peripheral	General disorders	MedDRA 19.1	Systematic Assessment	EG0007 events7 affected48 at risk EG0015 events4 affected49 at risk EG0020 events0 affected8 at risk
Pain	General disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected49 at risk EG0022 events1 affected8 at risk
Rhinitis	Infections and infestations	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0011 events1 affected49 at risk EG0021 events1 affected8 at risk
Sinusitis	Infections and infestations	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected49 at risk EG0021 events1 affected8 at risk
Increased appetite	Metabolism and nutrition disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected49 at risk EG0021 events1 affected8 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0018 events3 affected49 at risk EG0020 events0 affected8 at risk
Joint swelling	Musculoskeletal and connective tissue disorders	MedDRA 19.1	Systematic Assessment	EG00012 events10 affected48 at risk EG00113 events9 affected49 at risk EG0021 events1 affected8 at risk
Dizziness	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG0004 events3 affected48 at risk EG0011 events1 affected49 at risk EG0020 events0 affected8 at risk
Headache	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG00010 events5 affected48 at risk EG00110 events9 affected49 at risk EG0023 events2 affected8 at risk
Lethargy	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected49 at risk EG0021 events1 affected8 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0012 events2 affected49 at risk EG0021 events1 affected8 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0012 events2 affected49 at risk EG0021 events1 affected8 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA 19.1	Systematic Assessment	EG0003 events3 affected48 at risk EG0010 events0 affected49 at risk EG0020 events0 affected8 at risk
Flushing	Vascular disorders	MedDRA 19.1	Systematic Assessment	EG0002 events2 affected48 at risk EG0012 events2 affected49 at risk EG0022 events2 affected8 at risk

ID	Term
D014652	Vascular Diseases
D002318	Cardiovascular Diseases

ID	Term
D004095	Dihydropyridines
D011725	Pyridines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D000096926	Benzenesulfonamides
D013449	Sulfonamides
D000577	Amides
D009930	Organic Chemicals
D001555	Benzene Derivatives
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D013450	Sulfones
D013457	Sulfur Compounds
D011720	Pyrazoles
D001393	Azoles

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Amlodipine+Celecoxib	OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	48	48	25	48
EG001	Amlodipine+Placebo	OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	49	49	23	49
EG002	Placebo+Placebo	Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	8	8	6	8