Comparison of Awakening Versus Bedtime Dosing of Aspirin in Pre-Hypertension or Mild Essential Hypertension

NCT ID: NCT00449618

Last Updated: 2009-01-05

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 23 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-31
• Study Completion Date: 2008-12-31

Brief Summary

Aspirin (ASA) has been shown to provide marked benefits in the prevention of cardiovascular events, although the potential direct effects of ASA on cardiovascular function remain uncertain. Previous studies have demonstrated that ASA is a potent antioxidative agent that markedly reduces vascular production of superoxide in normotensive and hypertensive rats. In addition, ASA was found to prevent angiotensin II-induced hypertension and cardiovascular hypertrophy, mainly through its antioxidative properties in preventing the generation of superoxide, although ASA apparently did not appear to reduce hypertensive levels of blood pressure (BP). Moreover, recent results have demonstrated that ASA induces nitric oxide (NO) release from vascular endothelium. No attention has been paid, so far, to potential administration time-dependent effects in these studies.

Previous laboratory animal and clinical trial research convincingly demonstrates administration time-dependent (with reference to circadian rhythms) effects of ASA. Thus, the effects of ASA upon lipoperoxides, β-adrenergic receptors, and BP in clinically healthy subjects depend on the circadian timing of ASA administration. Most important, the administration time-dependent influence of ASA on BP was previously demonstrated in a randomized trial on healthy women and in other independent, double-blind, randomized, placebo-controlled clinical trials. The first was conducted on clinically healthy subjects, a second one on normotensive and hypertensive subjects, a third one on pregnant women at high risk for preeclampsia and a fourth one in previously untreated patients with mild hypertension. The findings of these BP studies are consistent; the BP-lowering effect of low-dose ASA is achieved when administered at bedtime but not upon awakening.

In keeping with the chronopharmacological effects of ASA and the previous findings suggesting that ASA at low dose may have a potential beneficial effect on BP, this prospective, randomized, double-blind, crossover study will investigate the potential influence of ASA on BP in subjects with either high-normal BP or diagnosis of mild (grade 1) hypertension. The subjects will receive low-dose ASA or placebo at different times of the day according to their rest-activity cycle, and will be evaluated by 48-hour ambulatory BP monitoring before and after 6 weeks of pharmacologic intervention.

Detailed Description

This is a multi-center, prospective, randomized, four-arm, crossover study with double-blind design.

At Visit 1 (week -1) patients will be assessed for eligibility for study participation. Subjects will be advised that study entry cannot be fully determined until the completion of the screening period when all exclusion/inclusion criteria are entirely assessed. Subjects will perform Visit 2 as soon as their laboratory results of Visit 1 are available. At baseline (Visit 2/Day 1), a total of 300 subjects whose eligibility is confirmed will be randomized in a 1:1:1 ratio to one of the treatment groups (aspirin upon awakening, aspirin at bedtime, or placebo--half on awakening, half at bedtime). Subjects will start a first double-blind treatment phase with a total duration of 6 weeks. During this period the subjects will be receiving either aspirin 100 mg or placebo at two different circadian times (either after awakening from nighttime sleep or before bedtime) until the end of this study phase (Visit 3). After this first treatment phase, all subjects will undergo a 2-week wash-out phase with placebo. At Visit 4 (week 8), all subjects will be crossed-over in terms of the circadian time, but keeping their original treatment (either aspirin or placebo), and followed up for a second treatment phase of 6 weeks.

The study duration including all the phases will be 15 weeks.

Safety and efficacy will be assessed at the end of every treatment phase, i.e., at Visits 3 and 5. Safety will also be assessed by phone calls 2 weeks after the initiation of each active treatment phase (weeks 2 and 10). Subjects may be requested to attend the clinic for further evaluation on those weeks if they present any adverse effect.

Conditions

High-Normal Blood Pressure; Mild Essential Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

1

Aspirin 100 mg on awakening

Group Type: ACTIVE_COMPARATOR

Aspirin 100 mg

Intervention Type: DRUG

dose of 100 mg administered on awakening or at bedtime

Ambulatory blood pressure monitoring

Intervention Type: DEVICE

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

Chronotherapy, timing of medication

Intervention Type: PROCEDURE

Dosing on awakening versus bedtime

2

Aspirin 100 mg at bedtime

Group Type: ACTIVE_COMPARATOR

Aspirin 100 mg

Intervention Type: DRUG

dose of 100 mg administered on awakening or at bedtime

Ambulatory blood pressure monitoring

Intervention Type: DEVICE

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

Chronotherapy, timing of medication

Intervention Type: PROCEDURE

Dosing on awakening versus bedtime

3

Placebo on awakening

Group Type: PLACEBO_COMPARATOR

Ambulatory blood pressure monitoring

Intervention Type: DEVICE

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

Chronotherapy, timing of medication

Intervention Type: PROCEDURE

Dosing on awakening versus bedtime

Placebo

Intervention Type: DRUG

Use of placebo on awakening versus bedtime

4

Placebo at bedtime

Group Type: PLACEBO_COMPARATOR

Ambulatory blood pressure monitoring

Intervention Type: DEVICE

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

Chronotherapy, timing of medication

Intervention Type: PROCEDURE

Dosing on awakening versus bedtime

Placebo

Intervention Type: DRUG

Use of placebo on awakening versus bedtime

Interventions

Aspirin 100 mg

dose of 100 mg administered on awakening or at bedtime

Intervention Type: DRUG

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

Intervention Type: DEVICE

Chronotherapy, timing of medication

Dosing on awakening versus bedtime

Intervention Type: PROCEDURE

Placebo

Use of placebo on awakening versus bedtime

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• High-normal blood pressure
• Mild essential hypertension

Exclusion Criteria

• Moderate-severe hypertension.
• Secondary hypertension.
• Grade III/IV hypertensive retinopathy.
• Type 1 diabetes.
• Body mass index ≥ 35 kg/m2
• 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 ambulatory BP monitoring (ABPM).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hospital Clinico Universitario de Santiago

OTHER

Sponsor Role: collaborator

Bayer

INDUSTRY

Sponsor Role: collaborator

University of Vigo

OTHER

Sponsor Role: lead

Responsible Party

University of Vigo

Principal Investigators

Ramon C Hermida, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

University of Vigo

Locations

Centro de Salud de A Guarda

La Guardia, Pontevedra, Spain

Centro de Salud de Sardoma

Vigo, Pontevedra, Spain

Centro de Salud de A Doblada

Vigo, Pontevedra, Spain

C.S. Lérez

Pontevedra, , Spain

Hospital Clínico Universitario de Santiago

Santiago de Compostela, , Spain

Countries

Spain

Other Identifiers

2004-004987-65

Identifier Type: -

Identifier Source: secondary_id

2006-004652-21

Identifier Type: -

Identifier Source: secondary_id

ASA100-2004/2

Identifier Type: -

Identifier Source: org_study_id