This is a national, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE), phase IV clinical trial with a parallel-group design involving two active treatment arms (triple versus dual therapy). The trial is registered in the Brazilian Clinical Trials Registry (ReBEC RBR-5p9w6vz; UTN U1111-1318-0831) and follows the SPIRIT recommendations.
It will be conducted across six Brazilian academic referral centers, coordinated by the Hypertension Unit of the Federal University of Goiás, and will enroll participants with arterial hypertension. Individual study duration is approximately 101 days, including an 11-day screening and a 90 ± 4-day treatment period. The study aims to compare the efficacy of two antihypertensive strategies in reducing peripheral and central BP, as well as in improving markers of arterial stiffness and endothelial function.
For this study, the inclusion and exclusion criteria will be widely disseminated among cardiologists at the participating institutions. Additionally, a thorough review of electronic patient databases will be conducted to identify potential candidates. Eligible participants will be contacted by telephone to schedule the initial visit at the research center.
The study will include three main visits: a screening/selection visit (V −1), a randomization visit (V0), and a final visit (V1). The study workflow is described in
During the screening visit, a researcher will explain the study objectives and procedures to potential participants. Individuals meeting the eligibility criteria and agreeing to participate will provide written informed consent by signing the informed consent form. The consent process will include a detailed explanation of the study's objectives, potential risks and benefits, and the participant's right to withdraw from the study at any time without penalty.
Following consent, a blood sample will be collected to assess renal function (creatinine and potassium) and pregnancy status (beta-human chorionic gonadotropin [β-hCG] in women of childbearing potential). Renal function will be evaluated by eGFR using the CKD-EPI equation.
Inclusion criteria for this study are as follows: (1) adults aged 18 years or older; (2) diagnosis of arterial hypertension currently managed with a low-dose dual drug combination, presenting with office systolic BP ≥140 mmHg and/or diastolic BP ≥ 90 mmHg.
Exclusion criteria are: (1) presence of any clinical or laboratory condition that, in the investigator's judgment, poses a risk to study participation or indicates uncontrolled chronic disease (e.g., diabetes mellitus with HbA1c > 9%); (2) history of alcohol or illicit drug use disorder within the preceding 2 years; (3) women of childbearing potential not using reliable contraception or who are pregnant, breastfeeding, or planning pregnancy during the study period; (4) known allergy or hypersensitivity to any study drug (olmesartan, hydrochlorothiazide, or amlodipine); (5) chronic kidney disease with a persistent eGFR < 30 mL/min/1.73 m², calculated using the CKD-EPI equation; (6) participation in another interventional clinical trial within the past 12 months, unless the investigator determines potential direct benefit to the patient.
The sample size was calculated based on the mean and standard deviation of systolic BP reduction reported by Oparil et al.
The study population will consist of participants with arterial hypertension, recruited from academic referral centers. The sample size was set at 336 individuals, considering a 10% margin for potential dropouts. Thus, the final sample should consist of approximately 300 participants, equally distributed into two groups of 150 subjects each.
After confirming all inclusion and exclusion criteria, peripheral and central BP measurements will be performed. Participants will then be randomized in a 1:1 ratio to one of the two treatment arms using a secure, web-based platform (Randomizer.org). Patients enrolled through the Hypertension Unit will undergo assessment of endothelial function by FMD.
Treatment will be maintained for 90 ± 4 days. Between visits V0 and V1, participants will be instructed to immediately report any suspected adverse events to the study team. All reported events will be recorded by the investigator in the medical record and coded according to Medical Dictionary for Regulatory Activities (MedDRA) terminology.
No washout will be implemented. Participants are hypertensive patients with uncontrolled BP despite ongoing dual therapy; therefore, temporary discontinuation of antihypertensive treatment could expose them to unnecessary clinical risk. The study was designed as a pragmatic comparison of treatment intensification strategies, reflecting real-world practice. Baseline assessments will be performed under stable therapy prior to randomization.
At the initial medical evaluation, the investigator will determine the appropriate therapeutic level (level 1 or level 2) for dose intensification based on predefined clinical criteria, including baseline BP values and prior antihypertensive therapy, in order to ensure patient safety and reflect routine clinical practice. This information will be provided to an unblinded member of the research team, who will perform the randomization and dispense the study medication. The investigator responsible for outcome assessments will remain blinded to the treatment allocation.
Intervention group (triple therapy): Participants will receive a fixed-dose combination of olmesartan/hydrochlorothiazide/amlodipine at a dose of 20/12.5/5 mg (level 1) or 40/12.5/5 mg (level 2), administered once daily for 90 ± 4 days.
Control group (dual therapy): Participants will receive a fixed-dose combination of olmesartan/hydrochlorothiazide at a dose of 20/12.5 mg (level 1) or 40/25 mg (level 2), administered once daily for 90 ± 4 days.
The primary outcomes of the study are the changes in systolic and diastolic BP, both peripheral and central, from baseline (V0) to day 90 (V1), and the change in arterial stiffness assessed by PWV using an Arteriograph AOP device.
The secondary outcomes include the proportion of participants achieving BP control, the change in endothelial function assessed by FMD using an UNEX EF 38G ultrasound system in a predefined subgroup.
As a safety outcome, renal function will be monitored through eGFR, calculated using the CKD-EPI equation based on serum creatinine, to evaluate the safety of the proposed interventions.
During the screening visit, after signing the informed consent form, peripheral blood samples will be collected for the measurement of creatinine, potassium, and β-hCG (in women of childbearing potential). These tests will provide baseline information on renal function and exclude pregnancy prior to randomization, ensuring participant safety before initiation of treatment. The study assessment schedule is summarized in
| Visit | Timing | Key assessments |
|---|---|---|
| V −1 (Screening) | Within 11 days before baseline | Eligibility check, consent, creatinine, potassium, β-hCG (women) |
| V0 (Randomization) | Day 0 | Baseline office BP, central BP, PWV, FMD (subgroup); randomization; dispensing medication |
| V1 (Final visit) | Day 90 ± 4 | Repeat all baseline measures; return of unused tablets for adherence check |
All data are entered into the REDCap electronic case-report form (eCRF). BP: blood pressure; FMD: flow-mediated dilation; PWV: pulse wave velocity; β-hCG: beta-human chorionic gonadotropin.
Central BP will be assessed at two time points, randomization (V0) and the final visit (V1), using an Arteriograph AOP device, a validated non-invasive system capable of simultaneously measuring central and peripheral BP, PWV, augmentation index, central pulse pressure, and amplified pulse pressure. These parameters provide comprehensive information on arterial resistance and compliance, allowing the evaluation of both hemodynamic and vascular effects of the study interventions over time.
Endothelial function will be evaluated by measuring FMD of the brachial artery in a predefined subgroup of participants. FMD will be assessed in a predefined subgroup of participants enrolled at the coordinating center, where certified equipment and trained personnel are available for standardized analysis. The subgroup is defined solely based on logistical feasibility, as only one center has the necessary infrastructure to perform this examination.
This technique is safe, non-invasive, and reproducible, and it reflects the functional status of the vascular endothelium.
Office BP will be measured at all study visits according to national and international guideline recommendations. Measurements will be taken by trained members of the research team using a validated semi-automatic oscillometric device (Omron HEM-7113). Three consecutive readings will occur after a 5-minute rest in a quiet environment, with the participant seated, legs uncrossed, and back supported. The mean of the last two readings will be used for analysis, ensuring greater accuracy and reproducibility across assessments.
Data will be recorded in the electronic case report form via the REDCap platform and exported for analysis using Stata version 14. Variables related to the effectiveness and safety of the interventions will be evaluated. Qualitative variables will be described as absolute and relative frequencies, while quantitative variables will be expressed as means and standard deviations or medians and interquartile ranges, depending on the distribution as assessed by the Kolmogorov–Smirnov test. Comparisons of baseline characteristics between groups will be performed using the chi-square test for qualitative variables and the Student's t-test or Mann–Whitney U test for quantitative variables, as appropriate.
The primary analysis will be conducted on the intention-to-treat population, defined as all randomized participants analyzed in the group to which they were assigned, regardless of adherence or protocol deviations. The primary outcomes (change in BP and PWV) will be compared between groups using an analysis of covariance (ANCOVA) model, with the baseline value of the respective outcome included as a covariate. A significance level of p < 0.05 will be adopted for all analyses. A per-protocol analysis will also be performed as a sensitivity analysis.
Study data will be securely recorded in REDCap and accessible only to authorized investigators. Participants will be identified by coded IDs, ensuring confidentiality. Records will be stored for ≥ 5 years after trial completion.
Participants or the public were not involved in designing, conducting, or reporting this trial.
The clinical trial will be conducted in accordance with the ethical principles of the Declaration of Helsinki, the guidelines of the ICH Good Clinical Practice Manual, and current Brazilian legislation, including Brazilian National Health Council (CNS) Resolution No. 466/12. The protocol was approved by the Research Ethics Committee of the Clinical Hospital of the Federal University of Goiás (CAAE: 80032924.8.0000.5078) on July 11, 2024.
All participants will sign the informed consent form prior to undergoing any study-related procedures. Potential risks, such as discomfort from venipuncture and BP measurements, will be minimized through the application of standardized techniques performed by properly trained professionals. The research team will be available full-time to provide continuous monitoring and appropriate management of any adverse events that may occur during the study.
Participants’ information will be coded to ensure confidentiality, and the data will be securely stored for a minimum period of 5 years, after which it will be properly discarded. There will be no cost to participants for any procedures performed within the scope of the study.
Participants will be instructed to report any adverse events throughout the 90 ± 4-day treatment. All events will be recorded and coded using MedDRA terminology. The research team will provide continuous clinical monitoring and appropriate management of adverse events.
Participants may discontinue the study treatment or be withdrawn from the trial under the following circumstances:
Serious adverse events: Occurrence of any serious adverse event related to the study medication or that, in the investigator's judgment, compromises participant safety.
Clinically relevant symptoms or clinical conditions considered by the investigator to be related to the study intervention include recurrent episodes of symptomatic hypotension requiring medical evaluation, therapeutic intervention, or adjustment of the study medication outside the protocol specifications, as well as uncontrolled hypertension defined as persistent systolic BP ≥ 180 mmHg or diastolic BP ≥ 110 mmHg despite confirmed adherence to the study medication, requiring additional therapeutic intervention.
Participant withdrawal: Withdrawal of informed consent at any time, without need for justification.
Investigator decision: If, in the investigator's clinical judgment, continued participation is not in the best interest of the participant.
Protocol non-adherence: Significant non-compliance with study procedures that may affect data integrity or participant safety.
Participants who discontinue treatment will be encouraged to complete outcome assessments whenever possible to preserve intention-to-treat analysis.
The early use of fixed-dose combinations of three antihypertensive agents for treatment intensification may provide more effective control of both peripheral and central BP compared to escalating dual-therapy doses. This strategy has the potential to improve key hemodynamic parameters, such as arterial compliance, which may indicate additional cardiovascular benefits beyond BP reduction alone. The overall rationale, intervention strategy, participating centers, and primary outcomes evaluated in the NEXT trial are summarized in
If the hypothesis of the superiority of triple therapy is confirmed, the results could underscore the need to revise current therapeutic approaches for the management of hypertension in patients requiring treatment intensification. This evidence may support changes in treatment guidelines, promoting more effective interventions with a measurable impact on cardiovascular morbidity and mortality.
This is a national, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE), phase IV clinical trial, providing high external validity while ensuring blinded outcome assessment.
The study evaluates both peripheral and central BP and includes arterial stiffness and endothelial function, which are advanced vascular biomarkers with proven prognostic value.
The design follows intention-to-treat analysis principles, strengthening the robustness and clinical applicability of results.
The protocol explores an early fixed-dose triple-combination strategy, potentially shifting the paradigm of hypertension treatment intensification and supporting future guideline updates.
The trial uses standardized, validated equipment (ArteriS AOP and UNEX EF 38G) across all sites to ensure methodological consistency and reproducibility.
The short follow-up period (90 days) may not capture long-term cardiovascular outcomes.
FMD will be measured only in a predefined subgroup, which may limit the generalizability of endothelial function findings.
The study population consists of patients under specialist care, which may reduce extrapolation to primary care settings.