Effectiveness and Safety of Combination of Amlodipine and Zofenopril in Hypertensive Patients Versus Each Monotherapy

Interventional Clinical Trial to Assess Efficacy and Safety of the Extemporaneous Combination of Zofenopril Calcium and Amlodipine in Grade 1-2 Hypertensive Patients Versus Each Monotherapy - (MASOLINO Study)

Study to assess the anti-hypertensive efficacy and safety of the extemporaneous combination of Zofenopril 30 mg in combination with Amlodipine 5 mg or AML 10 mg in lowering the sitting diastolic BP after 8 weeks of treatment in patients with uncontrolled BP previously treated with Zofenopril or Amlodipine (5 mg) monotherapies for at least 4 weeks.

Approximately 290 patients are planned to be screened to ensure at least 216 patients complete the run-in period and start with the assessment period.

Patients with 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 (ACE-i) including Zofenopril (ZOF)30 mg or with calcium channel blockers (CCBs) including Amlodipine (AML)5 mg will be screened for eligibility (Visit 1).

Allowed CCBs: Felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, and nisoldipine. Patients treated with other dosages of ZOF (other than 30 mg) are not allowed to be screened. After screening, on the same day, eligible patients, will enter into a 4-week run-in period, during which patients on other ACE-i will be assigned to monotherapy with ZOF 30 mg while patients on CCBs will be assigned to monotherapy with AML 5 mg for 4 weeks. Patients with on-going treatment zofenopril 30 mg and amlodipine 5mg will continue on the same treatment for 4 weeks.

After the run-in period (4 weeks ± 2 days), BP will be further assessed (Visit 2), if BP levels are over the defined controlled target goal, sitting Systolic Blood Pressure (SBP)/Diastolic Blood Pressure (DBP) >130/80 mmHg, treatment is well tolerated and adherence to the treatments ranges from 80% to 120%, patients will enter the assessment period, where they will be assigned to the extemporaneous combination of ZOF 30 mg and AML 5 mg. At Visit 2 patients with SBP/DBP values classified as Grade 3 (SBP ≥ 180 or DBP ≥ 110 mmHg) hypertension will be withdrawn from the study.

If patients, at Visit 2, after the run-in period, have a controlled BP (sitting SBP/DBP≤130/80 mmHg) or do not tolerate the treatment or have an adherence range below 80% or superior to 120%, they will be withdrawn from the study.

The patients will be assessed for further 8 weeks (assessment period). After 4 weeks ± 2 days from Visit 2,during the assessment period patients receiving the extemporaneous combination of ZOF 30 mg and AML 5 mg, will be further evaluated (Visit 3): controlled patients (sitting SBP/DBP ≤130/80 mmHg) will continue the same extemporaneous combination for additional 4 weeks ± 2 days, while uncontrolled patients (sitting SBP/DBP >130/80 mmHg) will be up-titrated from ZOF/AML 30/5 mg to ZOF/AML 30/10 mg for further 4 weeks ± 2 days. At Visit 3 patients with SBP/DBP values classified as Grade 3 (SBP ≥ 180 or DBP ≥ 110 mmHg) hypertension will be withdrawn from the study. If patients at Visit 3, do not tolerate the extemporaneous combination treatment or they have an adherence range below 80% or superior to 120%, they will be withdrawn from the study.

At the end of the assessment period (8 weeks ± 4 days) at Visit 4, the anti-hypertensive effect of the extemporaneous combination (ZOF/AML 30/5 mg and ZOF/AML 30/10 mg) will be evaluated.

Efforts will be made to achieve 1:1 ratio in the enrolment of patients receiving any ACE-i or allowed CCBs (refer to section Subject Study Phases Duration for allowed CCBs). At Visit 2, a minimum of 45% of uncontrolled patients receiving treatment with ZOF 30 mg or AML 5 mg are required to enter the assessment period, in order to maintain a balance between the 2 treatments during the assessment period.

Inclusion Criteria:

1. Male or female Grade 1-2 hypertensive patients: with mean sitting SBP ≥140 mmHg and ≤179 mmHg and/or mean sitting DBP ≥ 90 mmHg and ≤109 mmHg at Screening, with ≥18 and ≤65 years of age, on monotherapy either with ZOF 30 mg or AML 5mg or any other ACE-I or CCBs (Felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, and nisoldipine) for at least 1 month before Visit 1 (Screening).

2. Patients who are able to understand and give written informed consent at Screening

3. Patients who are available for the entire trial period and willing to adhere to the protocol requirements

4. Ability to take oral medication and willing to adhere to the drug regimen

5. Female patients are eligible to participate if not pregnant, or not breastfeeding and must refrain from donating or storing eggs. For females of reproductive potential: use of highly effective contraception (e.g., 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) such as:

   • Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
   • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
   • Intrauterine device (IUD)
   • Intrauterine hormone-releasing system (IUS)
   • Bilateral tubal occlusion
   • Vasectomized partner (performed at least 2 months before screening) (if the partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success)

6. A male patient 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, presence of not recommended/contraindicated concomitant therapy allergies, or significant history of hypersensitivity to zofenopril, amlodipine, other ACE-inhibitors or dihydropyridines, or any related products including excipients of the formulations as outlined in the Investigator's Brochure (IB), or summary of product characteristics (SmPCs) or local package inserts for AML 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, haematological, 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, valve replacement (transcatheter aortic valve implantation, mitral-clip),cerebrovascular accident (stroke, heart failure, hypertensive encephalopathy, cerebrovascular accident (stroke), or transient ischemic attack. Patients with who have undergone other surgery that in the in the opinion of the Investigator may limit the ability to evaluate the efficacy or safety of the tested medications.
4. Patients with secondary hypertension of any aetiology such as renal diseases, pheochromocytoma, Cushing's syndrome hyperaldosteronism, renovascular disease, thyroid disorders
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. Patients with history of angioneurotic oedema
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. Participation in any other interventional drug trial or exposure to other investigational agents within 30 days before Screening (Visit 1)
12. Inability to cooperate or any condition that, in the opinion of the Investigator, could increase the patient's risk of participating in the study or confound the outcome of the study
13. Patients with conditions that, in the opinion of the Investigator, would prevent a careful adherence to the protocol
14. Patients with severe hypotension
15. Patients who suffer from shock (including cardiogenic shock)
16. Patients treated with Amlodipine 10 mg and Zofenopril (other than 30 mg)