Cardiovascular DiseasesPhase 4UMODNCT03354897
Clinical Study of UMOD NKCC2 Interaction on Salt-sensitivity in Hypertension
A Phase 4 study testing Torasemide 5Mg Tablet in people with Cardiovascular Diseases and Hypertension, run by NHS Greater Glasgow and Clyde at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cardiovascular Diseases, Hypertension
- What is being tested?
- Torasemide 5Mg Tablet
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 228 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 5 Apr 2017to 30 Oct 2021
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 27Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Glasgow Clinical Research Facility
Glasgow, G51 4TF
About this study
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.
Read the detailed description
There are over 1 billion people with HTN worldwide, and the World Health Organisation suggests this will rise to 1.5 billion by 2020.(1) Up to 30% of hypertensive patients have resistant HTN (uncontrolled BP on > 3 drugs of which one must be a diuretic) and ~50% have uncontrolled HTN, with a 7-fold higher cardiovascular risk.
In clinical practice, criteria such as ancestry and serum renin levels provide only a rough indication of the underlying disease pathway and, while pharmacotherapy is the mainstay of HTN management, the selection of antihypertensive therapy is essentially by trial-and-error. Five drug classes are the main first-line agents for HTN, but response rates to any given drug are only ~50%. There are no new anti-hypertensive drugs in clinical trials and there is a need to either develop newer agents or target existing drugs to specific strata of hypertensive patients in whom they would be beneficial. The recent failure of the Renal Sympathetic Denervation trial, which used a novel device strategy for resistant HTN, highlights the limited options available in the management of uncontrolled or resistant HTN.
HTN as a phenotype demonstrates stratification in the population, based on the specific pathophysiological and molecular pathways that are operative and this is reflected in the current NICE guidelines. However, there has been little progress in stratification by leveraging genomic and molecular information, although there is evidence that this may be useful. Monogenic forms of HTN show that identification of the many causative mutations, primarily affecting the kidney and sodium balance, can inform therapy - for example, glucocorticoids in glucocorticoid remediable aldosteronism and amiloride in Liddle syndrome. Despite the successful adoption of the BHS/NICE treatment algorithm for the treatment of HTN, there remains substantial clinical uncertainty about the preferred clinical management of people with uncontrolled or treatment resistant HTN. Moreover, the choice of diuretic, suggested in HTN guidelines, is not based on clinical trials for third line antihypertensive agents. There is general consensus that resistant HTN is due to excessive sodium retention and thus "further diuretic therapy" may be an effective treatment. The choice that one type of diuretic will be superior to another has however not been studied and is usually prescribed in a trial and error manner with diuretics that primarily target the distal nephron (thiazide-like diuretic or spironolactone).
- Conditions
- Cardiovascular Diseases, Hypertension
- Being tested
- Torasemide 5Mg Tablet
- Keywords
- stratified medicine, UMOD, torasemide
- Medical subject headings
- Cardiovascular Diseases, Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Torasemide 5Mg TabletDrug
16 weeks treatment
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Other | 16 weeks treatment 5mg/day Receives: Drug: Torasemide 5Mg Tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in ABPM
Change in 24h ABPM systolic BP AUC at the end of the 16-week treatment phase compared to baseline
Measured: 16 weeks
Secondary outcomes (5)
change in 24h ABPM diastolic BP AUC
change in 24h ABPM diastolic BP AUC between baseline and the end of treatment
Measured: 16 weeks
change in day time ABPM systolic and diastolic BP AUC
change in day time ABPM systolic and diastolic BP AUC between baseline and the end of treatment
Measured: 16 weeks
change in night time ABPM systolic and diastolic BP AUC
change in night time ABPM systolic and diastolic BP AUC between baseline and the end of treatment
Measured: 16 weeks
change in HBPM SBP and DBP AUC
change in HBPM SBP and DBP AUC over the entire study period
Measured: 16 weeks
changes in serum electrolytes
changes in serum electrolytes over the entire study period
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Nov 2017
- Study start5 Apr 2017
- Primary completion30 Oct 2021
- Study completion30 Oct 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Cardiovascular DiseasesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 228 participants (actual)
Sponsor and investigators
- Lead sponsor
- NHS Greater Glasgow and Clyde
- Sponsor type
- University, hospital or other
- Collaborators
- University of Glasgow, British Heart Foundation
- Responsible party
- Sponsor
- Investigators
- Sandosh Padmanabhan, MbChB PhD, Study chair, University of Glasgow
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03354897
- Sponsor's protocol ID
- GN14CE400
- Acronym
- UMOD
- Status last verified
- Sep 2023
- First submitted
- 28 Sep 2017
- Last updated
- 25 Sep 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 39077768McCallum 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.
PubMed 33084880
Study at a glance
From the registry record, last updated by the sponsor on 25 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical Study of UMOD NKCC2 Interaction on Salt-sensitivity in Hypertension
- ClinicalTrials.gov ID
- NCT03354897
- Acronym / sponsor ID
- UMOD / GN14CE400
- Conditions
- Cardiovascular Diseases, Hypertension
- Keywords
- stratified medicine, UMOD, torasemide
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 228 participants (actual)
- Lead sponsor
- NHS Greater Glasgow and ClydeUniversity, hospital or other
- Collaborators
- University of Glasgow, British Heart Foundation
- Study start
- 5 Apr 2017 (actual)
- Primary completion
- 30 Oct 2021 (actual)
- Study completion
- 30 Oct 2021 (actual)
- First posted
- 28 Nov 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
There are over 1 billion people with HTN worldwide, and the World Health Organisation suggests this will rise to 1.5 billion by 2020.(1) Up to 30% of hypertensive patients have resistant HTN (uncontrolled BP on > 3 drugs of which one must be a diuretic) and ~50% have uncontrolled HTN, with a 7-fold higher cardiovascular risk.
In clinical practice, criteria such as ancestry and serum renin levels provide only a rough indication of the underlying disease pathway and, while pharmacotherapy is the mainstay of HTN management, the selection of antihypertensive therapy is essentially by trial-and-error. Five drug classes are the main first-line agents for HTN, but response rates to any given drug are only ~50%. There are no new anti-hypertensive drugs in clinical trials and there is a need to either develop newer agents or target existing drugs to specific strata of hypertensive patients in whom they would be beneficial. The recent failure of the Renal Sympathetic Denervation trial, which used a novel device strategy for resistant HTN, highlights the limited options available in the management of uncontrolled or resistant HTN.
HTN as a phenotype demonstrates stratification in the population, based on the specific pathophysiological and molecular pathways that are operative and this is reflected in the current NICE guidelines. However, there has been little progress in stratification by leveraging genomic and molecular information, although there is evidence that this may be useful. Monogenic forms of HTN show that identification of the many causative mutations, primarily affecting the kidney and sodium balance, can inform therapy - for example, glucocorticoids in glucocorticoid remediable aldosteronism and amiloride in Liddle syndrome. Despite the successful adoption of the BHS/NICE treatment algorithm for the treatment of HTN, there remains substantial clinical uncertainty about the preferred clinical management of people with uncontrolled or treatment resistant HTN. Moreover, the choice of diuretic, suggested in HTN guidelines, is not based on clinical trials for third line antihypertensive agents. There is general consensus that resistant HTN is due to excessive sodium retention and thus "further diuretic therapy" may be an effective treatment. The choice that one type of diuretic will be superior to another has however not been studied and is usually prescribed in a trial and error manner with diuretics that primarily target the distal nephron (thiazide-like diuretic or spironolactone).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Treatment | Other | Drug: Torasemide 5Mg Tablet16 weeks treatment 5mg/day |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (27 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Torasemide 5Mg Tablet16 weeks treatment | Drug | Treatment |
Primary outcome
Change in ABPM
Time frame: 16 weeks
Change in 24h ABPM systolic BP AUC at the end of the 16-week treatment phase compared to baseline
5 secondary outcomes
change in 24h ABPM diastolic BP AUC
Time frame: 16 weeks
change in day time ABPM systolic and diastolic BP AUC
Time frame: 16 weeks
change in night time ABPM systolic and diastolic BP AUC
Time frame: 16 weeks
change in HBPM SBP and DBP AUC
Time frame: 16 weeks
changes in serum electrolytes
Time frame: 16 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Sep 2023.
- Derived from this study: PubMed 39077768McCallum 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.
- Derived from this study: PubMed 33084880McCallum 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sandosh Padmanabhan, MbChB PhD study chair
University of Glasgow
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Torasemide 5Mg Tablet in people with Cardiovascular Diseases and Hypertension, run by NHS Greater Glasgow and Clyde at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in ABPM (time frame: 16 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03354897, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2023.