Clinical trial NCT00725127: Chronotherapy with Low-dose Aspirin for Primary Prevention
Official title: Chronotherapy with Low-dose Aspirin for Primary Prevention of Cardiovascular Events in Subjects with Impaired Fasting Glucose or Diabetes (CARING Study).
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Type 2 Diabetes
Keywords: Aspirin
Chronotherapy
Primary prevention
Impaired fasting glucose
Type 2 diabetes
Total mortality
Myocardial infarction
Stroke
Angina pectoris
Chronic kidney disease
Lead sponsor: University of Vigo
Sponsor class: OTHER
First posted: 2008-07-30
Enrollment: 3200
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Brief summary:

Aspirin (ASA) has been shown to provide marked benefits in primary and secondary prevention of cardiovascular events. Substantial evidence suggests that low-dose ASA therapy should also be used as a primary prevention strategy in men and women with diabetes who are at high cardiovascular risk. On the other hand, there is current evidence on the potential benefits of low-dose ASA therapy in subjects with impaired fasting glucose, including those with metabolic syndrome. Most important, 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, b-adrenergic receptors, and blood pressure (BP) in clinically healthy subjects depend on the circadian timing of ASA administration. The administration-time-dependent influence of ASA on BP was previously demonstrated in a randomized trial on healthy women and other independent double-blind, randomized, placebo-controlled clinical trials conducted, first, 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; 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 exert a potential beneficial effect on BP, endothelium function and cardiovascular function, this prospective, randomized, parallel-arm study will investigate the potential influence of ASA on the primary prevention of cardiovascular, cerebrovascular and renal events in subjects with either impaired fasting glucose (≥ 100 mg/dl) or previous diagnosis of type 2 diabetes mellitus, who will receive low-dose ASA (100 mg/day) at different circadian times (upon awakening or at bedtime) in relation to their rest-activity cycle.


Eligibility criteria: Inclusion Criteria:

* Male or female subjects ≥ 50 years of age.
* Impaired fasting glucose (≥ 100 and \< 126 mg/dl) in the last available blood test prior (≤ 3 months) to randomization, or diagnosis of type 2 diabetes prior to randomization.
* All subjects must have at randomization a conventional clinic systolic/diastolic BP \< 160/100 mmHg.
* Informed consent to participate in the study prior to any study procedures.

Exclusion Criteria:

* Known or suspected contraindications, including history of allergy to ASA.
* Uncontrolled essential hypertension of Grade 2-3, i.e., systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg before randomization.
* Evidence of a secondary form of hypertension, to include coarctation of the aorta, hyperaldosteronism, renal artery stenosis, or pheochromocytoma.
* Known Keith-Wagener grade III or IV hypertensive retinopathy.
* History of hypertensive encephalopathy, cerebrovascular event, transient ischemic cerebral attack, or myocardial infarction prior to randomization.
* Type 1 diabetes mellitus.
* History of heart failure.
* Second or third degree heart block without a pacemaker.
* Concomitant unstable angina pectoris.
* Concomitant potentially life threatening arrhythmia or symptomatic arrhythmia.
* Clinically significant valvular heart disease.
* Evidence of hepatic disease as determined by one of the following: ALT or AST values \> 2 x UNL known before randomization, a history of hepatic encephalopathy, history of esophageal varices, or history of portocaval shunt.
* Diagnosis of chronic kidney disease prior to randomization.
* History of malignancy including leukemia and lymphoma (but not basal cell skin cancer), or any other severe, life-threatening disease within the past five years.
* Any previous history of a systemic autoimmune disease.
* History of drug or alcohol abuse within the last two years.
* Use of any disallowed concomitant medication.
* Inability to communicate and comply with all study requirements.
* Persons directly involved in the execution of this protocol.

Primary outcomes:
measure: To evaluate the effects of awakening vs. bedtime 100 mg/day ASA administration in subjects with impaired fasting glucose or type 2 diabetes on primary prevention of cardiovascular, cerebrovascular and renal fatal, and non-fatal events.
timeFrame: Five years
Secondary outcomes:
measure: To evaluate the effects of awakening vs. bedtime 100 mg/day ASA administration on primary prevention of cardiovascular fatal and non-fatal events (including cardiovascular death, myocardial infarction, angina pectoris, and coronary revascularization).
timeFrame: Five years
measure: To evaluate the effects of awakening vs. bedtime 100 mg/day ASA administration on primary prevention of cerebrovascular fatal and non-fatal events (including hemorrhagic stroke, ischemic stroke, and transient ischemic attack).
timeFrame: Five years
measure: To evaluate the effects of awakening vs. bedtime 100 mg/day ASA administration on primary prevention of chronic kidney disease and/or congestive heart failure, and/or peripheral artery disease.
timeFrame: Five years
measure: To demonstrate that 100 mg/day ASA at bedtime offers a similar safety profile than 100 mg/day ASA upon awakening
timeFrame: Five years
measure: To demonstrate that compliance with 100 mg/day ASA at bedtime is similar to that with 100 mg/day ASA upon awakening.
timeFrame: Five years
measure: To evaluate, for all previous objectives, potential gender differences in the benefits of low-dose ASA for primary prevention.
timeFrame: Five years
measure: To evaluate, for all previous objectives, potential differences in the benefits of low-dose ASA for primary prevention between patients with and without diabetes.
timeFrame: Five years
measure: To evaluate, for all previous objectives, potential differences in the benefits of low-dose ASA for primary prevention between subjects with and without metabolic syndrome.
timeFrame: Five years
Other outcomes:
Locations:
city: Friol
country: Spain
facility: CS Friol
state: Lugo
city: Baiona
country: Spain
facility: CS Baiona
state: Pontevedra
city: Bueu
country: Spain
facility: CS Bueu
state: Pontevedra
city: La Estrada
country: Spain
facility: CS A Estrada
state: Pontevedra
city: La Guardia
country: Spain
facility: CS A Guarda
state: Pontevedra
city: Nigran
country: Spain
facility: CS Valmiñor
state: Pontevedra
city: Nigrán
country: Spain
facility: CS Panxón
state: Pontevedra
city: Tomiño
country: Spain
facility: CS Tomiño
state: Pontevedra
city: Vigo
country: Spain
facility: Bioengineering & Chronobilogy Labs., University of Vigo
state: Pontevedra
city: Vigo
country: Spain
facility: CS Calle Cuba
state: Pontevedra
city: Vigo
country: Spain
facility: CS A Doblada
state: Pontevedra
city: Vigo
country: Spain
facility: CS Coia
state: Pontevedra
city: Vigo
country: Spain
facility: CS Sardoma
state: Pontevedra
city: Vigo
country: Spain
facility: CS Teis
state: Pontevedra
city: Vilaboa
country: Spain
facility: CS Vilaboa
state: Pontevedra
city: Vilagarcía De Arousa
country: Spain
facility: CS San Roque
state: Pontevedra
city: Lugo
country: Spain
facility: CS Fingoi
city: Orense
country: Spain
facility: Complexo Hospitalario Universitario de Ourense
city: Pontevedra
country: Spain
facility: CS Lerez
Study officials:
affiliation: University of Vigo
name: Ramon C Hermida, PhD
role: STUDY_DIRECTOR
References: