- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02499822
REducing Blood Pressure Variability in Essential Hypertension With RAmipril vErsus Nifedipine GITS Trial (REVERENT)
September 29, 2021 updated by: Istituto Auxologico Italiano
Short - Medium and Long Term Blood Pressure Variability in Essential Hypertensive Patients Treated With Nifedipine GITS or Ramipril - a Randomized Trial
The purpose of this study is
- to compare the effects of nifedipine GITS and ramipril on blood pressure variability in subjects with elevated blood pressure variability.
- to assess whether the degree of treatment-induced changes in blood pressure variability, is related to the degree of regression (or progression) of organ damage in heart, kidneys and carotid arteries.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
Elevated blood pressure variability (BPV) is associated with adverse cardiovascular outcomes and organ damage in hypertensive subjects.
An antihypertensive treatment able to reduce BPV independently of BP lowering effect might thus provide additional protection in terms of cardiovascular risk in subjects with elevated BPV, independently on its effect of BP itself.
However, data on the effects of different classes of antihypertensive drugs on BPV are limited and inconsistent.
Some studies have suggested a possible usefulness of calcium antagonists in this setting.
Based on the above considerations the investigators hypothesize that a calcium channel blocker nifedipine GITS, will provide a greater BPV lowering effect, when compared with ramipril, independently from the reduction in mean BP level.
Based on the above considerations, the primary objective of this study is to compare the effects of nifedipine GITS and ramipril on different estimates of BPV (24 h BPV, home BPV, and visit-to-visit BPV) in subjects with elevated BPV.
The secondary objective is to assess whether the degree of treatment-induced changes in BPV, is related to the degree of regression (or progression) of organ damage, after accounting for mean BP reduction by treatment.
Study Type
Interventional
Enrollment (Actual)
168
Phase
- Phase 4
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Shanghai, China
- Centre for Epidemiological Studies and Clinical Trials, Ruijin Hospital Shanghai Institute of Hypertension, Shanghai Jiaotong University School of Medicine
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Athens, Greece
- Hypertension Center, Third University Department of Medicine, Sotiria Hospital
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Milan, Italy
- Istituto Auxologico Italiano
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
35 years to 75 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Male and female subjects
- Age 35-75 years
- Clinic systolic BP ≥140 mmHg and/or diastolic BP ≥ 90 mmHg (under no antihypertensive treatment)
- Daytime BP on ambulatory BP monitoring (ABPM) ≥135 mmHg systolic and/or ≥85 mmHg diastolic (under no antihypertensive treatment)
- Home SBP standard deviation (SD) >7 mmHg and/or daytime ambulatory SBP SD >12 mmHg
- Patients may be included if untreated or, if treated with one antihypertensive drug or two drugs in low doses, after 2 weeks' washout period
- Written informed consent to participate in the study
Exclusion Criteria:
- Subjects treated with ≥ 2 antihypertensive drugs (except those on two drugs in low doses)
- Treated subjects with on-treatment clinic BP ≥160 mmHg systolic and/or 100 mmHg diastolic
- Treated antihypertensive subjects in whom withdrawal of treatment is deemed unethical by the investigator (e.g. because of the existence of compelling indications other than hypertension for continuous use of previously used antihypertensive agent)
- Contraindications to study treatments as detailed in the relative Summaries of Medical Product Characteristics for ramipril (hypersensitivity to ramipril or any of the excipients or any other ACE inhibitor, history of angioneurotic oedema, extracorporeal treatments leading to contact of blood with negatively charged surfaces, significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney, second and third trimesters of pregnancy, lactation, haemodynamically relevant renal artery stenosis, hypotensive or haemodynamically unstable patients) or nifedipine GITS (known hypersensitivity to nifedipine or to any of the excipients, pregnancy before week 20 and during breastfeeding, cardiovascular shock, concomitant treatment with rifampicin, patients with a Kock pouch)
- Cardiovascular diseases other than hypertension (coronary heart disease, heart failure or left ventricular systolic dysfunction of any degree, atrial fibrillation or frequent arrhythmias, valvular or congenital heart disease, cardiomyopathies, cerebrovascular disease, peripheral artery disease, aortic aneurysm)
- Chronic kidney disease
- Suspected or confirmed secondary hypertension
- Diabetes mellitus
- Subjects with conditions other than those mentioned above, where compelling indications for the use of any specific class of antihypertensive medication exist, according to current (e.g. European Society of Cardiology) guidelines
- Other conditions deemed relevant by the investigator (including respiratory disorders, liver disease, renal disease, thyroid disorders)
- BMI ≥35 kg/m2
- Known severe obstructive sleep apnea (apnea-hypopnea index > 30 or use of CPAP)
- Premenopausal women not using effective contraceptive methods
- Elevated probability of noncompliance with the study procedures
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Nifedipine GITS 30 mg slow release
Nifedipine GITS 30 mg slow release in tablets.
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Commercially available drug formulations are used.
Study medication will be assumed in a single morning (7-10 a.m.) administration per os.
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Experimental: Ramipril 10 mg
Ramipril 10 mg in tablets.
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Commercially available drug formulations are used.
Study medication will be assumed in a single morning (7-10 a.m.) administration per os.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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Variability (standard deviation) of home systolic blood pressure at final visit
Time Frame: After 10 weeks of study treatment
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After 10 weeks of study treatment
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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Variability (standard deviation) of home diastolic blood pressure measured at final visit
Time Frame: At baseline and after 10 weeks of study treatment
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At baseline and after 10 weeks of study treatment
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Short term 24h variability of systolic blood pressure at final visit (24h weighted standard deviation)
Time Frame: At baseline and after 10 weeks of study treatment
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At baseline and after 10 weeks of study treatment
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Short term 24h variability of diastolic blood pressure at final visit (24h weighted standard deviation)
Time Frame: At baseline and after 10 weeks of study treatment
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At baseline and after 10 weeks of study treatment
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Visit-to-visit variability (standard deviation) of systolic blood pressure assessed over the three last visits
Time Frame: At baseline and after 6, 8 and 10 weeks of study treatment
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At baseline and after 6, 8 and 10 weeks of study treatment
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Visit-to-visit variability (standard deviation) of diastolic blood pressure assessed over the three last visits
Time Frame: At baseline and after 6, 8 and 10 weeks of study treatment
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At baseline and after 6, 8 and 10 weeks of study treatment
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Mean 24 hour systolic blood pressure at final visit
Time Frame: At baseline and after 10 weeks of study treatment
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At baseline and after 10 weeks of study treatment
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Mean 24 hour diastolic blood pressure at final visit
Time Frame: At baseline and after 10 weeks of study treatment
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At baseline and after 10 weeks of study treatment
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Sokolow index at the end of the extension study
Time Frame: At baseline and after 12 months of study treatment
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At baseline and after 12 months of study treatment
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Cornell voltage duration index at the end of the extension study
Time Frame: At baseline and after 12 months of study treatment
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At baseline and after 12 months of study treatment
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Left ventricular mass index at the end of the extension study
Time Frame: At baseline and after 12 months of study treatment
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At baseline and after 12 months of study treatment
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Microalbuminuria (albumin-creatinine ratio) at the end of the extension study
Time Frame: At baseline and after 12 months of study treatment
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At baseline and after 12 months of study treatment
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Estimated glomerular filtration rate (eGFR, by CKD-EPI formula) at the end of the extension study
Time Frame: At baseline and after 12 months of study treatment
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At baseline and after 12 months of study treatment
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Carotid-femoral pulse wave velocity (cfPWV) at the end of the extension study
Time Frame: At baseline and after 12 months of study treatment
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At baseline and after 12 months of study treatment
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Gianfranco Parati, MD, Istituto Auxologico Italiano - Milan, Italy
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Rothwell PM, Howard SC, Dolan E, O'Brien E, Dobson JE, Dahlof B, Sever PS, Poulter NR. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010 Mar 13;375(9718):895-905. doi: 10.1016/S0140-6736(10)60308-X.
- Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013 Jul;31(7):1281-357. doi: 10.1097/01.hjh.0000431740.32696.cc. No abstract available.
- Parati G, Ochoa JE, Lombardi C, Bilo G. Assessment and management of blood-pressure variability. Nat Rev Cardiol. 2013 Mar;10(3):143-55. doi: 10.1038/nrcardio.2013.1. Epub 2013 Feb 12. Erratum In: Nat Rev Cardiol. 2014 Jun;11(6):314.
- Liu JG, Xu LP, Chu ZX, Miao CY, Su DF. Contribution of blood pressure variability to the effect of nitrendipine on end-organ damage in spontaneously hypertensive rats. J Hypertens. 2003 Oct;21(10):1961-7. doi: 10.1097/00004872-200310000-00025.
- Webb AJ, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet. 2010 Mar 13;375(9718):906-15. doi: 10.1016/S0140-6736(10)60235-8.
- Ushigome E, Fukui M, Hamaguchi M, Tanaka T, Atsuta H, Ohnishi M, Oda Y, Yamazaki M, Hasegawa G, Nakamura N. Beneficial effect of calcium channel blockers on home blood pressure variability in the morning in patients with type 2 diabetes. J Diabetes Investig. 2013 Jul 8;4(4):399-404. doi: 10.1111/jdi.12052. Epub 2013 Mar 4.
- Wang JG, Yan P, Jeffers BW. Effects of amlodipine and other classes of antihypertensive drugs on long-term blood pressure variability: evidence from randomized controlled trials. J Am Soc Hypertens. 2014 May;8(5):340-9. doi: 10.1016/j.jash.2014.02.004. Epub 2014 Feb 15.
- Levi-Marpillat N, Macquin-Mavier I, Tropeano AI, Parati G, Maison P. Antihypertensive drug classes have different effects on short-term blood pressure variability in essential hypertension. Hypertens Res. 2014 Jun;37(6):585-90. doi: 10.1038/hr.2014.33. Epub 2014 Mar 27.
- Mancia G, Facchetti R, Parati G, Zanchetti A. Visit-to-visit blood pressure variability in the European Lacidipine Study on Atherosclerosis: methodological aspects and effects of antihypertensive treatment. J Hypertens. 2012 Jun;30(6):1241-51. doi: 10.1097/HJH.0b013e32835339ac.
- Matsui Y, O'Rourke MF, Hoshide S, Ishikawa J, Shimada K, Kario K. Combined effect of angiotensin II receptor blocker and either a calcium channel blocker or diuretic on day-by-day variability of home blood pressure: the Japan Combined Treatment With Olmesartan and a Calcium-Channel Blocker Versus Olmesartan and Diuretics Randomized Efficacy Study. Hypertension. 2012 Jun;59(6):1132-8. doi: 10.1161/HYPERTENSIONAHA.111.189217. Epub 2012 Apr 30.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
October 1, 2015
Primary Completion (Actual)
July 3, 2020
Study Completion (Actual)
November 1, 2020
Study Registration Dates
First Submitted
July 10, 2015
First Submitted That Met QC Criteria
July 14, 2015
First Posted (Estimate)
July 16, 2015
Study Record Updates
Last Update Posted (Actual)
September 30, 2021
Last Update Submitted That Met QC Criteria
September 29, 2021
Last Verified
September 1, 2021
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Hypertension
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Vasodilator Agents
- Enzyme Inhibitors
- Protease Inhibitors
- Membrane Transport Modulators
- Calcium-Regulating Hormones and Agents
- Reproductive Control Agents
- Calcium Channel Blockers
- Angiotensin-Converting Enzyme Inhibitors
- Tocolytic Agents
- Nifedipine
- Ramipril
Other Study ID Numbers
- 09F401
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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