Hypertension, Resistant to Conventional TherapyPhase 4PATHWAY2NCT02369081
Optimum Treatment for Drug-Resistant Hypertension
A Phase 4 study testing Spironolactone, Bisoprolol and Doxazosin in people with Hypertension, Resistant to Conventional Therapy, run by University of Cambridge at 16 sites in United Kingdom.
Trial summary
This study was recommended by NICE, as part of its 2006 guidance for the treatment of hypertension, and is urgently required to provide evidence for the treatment recommendations in patients with resistant hypertension. Read more about this study
- Who is it for?
- Ages 18 to 79 years
- Conditions the study is for
- Hypertension, Resistant to Conventional Therapy
- What is being tested?
- Spironolactone, Bisoprolol and Doxazosin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 348 participants
- Where
- 16 sitesUnited Kingdom
- Study dates
- May 2009to Aug 2015
- 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 to 79 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- Inability to give informed consent;
- Participation in a clinical study involving an investigational drug or device within 4 weeks of screening;
- Secondary or accelerated hypertension;
- Type 1 diabetes;
- eGFR<45 mls/min;
- Plasma potassium outside of normal range on two successive measurements during screening;
Show all 25Show fewer
- Pregnancy, planning to conceive, or women of child-bearing potential not taking adequate contraception
- Anticipated change of medical status during the trial - Absolute contra-indication to study drugs or previous intolerance of trial therapy;
- Sustained atrial fibrillation;
- Recent cardiovascular event requiring hospitalisation
- Suspected non-adherence to antihypertensive treatment
- Requirement for study drug for reason other than to treat hypertension, - Current therapy for cancer;
- Concurrent chronic illness, likely to preclude 52 week participation in the study;
- Clinic Systolic BP >200 mmHg or diastolic BP >120mmHg, with PI discretion to override if home BP measurements are lower
- Any concomitant condition that may adversely affect the safety/ efficacy of study drug or severely limit that patients life-span or ability to complete the study
- 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) is prohibited. Chronic use defined as >3 consecutive or non-consecutive days of treatment per week. In addition intermittent use of NSAIDs is strongly discouraged; if required, must not be used for more than a total of 2 days. For those requiring analgesics; paracetamol is recommended.
- The use of short acting nitrates is permitted, but must not be taken within 4 hours of screening or subsequent visits
- The use of long acting nitrates is permitted but dose must be stable for at least 2 weeks prior to screening and randomisation;
- The use of sympathomimetic decongestants is permitted;but not within 1 day prior to any study visit/BP assessment;
- The use of theophylline is permitted but dose must be stable for 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 1 day prior to screening or any subsequent study visits;
- The use of alpha-blockers is not permitted, with the exception of afluzosin and tamsulosin for prostatic symptoms
- A pill count will be made at the end of the 4 week run-in period and those with adherence <70% will be excluded from randomisation
Trial locations and contacts
16 sites in 1 country.
16 sites in 1 country
United Kingdom16 sites
NHS Ayrshire
Ayrshire
University Hospitals Birmingham NHS Foundation Trust
Birmingham
University of Birmingham
Birmingham
University of Cambridge - Addenbrookes Hospital
Cambridge, CB2 2QQ
NHS Tayside/University of Dundee
Dundee
NHS Lothian/University of Edinburgh
Edinburgh
Royal Devon & Exeter NHS Foundation Trust
Exeter
NHS Greater Glasgow and Clyde/University of Glasgow
Glasgow
Ixworth GP Practice
Ixworth
University Hospitals of Leicester NHS Trust
Leicester
Barts and the London School of Medicine and Dentistry
London
Guys and St Thomas' NHS Foundation Trust
London
Imperial College Healthcare NHS Trust
London
Central Manchester University Hospitals NHS Foundation Trust
Manchester
Norfolk and Norwich University Hospital NHS Trust
Norwich
West Hertfordshire Hospitals NHS Trust
Watford
About this study
This study was recommended by NICE, as part of its 2006 guidance for the treatment of hypertension, and is urgently required to provide evidence for the treatment recommendations in patients with resistant hypertension. The study will be a randomised placebo-controlled double-blind crossover comparison of an α-blocker (α), β-blocker (β), and K+-sparing diuretic (∆).
Patients will have a BP at entry above target on ABPM or home monitoring despite supervised administration of maximum tolerated doses of A+C+D. Over 48 weeks they will then receive, in random order either placebo or two doses each of doxazosin (α), bisoprolol (β) or spironolactone (∆). Each treatment cycle will last 12 weeks, with a forced dose-doubling at 6 weeks.
The time course for the study will be similar to study one. 340 patients will provide 90% power, at α=0.01 to detect a 3 mmHg overall difference in home sBP between any one drug and placebo, with spironolactone hypothesized to be best overall. The study will be able to detect a 6 mmHg difference in sBP between each subject's best and second-best drug predicted by tertile of plasma renin, justifying routine use of the measurement in patients with resistant hypertension.
Read the detailed description
In published surveys throughout the world the majority of patients with hypertension do not achieve target blood pressure. According to most guidelines including NICE, target blood pressure is 130/80 mmHg in patients with diabetes, 140/90 mmHg in other patients. In the UK there are currently at least 3 million people with treated hypertension whose blood pressure is not controlled. A significant number of these patients will have drug resistant hypertension, defined as:
"a blood pressure that is not adequately controlled to recommended treatment targets despite treatment with maximal recommended and tolerated doses of 3 drugs according to the current BHS/NICE guidelines and treatment algorithm, i.e. (*ACE-inhibitor or *ARB or direct renin inhibitor + *CCB + Diuretic (any diuretic except spironolactone), i.e. A+C+D)".
(*where ACE-inhibitor=angiotensin converting enzyme inhibitor, ARB=angiotensin receptor blocker, CCB=calcium channel blocker)
The causes of treatment resistance are unknown, and the choice of fourth-line drug almost entirely empirical. At present there is little comparative data for available drugs. There is considerable evidence pointing to Na+ retention as a common culprit, and some data supporting additional diuretics, or alpha blockade in resistant hypertension, though mainly added to two rather than three drugs.20,29,30 A retrospective analysis of two-drug combinations in trials reported that it makes no difference what is combined with what. 31 However, this conclusion conflicts with the view that drugs for hypertension fall into two main categories, acting respectively on the renin and volume components of hypertension, and that most benefit can be derived from combining drugs from different categories.10,32
Despite the successful adoption of the BHS/NICE treatment algorithm for the treatment of hypertension, there remains substantial clinical uncertainty about the preferred clinical management of people with drug resistant hypertension. This is an important question because such patients are at the highest risk for cardiovascular events. The current guidelines acknowledge that there is currently no adequate clinical trial evidence upon which to base recommendations for the preferred 4th line drug treatment for those with resistant hypertension.
It is possible that it makes no difference what drug is added as fourth-line treatment and that the response, on average, will be the same for all classes. Alternatively, it is also possible that one class of drug will always be superior to all the others because the mechanism underpinning resistant hypertension is common to all patients. In this regard, a popular view is that resistant hypertension is invariably due to excessive sodium retention and thus "further diuretic therapy" will always be the most effective treatment. A third possibility is that resistant hypertension is a heterogeneous state and that the study of average responses in cohorts in clinical studies masks substantial individual patient differences.
With regard to this, this study will address the hypothesis that the renin status of the patient defines the response to 4th line treatment in resistant hypertension, i.e. that low renin predicts sodium retention and the best response to diuretic therapy, whereas high renin predicts a better response to drugs that suppress renin, i.e. a β-blocker.
Hypothesis and Novel Aspects of the Trial
The primary hypothesis of the study is that the commonest cause of resistant hypertension is excessive Na+-retention, and that further diuretic therapy (spironolactone used in this study) will be superior to other potential "add-on drugs" for people with inadequate blood pressure control despite treatment with optimal or highest tolerated doses of the three drug classes recommended by the BHS/NICE treatment algorithm, i.e. A+C+D.
The main secondary objective is to use plasma renin measurements to evaluate an 'α, β, ∆' rule for the selection of the 4th line drug for patients with drug resistant hypertension - where α represents α-blockade, β represents β-blockade and ∆ represents "further diuretic therapy" as cited above. The main secondary hypothesis states that plasma renin (measured on a background of 3 drugs, i.e. A+C+D), will predict the most effective 4th line drug. We propose that:
α-blockade will be the most effective 4th line drug at lowering BP in patients in the mid-tertile of plasma renin, expected to be ≥20mU/L but <100mU/L; β-blockade will be the most effective drug when renin is in the top tertile (expected to be ≥100Mu/L) as the drug blocks renin secretion; Further diuretic therapy with spironolactone will be most effective when plasma renin is in the lowest tertile (expected to be <20mU/L), indicative of excessive sodium retention.
The study will also evaluate whether the routine use of plasma renin to predict best treatment in individual patients with resistant hypertension will be more cost-effective than using further diuretic therapy indiscriminately as the preferred 4th line drug for all patients.
Finally the study will investigate whether non-invasive assessment of haemodynamic parameters indicative of sodium retention and volume status, i.e. cardiac output, peripheral resistance and bioimpedance, can be used to predict the response to each drug in the α, β, ∆ sequence.
- Being tested
- Spironolactone, Bisoprolol, Doxazosin, Placebo
- Keywords
- Hypertension
- Medical subject headings
- Hypertension Resistant to Conventional Therapy, Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SpironolactoneDrug
Spironolactone 25mg tablet orally once daily for 6 weeks, followed by Spironolactone 50mg tablet orally once daily for a further 6 weeks.
BisoprololDrug
Bisoprolol 5mg tablet orally once each day for 6 weeks, followed by Bisoprolol 10mg tablet orally once each day for a further 6 weeks.
DoxazosinDrug
Doxazosin 4mg tablet orally once daily for 6 weeks, followed by Doxazosin 8mg tablet orally once daily for a further 6 weeks.
PlaceboDrug
Placebo treatment for 12 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Spironolactone | Active comparator | Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase. Receives: Drug: Spironolactone |
| Placebo | Placebo comparator | Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase Receives: Drug: Placebo |
| Doxazosin | Active comparator | Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase Receives: Drug: Doxazosin |
| Bisoprolol | Active comparator | Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase Receives: Drug: Bisoprolol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Treatment arm comparison according to home blood pressure measurement
We will adopt a hierarchical procedure to test, in order, the differences in home systolic BP between spironolactone and
- placebo
- the average of the other two active drugs
- each of the other two drugs. The second and third tests will be carried out if and only if the preceding test(s) are significant (P<0.05).
We shall use a mixed model to analyse home BP, with unstructured covariances for the repeated measures across the two doses for each treatment within a patient. The model will include terms for gender, age, height, weight, smoking history and a diagnosis of diabetes at baseline. We will also adjust for baseline BP.
Measured: 48 weeks
Secondary outcomes (1)
Measurement of plasma renin as predictor of effective treatment
The difference in home systolic BP averages between the best drug predicted by the patient's plasma renin (according to the 'α, β, ∆' rule cited above) and further diuretic therapy;ie with spironolactone, which we have predicted will be the most effective treatment on average.
Measured: 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2015 (estimated)
- Study startMay 2009
- Primary completionJul 2015 (estimated)
- Study completionAug 2015 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Hypertension, Resistant to Conventional TherapyStudies 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
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 348 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Cambridge
- Sponsor type
- University, hospital or other
- Collaborators
- British Heart Foundation
- Responsible party
- Principal investigator, Morris Brown, University of Cambridge
- Investigators
- Prof MJ Brown, Principal investigator, University of Cambridge
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02369081
- Sponsor's protocol ID
- UKCRN 4500
- Other IDs
- 2008-007149-30, 2008
- Acronym
- PATHWAY2
- Status last verified
- Jul 2015
- First submitted
- 11 Jun 2013
- Last updated
- 3 Jul 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
NICE/BHS. CG34 Hypertension - NICE guideline (all the recommendations). http://www.nice.org.uk/guidance/CG34/niceguidance /pdf/english 2006
Dickerson JE, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet. 1999 Jun 12;353(9169):2008-13. doi: 10.1016/s0140-6736(98)07614-4.
PubMed 10376615Deary AJ, Schumann AL, Murfet H, Haydock SF, Foo RS, Brown MJ. Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. J Hypertens. 2002 Apr;20(4):771-7. doi: 10.1097/00004872-200204000-00037.
PubMed 11910315Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing hemodynamic management to specialist care. Hypertension. 2002 May;39(5):982-8. doi: 10.1161/01.hyp.0000016176.16042.2f.
PubMed 12019280Kaplan NM. Resistant hypertension. J Hypertens. 2005 Aug;23(8):1441-4. doi: 10.1097/01.hjh.0000174968.72212.ac.
PubMed 16003165Black HR, Keck M, Meredith P, Bullen K, Quinn S, Koren A. Controlled-release doxazosin as combination therapy in hypertension: the GATES study. J Clin Hypertens (Greenwich). 2006 Mar;8(3):159-66; quiz 167-8. doi: 10.1111/j.1524-6175.2006.04811.x.
PubMed 16522992Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003 Jun 28;326(7404):1427. doi: 10.1136/bmj.326.7404.1427.
PubMed 12829555Brown MJ, Cruickshank JK, Dominiczak AF, MacGregor GA, Poulter NR, Russell GI, Thom S, Williams B; Executive Committee, British Hypertension Society. Better blood pressure control: how to combine drugs. J Hum Hypertens. 2003 Feb;17(2):81-6. doi: 10.1038/sj.jhh.1001511.
PubMed 12574784Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes GT, Ford I, Cruickshank JK, Caulfield MJ, Padmanabhan S, Mackenzie IS, Salsbury J, Brown MJ; British Hypertension Society programme of Prevention And Treatment of Hypertension With Algorithm based Therapy (PATHWAY) Study Group. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. 2018 Jun;6(6):464-475. doi: 10.1016/S2213-8587(18)30071-8. Epub 2018 Apr 11.
PubMed 29655877Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ; British Hypertension Society's PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015 Nov 21;386(10008):2059-2068. doi: 10.1016/S0140-6736(15)00257-3. Epub 2015 Sep 20.
PubMed 26414968Williams B, MacDonald TM, Caulfield M, Cruickshank JK, McInnes G, Sever P, Webb DJ, Salsbury J, Morant S, Ford I, Brown MJ. Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension. BMJ Open. 2015 Aug 7;5(8):e008951. doi: 10.1136/bmjopen-2015-008951.
PubMed 26253568
Study at a glance
From the registry record, last updated by the sponsor on 3 Jul 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimum Treatment for Drug-Resistant Hypertension
- ClinicalTrials.gov ID
- NCT02369081
- Acronym / sponsor ID
- PATHWAY2 / UKCRN 4500
- Keywords
- Hypertension
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 348 participants (actual)
- Lead sponsor
- University of CambridgeUniversity, hospital or other
- Collaborators
- British Heart Foundation
- Study start
- May 2009
- Primary completion
- Jul 2015 (estimated)
- Study completion
- Aug 2015 (estimated)
- First posted
- 23 Feb 2015 (estimated)
- 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.
This study was recommended by NICE, as part of its 2006 guidance for the treatment of hypertension, and is urgently required to provide evidence for the treatment recommendations in patients with resistant hypertension. The study will be a randomised placebo-controlled double-blind crossover comparison of an α-blocker (α), β-blocker (β), and K+-sparing diuretic (∆).
Patients will have a BP at entry above target on ABPM or home monitoring despite supervised administration of maximum tolerated doses of A+C+D. Over 48 weeks they will then receive, in random order either placebo or two doses each of doxazosin (α), bisoprolol (β) or spironolactone (∆). Each treatment cycle will last 12 weeks, with a forced dose-doubling at 6 weeks.
The time course for the study will be similar to study one. 340 patients will provide 90% power, at α=0.01 to detect a 3 mmHg overall difference in home sBP between any one drug and placebo, with spironolactone hypothesized to be best overall. The study will be able to detect a 6 mmHg difference in sBP between each subject's best and second-best drug predicted by tertile of plasma renin, justifying routine use of the measurement in patients with resistant hypertension.
Detailed description
In published surveys throughout the world the majority of patients with hypertension do not achieve target blood pressure. According to most guidelines including NICE, target blood pressure is 130/80 mmHg in patients with diabetes, 140/90 mmHg in other patients. In the UK there are currently at least 3 million people with treated hypertension whose blood pressure is not controlled. A significant number of these patients will have drug resistant hypertension, defined as:
"a blood pressure that is not adequately controlled to recommended treatment targets despite treatment with maximal recommended and tolerated doses of 3 drugs according to the current BHS/NICE guidelines and treatment algorithm, i.e. (*ACE-inhibitor or *ARB or direct renin inhibitor + *CCB + Diuretic (any diuretic except spironolactone), i.e. A+C+D)".
(*where ACE-inhibitor=angiotensin converting enzyme inhibitor, ARB=angiotensin receptor blocker, CCB=calcium channel blocker)
The causes of treatment resistance are unknown, and the choice of fourth-line drug almost entirely empirical. At present there is little comparative data for available drugs. There is considerable evidence pointing to Na+ retention as a common culprit, and some data supporting additional diuretics, or alpha blockade in resistant hypertension, though mainly added to two rather than three drugs.20,29,30 A retrospective analysis of two-drug combinations in trials reported that it makes no difference what is combined with what. 31 However, this conclusion conflicts with the view that drugs for hypertension fall into two main categories, acting respectively on the renin and volume components of hypertension, and that most benefit can be derived from combining drugs from different categories.10,32
Despite the successful adoption of the BHS/NICE treatment algorithm for the treatment of hypertension, there remains substantial clinical uncertainty about the preferred clinical management of people with drug resistant hypertension. This is an important question because such patients are at the highest risk for cardiovascular events. The current guidelines acknowledge that there is currently no adequate clinical trial evidence upon which to base recommendations for the preferred 4th line drug treatment for those with resistant hypertension.
It is possible that it makes no difference what drug is added as fourth-line treatment and that the response, on average, will be the same for all classes. Alternatively, it is also possible that one class of drug will always be superior to all the others because the mechanism underpinning resistant hypertension is common to all patients. In this regard, a popular view is that resistant hypertension is invariably due to excessive sodium retention and thus "further diuretic therapy" will always be the most effective treatment. A third possibility is that resistant hypertension is a heterogeneous state and that the study of average responses in cohorts in clinical studies masks substantial individual patient differences.
With regard to this, this study will address the hypothesis that the renin status of the patient defines the response to 4th line treatment in resistant hypertension, i.e. that low renin predicts sodium retention and the best response to diuretic therapy, whereas high renin predicts a better response to drugs that suppress renin, i.e. a β-blocker.
Hypothesis and Novel Aspects of the Trial
The primary hypothesis of the study is that the commonest cause of resistant hypertension is excessive Na+-retention, and that further diuretic therapy (spironolactone used in this study) will be superior to other potential "add-on drugs" for people with inadequate blood pressure control despite treatment with optimal or highest tolerated doses of the three drug classes recommended by the BHS/NICE treatment algorithm, i.e. A+C+D.
The main secondary objective is to use plasma renin measurements to evaluate an 'α, β, ∆' rule for the selection of the 4th line drug for patients with drug resistant hypertension - where α represents α-blockade, β represents β-blockade and ∆ represents "further diuretic therapy" as cited above. The main secondary hypothesis states that plasma renin (measured on a background of 3 drugs, i.e. A+C+D), will predict the most effective 4th line drug. We propose that:
α-blockade will be the most effective 4th line drug at lowering BP in patients in the mid-tertile of plasma renin, expected to be ≥20mU/L but <100mU/L; β-blockade will be the most effective drug when renin is in the top tertile (expected to be ≥100Mu/L) as the drug blocks renin secretion; Further diuretic therapy with spironolactone will be most effective when plasma renin is in the lowest tertile (expected to be <20mU/L), indicative of excessive sodium retention.
The study will also evaluate whether the routine use of plasma renin to predict best treatment in individual patients with resistant hypertension will be more cost-effective than using further diuretic therapy indiscriminately as the preferred 4th line drug for all patients.
Finally the study will investigate whether non-invasive assessment of haemodynamic parameters indicative of sodium retention and volume status, i.e. cardiac output, peripheral resistance and bioimpedance, can be used to predict the response to each drug in the α, β, ∆ sequence.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Spironolactone | Active comparator | Drug: SpironolactoneEach patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase. |
| Placebo | Placebo comparator | Drug: PlaceboEach patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase |
| Doxazosin | Active comparator | Drug: DoxazosinEach patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase |
| Bisoprolol | Active comparator | Drug: BisoprololEach patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase |
Who may qualify
- Ages
- 18 to 79 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (25 listed)
- Inability to give informed consent;
- Participation in a clinical study involving an investigational drug or device within 4 weeks of screening;
- Secondary or accelerated hypertension;
- Type 1 diabetes;
- eGFR<45 mls/min;
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 |
|---|---|---|
| SpironolactoneSpironolactone 25mg tablet orally once daily for 6 weeks, followed by Spironolactone 50mg tablet orally once daily for a further 6 weeks. | Drug | Spironolactone |
| BisoprololBisoprolol 5mg tablet orally once each day for 6 weeks, followed by Bisoprolol 10mg tablet orally once each day for a further 6 weeks. | Drug | Bisoprolol |
| DoxazosinDoxazosin 4mg tablet orally once daily for 6 weeks, followed by Doxazosin 8mg tablet orally once daily for a further 6 weeks. | Drug | Doxazosin |
| PlaceboPlacebo treatment for 12 weeks. | Drug | Placebo |
Primary outcome
Treatment arm comparison according to home blood pressure measurement
Time frame: 48 weeks
We will adopt a hierarchical procedure to test, in order, the differences in home systolic BP between spironolactone and 1. placebo 2. the average of the other two active drugs 3. each of the other two drugs. The second and third tests will be carried out if and only if the preceding test(s) are significant (P<0.05). We shall use a mixed model to analyse home BP, with unstructured covariances for the repeated measures across the two doses for each treatment within a patient. The model will include terms for gender, age, height, weight, smoking history and a diagnosis of diabetes at baseline. We will also adjust for baseline BP.
1 secondary outcome
Measurement of plasma renin as predictor of effective treatment
Time frame: 48 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jul 2015.
- BackgroundNICE/BHS. CG34 Hypertension - NICE guideline (all the recommendations). http://www.nice.org.uk/guidance/CG34/niceguidance /pdf/english 2006
- Background: PubMed 10376615Dickerson JE, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet. 1999 Jun 12;353(9169):2008-13. doi: 10.1016/s0140-6736(98)07614-4.
- Background: PubMed 11910315Deary AJ, Schumann AL, Murfet H, Haydock SF, Foo RS, Brown MJ. Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. J Hypertens. 2002 Apr;20(4):771-7. doi: 10.1097/00004872-200204000-00037.
- Background: PubMed 12019280Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing hemodynamic management to specialist care. Hypertension. 2002 May;39(5):982-8. doi: 10.1161/01.hyp.0000016176.16042.2f.
- Background: PubMed 16003165Kaplan NM. Resistant hypertension. J Hypertens. 2005 Aug;23(8):1441-4. doi: 10.1097/01.hjh.0000174968.72212.ac.
- Background: PubMed 16522992Black HR, Keck M, Meredith P, Bullen K, Quinn S, Koren A. Controlled-release doxazosin as combination therapy in hypertension: the GATES study. J Clin Hypertens (Greenwich). 2006 Mar;8(3):159-66; quiz 167-8. doi: 10.1111/j.1524-6175.2006.04811.x.
- Background: PubMed 12829555Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003 Jun 28;326(7404):1427. doi: 10.1136/bmj.326.7404.1427.
- Background: PubMed 12574784Brown MJ, Cruickshank JK, Dominiczak AF, MacGregor GA, Poulter NR, Russell GI, Thom S, Williams B; Executive Committee, British Hypertension Society. Better blood pressure control: how to combine drugs. J Hum Hypertens. 2003 Feb;17(2):81-6. doi: 10.1038/sj.jhh.1001511.
- Derived from this study: PubMed 29655877Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes GT, Ford I, Cruickshank JK, Caulfield MJ, Padmanabhan S, Mackenzie IS, Salsbury J, Brown MJ; British Hypertension Society programme of Prevention And Treatment of Hypertension With Algorithm based Therapy (PATHWAY) Study Group. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. 2018 Jun;6(6):464-475. doi: 10.1016/S2213-8587(18)30071-8. Epub 2018 Apr 11.
- Derived from this study: PubMed 26414968Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ; British Hypertension Society's PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015 Nov 21;386(10008):2059-2068. doi: 10.1016/S0140-6736(15)00257-3. Epub 2015 Sep 20.
- Derived from this study: PubMed 26253568Williams B, MacDonald TM, Caulfield M, Cruickshank JK, McInnes G, Sever P, Webb DJ, Salsbury J, Morant S, Ford I, Brown MJ. Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension. BMJ Open. 2015 Aug 7;5(8):e008951. doi: 10.1136/bmjopen-2015-008951.
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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.
Prof MJ Brown principal investigator
University of Cambridge
16 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Spironolactone, Bisoprolol and Doxazosin in people with Hypertension, Resistant to Conventional Therapy, run by University of Cambridge at 16 sites 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 0 inclusion and 25 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: status not confirmed, as of the sponsor's last update on 3 Jul 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites 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. Some participants in this study may receive a placebo. 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?
Results are not available in the source record.
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?
Treatment arm comparison according to home blood pressure measurement (time frame: 48 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 NCT02369081, which also lists 11 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 3 Jul 2015.