Resistant Hypertension
Conditions
Keywords
hypertension, resistant hypertension, rHTN, not controlled hypertension
Brief summary
The purpose of this 20-week randomized double-blind study in patients with resistant hypertension (rHTN) is to evaluate the efficacy, safety, and tolerability, of different doses of XXB750 administered as subcutaneous (SC) injections, compared to placebo. Since all study participants will be patients with rHTN, all study treatments will be given on top of maximally tolerated background antihypertensive therapy recommended by international guidelines for treatment of HTN (i.e., a thiazide or a thiazide-like diuretic, an angiotensin converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), and a long-acting dihydropyridine calcium channel blocker (CCB).
Detailed description
Subjects will enter run-in period which lasts for approximately 2 weeks. The study duration is for 20 weeks during which each participant will receive a total of 3 doses of study medication (in addition to 1 dose of study medication during run-in). Participants will be followed to monitor their safety for an additional 8 weeks during which time no active study medication will be given.
Interventions
BIOLOGICALXXB750 drug
SC injection
OTHERPlacebo
SC injection
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Participants, investigator staff, persons performing the assessments and blinded clinical research associate (CRA) monitoring study conduct remained blinded to the identity of the treatment from the time of randomization until database lock. The study site pharmacist/nurse or other designated qualified site personnel who prepares the study drug and the unblinded clinical research associates (CRA monitoring drug supply and preparation) remained unblinded.
Intervention model description
The planned duration of treatment is 12 weeks per participant. Participants may be discontinued from treatment earlier due to unacceptable adverse events, disease progression and/or if treatment is discontinued at the discretion of the investigator or the participant. Following the conclusion of the 12-week Randomized Treatment Period, participants will enter an 8-week Safety Follow-up Period in which participants may be treated at the discretion of the investigator taking into account that their blood pressure may still be affected by the study treatment for some time after its discontinuation, especially those who were randomized to XXB750.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1. Male and female participants who are ≥ 18 years old. 2. Signed informed consent prior to participation in the study. 3. Apparent rHTN at screening (Visit 1) defined as uncontrolled BP with an office msSBP ≥ 140 mmHg despite treatment with stable (i.e., unchanged for ≥4 weeks), optimal or maximally tolerated doses of three or four antihypertensive drugs of different classes, including an ACEI/ARB, a long-acting dihydropyridine CCB, and a thiazide or thiazide-like diuretic. Participant with documented intolerance to any doses of CCBs may be eligible if receiving another class of antihypertensive medication at an optimal or maximally tolerated dose (referred to as triple background antihypertensive therapy. An optimal dose is defined as the highest dose taking in to account participant's documented comorbidities and tolerability per investigator's clinical judgment. 4. Mean 24hr SBP ≥135 mmHg (measured by ABPM) at the end-of Run-in-Visit (Visit 30) on treatment with optimal or maximally tolerated doses of an ACEI/ARB, a long-acting dihydropyridine CCB (or a suitable alternative in case of intolerance per inclusion criterion above), and a thiazide or thiazide-like diuretic.
Exclusion criteria
1. Subjects with the following blood pressures at the specified time points are not eligible to participate in the study: 1. Office msSBP \<140 mmHg at Visit 20 OR 2. Office msSBP ≥180 mmHg or office msDBP ≥110 mmHg at the end-of-run-in visit (Visit 30) OR 3. 24h mean SBP \>170 mmHg or 24h mean DBP \>105mmHg measured by ABPM at the end of the run-in (Visit 30). 2. Known history of secondary hypertension (moderate-to-severe obstructive sleep apnea without receiving CPAP therapy (either face mask or nasal device), renovascular hypertension, primary aldosteronism, pheochromocytoma, Cushing syndrome, aortic coarctation or other cause of secondary hypertension). 3. Estimated GFR \<30 mL/min/1.73m2 using CKD-Epi equation at screening (Visit 1) or at end-of-run-in visit (Visit 30). 4. Serum potassium \>5.0 mmol/L (or equivalent plasma potassium value) at screening or end-of-run-in visit (Visit 30). 5. Current therapy with a mineralocorticoid receptor antagonist (MRA) or sacubitril/valsartan or received an MRA or sacubitril/valsartan within the 4 weeks prior to screening. 6. Type I diabetes mellitus or uncontrolled Type II diabetes (defined as a plasma HbA1c ≥9%) 7. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), high-grade AV block (e.g., Mobitz type II and third-degree AV block in absence of a pacemaker) within 6 months of screening according to investigator's judgement. 8. Chronic non-paroxysmal atrial fibrillation. 9. Acute myocardial infarction (AMI) or unstable angina, or any history of ischemic or hemorrhagic stroke within 12 months of screening; or any percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) within 12 months of screening 10. History of a renal denervation procedure. 11. Mid-arm circumference ≥44 cm. The cuff should snugly fit on the arm with out the margins of cuff overhanging arm musculature. 12. Patients with history of hospitalisation for hypertensive emergencies characterised by severe hypertension (usually grade 3) associated with funduscopic changes (flame haemorrhages and/or papilloedema), microangiopathy, disseminated intravascular coagulation, encephalopathy, acute aortic dissection, acute myocardial ischaemia, or acute heart failure any time prior to screening or hospitalisation for non-emergent/non-urgent uncontrolled hypertension without target organ damage within 3 months prior to screening 13. Receiving more than 4 antihypertensive medications. 14. Night shift workers. 15. History of presence of any other disease where the life expectancy is less than 3 years. 16. History of malignancy of any organ system (other than localized basal or squamous cell carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 3 years, regardless of whether there is evidence of local recurrence or metastases. 17. Evidence of hepatic disease as determined by any one of the following: SGOT (AST) or SGPT (ALT) values exceeding 3x the upper limit of normal (ULN), or bilirubin \>1.5 mg/dl at Visit 1. 18. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer. 19. History of drug abuse or alcohol dependency. 20. Lacking the ability to comprehend or follow instructions, or for any reason in the opinion of the investigator, a participant that would be unlikely or unable to comply with study protocol. 21. Concurrent enrollment in any other investigational drug or device trial (participation in non-interventional registries is acceptable). 22. Requiring prolonged/regular use of NSAIDs except for prophylactic use of low dose aspirin up to 325 mg QD or other prohibited medications during of the study (i.e., required use for longer than 1 week). 23. Pregnant, nursing or planning to become pregnant (documented negative pregnancy test required within a maximum of 7 days prior to enrollment of all women of childbearing potential). Documentation of highly effective contraception is also required for women of childbearing potential (see below). Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 3 months after stopping medication. Highly effective contraception methods include: * Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment. * Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant. * Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms). Women are considered not of childbearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF. 24. History of hypersensitivity to any of the study drugs, excipients or drugs of similar class.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-response (DR) Relationship of XXB750 With Respect to Change From Baseline in Systolic Blood Pressure (SBP) 24 Hours | Baseline, Week 12 | To evaluate the efficacy and dose-response relationship of different doses of XXB750 compared to placebo in reducing the mean 24 hours ambulatory systolic blood pressure from baseline at Week 12. Automated arterial BP determinations and pulse rate readings were made with Microlife Watch BP Office 2G, an automated digital BP device. The primary outcome measure was evaluated using an optimally weighted contrast test following the Multiple Comparison Procedure-Modeling (MCP-MOD) methodology. There were five candidate models to capture the shape of the dose-response relationship for XXB750 at Week 12 endpoint. The outcome for the single best candidate model is shown in the Statistical Analysis section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in SBP 24 Hours at Week 12 (Difference Between Highest XXB750 Dose and Placebo) | Baseline, Week 12 | To evaluate the treatment effect of the highest XXB750 dose versus placebo in reducing the mean 24 hours SBP from baseline to Week 12. Automated arterial BP determinations and pulse rate readings were made with Microlife Watch BP Office 2G, an automated digital BP device. |
| Change From Baseline in SBP 24 Hours of Average of Week 9 and Week 12 (Difference Between Highest XXB750 Dose and Placebo) | Baseline, Week 9 and Week 12 | To evaluate the treatment effect of the highest XXB750 dose versus placebo in the dosing interval average of ambulatory SBP as assessed by average of mean 24 hours SBP measured at week 9 and week 12. Automated arterial BP determinations and pulse rate readings were made with Microlife Watch BP Office 2G, an automated digital BP device. |
| The Model-based Estimated Percentage of Participants Achieving Blood Pressure (BP) Control | Week 12 | To evaluate the percentage of participants achieving ambulatory BP control defined as mean 24 hours SBP \<130 mmHg and mean 24 hours DBP \< 80 mmHg with respect to the dose-response relationship of the four XXB750 dose level groups compared to placebo at week 12. Automated arterial BP determinations and pulse rate readings were made with Microlife Watch BP Office 2G, an automated digital BP device. Percentage of participants is derived from dose response analysis, using generalized MCP-Mod methodology for binary data. |
Countries
Australia, Austria, Bulgaria, China, Czechia, France, Germany, Italy, Japan, Netherlands, Poland, Slovakia, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in 135 investigative sites in 16 countries.
Pre-assignment details
The study consisted of a screening period of approximately 7 days.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo subcutaneous (s.c) every 4 weeks, total of 3 doses. | 42 |
| XXB750 30 mg XXB750 30 mg s.c every 4 weeks, total of 3 doses. | 32 |
| XXB750 60 mg XXB750 60 mg s.c every 4 weeks, total of 3 doses. | 36 |
| XXB750 120 mg XXB750 120 mg s.c every 4 weeks, total of 3 doses. | 37 |
| XXB750 120 mg/240 mg XXB750 120 mg s.c at the randomization visit followed by 240 mg s.c at Week 4 and Week 8. | 42 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | XXB750 30 mg | XXB750 60 mg | XXB750 120 mg | XXB750 120 mg/240 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 60.14 years STANDARD_DEVIATION 10.862 | 58.53 years STANDARD_DEVIATION 11.565 | 63.44 years STANDARD_DEVIATION 10.191 | 62.41 years STANDARD_DEVIATION 11.642 | 60.64 years STANDARD_DEVIATION 10.085 | 61.05 years STANDARD_DEVIATION 10.863 |
| Race/Ethnicity, Customized Asian | 8 Participants | 5 Participants | 6 Participants | 8 Participants | 10 Participants | 37 Participants |
| Race/Ethnicity, Customized Black Or African American | 6 Participants | 7 Participants | 4 Participants | 4 Participants | 6 Participants | 27 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 27 Participants | 16 Participants | 24 Participants | 24 Participants | 25 Participants | 116 Participants |
| Sex: Female, Male Female | 13 Participants | 8 Participants | 6 Participants | 18 Participants | 13 Participants | 58 Participants |
| Sex: Female, Male Male | 29 Participants | 24 Participants | 30 Participants | 19 Participants | 29 Participants | 131 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 / 42 | 0 / 32 | 0 / 36 | 0 / 37 | 0 / 42 |
| other Total, other adverse events | 27 / 42 | 19 / 32 | 18 / 36 | 16 / 37 | 18 / 42 |
| serious Total, serious adverse events | 1 / 42 | 2 / 32 | 3 / 36 | 1 / 37 | 3 / 42 |
Outcome results
Primary
Dose-response (DR) Relationship of XXB750 With Respect to Change From Baseline in Systolic Blood Pressure (SBP) 24 Hours
To evaluate the efficacy and dose-response relationship of different doses of XXB750 compared to placebo in reducing the mean 24 hours ambulatory systolic blood pressure from baseline at Week 12. Automated arterial BP determinations and pulse rate readings were made with Microlife Watch BP Office 2G, an automated digital BP device. The primary outcome measure was evaluated using an optimally weighted contrast test following the Multiple Comparison Procedure-Modeling (MCP-MOD) methodology. There were five candidate models to capture the shape of the dose-response relationship for XXB750 at Week 12 endpoint. The outcome for the single best candidate model is shown in the Statistical Analysis section.
Time frame: Baseline, Week 12
Population: Full analysis set (FAS): All participants to whom study treatment was assigned by randomization. Only participants with a valid assessment for this endpoint were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Dose-response (DR) Relationship of XXB750 With Respect to Change From Baseline in Systolic Blood Pressure (SBP) 24 Hours | -5.77 mmHg |
| XXB750 30 mg | Dose-response (DR) Relationship of XXB750 With Respect to Change From Baseline in Systolic Blood Pressure (SBP) 24 Hours | -6.41 mmHg |
| XXB750 60 mg | Dose-response (DR) Relationship of XXB750 With Respect to Change From Baseline in Systolic Blood Pressure (SBP) 24 Hours | -6.63 mmHg |
| XXB750 120 mg | Dose-response (DR) Relationship of XXB750 With Respect to Change From Baseline in Systolic Blood Pressure (SBP) 24 Hours | -6.66 mmHg |
| XXB750 120 mg/240 mg | Dose-response (DR) Relationship of XXB750 With Respect to Change From Baseline in Systolic Blood Pressure (SBP) 24 Hours | -5.40 mmHg |
p-value: 0.5651Multiple Comparisons Procedure-MOD
Secondary
Change From Baseline in SBP 24 Hours at Week 12 (Difference Between Highest XXB750 Dose and Placebo)
To evaluate the treatment effect of the highest XXB750 dose versus placebo in reducing the mean 24 hours SBP from baseline to Week 12. Automated arterial BP determinations and pulse rate readings were made with Microlife Watch BP Office 2G, an automated digital BP device.
Time frame: Baseline, Week 12
Population: Full analysis set (FAS): All participants to whom study treatment was assigned by randomization. Only participants from the highest XXB750 dose and placebo with valid measurements are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in SBP 24 Hours at Week 12 (Difference Between Highest XXB750 Dose and Placebo) | -6.01 mmHg | Standard Error 2.42 |
| XXB750 30 mg | Change From Baseline in SBP 24 Hours at Week 12 (Difference Between Highest XXB750 Dose and Placebo) | -4.64 mmHg | Standard Error 2.49 |
p-value: 0.695595% CI: [-5.48, 8.21]ANCOVA
Secondary
Change From Baseline in SBP 24 Hours of Average of Week 9 and Week 12 (Difference Between Highest XXB750 Dose and Placebo)
To evaluate the treatment effect of the highest XXB750 dose versus placebo in the dosing interval average of ambulatory SBP as assessed by average of mean 24 hours SBP measured at week 9 and week 12. Automated arterial BP determinations and pulse rate readings were made with Microlife Watch BP Office 2G, an automated digital BP device.
Time frame: Baseline, Week 9 and Week 12
Population: Full analysis set (FAS): All participants to whom study treatment was assigned by randomization. Only participants from the highest XXB750 dose and placebo with valid measurements (with non-missing observed change from baseline either at Week 9 or Week 12) are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in SBP 24 Hours of Average of Week 9 and Week 12 (Difference Between Highest XXB750 Dose and Placebo) | -5.77 mmHg | Standard Error 2.13 |
| XXB750 30 mg | Change From Baseline in SBP 24 Hours of Average of Week 9 and Week 12 (Difference Between Highest XXB750 Dose and Placebo) | -4.62 mmHg | Standard Error 2.21 |
p-value: 0.710895% CI: [-4.9, 7.18]ANCOVA
Secondary
The Model-based Estimated Percentage of Participants Achieving Blood Pressure (BP) Control
To evaluate the percentage of participants achieving ambulatory BP control defined as mean 24 hours SBP \<130 mmHg and mean 24 hours DBP \< 80 mmHg with respect to the dose-response relationship of the four XXB750 dose level groups compared to placebo at week 12. Automated arterial BP determinations and pulse rate readings were made with Microlife Watch BP Office 2G, an automated digital BP device. Percentage of participants is derived from dose response analysis, using generalized MCP-Mod methodology for binary data.
Time frame: Week 12
Population: Full analysis set (FAS): All participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Model-based Estimated Percentage of Participants Achieving Blood Pressure (BP) Control | 13.2 percentage |
| XXB750 30 mg | The Model-based Estimated Percentage of Participants Achieving Blood Pressure (BP) Control | 15.0 percentage |
| XXB750 60 mg | The Model-based Estimated Percentage of Participants Achieving Blood Pressure (BP) Control | 17.7 percentage |
| XXB750 120 mg | The Model-based Estimated Percentage of Participants Achieving Blood Pressure (BP) Control | 22.0 percentage |
| XXB750 120 mg/240 mg | The Model-based Estimated Percentage of Participants Achieving Blood Pressure (BP) Control | 25.9 percentage |