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Clinical trials landscape

TL;DR — The hypertension pipeline has three live fronts and one conspicuous absence. First, aldosterone synthase inhibition has moved from phase 2 to outcome trials: baxdrostat is in a 5,000-participant phase 3 renal-outcome and cardiovascular-mortality trial (NCT06742723) and a 2,554-participant CKD trial in combination with dapagliflozin (NCT06268873). Second, RNA interference: zilebesiran, after KARDIA-1 and KARDIA-2, is in an 11,000-participant phase 3 outcome trial (NCT07181109) — the first hard-endpoint trial of a twice-yearly antihypertensive. Third, devices, where the sham-controlled programme continues (SPYRAL HTN-ON MED NCT02439775 completed; multi-organ denervation and renal-nerve-stimulation pilots recruiting). The absence is that no device trial has a cardiovascular-outcome endpoint, and the drug outcome trials are only now starting despite the class being over a decade old. All identifiers below were retrieved from the ClinicalTrials.gov v2 API on 2026-09-01; status and enrolment are as posted on that date and will drift.

Aldosterone synthase inhibitors

NCT Study Phase Status n Sponsor Completion
NCT04519658 CIN-107 (baxdrostat) in treatment-resistant hypertension (BrigHTN) 2 Completed 275 CinCor 2022-06
NCT06168409 Baxdrostat effect on ambulatory blood pressure in resistant hypertension (Bax24) 3 Completed 218 AstraZeneca 2025-08
NCT06268873 Baxdrostat + dapagliflozin in CKD 3 Active, not recruiting 2,554 AstraZeneca 2028-02
NCT06742723 Baxdrostat + dapagliflozin — renal outcomes and cardiovascular mortality 3 Recruiting 5,000 AstraZeneca 2029-12
NCT07222917 Dapagliflozin + baxdrostat vs baxdrostat 2 Recruiting 218 AstraZeneca 2027-05
NCT07686120 Baxdrostat in Chinese participants with uncontrolled hypertension 3 Not yet recruiting 286 AstraZeneca 2028-02
NCT06336356 Cortisol reserve on ACTH stimulation after baxdrostat 2 Completed 48 AstraZeneca 2024-12
NCT05769608 Lorundrostat in uncontrolled hypertension on standardised therapy 2 Completed 285 Mineralys 2025-01
NCT06153693 Lorundrostat in uncontrolled and resistant hypertension (Launch-HTN) 3 Completed 1,083 Mineralys 2025-01
NCT05968430 Lorundrostat open-label extension 3 Active, not recruiting 1,076 Mineralys 2027-05
NCT06150924 Lorundrostat added to SGLT2 inhibitors 2 Completed 60 Mineralys 2025-04
NCT06785454 Lorundrostat in obstructive sleep apnoea with hypertension 2 Completed 48 Mineralys 2025-12

Published results for these programmes are in pharmacological therapy (Freeman 2023, PMID 36342143; Flack 2025, PMID 40888730; Azizi 2026, PMID 41794437; Dwyer 2026, PMID 40913594; Laffin 2023, PMID 37690061; Laffin 2025, PMID 40267417; Saxena 2025, PMID 40587141). Two features are notable: the pairing with an SGLT2 inhibitor in the pivotal renal programme, which makes the comparison a combination rather than a monotherapy question; and the deliberate cortisol-reserve safety study, which addresses the class's principal mechanistic risk of adrenal insufficiency.

RNA interference against angiotensinogen

NCT Study Phase Status n Completion
NCT03934307 ALN-AGT01 (zilebesiran) first-in-human 1 Completed 124 2023-01
NCT04936035 Zilebesiran in mild-to-moderate hypertension (KARDIA-1) 2 Completed 394 2024-12
NCT05103332 Zilebesiran add-on to standard therapy (KARDIA-2) 2 Completed 663 2024-09
NCT06272487 Zilebesiran add-on in high cardiovascular risk (KARDIA-3) 2 Completed 375 2025-12
NCT06423352 Zilebesiran in Japanese patients 1/2 Completed 36 2025-07
NCT07181109 Zilebesiran outcome trial in hypertension with established CVD or high risk 3 Recruiting 11,000 2030-09
NCT07553442 ALN-AGT01 RVR in patients pretreated with zilebesiran 2 Recruiting 93 2028-10

The 11,000-participant outcome trial is the single most consequential ongoing study in hypertension pharmacology: a positive result would establish that a twice-yearly injectable can substitute for daily oral therapy, which addresses adherence structurally rather than behaviourally — see adherence and implementation. Published phase 1–2 results: (Desai 2023, PMID 37467498; Bakris 2024, PMID 38363577; Desai 2025, PMID 40434761).

Endothelin antagonism

NCT Study Phase Status n
NCT02603809 Aprocitentan dose-finding in essential hypertension 2 Completed 1,659
NCT03541174 PRECISION — aprocitentan in resistant hypertension 3 Completed 730
NCT04162366 Aprocitentan in uncontrolled hypertension 3 Withdrawn 0
NCT07635914 Aprocitentan (SYH9108) in resistant hypertension, China 3 Not yet recruiting 382

PRECISION's published results are in resistant and refractory hypertension (Schlaich 2022, PMID 36356632). The withdrawn NCT04162366 is worth recording: the broader uncontrolled-hypertension indication was not pursued.

Devices

NCT Study Type Status n Note
NCT02439749 SPYRAL HTN-OFF MED Pivotal Interventional, sham-controlled Completed 366 Published (Böhm 2020, PMID 32234534)
NCT02439775 SPYRAL HTN-ON MED Interventional, sham-controlled Completed 337 On-medication counterpart
NCT01534299 Global SYMPLICITY Registry DEFINE Observational Recruiting 5,000 Long-term real-world safety, to 2031-12
NCT07174622 Longitudinal real-world outcomes on Symplicity denervation Observational Recruiting 1,000 To 2029-06
NCT07081243 Symplicity China study Observational Recruiting 500 To 2031-12
NCT06907147 SPYRAL GEMINI pilot — multi-organ denervation Interventional Recruiting 175 To 2029-12
NCT07013929 Spyral InSight — renal nerve stimulation Interventional Recruiting 19 Mapping/response prediction
NCT06877221 Modulated ultrasound renal denervation Interventional Recruiting 204 Shenzhen Pulsecare
NCT07051811 Single-use intravascular ultrasound ablation for primary hypertension Interventional Recruiting 213 Lepu Medical
NCT07336433 SMART-IC pilot — mapping/selective denervation Interventional Not yet recruiting 15 SyMap
NCT07664787 Renal denervation for untreated grade I hypertension Interventional Not yet recruiting 20 Pilot, sham-controlled
NCT07114757 REDs — renal denervation after stroke Interventional Not yet recruiting 108 Subacute post-stroke

The device pipeline has shifted in two directions: toward earlier disease (untreated grade 1 hypertension, NCT07664787) and toward response prediction (renal nerve stimulation mapping, NCT07013929; multi-gene panel, NCT04060641). Neither addresses the outstanding question of hard outcomes. See device and interventional therapy.

Strategy, diet and implementation

NCT Study Status n Note
NCT04797403 Multifaceted patient-centred strategies for intensive control in minority populations Active, not recruiting 1,306 SPRINT-derived stepped-care protocol
NCT07228065 Fixed-dose combinations pragmatic randomised implementation trial Enrolling by invitation 720 Provider nudge / patient nudge / pharmacist virtual visit
NCT07679828 Polypill approach for multiple cardiovascular risk factors Not yet recruiting 8,252 To 2030-03
NCT05405920 Caribbean and South America team-based strategy to control hypertension Active, not recruiting 1,280 Team-based care vs enhanced usual care
NCT05031819 Nurse-led task-shifting for hypertension control in people living with HIV (Nigeria) Completed 960 —
NCT05846503 iHEART-SA quality and information management intervention Completed 4,378 South Africa
NCT06959134 Community-health-worker multicomponent intervention, Rwanda Completed 200 —
NCT07460882 Low-sodium salt substitute and serum potassium in hypertension Recruiting 607 Johns Hopkins; addresses the SSaSS safety gap
NCT07178964 Potassium-rich salt substitutes in kidney transplant recipients Not yet recruiting 80 Directly tests an excluded population
NCT05425030 Community-health-worker-led low-sodium salt substitute, Bangladesh Completed 618 —
NCT01960972 Population-level salt substitute launch, Peru Completed 2,376 Stepped-wedge
NCT03909659 Salt substitute in adults with hypertension, India Completed 502 —
NCT02105727 Changing population salt consumption, Lithgow, Australia Completed 991 Community-level

The two recruiting salt-substitute trials are directly aimed at the safety gap left by SSaSS — potassium levels in unselected users (NCT07460882) and use in transplant recipients (NCT07178964) — which is exactly the open question flagged in lifestyle and dietary management.

Primary aldosteronism

NCT Study Status n Note
NCT07727252 Early aldosterone blockade in subclinical primary aldosteronism (eplerenone vs placebo) Not yet recruiting 880 Phase 2/3; directly tests the subclinical-PA hypothesis (Hundemer 2024, PMID 38031887)
NCT07328230 Superselective adrenal arterial embolisation vs spironolactone in idiopathic hyperaldosteronism Recruiting 172 —
NCT03398785 Endovascular chemical ablation of the adrenal gland Completed 66 Phase 3
NCT07027254 PETAL — ⁶⁸Ga-pentixafor PET/CT and surgical outcomes Recruiting 90 Imaging alternative to adrenal vein sampling
NCT07688928 Finerenone vs spironolactone in primary aldosteronism Recruiting 104 —
NCT06578975 HT-ENDO — multiomics biomarker for endocrine hypertension diagnosis Unknown 250 Pragmatic diagnostic RCT
NCT05658705 Preoperative supine time for adrenal venous sampling Unknown 120 Procedural standardisation

NCT07727252 is the trial the secondary hypertension evidence most needs: a randomised test of whether treating subclinical renin-independent aldosteronism changes anything.

Renin-guided and frailty-specific strategy trials

NCT Study Status n What it settles
NCT03453268 RETREAT-FRAIL — antihypertensive step-down in frail nursing-home residents Completed 1,048 Mortality-based deprescribing trial; published (Benetos 2025, PMID 40879421)
NCT05047731 OptimizeBP — antihypertensive deprescribing in long-term care Completed 522 Frailty-specific deprescribing implementation/outcomes
NCT06108427 RETAME-PA — renin-guided MRA titration in primary aldosteronism Recruiting 58 Biochemical efficacy of renin as a titration target (Merabtine 2025, PMID 41419284)
NCT07687160 SPIRO-First — renin-guided first-line therapy Not yet recruiting 30 Feasibility of renin-guided initial treatment in primary care

These records correct two stale absences in the authored corpus. Frail people have been randomised to antihypertensive step-down, and renin-guided selection has been tested in a small comparative-effectiveness pilot (Egan 2016, PMID 27076600). What remains absent is a frailty-specific intensive-versus-standard target trial and a renin-guided trial powered for cardiovascular events.

Structural gaps in the pipeline

  1. No device outcome trial. Every renal-denervation trial has a blood-pressure endpoint (Azizi 2026, PMID 41870448).
  2. No randomised test of treating asymptomatic elevated pressure during a non-cardiac hospital admission with clinical outcomes was located in PubMed or ClinicalTrials.gov on 2026-09-01, despite three large observational studies suggesting harm (Anderson 2023, PMID 37252732; Rastogi 2021, PMID 33369614; Canales 2025, PMID 39585709). Older emergency-department trials and a 2025 telehealth-referral pilot do not test inpatient pressure treatment.
  3. No randomised test of a hypertension diagnostic threshold with clinical outcomes was located in the 2026-09-01 searches — the definitional disputes in guidelines are argued from modelling and diagnostic-accuracy studies.
  4. No frailty-specific intensive-versus-standard target trial was located on 2026-09-01. RETREAT-FRAIL randomised deprescribing rather than targets (Benetos 2025, PMID 40879421), leaving intact the narrower gap identified by Cochrane (Falk 2024, PMID 39688187).
  5. No trial that deliberately reduced visit-to-visit variability and tested a hard cardiovascular endpoint was located on 2026-09-01. Trials can change variability, but the outcome literature remains post hoc (Rothwell 2010, PMID 20226988).
  6. No head-to-head comparison among the CRHCP, barbershop and HOPE 4 implementation models was located on 2026-09-01; each beat its own usual-care comparator (Sun 2022, PMID 35500594; Victor 2018, PMID 29527973; Schwalm 2019, PMID 31488369).

Open questions

  • Will the zilebesiran outcome trial (NCT07181109) show that infrequent dosing translates pressure reduction into event reduction as efficiently as daily therapy?
  • Baxdrostat's pivotal renal programme pairs the drug with dapagliflozin (NCT06742723, NCT06268873); how will the contribution of aldosterone synthase inhibition be isolated?
  • Will any sponsor fund a renal denervation outcome trial, given that the pressure effect is now well characterised and modest? (Azizi 2026, PMID 41870448)
  • Does treating subclinical primary aldosteronism improve outcomes (NCT07727252), and if so does that redefine "essential" hypertension? (Hundemer 2024, PMID 38031887; Brown 2020, PMID 32449886)
  • Two recruiting trials address salt-substitute safety in excluded populations (NCT07460882, NCT07178964) — will they be large enough to change guidance for people with CKD?

References

Registry records were retrieved from the ClinicalTrials.gov v2 API on 2026-09-01 and are cited inline by NCT identifier. Journal references below are those cited in the text.

  1. Freeman MW, et al. Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med. 2023;388:395-405. PMID 36342143
  2. Flack JM, et al. Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension. N Engl J Med. 2025;393:1363-1374. PMID 40888730
  3. Azizi M, et al. Effect of baxdrostat on ambulatory blood pressure in patients with resistant hypertension (Bax24). Lancet. 2026;407:988-999. PMID 41794437
  4. Dwyer JP, et al. Efficacy and Safety of Baxdrostat in Participants with CKD and Uncontrolled Hypertension. J Am Soc Nephrol. 2026;37:299-311. PMID 40913594
  5. Flack JM, et al. Baxdrostat for uncontrolled and resistant hypertension: rationale and design of BaxHTN, BaxAsia, and Bax24. Hypertens Res. 2025;48:2911-2923. PMID 40850955
  6. Laffin LJ, et al. Aldosterone Synthase Inhibition With Lorundrostat: Target-HTN. JAMA. 2023;330:1140-1150. PMID 37690061
  7. Laffin LJ, et al. Lorundrostat Efficacy and Safety in Patients with Uncontrolled Hypertension. N Engl J Med. 2025;392:1813-1823. PMID 40267417
  8. Saxena M, et al. Lorundrostat in Participants With Uncontrolled and Treatment-Resistant Hypertension: Launch-HTN. JAMA. 2025;334:409-418. PMID 40587141
  9. Desai AS, et al. Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension. N Engl J Med. 2023;389:228-238. PMID 37467498
  10. Bakris GL, et al. RNA Interference With Zilebesiran for Mild to Moderate Hypertension: KARDIA-1. JAMA. 2024;331:740-749. PMID 38363577
  11. Desai AS, et al. Add-On Treatment With Zilebesiran for Inadequately Controlled Hypertension: KARDIA-2. JAMA. 2025;334:46-55. PMID 40434761
  12. Schlaich MP, et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION). Lancet. 2022;400:1927-1937. PMID 36356632
  13. Danaietash P, et al. Identifying and treating resistant hypertension in PRECISION. J Clin Hypertens. 2022;24:804-813. PMID 35686330
  14. Böhm M, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal). Lancet. 2020;395:1444-1451. PMID 32234534
  15. Kandzari DE, et al. The SPYRAL HTN Global Clinical Trial Program: rationale and design. Am Heart J. 2016;171:82-91. PMID 26699604
  16. Böhm M, et al. Rationale and design of SPYRAL HTN-OFF MED Pivotal and SPYRAL HTN-ON MED Expansion. Clin Res Cardiol. 2020;109:289-302. PMID 32034481
  17. Mauri L, et al. A multinational clinical approach to assessing the effectiveness of catheter-based ultrasound renal denervation: RADIANCE-HTN and REQUIRE designs. Am Heart J. 2018;195:115-129. PMID 29224639
  18. Azizi M, et al. Diagnosis and Management of Resistant Hypertension: A Review. JAMA. 2026;335:1428-1439. PMID 41870448
  19. Hundemer GL, et al. Subclinical Primary Aldosteronism and Cardiovascular Health. Circulation. 2024;149:124-134. PMID 38031887
  20. Brown JM, et al. The Unrecognized Prevalence of Primary Aldosteronism. Ann Intern Med. 2020;173:10-20. PMID 32449886
  21. Anderson TS, et al. Clinical Outcomes of Intensive Inpatient Blood Pressure Management in Hospitalized Older Adults. JAMA Intern Med. 2023;183:715-723. PMID 37252732
  22. Rastogi R, et al. Treatment and Outcomes of Inpatient Hypertension Among Adults With Noncardiac Admissions. JAMA Intern Med. 2021;181:345-352. PMID 33369614
  23. Canales MT, et al. As-Needed Blood Pressure Medication and Adverse Outcomes in VA Hospitals. JAMA Intern Med. 2025;185:52-60. PMID 39585709
  24. Falk JM, et al. Higher blood pressure targets for hypertension in older adults. Cochrane Database Syst Rev. 2024;12:CD011575. PMID 39688187
  25. Rothwell PM, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375:895-905. PMID 20226988
  26. Sun Y, et al. A village doctor-led multifaceted intervention for blood pressure control in rural China. Lancet. 2022;399:1964-1975. PMID 35500594
  27. Victor RG, et al. A Cluster-Randomized Trial of Blood-Pressure Reduction in Black Barbershops. N Engl J Med. 2018;378:1291-1301. PMID 29527973
  28. Schwalm JD, et al. A community-based comprehensive intervention to reduce cardiovascular risk in hypertension (HOPE 4). Lancet. 2019;394:1231-1242. PMID 31488369
  29. Joseph P, et al. The International Polycap Study-3 (TIPS-3): design and baseline characteristics. Am Heart J. 2018;206:72-79. PMID 30342297
  30. Chow CK, et al. Ultra-low-dose quadruple combination blood pressure-lowering therapy: the QUARTET randomized controlled trial protocol. Am Heart J. 2021;231:56-67. PMID 33017580
  31. Salam A, et al. TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension (TRIUMPH): study protocol. Am Heart J. 2014;167:127-32. PMID 24439972
  32. Ishani A, et al. Design of a pragmatic clinical trial embedded in the Electronic Health Record: the VA's Diuretic Comparison Project. Contemp Clin Trials. 2022;116:106754. PMID 35390512
  33. Sun Y, et al. Rationale and Design of a Cluster Randomized Trial of a Village Doctor-Led Intervention on Hypertension Control in China. Am J Hypertens. 2021;34:831-839. PMID 33605981
  34. Li KC, et al. Protocol for the economic evaluation of the China Salt Substitute and Stroke Study (SSaSS). BMJ Open. 2021;11:e045929. PMID 34285006
  35. Sheppard JP, et al. OPTiMISE: protocol for a randomised controlled non-inferiority trial. BMJ Open. 2018;8:e022930. PMID 30287610
  36. Carr M, et al. OPTIMISE2: protocol for a primary care based randomised controlled non-inferiority trial. Trials. 2026;27. PMID 41689048
  37. Franssen M, et al. Telemonitoring and/or self-monitoring of blood pressure in hypertension (TASMINH4): protocol. BMC Cardiovasc Disord. 2017;17:58. PMID 28193176
  38. Benetos A, et al. Reduction of Antihypertensive Treatment in Nursing Home Residents. N Engl J Med. 2025;393:1990-2000. PMID 40879421
  39. Egan BM, et al. Aldosterone Antagonists or Renin-Guided Therapy for Treatment-Resistant Hypertension: A Comparative Effectiveness Pilot Study in Primary Care. Am J Hypertens. 2016;29:976-983. PMID 27076600
  40. Merabtine A, et al. Renin-guided therapy with mineralocorticoid receptor antagonists in primary aldosteronism: feasibility study (RETAME-PA). BMJ Open. 2025;15:e111167. PMID 41419284