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

Primary Purpose

Essential Hypertension

Status
Unknown status
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Rostafuroxin
Rostafuroxin
Rostafuroxin
Losartan
Sponsored by
RostaQuo S.p.A.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Essential Hypertension

Eligibility Criteria

25 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Portiuncula Hospital
  • James Connolly memorial Hospital
  • Clinical research centre, Beaumont Hospital
  • Unità Operativa di Nefrologia e Dialisi, Ospedale "S. Maria della Scaletta"
  • Ospedale "Santa Maria"
  • Divisione di Cardiologia e UTIC Ospedale "Marianna Giannuzzi"
  • Reparto di Emodialisi, Ospedale dell'Angelo
  • U.O. di Nefrologia e Dialisi, Ospedale San Donato
  • U.O Nefrologia, Dialisi e Ipertensione, Policlinico S. Orsola-Malpighi
  • Cattedra di Medicina Interna, U.O. Malattie Cardiovascolari, Policlinico Universitario Campus Germaneto
  • Centro per l'Ipertensione, Ospedale F. Veneziale
  • U.O.C. di Medicina Interna Universitaria 1, Ospedale San Salvatore
  • U.O. Nefrologia e Dialisi, Spedali Riuniti
  • Divisione di Nefrologia, Dialisi e Ipertensione Ospedale San Raffaele
  • U.O. Nefrologia e Dialisi, Università degli Studi di Milano Azienda Ospedaliera San Paolo
  • Clinica Medica 3, Dipartimento di Scienze Mediche e Chirurgiche
  • Reparto Emodialisi, Clinica "Domus Nova"
  • Nefrologia e Dialisi, Ospedale Infermi
  • Centro per l'Ipertensione, A.S.L. n° 1
  • U.O. Nefrologia e Dialisi Presidio Ospedaliero "Giuseppe Mazzini"
  • Centro Ipertensione Arteriosa, SCU Medicina Interna 4, A.O.U. San Giovanni Battista
  • Institute of Cardiology, Department of Coronary Disease, Jagiellonian University
  • Institute of Cardiology, I Department of Cardiology and Hypertension, Jagiellonian University
  • Internal Medicine and Gerontology, Jagiellonian University Medical College
  • Institute of Cardiology, Department of Hypertension, University of Medical Sciences
  • The Cardinal Stefan Wyszynski Institute of Cardiology - Arterial Hypertension Clinic

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Rostafuroxin 6 micrograms capsules

Rostafuroxin 50 micrograms capsules

Rostafuroxin 500 micrograms

Losartan 50 mg encapsulated

Arm Description

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

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

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

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

Outcomes

Primary Outcome Measures

Systolic Blood Pressure
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.

Secondary Outcome Measures

Diastolic blood pressure
Diastolic blood pressure measurements will be performed at the same times of the systolic blood pressure measurements, as described above.
Trough-to-peak ratio on Systolic Blood Pressure
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.
Number of participants with adverse events
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.

Full Information

First Posted
March 16, 2011
Last Updated
March 22, 2011
Sponsor
RostaQuo S.p.A.
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1. Study Identification

Unique Protocol Identification Number
NCT01320397
Brief Title
Antihypertensive Effect of Rostafuroxin Compared With Losartan in Hypertensive Patients Bearing Specified Gene Mutations
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2011
Overall Recruitment Status
Unknown status
Study Start Date
May 2011 (undefined)
Primary Completion Date
July 2012 (Anticipated)
Study Completion Date
December 2012 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
RostaQuo S.p.A.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Essential Hypertension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
240 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Rostafuroxin 6 micrograms capsules
Arm Type
Experimental
Arm Description
1 capsule of ROSTAFUROXIN (6 micrograms) once a day before breakfast.
Arm Title
Rostafuroxin 50 micrograms capsules
Arm Type
Experimental
Arm Description
1 capsule of ROSTAFUROXIN (50 micrograms) once a day before breakfast.
Arm Title
Rostafuroxin 500 micrograms
Arm Type
Experimental
Arm Description
1 capsule of ROSTAFUROXIN (500 micrograms) once a day before breakfast.
Arm Title
Losartan 50 mg encapsulated
Arm Type
Experimental
Arm Description
1 capsule containing one cpr of Losartan 50 mg once a day before breakfast.
Intervention Type
Drug
Intervention Name(s)
Rostafuroxin
Other Intervention Name(s)
PST2238
Intervention Description
6 microgram capsules
Intervention Type
Drug
Intervention Name(s)
Rostafuroxin
Other Intervention Name(s)
PST2238
Intervention Description
50 micrograms capsules
Intervention Type
Drug
Intervention Name(s)
Rostafuroxin
Other Intervention Name(s)
PST2238
Intervention Description
500 micrograms capsules
Intervention Type
Drug
Intervention Name(s)
Losartan
Other Intervention Name(s)
Losaprex
Intervention Description
Losartan 50 mg once a day
Primary Outcome Measure Information:
Title
Systolic Blood Pressure
Description
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.
Time Frame
Week 9 of treatment versus baseline
Secondary Outcome Measure Information:
Title
Diastolic blood pressure
Description
Diastolic blood pressure measurements will be performed at the same times of the systolic blood pressure measurements, as described above.
Time Frame
Baseline (two visits) and then at week 2, 5 and 9 of treatment
Title
Trough-to-peak ratio on Systolic Blood Pressure
Description
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.
Time Frame
Throughout 24 hours ABPM
Title
Number of participants with adverse events
Description
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.
Time Frame
throughout all the study period and follow-up (30 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Giovanni Valentini, MD
Phone
+39 06 91393916
Email
giovanni.valentini@sigma-tau.it
First Name & Middle Initial & Last Name or Official Title & Degree
Vittorio Dainese, Biologist
Phone
+39 06 913934285
Email
vittorio.dainese@sigma-tau.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jan A Staessen, MD PhD
Organizational Affiliation
Laboratory of Hypertension, University of Leuven, B-3000 Leuven - BELGIUM
Official's Role
Study Chair
Facility Information:
Facility Name
Portiuncula Hospital
City
Ballinasloe
State/Province
Galway
Country
Ireland
Facility Name
James Connolly memorial Hospital
City
Dublin
ZIP/Postal Code
15
Country
Ireland
Facility Name
Clinical research centre, Beaumont Hospital
City
Dublin
ZIP/Postal Code
9
Country
Ireland
Facility Name
Unità Operativa di Nefrologia e Dialisi, Ospedale "S. Maria della Scaletta"
City
Imola
State/Province
Bologna
ZIP/Postal Code
40026
Country
Italy
Facility Name
Ospedale "Santa Maria"
City
Borgo Val di Taro
State/Province
Parma
ZIP/Postal Code
43023
Country
Italy
Facility Name
Divisione di Cardiologia e UTIC Ospedale "Marianna Giannuzzi"
City
Manduria
State/Province
Taranto
ZIP/Postal Code
74024
Country
Italy
Facility Name
Reparto di Emodialisi, Ospedale dell'Angelo
City
Mestre
State/Province
Venezia
ZIP/Postal Code
30174
Country
Italy
Facility Name
U.O. di Nefrologia e Dialisi, Ospedale San Donato
City
Arezzo
ZIP/Postal Code
52100
Country
Italy
Facility Name
U.O Nefrologia, Dialisi e Ipertensione, Policlinico S. Orsola-Malpighi
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Facility Name
Cattedra di Medicina Interna, U.O. Malattie Cardiovascolari, Policlinico Universitario Campus Germaneto
City
Catanzaro
ZIP/Postal Code
88100
Country
Italy
Facility Name
Centro per l'Ipertensione, Ospedale F. Veneziale
City
Isernia
ZIP/Postal Code
86170
Country
Italy
Facility Name
U.O.C. di Medicina Interna Universitaria 1, Ospedale San Salvatore
City
L'Aquila
ZIP/Postal Code
67100
Country
Italy
Facility Name
U.O. Nefrologia e Dialisi, Spedali Riuniti
City
Livorno
ZIP/Postal Code
57100
Country
Italy
Facility Name
Divisione di Nefrologia, Dialisi e Ipertensione Ospedale San Raffaele
City
Milano
ZIP/Postal Code
20132
Country
Italy
Facility Name
U.O. Nefrologia e Dialisi, Università degli Studi di Milano Azienda Ospedaliera San Paolo
City
Milano
ZIP/Postal Code
20142
Country
Italy
Facility Name
Clinica Medica 3, Dipartimento di Scienze Mediche e Chirurgiche
City
Padova
ZIP/Postal Code
35128
Country
Italy
Facility Name
Reparto Emodialisi, Clinica "Domus Nova"
City
Ravenna
ZIP/Postal Code
48100
Country
Italy
Facility Name
Nefrologia e Dialisi, Ospedale Infermi
City
Rimini
ZIP/Postal Code
47900
Country
Italy
Facility Name
Centro per l'Ipertensione, A.S.L. n° 1
City
Sassari
ZIP/Postal Code
07100
Country
Italy
Facility Name
U.O. Nefrologia e Dialisi Presidio Ospedaliero "Giuseppe Mazzini"
City
Teramo
ZIP/Postal Code
64100
Country
Italy
Facility Name
Centro Ipertensione Arteriosa, SCU Medicina Interna 4, A.O.U. San Giovanni Battista
City
Torino
ZIP/Postal Code
10126
Country
Italy
Facility Name
Institute of Cardiology, Department of Coronary Disease, Jagiellonian University
City
Krakow
ZIP/Postal Code
31-202
Country
Poland
Facility Name
Institute of Cardiology, I Department of Cardiology and Hypertension, Jagiellonian University
City
Krakow
ZIP/Postal Code
31-501
Country
Poland
Facility Name
Internal Medicine and Gerontology, Jagiellonian University Medical College
City
Krakow
ZIP/Postal Code
31-501
Country
Poland
Facility Name
Institute of Cardiology, Department of Hypertension, University of Medical Sciences
City
Poznan
ZIP/Postal Code
01-848
Country
Poland
Facility Name
The Cardinal Stefan Wyszynski Institute of Cardiology - Arterial Hypertension Clinic
City
Warsaw
ZIP/Postal Code
04-628
Country
Poland

12. IPD Sharing Statement

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

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