Primary Hypertension
Conditions
Brief summary
The main purpose of this study is to evaluate the safety and effectiveness of the study drug known as LY2623091 in participants with high blood pressure.
Interventions
DRUGLY2623091
Administered orally
DRUGTadalafil
Administered orally
DRUGSpironolactone
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Have a history of hypertension. * If participants are naïve to treatment of hypertension, or have not been treated with any antihypertensive medications within the 30 days immediately prior to screening: * Have seated systolic (SBP) of ≥140 and \<170 millimeters of mercury (mmHg) at screening and at the end of the lead-in period. * If participants are currently being treated for hypertension: * Are taking a stable dose of 1 or 2 antihypertensive medications for at least the previous 30 days. A combination antihypertensive medication from 2 classes is considered as 2 antihypertensive medications. * Are willing to discontinue the antihypertensive medications during the study. * Have seated SBP of ≥140 and \<170 mmHg at the end of the lead-in period. * Have a body mass index (BMI) ≥18.5 and \<40 kilograms/m\^2.
Exclusion criteria
* Have a history of severe hypertension (defined as SBP ≥180 mmHg and/or diastolic (DBP) ≥120 mmHg), secondary hypertension, symptomatic postural hypotension, or hospitalization due to hypertension. * Have SBP ≥180 mmHg and/or DBP ≥110 mmHg at screening, lead-in period, or randomization. * Have a history of hospitalization due to hyperkalemia, or history of drug discontinuation due to elevated serum potassium levels. * Have a serum potassium ≤3.5 or \>5.0 millimoles per liter (mmol/L). * Have an estimated glomerular filtration rate (eGFR) \<50 milliliters/minute/1.73 m\^2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 4 Weeks in Seated Systolic Blood Pressure (SBP) | Baseline, 4 Weeks | Change from baseline in SBP as measured by a cuff. Least squares (LS) mean change from baseline was calculated using a mixed model repeating measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 4 Weeks in Seated Diastolic Blood Pressure (DBP) | Baseline, 4 Weeks | Change from baseline in DBP as measured by a cuff. LS mean change from baseline was calculated using a MMRM with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. |
| Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | Baseline, 4 Weeks | The LS mean change in blood pressure is calculated after adjusting for baseline, treatment and race using an analysis of covariance (ANCOVA). |
| Change From Baseline to 4 Weeks in Serum Potassium | Baseline, 4 Weeks | Potassium measurement as measured by standard laboratory tests. The LS mean change in potassium is calculated using MMRM with adjustment for baseline, treatment, visit, treatment\*visit and race. |
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2623091 | 2 hours post-dose at 4 Weeks | — |
Countries
Canada, Puerto Rico, United States
Participant flow
Pre-assignment details
Participants entered at lead-in for wash out and a placebo run-in period prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo for blinding administered orally once daily for 4 weeks. | 51 |
| 6 mg LY2623091 6 mg LY2623091 with placebo for blinding administered orally once daily for 4 weeks. | 50 |
| 13 mg LY2623091 13 mg LY2623091 with placebo for blinding administered orally once daily for 4 weeks. | 51 |
| 24.5 mg LY2623091 24.5 mg LY2623091 with placebo for blinding administered orally once daily for 4 weeks. | 49 |
| 13 mg LY2623091 + 20 mg Tadalafil 13 mg LY2623091 and 20 mg of tadalafil with placebo for blinding administered orally once daily for 4 weeks. | 51 |
| 20 mg Tadalafil 20 mg tadalafil with placebo for blinding administered orally once daily for 4 weeks. | 25 |
| Spironolactone 25 mg titrated to 50 mg as tolerated of spironolactone (open label) administered orally once daily for 4 weeks. | 26 |
| Total | 303 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 1 | 4 | 4 | 4 | 2 | 0 |
| Overall Study | Discontinued follow-up period | 0 | 2 | 1 | 0 | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 1 | 2 | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 1 | 2 | 2 | 1 | 2 |
Baseline characteristics
| Characteristic | 6 mg LY2623091 | Total | Spironolactone | 20 mg Tadalafil | Placebo | 13 mg LY2623091 + 20 mg Tadalafil | 24.5 mg LY2623091 | 13 mg LY2623091 |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.6 years STANDARD_DEVIATION 11.4 | 57.7 years STANDARD_DEVIATION 9.7 | 59.0 years STANDARD_DEVIATION 11 | 54.0 years STANDARD_DEVIATION 8.9 | 58.6 years STANDARD_DEVIATION 9.4 | 57.9 years STANDARD_DEVIATION 9.5 | 58.7 years STANDARD_DEVIATION 8.8 | 58.0 years STANDARD_DEVIATION 8.8 |
| Anti-Hypertensive Medication 0 | 10 Participants | 52 Participants | 3 Participants | 6 Participants | 8 Participants | 13 Participants | 7 Participants | 5 Participants |
| Anti-Hypertensive Medication 1 | 22 Participants | 130 Participants | 10 Participants | 10 Participants | 24 Participants | 17 Participants | 22 Participants | 25 Participants |
| Anti-Hypertensive Medication 2 | 17 Participants | 116 Participants | 13 Participants | 8 Participants | 19 Participants | 20 Participants | 19 Participants | 20 Participants |
| Anti-Hypertensive Medication 3 | 1 Participants | 4 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Anti-Hypertensive Medication 4 | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Baseline in Seated Diastolic Blood Pressure (DBP) | 88.2 millimeter of mercury (mmHg) STANDARD_DEVIATION 9.7 | 89.6 millimeter of mercury (mmHg) STANDARD_DEVIATION 9.3 | 88.6 millimeter of mercury (mmHg) STANDARD_DEVIATION 11.6 | 91.5 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.8 | 89.8 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.8 | 90.6 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.9 | 88.5 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.5 | 90.5 millimeter of mercury (mmHg) STANDARD_DEVIATION 9.5 |
| Baseline in Seated Systolic Blood Pressure (SBP) | 150.8 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.6 | 151.9 millimeter of mercury (mmHg) STANDARD_DEVIATION 9.1 | 153.4 millimeter of mercury (mmHg) STANDARD_DEVIATION 9 | 151.7 millimeter of mercury (mmHg) STANDARD_DEVIATION 9.6 | 151.2 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.8 | 152.1 millimeter of mercury (mmHg) STANDARD_DEVIATION 9.6 | 150.7 millimeter of mercury (mmHg) STANDARD_DEVIATION 10.2 | 153.7 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.3 |
| BMI | 30.2 kilogram/square meter (kg/m2) STANDARD_DEVIATION 5.2 | 30.6 kilogram/square meter (kg/m2) STANDARD_DEVIATION 4.8 | 31.4 kilogram/square meter (kg/m2) STANDARD_DEVIATION 4.5 | 29.6 kilogram/square meter (kg/m2) STANDARD_DEVIATION 4.2 | 30.5 kilogram/square meter (kg/m2) STANDARD_DEVIATION 4.5 | 29.5 kilogram/square meter (kg/m2) STANDARD_DEVIATION 4.7 | 32.7 kilogram/square meter (kg/m2) STANDARD_DEVIATION 4.5 | 30.2 kilogram/square meter (kg/m2) STANDARD_DEVIATION 4.9 |
| Chronic Kidney Disease (CKD) N | 47 Participants | 294 Participants | 24 Participants | 23 Participants | 51 Participants | 51 Participants | 49 Participants | 49 Participants |
| Chronic Kidney Disease (CKD) Y | 3 Participants | 9 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Diabetes N | 44 Participants | 252 Participants | 22 Participants | 19 Participants | 41 Participants | 46 Participants | 40 Participants | 40 Participants |
| Diabetes Y | 6 Participants | 51 Participants | 4 Participants | 6 Participants | 10 Participants | 5 Participants | 9 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 20 Participants | 1 Participants | 4 Participants | 2 Participants | 4 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 250 Participants | 23 Participants | 19 Participants | 42 Participants | 43 Participants | 39 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 33 Participants | 2 Participants | 2 Participants | 7 Participants | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 26 Participants | 3 Participants | 2 Participants | 7 Participants | 2 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 80 Participants | 6 Participants | 7 Participants | 13 Participants | 13 Participants | 12 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 5 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 30 Participants | 187 Participants | 16 Participants | 15 Participants | 28 Participants | 35 Participants | 29 Participants | 34 Participants |
| Region of Enrollment Canada | 12 Participants | 74 Participants | 4 Participants | 5 Participants | 18 Participants | 13 Participants | 13 Participants | 9 Participants |
| Region of Enrollment Puerto Rico | 2 Participants | 7 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 36 Participants | 222 Participants | 21 Participants | 19 Participants | 32 Participants | 38 Participants | 35 Participants | 41 Participants |
| Sex: Female, Male Female | 17 Participants | 113 Participants | 7 Participants | 8 Participants | 16 Participants | 21 Participants | 20 Participants | 24 Participants |
| Sex: Female, Male Male | 33 Participants | 190 Participants | 19 Participants | 17 Participants | 35 Participants | 30 Participants | 29 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 51 | 23 / 50 | 21 / 51 | 18 / 49 | 34 / 51 | 14 / 25 | 12 / 26 |
| serious Total, serious adverse events | 0 / 51 | 0 / 50 | 2 / 51 | 0 / 49 | 1 / 51 | 0 / 25 | 0 / 26 |
Outcome results
Primary
Change From Baseline to 4 Weeks in Seated Systolic Blood Pressure (SBP)
Change from baseline in SBP as measured by a cuff. Least squares (LS) mean change from baseline was calculated using a mixed model repeating measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate.
Time frame: Baseline, 4 Weeks
Population: All randomized participants receiving at least 1 dose of the study drug and had baseline and post baseline evaluable data for SBP.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 4 Weeks in Seated Systolic Blood Pressure (SBP) | -0.5 millimeter of mercury (mmHg) | Standard Error 11.6 |
| 6 mg LY2623091 | Change From Baseline to 4 Weeks in Seated Systolic Blood Pressure (SBP) | -13.1 millimeter of mercury (mmHg) | Standard Error 11.2 |
| 13 mg LY2623091 | Change From Baseline to 4 Weeks in Seated Systolic Blood Pressure (SBP) | -14.6 millimeter of mercury (mmHg) | Standard Error 12.3 |
| 24.5 mg LY2623091 | Change From Baseline to 4 Weeks in Seated Systolic Blood Pressure (SBP) | -14.3 millimeter of mercury (mmHg) | Standard Error 13.6 |
| 13 mg LY2623091 + 20 mg Tadalafil | Change From Baseline to 4 Weeks in Seated Systolic Blood Pressure (SBP) | -11.8 millimeter of mercury (mmHg) | Standard Error 12.5 |
| 20 mg Tadalafil | Change From Baseline to 4 Weeks in Seated Systolic Blood Pressure (SBP) | -7.1 millimeter of mercury (mmHg) | Standard Error 13.3 |
| Spironolactone | Change From Baseline to 4 Weeks in Seated Systolic Blood Pressure (SBP) | -15.4 millimeter of mercury (mmHg) | Standard Error 11.7 |
Secondary
Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM)
The LS mean change in blood pressure is calculated after adjusting for baseline, treatment and race using an analysis of covariance (ANCOVA).
Time frame: Baseline, 4 Weeks
Population: All randomized participants receiving at least 1 dose of the study drug and had evaluable data for 24 hour ABPM.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | SBP | 0.3 mmHg | Standard Error 11.3 |
| Placebo | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | DBP | 1.0 mmHg | Standard Error 7.7 |
| 6 mg LY2623091 | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | SBP | -4.9 mmHg | Standard Error 8.7 |
| 6 mg LY2623091 | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | DBP | -1.7 mmHg | Standard Error 6.3 |
| 13 mg LY2623091 | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | SBP | -11.1 mmHg | Standard Error 8.9 |
| 13 mg LY2623091 | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | DBP | -4.7 mmHg | Standard Error 6.1 |
| 24.5 mg LY2623091 | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | SBP | -10.4 mmHg | Standard Error 11.4 |
| 24.5 mg LY2623091 | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | DBP | -3.4 mmHg | Standard Error 4.8 |
| 13 mg LY2623091 + 20 mg Tadalafil | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | SBP | -10.4 mmHg | Standard Error 11.6 |
| 13 mg LY2623091 + 20 mg Tadalafil | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | DBP | -6.2 mmHg | Standard Error 8 |
| 20 mg Tadalafil | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | SBP | -6.3 mmHg | Standard Error 8.9 |
| 20 mg Tadalafil | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | DBP | -5.6 mmHg | Standard Error 4.9 |
| Spironolactone | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | SBP | -6.4 mmHg | Standard Error 6.8 |
| Spironolactone | Change From Baseline to 4 Weeks in 24 Hour Ambulatory Blood Pressure Monitoring (ABPM) | DBP | -2.0 mmHg | Standard Error 4.6 |
Secondary
Change From Baseline to 4 Weeks in Seated Diastolic Blood Pressure (DBP)
Change from baseline in DBP as measured by a cuff. LS mean change from baseline was calculated using a MMRM with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate.
Time frame: Baseline, 4 Weeks
Population: All randomized participants receiving at least 1 dose of the study drug and had baseline and post baseline evaluable data for DBP.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 4 Weeks in Seated Diastolic Blood Pressure (DBP) | 0.5 mmHg | Standard Error 7.9 |
| 6 mg LY2623091 | Change From Baseline to 4 Weeks in Seated Diastolic Blood Pressure (DBP) | -5.6 mmHg | Standard Error 9.2 |
| 13 mg LY2623091 | Change From Baseline to 4 Weeks in Seated Diastolic Blood Pressure (DBP) | -4.8 mmHg | Standard Error 7.2 |
| 24.5 mg LY2623091 | Change From Baseline to 4 Weeks in Seated Diastolic Blood Pressure (DBP) | -7.1 mmHg | Standard Error 7.6 |
| 13 mg LY2623091 + 20 mg Tadalafil | Change From Baseline to 4 Weeks in Seated Diastolic Blood Pressure (DBP) | -6.8 mmHg | Standard Error 8.7 |
| 20 mg Tadalafil | Change From Baseline to 4 Weeks in Seated Diastolic Blood Pressure (DBP) | -6.6 mmHg | Standard Error 8.7 |
| Spironolactone | Change From Baseline to 4 Weeks in Seated Diastolic Blood Pressure (DBP) | -1.2 mmHg | Standard Error 6.1 |
Secondary
Change From Baseline to 4 Weeks in Serum Potassium
Potassium measurement as measured by standard laboratory tests. The LS mean change in potassium is calculated using MMRM with adjustment for baseline, treatment, visit, treatment\*visit and race.
Time frame: Baseline, 4 Weeks
Population: All randomized participants receiving at least 1 dose of the study drug and had evaluable data for serum potassium.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 4 Weeks in Serum Potassium | -0.04 millimoles/L (mmol/L) | Standard Error 0.06 |
| 6 mg LY2623091 | Change From Baseline to 4 Weeks in Serum Potassium | 0.10 millimoles/L (mmol/L) | Standard Error 0.06 |
| 13 mg LY2623091 | Change From Baseline to 4 Weeks in Serum Potassium | 0.11 millimoles/L (mmol/L) | Standard Error 0.06 |
| 24.5 mg LY2623091 | Change From Baseline to 4 Weeks in Serum Potassium | 0.25 millimoles/L (mmol/L) | Standard Error 0.06 |
| 13 mg LY2623091 + 20 mg Tadalafil | Change From Baseline to 4 Weeks in Serum Potassium | 0.10 millimoles/L (mmol/L) | Standard Error 0.06 |
| 20 mg Tadalafil | Change From Baseline to 4 Weeks in Serum Potassium | -0.06 millimoles/L (mmol/L) | Standard Error 0.08 |
| Spironolactone | Change From Baseline to 4 Weeks in Serum Potassium | 0.30 millimoles/L (mmol/L) | Standard Error 0.08 |
Secondary
Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2623091
Time frame: 2 hours post-dose at 4 Weeks
Population: All participants who had evaluable PK data of LY2623091.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2623091 | 122 nanogram/milliliter (ng/ml) | Geometric Coefficient of Variation 32 |
| 6 mg LY2623091 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2623091 | 228 nanogram/milliliter (ng/ml) | Geometric Coefficient of Variation 37 |
| 13 mg LY2623091 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2623091 | 379 nanogram/milliliter (ng/ml) | Geometric Coefficient of Variation 51 |
| 24.5 mg LY2623091 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2623091 | 206 nanogram/milliliter (ng/ml) | Geometric Coefficient of Variation 53 |