High-Normal Blood Pressure Clinical Trial
Official title:
A Prospective, Randomized, Multi-Center, Double-Blind Crossover Study to Compare Awakening Versus Bedtime Administration of 100 mg Aspirin or Placebo in Subjects With High-Normal Blood Pressure or Mild Essential Hypertension
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
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