Comparison of Awakening Versus Bedtime Dosing of Ramipril in Subjects With Essential Hypertension (HYCCRA)

This study has been completed.
Sponsor:
Collaborator:
King Pharmaceuticals is now a wholly owned subsidiary of Pfizer
Information provided by:
University of Vigo
ClinicalTrials.gov Identifier:
NCT00473174
First received: May 11, 2007
Last updated: September 1, 2009
Last verified: September 2009
  Purpose

This prospective chronotherapy trial will investigate the potential differing efficacy of ramipril in doses from 5 to 10 mg/day when administered, as a monotherapy either upon awakening from nighttime sleep or at bedtime, to diurnally active patients with grade 1 or 2 essential hypertension, who will be evaluated by 48-hour ABPM before and after pharmacologic intervention. The benefits from this trial may be extremely important, taking into account

  1. the high prevalence of non-dipping among patients with essential hypertension
  2. the need for a proper 24-hour BP control with particular emphasis on the regulation of nighttime resting BP mean
  3. the lacking information on the administration-time dependent effects on BP of ramipril, a widely used ACEI in doses of 5-10 mg/day.

Condition Intervention Phase
Hypertension
Drug: Ramipril
Device: ambulatory blood pressure monitoring
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Prospective, Randomized, Open Label, Blinded-endpoint Study to Compare Awakening Versus Bedtime Administration of 5-10 mg Ramipril in Terms of Systolic Blood Pressure Lowering Determined by ABPM in Subjects With Mild-to-moderate Essential

Resource links provided by NLM:


Further study details as provided by University of Vigo:

Primary Outcome Measures:
  • To demonstrate the efficacy of bedtime administration of ramipril in subjects with essential hypertension by testing the hypothesis of superior nocturnal SBP lowering in ABPM measurements compared with ramipril administered on awakening [ Time Frame: Three months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To demonstrate that ramipril at bedtime is more effective than ramipril upon awakening in terms of nocturnal DBP lowering in ABPM [ Time Frame: Three months ] [ Designated as safety issue: No ]
  • To demonstrate that ramipril at bedtime is not inferior to ramipril upon awakening in terms of 24-hour SBP/DBP lowering in ABPM [ Time Frame: Three months ] [ Designated as safety issue: No ]
  • To demonstrate that ramipril at bedtime is more effective than ramipril upon awakening in terms of increasing the diurnal/nocturnal SBP and DBP ratio determined by ABPM [ Time Frame: Three months ] [ Designated as safety issue: No ]
  • To demonstrate that ramipril at bedtime offers a similar safety profile than ramipril upon awakening [ Time Frame: Three months ] [ Designated as safety issue: Yes ]
  • To demonstrate that compliance with ramipril at bedtime is similar to compliance of ramipril upon awakening [ Time Frame: Three months ] [ Designated as safety issue: No ]

Enrollment: 120
Study Start Date: March 2007
Study Completion Date: December 2008
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Ramipril on awakening
Drug: Ramipril
Dosing on awakening versus bedtime
Device: ambulatory blood pressure monitoring
Blood pressure measured at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours
Active Comparator: 2
Ramipril at bedtime
Drug: Ramipril
Dosing on awakening versus bedtime
Device: ambulatory blood pressure monitoring
Blood pressure measured at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours

Detailed Description:

Several attributes of the cardiovascular system, including blood pressure (BP) and heart rate (HR), are characterized by predictable changes during the 24 hours for the most part in synchrony with the rest-activity cycle. During the past two decades specific features of the 24-hour BP pattern have been assessed as potential sources of injury to target tissues and as triggers of cardiac and cerebrovascular events in hypertensive patients. A growing number of studies indicate the reduction of the normal 10 to 20% sleep-time BP decline (non-dipper pattern) is associated with elevated risk of end-organ injury, particularly to the heart (left ventricular hypertrophy and myocardial infarct), brain (stoke) and kidney (albuminuria and progression to end-stage renal failure). Accordingly, there is growing interest in how to tailor the treatment of hypertensive patients according to their circadian BP pattern.

Clinical studies demonstrated a different effect of the ACEIs benazepril, enalapril, perindopril, quinapril, spirapril, and trandolapril when dosed in the morning versus the evening. A small trial on 33 patients with essential hypertension showed that a low dose of 2.5 mg/day ramipril more effectively reduced daytime BP when it was administered in the morning and more effectively reduced nighttime BP when it was administered in the evening. In the HOPE (Heart Outcomes Prevention Evaluation) study patients in the active treatment group received ramipril at bedtime. Results from a small substudy, in which hypertensive patients were evaluated with 24-hour ambulatory BP monitoring (ABPM), showed a marked BP reduction particularly during nighttime sleep, thereby reducing the prevalence of non-dippers. The authors concluded that the effects on cardiovascular morbidity and mortality seen with ramipril in the HOPE study may relate to its improved effect (i.e., increase in the diurnal/nocturnal BP ratio) on the non-dipping BP patterns.

In keeping with the documented administration-time dependent effects on BP regulation of other ACEI, this prospective chronotherapy trial will investigate the potential differing efficacy of ramipril in doses from 5 to 10 mg/day when administered, as a monotherapy either upon awakening from nighttime sleep or at bedtime, to diurnally active patients with grade 1 or 2 essential hypertension, who will be evaluated by 48-hour ABPM before and after pharmacologic intervention. The benefits from this trial may be extremely important, taking into account 1) the high prevalence of non-dipping among patients with essential hypertension, 2) the need for a proper 24-hour BP control with particular emphasis on the regulation of nighttime resting BP mean, and 3) the lacking information on the administration-time dependent effects on BP of ramipril, a widely used ACEI in doses of 5-10 mg/day.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Essential hypertension

Exclusion Criteria:

  • Severe hypertension.
  • Secondary hypertension.
  • Grade III/IV hypertensive retinopathy.
  • Type 1 diabetes.
  • Cerebrovascular or cardiovascular event during the last 12 months prior to inclusion.
  • Pregnant or lactating females.
  • History of malignancy within the past five years.
  • Shift workers.
  • Obstructive sleep apnea.
  • Use of disallowed concomitant medication.
  • Intolerant to ABPM.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00473174

Locations
Spain
Hospital Clínico Universitario de Santiago
Santiago de Compostela, Spain, 15701
Sponsors and Collaborators
University of Vigo
King Pharmaceuticals is now a wholly owned subsidiary of Pfizer
Investigators
Principal Investigator: Ramon C Hermida, PhD University of Vigo
  More Information

Publications:
Responsible Party: Ramon C. Hermida, University of Vigo
ClinicalTrials.gov Identifier: NCT00473174     History of Changes
Other Study ID Numbers: HYCCRA-2006/01, Eudract-2006-006107-37
Study First Received: May 11, 2007
Last Updated: September 1, 2009
Health Authority: Spain: Ministry of Health

Keywords provided by University of Vigo:
Ramipril
Ambulatory blood pressure monitoring
Chronotherapy
Circadian
Non-dipper

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Ramipril
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 11, 2014