Hypertension
Conditions
Keywords
High blood pressure, Systolic blood pressure, Diastolic blood pressure, Antihypertensive
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.
Detailed description
This was a multi-center, randomized, double blind, placebo controlled study to evaluate the effect of celecoxib on the efficacy, safety, and pharmacokinetics of amlodipine in subjects with existing hypertension requiring antihypertensive therapy. Approximately 105 eligible subjects were to be randomized 3:3:1 to one of three treatment arms. Arm 1:OE 10 mg Norvasc tablet+OE 200 mg Celebrex capsule (amlodipine+celecoxib arm) Arm 2:OE 10 mg Norvasc tablet+matched placebo for OE Celebrex capsule (amlodipine+placebo arm) Arm 3:Matched placebo for OE Norvasc tablet+matched placebo for OE Celebrex capsule (placebo+placebo arm). Following an up to 14-day screening phase, eligible subjects were randomized to one of the 3 treatment arms. All drugs were to be administered orally qd for 14 days for a total of 14 doses. Visits at the clinic took place at the start and at the end of the screening phase, at Study Day 0 (start of treatment), Day 6, Day 7, Day 13 (end of treatment), Day 14 and Day 28 (end of follow-up).
Interventions
DRUGOE 10 mg amlodipine besylate tablet
DRUGOE 200 mg celecoxib capsule
DRUGMatched placebo for OE amlodipine besylate tablet
DRUGMatched placebo for OE celecoxib capsule
Sponsors
Kitov Pharma Ltd
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Adult 40 to 75 years of age 2. Existing hypertension that is being treated using pharmacological therapy with a single agent that is not a calcium channel blocker 3. 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) 4. Body Mass Index of 18.5 to 34.9 kg/m2 5. 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 6. A negative pregnancy test at initial screening visit 7. If woman of childbearing potential, agree to use a highly effective form of birth control while on study (from Screening through final study visit) 8. Able to comprehend and sign an informed consent form.
Exclusion criteria
1. 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) 2. Weight \< 55 kg 3. Fragile health 4. 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 5. Current or recent history (within four weeks prior to initial screening visit) of a clinically significant bacterial, fungal, or mycobacterial infection 6. Current clinically significant viral infection 7. History of malignancy, with the exception of cured basal cell or squamous cell carcinoma of the skin 8. Major surgery within four weeks prior to initial screening visit 9. Presence of a malabsorption syndrome possibly affecting drug absorption (e.g., Crohn's disease or chronic pancreatitis) 10. Active peptic ulceration or history of gastrointestinal bleeding 11. History of myocardial infarction, congestive heart failure, or stroke 12. Any current cardiovascular disease (other than hypertension) 13. History of psychotic disorder 14. 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 15. History of any illicit drug use within one year prior to initial screening visit 16. 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 17. 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 18. Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C 19. Known hypersensitivity to amlodipine or celecoxib 20. Known hypersensitivity to the inactive ingredients in the over-encapsulated (OE) study drugs 21. Asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic type reactions after taking acetylsalicylic acid or NSAIDs including cyclooxygenase-2 inhibitors 22. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with the dosing schedule and study evaluations 23. Pregnant or lactating 24. Unable to correctly use ambulatory blood pressure monitor after instruction on its use 25. Subjects with Child-Pugh Class B or C cirrhosis 26. 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 27. Subjects that took a calcium channel blocker in the past for any indication 28. Creatinine clearance \< 50 ml/min as estimated by the Cockroft-Gault equation 29. Known cytochrome P450 2C9 poor metabolizer 30. Subjects with allergy or hypersensitivity to sulfonamides
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday) | Baseline and 14 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight | Baseline and 14 days | 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. |
| Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h) | Baseline and 14 days | 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. |
| Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h) | Baseline and 14 days | 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. |
| Occurrence of Treatment Emergent Adverse Events | 1 month | 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. |
| Non-transformed Plasma Concentration of Amlodipine | 24 hours post-dose on Day 14 | 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. |
| Log-transformed Plasma Concentration of Amlodipine | 24 hours post-dose on Day 14 | 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. |
| Change in Creatinine Clearance | Baseline and 14 days | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Creatinine | Baseline and 14 Days | 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. |
Countries
United Kingdom
Participant flow
Pre-assignment details
Eligibility assessments were made at Initial Screening (Day -14 to -10), Final Screening (Day -1), and prior to randomization (Day 0). Subjects who met eligibility criteria at Initial Screening underwent a 10- to 14-day washout from their blood pressure medication and those who continued to meet criteria at the end of the washout were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Amlodipine+Celecoxib OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days | 48 |
| Amlodipine+Placebo OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days | 49 |
| Placebo+Placebo Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days | 8 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Subject unable to commit to study dates | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Amlodipine+Celecoxib | Amlodipine+Placebo | Placebo+Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 55.5 years STANDARD_DEVIATION 7.13 | 56.7 years STANDARD_DEVIATION 7.43 | 52.5 years STANDARD_DEVIATION 7.84 | 55.8 years STANDARD_DEVIATION 7.34 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 46 Participants | 47 Participants | 7 Participants | 100 Participants |
| Region of Enrollment United Kingdom | 48 participants | 49 participants | 8 participants | 105 participants |
| SBPday | 148.0 mmHg STANDARD_DEVIATION 7.95 | 150.0 mmHg STANDARD_DEVIATION 8.25 | 151.5 mmHg STANDARD_DEVIATION 10.91 | 149.2 mmHg STANDARD_DEVIATION 8.33 |
| Sex: Female, Male Female | 17 Participants | 18 Participants | 4 Participants | 39 Participants |
| Sex: Female, Male Male | 31 Participants | 31 Participants | 4 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 49 | 0 / 8 |
| other Total, other adverse events | 25 / 48 | 23 / 49 | 6 / 8 |
| serious Total, serious adverse events | 0 / 48 | 0 / 49 | 0 / 8 |
Outcome results
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.
Time frame: Baseline and 14 days
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine+Celecoxib | Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday) | -8.0 mmHg | Standard Deviation 8.24 |
| Amlodipine+Placebo | Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday) | -9.8 mmHg | Standard Deviation 8.89 |
Comparison: 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.p-value: 0.024t-test, 2 sided
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.
Time frame: Baseline and 14 days
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine+Celecoxib | Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h) | -4.4 mmHg | Standard Deviation 4.68 |
| Amlodipine+Placebo | Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h) | -3.8 mmHg | Standard Deviation 5.27 |
Comparison: A serial gatekeeping strategy was used for secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate secondary efficacy endpoints and was only to proceed from one to the next if the alpha was met for the prior; if the alpha was not met, analysis was performed for informational purposes only. Mean change in DBP24h was the 3rd of the 4 secondary efficacy endpoints.p-value: 0.5t-test, 2 sided
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.
Time frame: Baseline and 14 days
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine+Celecoxib | Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h) | -8.2 mmHg | Standard Deviation 7.8 |
| Amlodipine+Placebo | Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h) | -8.5 mmHg | Standard Deviation 8.47 |
Comparison: A serial gatekeeping strategy was used for secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate secondary efficacy endpoints and was only to proceed from one to the next if the alpha was met for the prior; if the alpha was not met, analysis was performed for informational purposes only. Mean change in SBP24h was the 2nd of the four secondary efficacy endpoints.p-value: 0.826t-test, 2 sided
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.
Time frame: Baseline and 14 days
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine+Celecoxib | Change in Body Weight | 0.3 kg | Standard Deviation 1.02 |
| Amlodipine+Placebo | Change in Body Weight | -0.3 kg | Standard Deviation 1.03 |
| Placebo+Placebo | Change in Body Weight | -1.5 kg | Standard Deviation 3.95 |
Comparison: A serial gatekeeping strategy was used for secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate secondary efficacy endpoints and was only to proceed from one to the next if the alpha was met for the prior; if the alpha was not met, analysis was performed for informational purposes only. Mean change in body weight was the 1st of the four secondary efficacy endpoints.p-value: 0.006ANOVA
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.
Time frame: Baseline and 14 days
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine+Celecoxib | Change in Creatinine Clearance | 4.9 mL/min | Standard Deviation 10.62 |
| Amlodipine+Placebo | Change in Creatinine Clearance | 3.4 mL/min | Standard Deviation 20.96 |
Comparison: A serial gatekeeping strategy was used for secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate secondary efficacy endpoints and was only to proceed from one to the next if the alpha was met for the prior; if the alpha was not met, analysis was performed for informational purposes only. Mean change in creatinine clearance was the 4th of 4 secondary efficacy endpoints.p-value: 0.668t-test, 2 sided
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.
Time frame: 24 hours post-dose on Day 14
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine+Celecoxib | Log-transformed Plasma Concentration of Amlodipine | 2.7 ng/mL | Standard Deviation 0.44 |
| Amlodipine+Placebo | Log-transformed Plasma Concentration of Amlodipine | 2.8 ng/mL | Standard Deviation 0.36 |
Comparison: 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.p-value: 0.215t-test, 2 sided
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.
Time frame: 24 hours post-dose on Day 14
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine+Celecoxib | Non-transformed Plasma Concentration of Amlodipine | 15.9 ng/mL | Standard Deviation 5.72 |
| Amlodipine+Placebo | Non-transformed Plasma Concentration of Amlodipine | 18.3 ng/mL | Standard Deviation 7.21 |
Comparison: For this analysis, all values below the limit of quantification were treated as 0.p-value: 0.226t-test, 2 sided
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.
Time frame: 1 month
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amlodipine+Celecoxib | Occurrence of Treatment Emergent Adverse Events | 35 Participants |
| Amlodipine+Placebo | Occurrence of Treatment Emergent Adverse Events | 32 Participants |
| Placebo+Placebo | Occurrence of Treatment Emergent Adverse Events | 6 Participants |
p-value: 0.675Chi-squared
p-value: 0.555Regression, Logistic
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.
Time frame: Baseline and 14 Days
Population: Safety population = all randomized subjects who received at least one dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine+Celecoxib | Change in Serum Creatinine | -2.8 μmol/L | Standard Deviation 5.56 |
| Amlodipine+Placebo | Change in Serum Creatinine | -2.4 μmol/L | Standard Deviation 10.19 |
| Placebo+Placebo | Change in Serum Creatinine | -1.9 μmol/L | Standard Deviation 4.61 |
Comparison: Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the Amlodipine+Celecoxib arm from baseline to Day 14.p-value: 0.0005ANCOVA
Comparison: Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the Amlodipine+Placebo arm from baseline to Day 14.p-value: 0.075ANCOVA
Comparison: Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the Placebo+Placebo arm from baseline to Day 14.p-value: 0.4184ANCOVA
Comparison: Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the comparison between the Amlodipine+Celecoxib and Amlodipine+Placebo arms.p-value: 0.2022ANCOVA
Comparison: Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the comparison between the Amlodipine+Celecoxib and Placebo+Placebo arms.p-value: 0.541ANCOVA
Comparison: Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the comparison between the Amlodipine+Placebo and Placebo+Placebo arms.p-value: 0.9397ANCOVA