Evaluation of the Clinical Efficacy and Safety of Amlodipine 5mg/ Bisoprolol Fumarate 5mg /Perindopril Arginine 5mg Fixed-dose Combination in Capsule and Free Monotherapy at the Same Dose in Patients With Uncontrolled Essential Hypertension.

Evaluation of the Clinical Efficacy and Safety of Amlodipine 5mg/ Bisoprolol Fumarate 5mg /Perindopril Arginine 5mg Fixed-dose Combination in Capsule and Free Monotherapy at the Same Dose in Patients With Uncontrolled Essential Hypertension. A Multicentre, Randomized, Open-label, 12-weeks Study.

The purpose of this study was to evaluate the efficacy and the safety of a fixed-dose combination in capsule of Amlodipine 5mg/ Bisoprolol fumarate 5mg/ Perindopril arginine 5mg, and free monotherapy at the same dose in patients with uncontrolled essential hypertension.

This was a phase III, multicenter, randomized, open-label, controlled study, over a 12-week treatment period with a single-capsule of fixed dose combination (FDC) of Amlodipine 5 mg/ Bisoprolol fumarate 5 mg / Perindopril arginine 5 mg and free monocomponents of Amlodipine 5 mg, Bisoprolol fumarate 5 mg and Perindopril arginine 5 mg given concomitantly, in 150 patients with uncontrolled essential HT.

Patients without any non-selection criteria, already treated by anti-hypertensive monotherapy at maximal dose or either by a dual therapy at minimum dose, other than study treatment, having an uncontrolled HT defined by SBP (Systolic Blood Pressure) ≥ 140 and <160 mmHg and DBP (Diastolic Blood Pressure) ≥ 90 and <100 mmHg (in supine position) at 2 different visits (selection and inclusion) were to be selected in this study and randomized to one of two treatment groups: single-capsule combination or free therapy without any wash-out period.

For all patients, controlled blood pressure (BP) was defined as SBP < 140 mmHg and DBP < 90 mmHg.

Selection criteria:

• Men or women of any ethnic origin ≥18 years old who signed Informed consent form.
• Patients with uncontrolled hypertension defined by SBP ≥140 and < 160 mmHg and DBP ≥90 and < 100 mmHg already treated by anti-hypertensive monotherapy at maximal dose or either by a dual therapy at minimum dose, other than study treatment (amlodipine or bisoprolol or perindopril), for at least 4 weeks.
• Women of potential childbearing and men (and/or their partners) must agree to use appropriate contraceptive measures. This applies since signing of the Informed Consent form until the last study drug administration.
• Willing to provide signed and dated informed consent.

Non selection criteria

• Unlikely to co-operate in the study, to comply with study treatment or with the study visits.
• Pregnancy, breastfeeding.
• Current participation in another randomized study or within the preceding 3 months.
• Participant already enrolled in the study.
• Alcohol or drug abuse and/or dependence.
• Body mass index > 32 kg/m².
• Grapefruit juice was forbidden during the study (interaction with amlodipine).

Concerning Hypertension (HT)

• DBP ≥100 mmHg and/or SBP ≥160 mmHg under treatment.
• Known or suspected symptomatic orthostatic hypotension.
• HT known to be resistant to Calcium Channel Blockers or Angiotensin Converting Enzyme (ACE) inhibitors or Beta Blockers.
• Secondary HT.
• Complicated HT: known stage III or IV hypertensive retinopathy, macroalbuminuria (patients with microalbuminuria could be selected).

Concerning concomitant diseases

• History of renal disease: Known renal impairment: Patients having a creatinine clearance value classifying them as moderate or severe renal failure (using national or international classification of chronic kidney disease), whatever the method for calculation used (Modification of Diet in Renal Disease (MDRD) or Cockcroft or any other Estimated Glomerular Filtration Rate (eGFR) formula), or bilateral renal artery stenosis or stenosis to a solitary kidney.
• History of cerebrovascular disease: ischemic stroke, cerebral hemorrhage, transient ischemic attack.
• History of heart disease: shock (including cardiogenic), myocardial infarction (within previous 6 months before selection), heart failure class II to IV NYHA (New York Heart Association), coronary revascularization (within the previous 6 months), severe aortic or mitral valve stenosis or hypertrophic obstructive myocardiopathy, unstable angina pectoris (including Prinzmetal's angina).
• History of recent (within previous 6 months before selection, accordingly to the doctor decision) ventricular rhythm disorders (except isolated extrasystoles), atrial fibrillation or atrial flutter, second or third degree atrioventricular (AV) block or other cardiac rhythm disorders leading to important beat-to-beat variations in BP (Left Ventricular Hypertrophy was authorized at selection and during the study).
• Known prolonged QT interval.
• Patients having resting HR <50 bpm.
• History of sick sinus syndrome.
• History of bradycardia clinically significant episode.
• Severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome.
• Severe bronchial asthma or severe chronic obstructive pulmonary disease.
• Severe gastro-intestinal tract disorders with possible influence on drug absorption or electrolytes.
• Known complicated liver disease (for example: chronic hepatitis, cirrhosis, hepatic encephalopathy…).
• Chronic pancreatitis.
• Endocrine diseases: uncontrolled dysthyroidia, Cushing's syndrome, acromegalia, hyperparathyroidia.
• Diabetes mellitus type I and type II under treatment (patients with diabetes type II well controlled at the selection visit by lifestyle and dietary rules alone could be selected).
• Any history or known severe disease likely to interfere with the conduct of the study, severe evolutive infection, evolutive malignant neoplasm.
• History of neutropenia.
• History of connective tissue disorders (systemic lupus erythematosus, progressive systemic sclerosis or other connective tissue disorders).
• History of severe mental or psychiatric disorder, severe depression or history of severe depression, e.g. requiring hospitalization or at high risk of suicide attempt.
• History of angioneurotic oedema.

Concerning concomitant medications

• β-blockers even if used for other reason than HT, in order to avoid the AE related to the immediate switch during selection visit.
• Antihypertensive treatments having central mechanism of action in order to avoid possible rebound effect at a full immediate stop at the randomization.
• Antiarrhythmic treatments in order to avoid possible interactions with bisoprolol.
• Inability to stop any of the medications listed in the prohibited concomitant medication list.
• Potassium supplement at selection and inclusion visit.
• Drugs contraindicated with the study treatments as defined in the Summaries of Product Characteristics of each study drugs

Concerning contra-indications to treatment with amlodipine, bisoprolol or perindopril

• Any history of angioedema, hereditary, idiopathic or associated with previous ACE inhibitor therapy.

• Allergy / hypersensitivity / history of intolerance or any contra-indications related to:

  • amlodipine or any other dihydropyridine and calcium inhibitors;
  • perindopril or any other ACE inhibitor;
  • bisoprolol or other beta-blockers;
  • any of the excipients of the study drugs.

Inclusion criteria :

• Respect of the previous selection and non-selection criteria.
• Confirmed essential uncontrolled HT under patient's current treatment at W000 visit, defined as SBP ≥140 and < 160 mmHg and DBP ≥90 and < 100 mmHg, measured with a validated automatic device in supine position after at least 10 minutes of rest. There were 3 BP measurements at 2-3 minutes of an interval between each measurement. The mean of the two last values of the three measurements was taken.
• Normal or without any clinically significant abnormality 12-lead ECG (left ventricular hypertrophy and post-MI ECG-changes are authorized at selection and during the study).
• Normal or without clinically significant abnormality of laboratory examinations. Microalbuminuria was authorized.

Non-inclusion criteria :

• As per non-selection criteria.
• Occurrence of an event requiring immediate notification since Selection.
• Laboratory results unavailable at the inclusion visit.
• Withdrawal of informed consent by patient.
• DBP ≥100 mmHg and/or SBP ≥160 mmHg under treatment since the selection visit.
• Positive orthostatic test at inclusion.
• Positive β-human Chorionic Gonadotrophin (β-HCG) pregnancy test (Blood test).
• Laboratory results unavailable at the inclusion visit or clinically significant abnormalities. Macroalbuminuria (>300 mg albumin/24h) was not authorized. ASpartate (Amino)Transferase (ASAT) or ALanine (Amino)Transferase (ALAT) ≥ 2 UNL (Upper Normal Limit) was not authorized.

If all Inclusion and non-inclusion criteria were satisfied, the patient was included and randomized to a treatment group.

Exclusion Criteria (withdrawal criteria) :

• Patients whose BP was still uncontrolled at two consecutive visits (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg) or whose SBP/DBP was above 160/100 mmHg (confirmed with 2 consecutive visits starting W004, at least 14 days apart).
• Onset of an adverse event (AE) which required prescription of a treatment incompatible with the protocol.
• Onset of an AE which, according to the investigator, makes it unsafe for the patient to continue with the study treatment. This includes clinically significant abnormal biochemical and haematological parameters, or clinically significant ECG abnormality.
• Pregnancy.
• Major protocol deviation preventing the analysis of the main endpoint, or which, in the opinion of the investigator, makes it unsafe for the patient to continue to take the study medication and to stay in the study.
• Non-medical reason (patient's personal decision to stop treatment).