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

GN14CE400

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.

2017-04-05

2021-10-30

2021-10-30

Completed

Early phase I

228

Inclusion Criteria: * 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 Exclusion Criteria: * 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 * Any concomitant condition that, in the opinion of the investigator, may adversely affect the safety and/or efficacy of the study drug or severely limit that patients life-span or ability to complete the study (e.g. alcohol or drug abuse, disabling or terminal illness, severe liver impairment, mental disorders) * Treatment with any of the following medications - * Oral corticosteroids within 3 months of screening. Treatment with systemic corticosteroids is also prohibited during study participation * Chronic stable use, or unstable use of NSAIDs (other than low dose aspirin or occasional OTC analgesic doses) is prohibited. Chronic use is defined as \>3 consecutive days of treatment per week. In addition intermittent use of NSAIDs is discouraged throughout the study. For those requiring analgesics during the study, paracetamol or opiate drugs are recommended. * Use of lithium * Participants on the following medications may be included provided they meet the following criteria * Use of thiazide or loop diuretics prior to the study if the diuretic can be stopped for 2 weeks (washout) before the study medication administered. * The use of short acting nitrates (e.g. sublingual nitroglycerin) is permitted. However, participants should avoid short acting oral nitrates within 4 hours of screening or an subsequent visit * The use of long acting nitrates (e.g. Isordil) is permitted but the dose must be stable for at least 2 weeks prior to screening and randomisation * The use of sympathomimetic decongestants is permitted, though not within 24 hours of any study visit/BP assessment * The use of theophylline is permitted but the dose must be stable for at least 4 weeks prior to screening and throughout the study * The use of phosphodiesterase type V inhibitors is permitted. However, study participants must refrain from taking these medications for at least 7 days prior to screening or any subsequent study visit

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE4'], 'designInfo': {'allocation': 'NA', 'interventionModel': 'SINGLE_GROUP', 'interventionModelDescription': '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.', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE', 'maskingDescription': 'prospective cohort study'}}, 'enrollmentInfo': {'count': 228, 'type': 'ACTUAL'}}

2023-09-25