Antihypertensive Effect of Rostafuroxin Compared With Losartan in Hypertensive Patients Bearing Specified Gene Mutations

NCT ID: NCT01320397

Last Updated: 2011-03-23

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 240 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-05-31
• Study Completion Date: 2012-12-31

Brief Summary

The principal aim of the study is to demonstrate that Rostafuroxin is able to induce a more pronounced reduction of arterial blood pressure respect to Losartan, in hypertensive patients carrying at least one of the pre-specified gene mutations. In previous studies has been demonstrated that these mutations are able to induce specific alterations inducing an increase of sodium (Na) reabsorption at renal tubular level and an increase of arterial blood pressure. Pilot studies have demonstrated that Rostafuroxin is able to reduce the impact of these alterations, and so directly reverse the increase in blood pressure.

Detailed Description

About 30% of the world adult population is affected by hypertension in industrialised countries. Elevated arterial pressure is the major cause of cardiovascular mortality and international guidelines emphasise the benefits of reducing blood pressure. The current antihypertensive strategies may reduce by 20-30% the cardiovascular risk of hypertensive patients when this efficacy is measured in clinical trials in comparison with placebo. A precise world-wide estimation of this efficacy both in term of patient burden and healthcare costs is not available; however, a recent analysis suggests that the world-wide cost of hypertension associated cardiovascular complications is around 1,000 billions dollars. Therefore, effective improvement in the diagnosis and treatment of hypertension can provide the most significant contribution to the decrease of cardiovascular mortality and reduction of the world-wide costs associated to treatment of hypertension complications.

Most of clinical trials, performed with the aim to show a reduction of the systolic blood pressure in hypertensive patients, show that reduction of systolic blood pressure is independent from the class of tested drugs as diuretics, β blockers, Ca channel blockers or inhibitors of RAS seem to have roughly the same efficacy. These findings have been used as an argument to support the notion that the antihypertensive therapy efficacy in reducing cardiovascular risk depends on the magnitude of the blood pressure fall rather than on the mechanism of action of the drug. This view contrasts with the well established notion that the secondary prevention capacity in other cardiovascular diseases differs among these classes of drugs with minor difference on the prevention of heart failure or stroke between the Ca antagonist and the other classes of drugs.

Furthermore, the recent findings on genetic of hypertension taken together with the previous data on pathophysiology of hypertension and its cardiovascular complications are consistent with the notion that a variety of heterogeneous genetic-molecular mechanisms concur to develop the rather uniform clinical picture of primary hypertension. Drugs are small molecules that produce their effects by interacting with larger molecules (proteins) whose function or reactivity may vary from one patient to another because the variations within the gene encoding them. Therefore, it is logical to postulate that the consequence of this different interaction either in term of blood pressure reduction or cardiovascular risk prevention may vary from a patient to another according to the peculiar function of the proteins involved in a given patient.

Rostafuroxin was selected during a research program aimed to synthesizing and selecting new antihypertensive compounds able to interfere with abnormalities in Na tubular reabsorption due to humoral and/or genetic mechanisms leading to essential (or genetic) hypertension. Many studies performed on the Milan hypertensive strain of rats (MHS), bearing a primary renal alteration in the ability to excrete sodium and increased blood pressure levels, showed a clear capacity of Rostafuroxin to revert these alteration, reducing systemic blood pressure.

Rostafuroxin selectively interferes with the Na-K pump correcting its functional abnormalities without interfering with other receptors involved in blood pressure regulation or hormonal homeostasis. At nanomolar concentration, rostafuroxin reduces the Na-K pump hyperactivation induced in renal cell cultures by either incubation with nanomolar ouabain concentrations or cell transfection with the 'hypertensive' variant of adducin.

Similarly, less than 1 μg/kg os of rostafuroxin is able to completely normalize both blood pressure and the increased renal Na-K pump activity in rats made hypertensive by a chronic infusion of low-dose ouabain. The antihypertensive effect of rostafuroxin is long-lasting since it is still present 24 hours after oral administration. It is not associated with changes in heart rate. Moreover, the long-term antihypertensive activity of rostafuroxin is not associated with alterations of plasma potassium, RAAS, insulin resistance, plasma lipid profile and uricemia. These findings indicate that the normalization of renal sodium handling brought about by this compound is not accompanied by the typical side effects of diuretics, such as: hypokaliemia, increased plasma levels of renin, aldosterone, triglycerides and uric acid, or insulin resistance.

Increased levels of EO and the mutated adducin are both associated with the organ complications related to hypertension, namely cardiac hypertrophy and progression toward renal insufficiency. Cardiac and renal hypertrophy is induced in rats by chronic ouabain infusion. Rostafuroxin prevents the ouabain-induced organ hypertrophy.

Rostafuroxin has shown a high safety ratio in toxicological studies and was well tolerated in previous clinical trials.

Patients with mutated adducin and increased EO plasma levels share many functional, hormonal and biochemical characteristics with MHS rats, therefore Rostafuroxin could become a first choice treatment in such patients bearing specific gene mutations and presenting high arterial blood pressure levels.

Preliminary proof of concept studies have shown ability of Rostafuroxin to reduce arterial blood pressure levels in such a patients.

Conditions

Essential Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Rostafuroxin 6 micrograms capsules

1 capsule of ROSTAFUROXIN (6 micrograms) once a day before breakfast.

Group Type: EXPERIMENTAL

Rostafuroxin

Intervention Type: DRUG

6 microgram capsules

Rostafuroxin 50 micrograms capsules

1 capsule of ROSTAFUROXIN (50 micrograms) once a day before breakfast.

Group Type: EXPERIMENTAL

Rostafuroxin

Intervention Type: DRUG

50 micrograms capsules

Rostafuroxin 500 micrograms

1 capsule of ROSTAFUROXIN (500 micrograms) once a day before breakfast.

Group Type: EXPERIMENTAL

Rostafuroxin

Intervention Type: DRUG

500 micrograms capsules

Losartan 50 mg encapsulated

1 capsule containing one cpr of Losartan 50 mg once a day before breakfast.

Group Type: EXPERIMENTAL

Losartan

Intervention Type: DRUG

Losartan 50 mg once a day

Interventions

Rostafuroxin

6 microgram capsules

Intervention Type: DRUG

Rostafuroxin

50 micrograms capsules

Intervention Type: DRUG

Rostafuroxin

500 micrograms capsules

Intervention Type: DRUG

Losartan

Losartan 50 mg once a day

Intervention Type: DRUG

Other Intervention Names

PST2238; PST2238; PST2238; Losaprex

Eligibility Criteria

Inclusion Criteria

• Signature of a written informed consent, included informed consent on genotype analysis.
• Naive hypertensive patient (new diagnosed patient, never treated before).
• Documented mild to moderate arterial hypertension: SBP comprised between 140 and 169 mmHg and DBP between 85 and 100 mmHg;
• Presence of at least one mutated genotype or combination of genotypes corresponding to the list provided in the protocol.

Exclusion Criteria

• Known causes of secondary or severe or malignant hypertension;
• Significant renal or hepatic disease;
• Cardiac disease requiring prohibited pharmacological treatment or history of myocardial infarction within the last 6 months;
• Atrial Fibrillation or Complete Ventricle Bundle Branch Block;
• First degree AV-block exceeding 240 msec;
• Electrocardiographic evidence of left ventricular hypertrophy;
• Pregnant or nursing women or women of childbearing potential not taking anti-contraceptive medication or not utilizing a double contraceptive method;
• Concomitant therapy with medications that may affect blood pressure;
• Diabetes mellitus (fasting plasma glucose > 125 mg/dl);
• Statins treatment.

• Minimum Eligible Age: 25 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

RostaQuo S.p.A.

INDUSTRY

Sponsor Role: lead

Responsible Party

RostaQuo S.p.A

Principal Investigators

Jan A Staessen, MD PhD

Role: STUDY_CHAIR

Laboratory of Hypertension, University of Leuven, B-3000 Leuven - BELGIUM

Locations

Portiuncula Hospital

Ballinasloe, Galway, Ireland

James Connolly memorial Hospital

Dublin, , Ireland

Clinical research centre, Beaumont Hospital

Dublin, , Ireland

Unità Operativa di Nefrologia e Dialisi, Ospedale "S. Maria della Scaletta"

Imola, Bologna, Italy

Ospedale "Santa Maria"

Borgo Val di Taro, Parma, Italy

Divisione di Cardiologia e UTIC Ospedale "Marianna Giannuzzi"

Manduria, Taranto, Italy

Reparto di Emodialisi, Ospedale dell'Angelo

Mestre, Venezia, Italy

U.O. di Nefrologia e Dialisi, Ospedale San Donato

Arezzo, , Italy

U.O Nefrologia, Dialisi e Ipertensione, Policlinico S. Orsola-Malpighi

Bologna, , Italy

Cattedra di Medicina Interna, U.O. Malattie Cardiovascolari, Policlinico Universitario Campus Germaneto

Catanzaro, , Italy

Centro per l'Ipertensione, Ospedale F. Veneziale

Isernia, , Italy

U.O. Nefrologia e Dialisi, Spedali Riuniti

Livorno, , Italy

U.O.C. di Medicina Interna Universitaria 1, Ospedale San Salvatore

L’Aquila, , Italy

Divisione di Nefrologia, Dialisi e Ipertensione Ospedale San Raffaele

Milan, , Italy

U.O. Nefrologia e Dialisi, Università degli Studi di Milano Azienda Ospedaliera San Paolo

Milan, , Italy

Clinica Medica 3, Dipartimento di Scienze Mediche e Chirurgiche

Padua, , Italy

Reparto Emodialisi, Clinica "Domus Nova"

Ravenna, , Italy

Nefrologia e Dialisi, Ospedale Infermi

Rimini, , Italy

Centro per l'Ipertensione, A.S.L. n° 1

Sassari, , Italy

U.O. Nefrologia e Dialisi Presidio Ospedaliero "Giuseppe Mazzini"

Teramo, , Italy

Centro Ipertensione Arteriosa, SCU Medicina Interna 4, A.O.U. San Giovanni Battista

Torino, , Italy

Institute of Cardiology, Department of Coronary Disease, Jagiellonian University

Krakow, , Poland

Institute of Cardiology, I Department of Cardiology and Hypertension, Jagiellonian University

Krakow, , Poland

Internal Medicine and Gerontology, Jagiellonian University Medical College

Krakow, , Poland

Institute of Cardiology, Department of Hypertension, University of Medical Sciences

Poznan, , Poland

The Cardinal Stefan Wyszynski Institute of Cardiology - Arterial Hypertension Clinic

Warsaw, , Poland

Countries

Ireland; Italy; Poland

Central Contacts

Giovanni Valentini, MD

Role: CONTACT

giovanni.valentini@sigma-tau.it

+39 06 91393916

Vittorio Dainese, Biologist

Role: CONTACT

vittorio.dainese@sigma-tau.it

+39 06 913934285

Other Identifiers

2010-022073-34

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PST 2238-DM-10-001

Identifier Type: -

Identifier Source: org_study_id