Uncontrolled Hypertension
Conditions
Brief summary
This is a Phase 2, randomized, multicenter study to evaluate the efficacy and safety of multiple dose strengths of baxdrostat (also called CIN-107) in the treatment of patients with uncontrolled hypertension. The primary objective was to demonstrate that treatment with baxdrostat for 8 weeks would lower the systolic blood pressure (SBP) in patients who were hypertensive despite taking one or two anti-hypertensive medications. Participants were assigned to take placebo or baxdrostat once per day for 8 weeks while they continued taking the regular anti-hypertensive medications. At the end of the 8-week period, qualified patients could participate in Part II of the study and receive 2 mg baxdrostat for 4 weeks while they discontinued taking the background anti-hypertensive medication.
Interventions
DRUGPlacebo
Placebo tablets by mouth once daily
DRUGCIN-107
CIN-107 tablets by mouth once daily
Sponsors
CinCor Pharma, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Is on a stable regimen of background antihypertensive agent(s) for at least 8 weeks and would be considered a candidate for an additional antihypertensive agent at the time of screening ; * Has a mean seated systolic blood pressure (SBP) ≥ 140 mmHg or ≥ 130 mmHg if diabetic; * Demonstrates ability to be adherent to the study drug and their anti-hypertensive medication during a run-in period * If taking an SGLT2 inhibitor, the regimen must be stable for at least 8 weeks prior to randomization; and * Agrees to comply with the contraception and reproduction restrictions of the study;
Exclusion criteria
* Has a mean seated systolic blood pressure (SBP) ≥180 mmHG; * Has a body mass index (BMI) \>50 kg/m2; * Is using alpha or beta blockers for any primary indication other than systemic hypertension (eg, migraine headache); * Is not willing or not able to discontinue an MRA or potassium sparing diuretic as part of an existing antihypertensive regimen; * Has documented estimated eGFR \<30 mL/min/1.73m2; * Has known and documented New York Heart Association stage III or IV chronic heart failure; * Has had a stroke, transient ischemic attack, hypertensive encephalopathy, acute coronary syndrome, or hospitalization for heart failure within 6 months before screening; * Major cardiac surgery within 6 months before Screening; * Has chronic permanent atrial fibrillation; * Has uncontrolled diabetes with glycated hemoglobin \>10% at Screening; * Has planned dialysis or kidney transplantation planned during the course of the study; * Prior solid organ transplant and/or cell transplants; * Sodium \<130 mEq/L; * Potassium \<3.5 mEq/L; * Potassium \>5 mEq/L; * White blood cell count \>15 × E9/L or absolute neutrophil count \<1 × E9/L at Screening; * Is positive for HIV antibody, hepatitis C virus RNA, or hepatitis B surface antigen; * Has typical consumption of ≥14 alcoholic drinks weekly;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Seated Systolic BP (SBP) | 8 weeks | The primary efficacy endpoint was the change from baseline in mean seated SBP after 8 weeks of treatment in patients with uncontrolled HTN (Part 1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-hour Urine Aldosterone | 8 weeks | The change from baseline in 24-hour urine aldosterone levels with CIN 107 compared to placebo after 8 weeks of treatment (Part 1) |
| Change From Baseline in 24-hour Serum Aldosterone | 8 weeks | The change from baseline in 24-hour serum aldosterone levels with CIN 107 compared to placebo after 8 weeks of treatment (Part 1) |
| Change From Baseline in Mean Seated Diastolic BP (DBP) | 8 weeks | The change from baseline in mean seated DBP with CIN-107 compared to placebo after 8 weeks of treatment (Part 1) |
| Change From Baseline in 24-hour Urine Renin | 8 weeks | The change from baseline in 24-hour urine renin levels with CIN-107 compared to placebo after 8 weeks of treatment (Part 1) |
| Change From Baseline in 24-hour Serum Renin | 8 weeks | The change from baseline in 24-hour serum renin levels with CIN-107 compared to placebo after 8 weeks of treatment (Part 1) |
| Percentage of Patients Achieving a Mean Seated SBP <130 mmHg | 8 weeks | The percentage of patients achieving a mean seated SBP \<130 mmHg (responders) with CIN-107 compared to placebo after 8 weeks of treatment (Part 1; Weeks 1 to 8) |
Countries
United States
Participant flow
Pre-assignment details
A Run-In Period up to 4 weeks before randomization, to confirm the patient's adherence to their background antihypertensive medication(s) and placebo was done. A total of 631 patients were screened for the study, of which 382 (60.5%) patients failed the screening. Two hundred forty-nine patients were randomized to 1 of the 4 treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Remain on background anti-hypersensitive regimen for 8 weeks. After 8 weeks, patient will receive the highest dose of CIN-107 (2mg) and discontinue their background antihypertensive agent(s) for 4 weeks
Placebo: Placebo tablets by mouth once daily | 64 |
| CIN-107 0.5 mg Remain on background anti-hypersensitive regimen for 8 weeks. After 8 weeks, patient will receive the highest dose of CIN-107 (2 mg) and discontinue their background antihypertensive agent(s) for 4 weeks
CIN-107: CIN-107 tablets by mouth once daily | 63 |
| CIN-107 1 mg Remain on background anti-hypersensitive regimen for 8 weeks. After 8 weeks, patient will receive the highest dose of CIN-107 (2 mg) and discontinue their background antihypertensive agent(s) for 4 weeks
CIN-107: CIN-107 tablets by mouth once daily | 62 |
| CIN-107 2 mg Remain on background anti-hypersensitive regimen for 8 weeks. After 8 weeks, patient may remain on CIN-107 (2 mg) and discontinue their background antihypertensive agent(s) for 4 weeks or withdraw study participation depending on BP control
CIN-107: CIN-107 tablets by mouth once daily | 60 |
| Total | 249 |
Baseline characteristics
| Characteristic | CIN-107 0.5 mg | CIN-107 1 mg | Placebo | CIN-107 2 mg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 26 Participants | 25 Participants | 24 Participants | 19 Participants | 94 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants | 37 Participants | 40 Participants | 41 Participants | 155 Participants |
| Age, Continuous | 59.9 years STANDARD_DEVIATION 10.85 | 61.2 years STANDARD_DEVIATION 10.69 | 60.5 years STANDARD_DEVIATION 10.61 | 59.2 years STANDARD_DEVIATION 11.88 | 60.2 years STANDARD_DEVIATION 10.96 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 39 Participants | 28 Participants | 31 Participants | 35 Participants | 133 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 34 Participants | 33 Participants | 25 Participants | 116 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 15 Participants | 17 Participants | 14 Participants | 60 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 48 Participants | 43 Participants | 46 Participants | 44 Participants | 181 Participants |
| Region of Enrollment United States | 63 participants | 62 participants | 64 participants | 60 participants | 249 participants |
| Seated SBP | 146.3 mmHg STANDARD_DEVIATION 8.6 | 147.0 mmHg STANDARD_DEVIATION 9.07 | 147.9 mmHg STANDARD_DEVIATION 9.33 | 146.3 mmHg STANDARD_DEVIATION 7.83 | 146.9 mmHg STANDARD_DEVIATION 8.71 |
| Sex: Female, Male Female | 28 Participants | 37 Participants | 37 Participants | 30 Participants | 132 Participants |
| Sex: Female, Male Male | 35 Participants | 25 Participants | 27 Participants | 30 Participants | 117 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 0 / 63 | 0 / 62 | 1 / 60 | 0 / 213 |
| other Total, other adverse events | 5 / 64 | 8 / 63 | 6 / 62 | 3 / 60 | 6 / 213 |
| serious Total, serious adverse events | 0 / 64 | 0 / 63 | 1 / 62 | 1 / 60 | 3 / 213 |
Outcome results
Primary
Change From Baseline in Mean Seated Systolic BP (SBP)
The primary efficacy endpoint was the change from baseline in mean seated SBP after 8 weeks of treatment in patients with uncontrolled HTN (Part 1).
Time frame: 8 weeks
Population: mITT Population - Four subjects (1, 2, 1 subjects from Placebo, 0.5mg CIN 107, and 2mg CIN 107, respectively) discontinued Part 1 early, but had their early termination (ET) visits within Week 8/Visit 6 analysis visit window.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Seated Systolic BP (SBP) | -16.6 mmHg | Standard Error 1.58 |
| CIN-107 0.5 mg | Change From Baseline in Mean Seated Systolic BP (SBP) | -17.0 mmHg | Standard Error 1.63 |
| CIN-107 1 mg | Change From Baseline in Mean Seated Systolic BP (SBP) | -16.0 mmHg | Standard Error 1.62 |
| CIN-107 2 mg | Change From Baseline in Mean Seated Systolic BP (SBP) | -19.8 mmHg | Standard Error 1.67 |
Secondary
Change From Baseline in 24-hour Serum Aldosterone
The change from baseline in 24-hour serum aldosterone levels with CIN 107 compared to placebo after 8 weeks of treatment (Part 1)
Time frame: 8 weeks
Population: mITT population - Four subjects discontinued Part 1 early, but had their ET measures taken within Week8/Visit 6 analysis visit window: 1, 2, 1 subjects from Placebo, 0.5mg CIN 107, and 2mg CIN 107, respectively. In addition, 13 subjects completed Part 1 but either did not have baseline measure or did not have Week 8/Visit 6 measure: 4, 6, 3 subjects from Placebo, 1mg CIN 107, and 2mg CIN 107, respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 24-hour Serum Aldosterone | -0.70 ng/dL | Standard Error 0.49 |
| CIN-107 0.5 mg | Change From Baseline in 24-hour Serum Aldosterone | -2.76 ng/dL | Standard Error 0.493 |
| CIN-107 1 mg | Change From Baseline in 24-hour Serum Aldosterone | -2.95 ng/dL | Standard Error 0.508 |
| CIN-107 2 mg | Change From Baseline in 24-hour Serum Aldosterone | -2.92 ng/dL | Standard Error 0.515 |
Secondary
Change From Baseline in 24-hour Serum Renin
The change from baseline in 24-hour serum renin levels with CIN-107 compared to placebo after 8 weeks of treatment (Part 1)
Time frame: 8 weeks
Population: mITT population - The 24 hour serum renin pharmacodynamic analyte was added in later, with protocol v3.0. Only subjects who had this measured at baseline are included in overall number of participants analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 24-hour Serum Renin | 92.902 ng/L | Standard Error 144.3969 |
| CIN-107 0.5 mg | Change From Baseline in 24-hour Serum Renin | 63.565 ng/L | Standard Error 195.0495 |
| CIN-107 1 mg | Change From Baseline in 24-hour Serum Renin | 88.041 ng/L | Standard Error 91.2996 |
| CIN-107 2 mg | Change From Baseline in 24-hour Serum Renin | -140.961 ng/L | Standard Error 151.5431 |
Secondary
Change From Baseline in 24-hour Urine Aldosterone
The change from baseline in 24-hour urine aldosterone levels with CIN 107 compared to placebo after 8 weeks of treatment (Part 1)
Time frame: 8 weeks
Population: mITT population - Two subjects discontinued Part 1 early, but had their ET measures taken within Week8/Visit 6 analysis visit window: 1 from Placebo and 1 from 0.5mg. In addition, 7 subjects completed Part 1 but either did not have baseline measure or did not have Week 8/Visit 6 measure: 2, 2, 3 subjects from Placebo, 0.5mg CIN 107, and 1mg CIN 107, respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 24-hour Urine Aldosterone | -19.90 ng/g | Standard Error 29.183 |
| CIN-107 0.5 mg | Change From Baseline in 24-hour Urine Aldosterone | -114.16 ng/g | Standard Error 31.305 |
| CIN-107 1 mg | Change From Baseline in 24-hour Urine Aldosterone | -140.45 ng/g | Standard Error 29.999 |
| CIN-107 2 mg | Change From Baseline in 24-hour Urine Aldosterone | -121.64 ng/g | Standard Error 30.76 |
Secondary
Change From Baseline in 24-hour Urine Renin
The change from baseline in 24-hour urine renin levels with CIN-107 compared to placebo after 8 weeks of treatment (Part 1)
Time frame: 8 weeks
Population: mITT population - The 24 hour urine renin pharmacodynamic analyte was added in later, with protocol v3.0. Only subjects who had this measured at baseline are included in overall number of participants analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 24-hour Urine Renin | -20.08 ng/day | Standard Error 16.584 |
| CIN-107 0.5 mg | Change From Baseline in 24-hour Urine Renin | -6.54 ng/day | Standard Error 15.739 |
| CIN-107 1 mg | Change From Baseline in 24-hour Urine Renin | -5.74 ng/day | Standard Error 10.703 |
| CIN-107 2 mg | Change From Baseline in 24-hour Urine Renin | 4.11 ng/day | Standard Error 17.93 |
Secondary
Change From Baseline in Mean Seated Diastolic BP (DBP)
The change from baseline in mean seated DBP with CIN-107 compared to placebo after 8 weeks of treatment (Part 1)
Time frame: 8 weeks
Population: mITT Population - Four subjects (1, 2, 1 subjects from Placebo, 0.5mg CIN 107, and 2mg CIN 107, respectively) discontinued Part 1 early, but had their early termination (ET) visits within Week 8/Visit 6 analysis visit window.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Seated Diastolic BP (DBP) | -5.9 mmHg | Standard Error 1.17 |
| CIN-107 0.5 mg | Change From Baseline in Mean Seated Diastolic BP (DBP) | -5.8 mmHg | Standard Error 1.2 |
| CIN-107 1 mg | Change From Baseline in Mean Seated Diastolic BP (DBP) | -5.0 mmHg | Standard Error 1.19 |
| CIN-107 2 mg | Change From Baseline in Mean Seated Diastolic BP (DBP) | -5.4 mmHg | Standard Error 1.23 |
Secondary
Percentage of Patients Achieving a Mean Seated SBP <130 mmHg
The percentage of patients achieving a mean seated SBP \<130 mmHg (responders) with CIN-107 compared to placebo after 8 weeks of treatment (Part 1; Weeks 1 to 8)
Time frame: 8 weeks
Population: mITT population - Patients without a Week 8/Visit 6 systolic blood pressure measure were considered non-responders. So, if a subject was in the mITT Population but discontinued the study early or if SBP measure was unavailable at Week 8, then they were considered non responders and still contributed to the total number of participants used in analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Percentage of Patients Achieving a Mean Seated SBP <130 mmHg | 36 Participants |
| CIN-107 0.5 mg | Percentage of Patients Achieving a Mean Seated SBP <130 mmHg | 36 Participants |
| CIN-107 1 mg | Percentage of Patients Achieving a Mean Seated SBP <130 mmHg | 33 Participants |
| CIN-107 2 mg | Percentage of Patients Achieving a Mean Seated SBP <130 mmHg | 43 Participants |