Pharmacogenetics of Torasemide and Spironolactone in Hypertension Treatment (ALTUM)

Pharmacogenetics of Hypertension: a Single-centre Randomized Study in Patients With Essential Hypertension Treated With Spironolactone or Torasemide

Phase III interventional study to evaluate the different efficacy of Torasemide and Spironolactone in reducing systolic blood pressure in carriers and non-carriers of the different genotypic combinations for Lanosterol and Uromodulin

Study Overview

• Status: Completed
• Conditions: Hypertension; Drug Effect; Genetic Predisposition
• Intervention / Treatment: Drug: Torasemide; Drug: Spironolactone

Detailed Description

The investigators will enroll 144 naïve hypertensive subjects who will undertake 2-4 weeks of run-in and 4 weeks of treatment (7 day window at each visit). During this period partecipants will follow a low sodium diet (about 5g/day) and will be monitored with blood chemistry tests

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • IRCCS Ospedale San Raffaele
  • Lombardia
    • Milan, Lombardia, Italy, 20132
      • San Raffaele Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• male (25-65 years) and female (45-65 years in menopause defined as "12 consecutive months of amenorrhea for which no other physiological or pathological cause has been identified in woman over 45 years of age")
• newly diagnosed hypertensive patients never treated before or on single antihypertensive drug therapy

• hypertension grade I or II (according to 2013 ESH guidelines, in the patient untreated or despite therapy), defined as the following:

  • at visits T-4 and T-2 (week -4 and week -2 ± 7 days, run-in period) the mean of the last 3 consecutive SBP measurements must be >=140 mmHg and/or diastolic BP>= 90mmHg
  • at the T0 visit (week 0 ± 7 days, enrollment), the mean of the last 3 consecutive systolic BP measurements must be >=140 mmHg and <180 mmHg and diastolic BP must be >=90 mmHg and <110 mmHg
• signing of the informed consent for participation in the study and for genotyping.

Exclusion Criteria:

• known causes of secondary hypertension
• stage II hypertension (SBP>= 180 and SBP>=110 mmHg
• history of renal artery stenosis
• significant kidney disease (eGFR-CK-EPI less than 60 mL/min)
• refractory hypokalemia or hyponatremia (Napl < 126 mEq/L)
• hyperkalemia (K > 5.5 mEq/l)
• hypercalcemia
• symptomatic hyperuricemia
• liver disease (transaminases greater than 3 times the maximum laboratory value)
• cardiac pathologies (previous myocardial infarction, atrial fibrillation in progress, etc.)

• diabetes (fasting blood sugar >126mg/dL)

  -. current statin treatment

• obesity (BMI >30 kg/m2)
• ongoing pregnancy
• breastfeeding in progress
• anuria
• hypovolemia and dehydration
• known hypersensitivity to the study drugs (Spironolactone or Torasemide) or to any of the excipients
• ongoing therapy with aminoglycosides or cephalosporins
• participation in a clinical study in which an investigational drug was administered within 30 days or 5 half-lives prior to the study drug
• patients unable to express valid consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Torasemide; The study involves the administration of Torasemide 2.5 mg.	Drug: Torasemide; The assignment to each drug will be carried out randomly in each genotypic group with the aim of reaching the same number of patients treated with the two drugs in the different genotypic groups; Other Names: Demadex; Torsemide; Tortas; Wator
Experimental: Spironolactone; The study involves the administration of Spironolactone 50 mg orally every day.	Drug: Spironolactone; The assignment to each drug will be carried out randomly in each genotypic group with the aim of reaching the same number of patients treated with the two drugs in the different genotypic groups; Other Names: Aldactone; Carospir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
difference in the change of systolic blood pressure(deltaSBP)	the difference in the reduction of systolic blood pressure (deltaSBP) values in essential hypertensive patients who are carriers and noncarriers of the different genotypic combinations for the LSS (lanosterol synthase) and UMOD (uromodulin) genes in response to Spironolactone or Torasemide	week 4 vs. week 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
variation of plasma aldosterone	variation of plasma aldosterone levels in the different genotypic and treatment groups after 4 weeks of treatment.	week 4 vs. week 0
difference in diastolic blood pressure change after treatment with Spironolactone or difference in diastolic blood pressure reduction (deltaDBP)	the difference in the reduction of diastolic blood pressure (deltaDBP) values in essential hypertensive patients who are carriers and noncarriers of the different genotypic combinations for the LSS (lanosterol synthase) and UMOD (uromodulin) genes in response to Spironolactone or Torasemide	week 4 vs. week 0

Collaborators and Investigators

• Sponsor: Ospedale San Raffaele
• Investigators: Study Director: Paolo Manunta, MD, San Raffaele Hospital Milan, Italy

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2021
• Primary Completion (Actual): July 7, 2023
• Study Completion (Actual): September 3, 2023

Study Registration Dates

• First Submitted: September 4, 2023
• First Submitted That Met QC Criteria: May 11, 2024
• First Posted (Actual): May 14, 2024

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 14, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: pharmacogenetics; genetics; hypertension; spironolactone; torasemide
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Disease Attributes; Disease Susceptibility; Hypertension; Genetic Predisposition to Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Sodium Potassium Chloride Symporter Inhibitors; Spironolactone; Torsemide
• Other Study ID Numbers: ALTUM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IDP will be stored in the institutional repository.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No