A Phase 2 interventional study of Rostafuroxin and Losartan in Hypertension, sponsored by Windtree Therapeutics. Completed at 1 site in Taiwan. Open to participants aged 25 Years to 60 Years. Per ClinicalTrials.gov, last updated 2023-02-21.
Sponsored by Windtree Therapeutics · Phase 2, Interventional, and Treatment
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.
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.
6,689 studies on the registry are indexed under Hypertension; 965 are open to participants now.
This study's enrollment of 240 is above the median of 90 across 4,995 interventional studies indexed under Hypertension.
Browse Hypertension studies →Windtree Therapeutics is the lead sponsor of 13 studies on the registry; none are open to participants now.
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Exclusion Criteria:
1 capsule of ROSTAFUROXIN (6 micrograms) once a day before breakfast.
Drug: Rostafuroxin
1 capsule of ROSTAFUROXIN (50 micrograms) once a day before breakfast.
Drug: Rostafuroxin
1 capsule of ROSTAFUROXIN (500 micrograms) once a day before breakfast.
Drug: Rostafuroxin
1 capsule containing one cpr of Losartan 50 mg once a day before breakfast.
Drug: Losartan
This is a potent, selective and safe inhibitor of this altered mechanism and has been proved to be effective in reducing blood pressure levels in Adducin mutated rat strains and in chronic Ouabain infused rat model.
Also known as: Rosta
COZAAR (losartan potassium) is an angiotensin II receptor (type AT1) antagonist. Losartan potassium, a nonpeptide molecule, is chemically described as 2-butyl-4-chloro-1-\[p-(o-1H-tetrazol-5-ylphenyl)benzyl\]imidazole- 5-methanol monopotassium salt.
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.
Time frame: Week 9 of treatment versus baseline
Diastolic blood pressure
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
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
Time frame: Throughout 24 hours ABPM
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.
Time frame: throughout all the study period and follow-up (30 days)
Plan to share: No
This study is completed, as verified in Feb 2023. You cannot join it, but the record below documents what was studied.
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