Clinical Study of UMOD NKCC2 Interaction on Salt-sensitivity in Hypertension

NCT03354897 | Completed Phase 4 DMC

• 1 other identifier: GN14CE400
• Study Type: interventional
• Target: 228
• Locations: 1 country
• Sites: 1

Brief Summary

The hypothesis is based on UMOD rs13333226 genotype, there are two strata of hypertensive patients. The High-UMOD group (AA genotype) has increased UMOD excretion, greater salt sensitivity, HTN, normal eGFR and greater BP response to loop diuretics like furosemide. The Low-UMOD group (G allele) has decreased UMOD excretion, salt resistance, increased eGFR, increased proximal tubular reabsorption of Na (possibly related to increased GFR), a poor BP response to loop diuretics, and possibly diminished function of NKCC2. The High-UMOD strata will have decreased delivery of Na+ to the distal tubule and collecting duct because NKCC2 function is normal and the study hypothesis is that the participants will be more responsive to loop diuretics. In contrast, the Low-UMOD group (G allele) will not show a similar response to loop diuretics. This may be related either to lower Na delivery to the TAL, because of increased proximal tubular reabsorption of Na+, or a suppressed function of NKCC2. The population distribution of the High-UMOD group (AA) is 67%. Our overall objective is to test the hypothesis that hypertensive subjects with uncontrolled HTN open possessing the AA genotype of rs13333226 will be better responders to loop diuretics compared to those possessing the G allele.

Conditions

Cardiovascular Diseases; Hypertension

Keywords

stratified medicine, UMOD, torasemide

Outcome Measures

Primary Outcomes (1)

• Change in ABPM

  Change in 24h ABPM systolic BP AUC at the end of the 16-week treatment phase compared to baseline

  16 weeks

Secondary Outcomes (5)

• change in 24h ABPM diastolic BP AUC

  16 weeks

• change in day time ABPM systolic and diastolic BP AUC

  16 weeks

• change in night time ABPM systolic and diastolic BP AUC

  16 weeks

• change in HBPM SBP and DBP AUC

  16 weeks

• changes in serum electrolytes

  16 weeks

Study Arms (1)

Treatment

OTHER

16 weeks treatment 5mg/day

Drug: Torasemide 5Mg Tablet

Interventions

Torasemide 5Mg Tablet DRUG

16 weeks treatment

Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Hypertensive patients aged ≥18 years of age
• Patients will all have hypertension that is not controlled to home target: SBP \>135 mmHg and/or DBP \>85 mmHg on therapy with one or more antihypertensive drugs for at least 3 months.
• Able to attend one of the three study centres

You may not qualify if:

• Inability to give informed consent
• Participation in a clinical study involving an investigational drug or device within 3 months of screening
• Secondary or accelerated hypertension (investigator opinion)
• Diabetes mellitus (Type 1 or type 2)
• eGFR \<60 mls/min, hyponatraemia, hypokalaemia
• Pregnancy, breast feeding
• Women of child bearing potential who are unwilling to use effective contraception
• Childbearing potential is defined as women who have experienced menarche and who have not undergone successful surgical sterilisation or who are not post-menopausal (irregular menstrual periods, or amenorrhoea \>12 months, with serum follicle stimulating hormone (FSH) \>35mIU/ml; women taking hormone replacement therapy (HRT)
• Women of childbearing potential will be eligible if they are willing to use acceptable contraception (combined oral contraceptives, progesterone only contraceptives, intrauterine device, barrier methods) or they are abstinence due to lifestyle choice or their partner is sterile (vasectomy).
• Anticipated change of medical status during the trial (e.g. surgical intervention requiring \>2 weeks convalescence)
• Recent (\<6 months) cardiovascular event requiring hospitalisation (e.g. myocardial infarction or stroke)
• Requirement for study drug or other loop diuretic for reason other than to treat hypertension
• Clinically relevant contra-indication to treatment with torasemide: hypersensitivity, hereditary problems of glucose intolerance, Lapp lactase deficiency of glucose-galactose malabsorption
• Current therapy for cancer
• Concurrent chronic illness, or other reasons likely to preclude 18-week participation in the study

Sponsors & Collaborators

• NHS Greater Glasgow and Clyde: lead
• University of Glasgow: collaborator
• British Heart Foundation: collaborator

Study Sites (1)

Glasgow Clinical Research Facility

Glasgow, G51 4TF, United Kingdom

Location

Related Publications (2)

• McCallum L, Lip S, McConnachie A, Brooksbank K, MacIntyre IM, Doney A, Llano A, Aman A, Caparrotta TM, Ingram G, Mackenzie IS, Dominiczak AF, MacDonald TM, Webb DJ, Padmanabhan S. UMOD Genotype-Blinded Trial of Ambulatory Blood Pressure Response to Torasemide. Hypertension. 2024 Oct;81(10):2049-2059. doi: 10.1161/HYPERTENSIONAHA.124.23122. Epub 2024 Jul 30.

  PMID: 39077768 DERIVED

• McCallum L, Brooksbank K, McConnachie A, Aman A, Lip S, Dawson J, MacIntyre IM, MacDonald TM, Webb DJ, Padmanabhan S. Rationale and Design of the Genotype-Blinded Trial of Torasemide for the Treatment of Hypertension (BHF UMOD). Am J Hypertens. 2021 Feb 18;34(1):92-99. doi: 10.1093/ajh/hpaa166.

  PMID: 33084880 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases; Hypertension

Interventions

Torsemide; Tablets

Condition Hierarchy (Ancestors)

Vascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dosage Forms; Pharmaceutical Preparations

Study Officials

• Sandosh Padmanabhan, MbChB PhD

  University of Glasgow

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Masking Details: prospective cohort study
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study is a multi-centre prospective cohort study to investigate whether individuals possessing the AA genotype of the single nucleotide polymorphism, rs13333226, are better responders to loop diuretics compared to those possessing the G allele.

Study Record Dates

• First Submitted: September 28, 2017
• First Posted: November 28, 2017
• Study Start: April 5, 2017
• Primary Completion: October 30, 2021
• Study Completion: October 30, 2021
• Last Updated: September 25, 2023

Record last verified: 2023-09

Locations

GB (1)