Hypertension
Conditions
Keywords
Hypertension, Combination Therapy, Zofenopril, Nebivolol, Fixed Dose Combination
Brief summary
Open-label, interventional clinical trial to assess effectiveness and safety of the extemporaneous combination of nebivolol and zofenopril calcium in grade 1 to 2 hypertensive patients versus each monotherapy
Detailed description
This is a study with 2 periods (a run-in period of 4 weeks and an assessment period of 8 weeks). Grade 1-2 hypertensive patients (blood pressure \[BP\] ranging from ≥140/90 mmHg to ≤179/109 mmHg) on treatment with any angiotensin converting enzyme-inhibitors (ACEi) or beta blockers (BBs) including ZOF 30 mg or NEB 5 mg respectively will be screened for eligibility (Visit 1). On the same day, the eligible patients will enter into a run-in period after Screening, during which: * Patients on ZOF 30 mg or NEB 5 mg will continue the same therapy for 4 weeks * Patients on any other ACE-i will be assigned to monotherapy with ZOF 30 mg while patients on any other BB will be assigned to monotherapy with NEB 5 mg, respectively, for 4 weeks. After the 4 weeks of monotherapy in the run-in period, if BP at Visit 2, remains uncontrolled (sitting Systolic Blood Pressure/Diastolic Blood Pressure \>130/80 mmHg) despite an adherence to the treatments ranging from 80% to 120%, the patients will start treatment (Week 0, Visit 2) with the extemporaneous combination of NEB 5 mg/ZOF 30 mg (NEB/ZOF) and will be assessed for further 8 weeks (assessment period). If the patients, at Visit 2 after the Run-In period, have controlled BP (sitting Systolic Blood Pressure/Diastolic Blood Pressure ≤130/80 mmHg), and/or do not tolerate the treatment, and/or do not maintain the adherence to the therapy (range from 80% to 120%), these patients will not be continued further in the study. At the end of the assessment period (Visit 3) the anti-hypertensive effect of the extemporaneous combination of NEB 5 mg and ZOF 30 mg will be evaluated. A total number of 290 patients will be screened considering 25% of drop-out rate, to obtain approximately 216 completed patients at the end of the study.
Interventions
DRUGZofenopril 30 mg
Film-Coated tablets administered as one single dose to be taken in the morning (from 6 am to 10 am) with no restriction on food intake
DRUGNebivolol 5 mg
Tablet administered as one single dose to be taken in the morning (from 6 am to 10 am) with no restriction on food intake
DRUGZofenopril 30 mg + Nebivolol 5 mg
Both Film coated tablets of Zofenopril 30 mg and Nebivolol 5 mg Tablets will be taken in the morning (from 6 am to 10 am) with no restriction on food intake
Sponsors
Menarini International Operations Luxembourg SA
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open Label, two period study. Patients eligible from screening will enter the run-in period on the same day. Patients previously receiving Zofenopril or any other ACE-inhibitor will enter into the run-in period with Zofenopril monotherapy while patients receiving Nebivolol or any other Beta Blockers will enter into the Run-in period with Nebivolol monotherapy in a 1:1 ratio. Only patients with uncontrolled BP (sitting Systolic Blood Pressure/Diastolic Blood Pressure\>130/80 mmHg) and whose adherence to the treatment ranges from 80% to 120%, will enter the assessment period to receive the extemporaneous combination of NEB and ZOF; while the patients with controlled sitting BP (Systolic Blood Pressure/Diastolic Blood Pressure ≤130/80 mmHg) and/or the patients who do not tolerate the treatment and patients with uncontrolled BP whose adherence to the therapy do not range from 80% to 120%, will be withdrawn from the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female Caucasian uncontrolled hypertensive patients (see definition in criterion 3) ≥18 and \<65 years of age, in monotherapy either with ACE-i or BBs since at least 1 month, at Screening (Visit 1) 2. Patients are able to understand and have freely given written informed consent at Screening 3. Patients with mean sitting Systolic Blood Pressure ≥140 mmHg and ≤179 mmHg and/or mean sitting Diastolic Blood Pressure ≥ 90 mmHg and ≤109 mmHg at Screening (Visit 1) 4. Patient who are able to comply with all study procedures and who are available for the duration of the study 5. Ability to take oral medication and willing to adhere to the drug regimen 6. A female patient of childbearing potential is eligible to participate if she is not pregnant, or not breastfeeding. A woman is considered fertile following menarche and until becoming postmenopausal unless permanently sterile. Women of childbearing potential must agree to use of highly effective contraception (eg, method of birth control throughout the study period and for 4 weeks after study completion defined as a method which results in a failure rate of less than 1% per year) and also must refrain from donating or storing eggs during this time. Highly effective contraception methods can be: a Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) b Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) c Intrauterine device (IUD) d Intrauterine hormone-releasing system (IUS) e Bilateral tubal occlusion f Vasectomized partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success) 7. A male patient with female partner must agree to use contraception during the whole study period and for at least 1 week after the last dose of study treatment and refrain from donating sperms during this period.
Exclusion criteria
1. Known contraindications, allergies, or hypersensitivities to any of the study medications or excipient as outlined in the investigators brochures (IBs), summary of product characteristics (SmPCs) or local package inserts for NEB and ZOF 2. Patients with serious disorders (in the opinion of the Investigator) which may limit the ability to evaluate the efficacy or safety of the tested medications, including cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine/ or metabolic, hematological, or oncological, neurological, and psychiatric diseases. The same applies for immunocompromised and/or neutropenic patients 3. Patients having a history of the following within the last 6 months: myocardial infarction, unstable angina pectoris, percutaneous coronary intervention, bypass surgery, heart failure, hypertensive encephalopathy, cerebrovascular accident (stroke), or transient ischemic attack 4. Patients with secondary hypertension of any etiology such as renal diseases, pheochromocytoma, or Cushing's syndrome 5. Patients with severe heart failure (New York Heart Association classification III-IV), a narrowing of the aortic or bicuspid valve, an obstruction of cardiac outflow (obstructive, hypertrophic cardiomyopathy) or symptomatic coronary disease 6. Patients with clinical evidence of renal disease as per the Investigator's judgement (including renovascular occlusive disease, nephrectomy and/or renal transplant, bilateral renal artery stenosis or unilateral renal artery stenosis in a solitary kidney, or severe renal impairment) 7. History of angioneurotic edema 8. Patients with clinically relevant hepatic impairment 9. Patients with sick sinus syndrome, including sino-atrial block 10. Patients with second- or third-degree heart block (without a pacemaker) 11. History of bronchospasm and bronchial asthma 12. Patients with bradycardia (heart rate \<60 bpm) 13. Patient with metabolic acidosis 14. Patients with severe peripheral circulatory disturbances 15. Participation in another study within the last 4 weeks 16. Patients with diseases that, in the opinion of the Investigator, prevent a careful adherence to the protocol 17. Pregnant and breastfeeding women. A pregnancy test will be performed on all women of childbearing potential at each study visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Sitting DBP Between Week 0 (Visit 2) and Week 8 (Visit 3) | From Baseline (Week 0 - Visit 2) to week 8 (Visit 3) | To assess the antihypertensive efficacy of the extemporaneous combination of Nebivolol (NEB) 5 mg and Zofenopril (ZOF) 30 mg in lowering sitting diastolic blood pressure (DBP) from baseline (Visit 2) after 8 weeks of treatment (Visit 3), in patients with uncontrolled blood pressure (BP) who were previously treated with NEB or ZOF monotherapies for at least 4 weeks. |
Countries
Italy
Participant flow
Recruitment details
Study started on 26 May 2021 and terminated on 22 December 2021 296 patients were screened for the study. 283 patients entered the run-in period and were assigned for monotherapy to Nebivolol (NEB) 5 mg or Zofenopril (ZOF) 30 mg. Of the 269 completed patients in monotherapy, 246 were assigned to combination therapy and 238 competed the study
Pre-assignment details
Run-in period (Week -4 to Week 0): • Patients on ZOF 30 mg or NEB 5 mg continued the same therapy. Patients on any other angiotensin I-converting enzyme (ACE-i) were assigned to monotherapy with ZOF 30 mg and the patients on any other betablocker (BB) were assigned to monotherapy with NEB 5 mg, respectively.
Participants by arm
| Arm | Count |
|---|---|
| COMBINATION THERAPY PERIOD Zofenopril 30mg/Nebivolol 5mg During the assessment period of 8 weeks, the eligible patients (uncontrolled hypertension with sitting BP of SBP/DBP \> 130/80 mmHg, who tolerated the treatment and whose adherence to the therapies ranged from 80% to 120%) received a combination of NEB 5 mg and ZOF 30 mg to be taken orally once daily. | 246 |
| Total | 246 |
Baseline characteristics
| Characteristic | COMBINATION THERAPY PERIOD Zofenopril 30mg/Nebivolol 5mg |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 246 Participants |
| Age, Continuous | 52.2 years STANDARD_DEVIATION 9.74 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 246 Participants |
| Region of Enrollment Italy | 16 participants |
| Region of Enrollment Poland | 230 participants |
| Sex: Female, Male Female | 106 Participants |
| Sex: Female, Male Male | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 137 | 0 / 146 | 0 / 246 |
| other Total, other adverse events | 9 / 137 | 2 / 146 | 18 / 246 |
| serious Total, serious adverse events | 0 / 137 | 0 / 146 | 0 / 246 |
Outcome results
Primary
Change in Mean Sitting DBP Between Week 0 (Visit 2) and Week 8 (Visit 3)
To assess the antihypertensive efficacy of the extemporaneous combination of Nebivolol (NEB) 5 mg and Zofenopril (ZOF) 30 mg in lowering sitting diastolic blood pressure (DBP) from baseline (Visit 2) after 8 weeks of treatment (Visit 3), in patients with uncontrolled blood pressure (BP) who were previously treated with NEB or ZOF monotherapies for at least 4 weeks.
Time frame: From Baseline (Week 0 - Visit 2) to week 8 (Visit 3)
Population: Intention to Treat Population composed by all patients who were enrolled and received at least 1 dose of the combination therapy and have at least 1 post baseline safety assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| COMBINATION THERAPY PERIOD Zofenopril 30mg/Nebivolol 5mg | Change in Mean Sitting DBP Between Week 0 (Visit 2) and Week 8 (Visit 3) | -9.3 mmHg | Standard Deviation 8.94 |
p-value: <0.001t-test, 2 sided