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

March 22, 2011 updated by: RostaQuo S.p.A.

Antihypertensive Effect of Different Doses of Rostafuroxin in Comparison With Losartan, Assessed by Office and Ambulatory Blood Pressure Monitoring in a Hypertensive Population Selected According to a Specific Genetic Profile

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
240

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Ireland
      • Dublin, Ireland, 15
        • James Connolly memorial Hospital
      • Dublin, Ireland, 9
        • Clinical research centre, Beaumont Hospital
    • Galway
      • Ballinasloe, Galway, Ireland
        • Portiuncula Hospital
  • Italy
      • Arezzo, Italy, 52100
        • U.O. di Nefrologia e Dialisi, Ospedale San Donato
      • Bologna, Italy, 40138
        • U.O Nefrologia, Dialisi e Ipertensione, Policlinico S. Orsola-Malpighi
      • Catanzaro, Italy, 88100
        • Cattedra di Medicina Interna, U.O. Malattie Cardiovascolari, Policlinico Universitario Campus Germaneto
      • Isernia, Italy, 86170
        • Centro per l'Ipertensione, Ospedale F. Veneziale
      • L'Aquila, Italy, 67100
        • U.O.C. di Medicina Interna Universitaria 1, Ospedale San Salvatore
      • Livorno, Italy, 57100
        • U.O. Nefrologia e Dialisi, Spedali Riuniti
      • Milano, Italy, 20132
        • Divisione di Nefrologia, Dialisi e Ipertensione Ospedale San Raffaele
      • Milano, Italy, 20142
        • U.O. Nefrologia e Dialisi, Università degli Studi di Milano Azienda Ospedaliera San Paolo
      • Padova, Italy, 35128
        • Clinica Medica 3, Dipartimento di Scienze Mediche e Chirurgiche
      • Ravenna, Italy, 48100
        • Reparto Emodialisi, Clinica "Domus Nova"
      • Rimini, Italy, 47900
        • Nefrologia e Dialisi, Ospedale Infermi
      • Sassari, Italy, 07100
        • Centro per l'Ipertensione, A.S.L. n° 1
      • Teramo, Italy, 64100
        • U.O. Nefrologia e Dialisi Presidio Ospedaliero "Giuseppe Mazzini"
      • Torino, Italy, 10126
        • Centro Ipertensione Arteriosa, SCU Medicina Interna 4, A.O.U. San Giovanni Battista
    • Bologna
      • Imola, Bologna, Italy, 40026
        • Unità Operativa di Nefrologia e Dialisi, Ospedale "S. Maria della Scaletta"
    • Parma
      • Borgo Val di Taro, Parma, Italy, 43023
        • Ospedale "Santa Maria"
    • Taranto
      • Manduria, Taranto, Italy, 74024
        • Divisione di Cardiologia e UTIC Ospedale "Marianna Giannuzzi"
    • Venezia
      • Mestre, Venezia, Italy, 30174
        • Reparto di Emodialisi, Ospedale dell'Angelo
  • Poland
      • Krakow, Poland, 31-202
        • Institute of Cardiology, Department of Coronary Disease, Jagiellonian University
      • Krakow, Poland, 31-501
        • Institute of Cardiology, I Department of Cardiology and Hypertension, Jagiellonian University
      • Krakow, Poland, 31-501
        • Internal Medicine and Gerontology, Jagiellonian University Medical College
      • Poznan, Poland, 01-848
        • Institute of Cardiology, Department of Hypertension, University of Medical Sciences
      • Warsaw, Poland, 04-628
        • The Cardinal Stefan Wyszynski Institute of Cardiology - Arterial Hypertension Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

25 years to 60 years (ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Rostafuroxin 6 micrograms capsules
1 capsule of ROSTAFUROXIN (6 micrograms) once a day before breakfast.
Drug: Rostafuroxin
6 microgram capsules
Other Names:
  • PST2238
Drug: Rostafuroxin
50 micrograms capsules
Other Names:
  • PST2238
Drug: Rostafuroxin
500 micrograms capsules
Other Names:
  • PST2238
EXPERIMENTAL: Rostafuroxin 50 micrograms capsules
1 capsule of ROSTAFUROXIN (50 micrograms) once a day before breakfast.
Drug: Rostafuroxin
6 microgram capsules
Other Names:
  • PST2238
Drug: Rostafuroxin
50 micrograms capsules
Other Names:
  • PST2238
Drug: Rostafuroxin
500 micrograms capsules
Other Names:
  • PST2238
EXPERIMENTAL: Rostafuroxin 500 micrograms
1 capsule of ROSTAFUROXIN (500 micrograms) once a day before breakfast.
Drug: Rostafuroxin
6 microgram capsules
Other Names:
  • PST2238
Drug: Rostafuroxin
50 micrograms capsules
Other Names:
  • PST2238
Drug: Rostafuroxin
500 micrograms capsules
Other Names:
  • PST2238
EXPERIMENTAL: Losartan 50 mg encapsulated
1 capsule containing one cpr of Losartan 50 mg once a day before breakfast.
Drug: Losartan
Losartan 50 mg once a day
Other Names:
  • Losaprex

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Systolic Blood Pressure
Time Frame: Week 9 of treatment versus baseline

Automated sitting and standing SBP and DBP will be recorded by physician at baseline (two visits) and at week 2, 5 and 9 of treatement.

sitting: after the patient has rested for at least 10 minutes in a quiet room. There are five consecutive sitting BP readings with a 30 to 60 seconds interval between the readings; the mean of the last three sitting BP will be used.

The standing BP is measured twice immediately after the patient assumed the standing position.
Week 9 of treatment versus baseline

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Diastolic blood pressure
Time Frame: Baseline (two visits) and then at week 2, 5 and 9 of treatment
Diastolic blood pressure measurements will be performed at the same times of the systolic blood pressure measurements, as described above.
Baseline (two visits) and then at week 2, 5 and 9 of treatment
Trough-to-peak ratio on Systolic Blood Pressure
Time Frame: Throughout 24 hours ABPM
Ambulatory Blood Pressure Monitoring (ABPM)will be performed throuhgout 24 hours at baseline and at week 9 of treatement. Readings will be Centralized. The Core Laboratory will be in charge for data interpretation.
Throughout 24 hours ABPM
Number of participants with adverse events
Time Frame: throughout all the study period and follow-up (30 days)
All the Adverse Events will be recorded and followed-up till their resolution. Number of Adverse Events in each group treatment will be computed, including single event frequencies and number of patients with adverse events. AEs will be collected on spontaneous reporting by patients and a number of standard safety procedure: i.e. recording of ECGs, standard blood chemistry and haematology, performed before, during and at the end of the treatment period.
throughout all the study period and follow-up (30 days)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
RostaQuo S.p.A.

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Jan A Staessen, MD PhD, Laboratory of Hypertension, University of Leuven, B-3000 Leuven - BELGIUM

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 1, 2011

Primary Completion (ANTICIPATED)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2012

Study Completion (ANTICIPATED)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2012

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 16, 2011

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 21, 2011

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 22, 2011

Study Record Updates

Last Update Posted (ESTIMATE)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 23, 2011

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 22, 2011

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2011

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • PST 2238-DM-10-001
  • 2010-022073-34 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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