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Chronotherapy With Low-dose Aspirin for Primary Prevention (CARING)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT00725127
Recruitment Status : Recruiting
First Posted : July 30, 2008
Last Update Posted : February 15, 2019
Information provided by (Responsible Party):
Ramon C. Hermida, University of Vigo

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.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Drug: aspirin Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: 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 Start Date : October 2008
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : June 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Aspirin

Arm Intervention/treatment
Active Comparator: 1
100 mg/day ASA upon awakening.
Drug: aspirin
100 mg/day upon awakening for five years
Other Name: Aspirin on awakening

Active Comparator: 2
100 mg/day ASA at bedtime
Drug: aspirin
100 mg/day at bedtime for five years
Other Name: Aspirin at bedtime

Primary Outcome Measures :
  1. 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. [ Time Frame: Five years ]

Secondary Outcome Measures :
  1. 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). [ Time Frame: Five years ]
  2. 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). [ Time Frame: Five years ]
  3. 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. [ Time Frame: Five years ]
  4. To demonstrate that 100 mg/day ASA at bedtime offers a similar safety profile than 100 mg/day ASA upon awakening [ Time Frame: Five years ]
  5. To demonstrate that compliance with 100 mg/day ASA at bedtime is similar to that with 100 mg/day ASA upon awakening. [ Time Frame: Five years ]
  6. To evaluate, for all previous objectives, potential gender differences in the benefits of low-dose ASA for primary prevention. [ Time Frame: Five years ]
  7. To evaluate, for all previous objectives, potential differences in the benefits of low-dose ASA for primary prevention between patients with and without diabetes. [ Time Frame: Five years ]
  8. 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. [ Time Frame: Five years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00725127

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Contact: Ramon C Hermida, PhD 34986812148
Contact: Diana E Ayala, MD, PhD 34986812148

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CS Friol Recruiting
Friol, Lugo, Spain, 27220
Contact: Esther Gomez, MD    34639512093   
Principal Investigator: Esther Gomez, MD         
CS Baiona Recruiting
Baiona, Pontevedra, Spain, 36300
Contact: Francisco J Iglesias, MD    34986357239   
Principal Investigator: Francisco J Iglesias, MD         
CS Bueu Recruiting
Bueu, Pontevedra, Spain, 36930
Contact: Miguel A Aboal, MD    34986323313   
Principal Investigator: Miguel A Aboal, MD         
CS A Estrada Recruiting
La Estrada, Pontevedra, Spain, 26680
Contact: Luis Meijide, MD    34986573459   
Principal Investigator: Luis Meijide, MD         
Sub-Investigator: Mariana Carbon, MD         
Sub-Investigator: Maria C Garcia, MD         
Sub-Investigator: Francisco Romero, MD         
Sub-Investigator: Maria P Brea         
CS A Guarda Recruiting
La Guardia, Pontevedra, Spain, 36780
Contact: Juan J Crespo, MD    34986614450   
Principal Investigator: Juan J Crespo, MD         
Sub-Investigator: Raquel Fernandez, MD         
Sub-Investigator: Carmen M Fernandez, MD         
Sub-Investigator: Amelia Ferreras, MD         
Sub-Investigator: Manuel F Quintans, MD         
Sub-Investigator: Javier Rodriguez, MD         
Sub-Investigator: Pilar Rua         
Sub-Investigator: Aurelio Alvarez         
Sub-Investigator: Asuncion Cadilla         
Sub-Investigator: Carmen Outeiro         
Sub-Investigator: Carmen Soto-Davila         
CS Valmiñor Recruiting
Nigran, Pontevedra, Spain, 36250
Contact: Susana Hernaiz, MD    34655391498   
Principal Investigator: Susana Hernaiz, MD         
CS Panxón Recruiting
Nigrán, Pontevedra, Spain, 36340
Contact: Jose L Salgado, MD    34986368615   
Principal Investigator: Jose L Salgado, MD         
Sub-Investigator: Esperanza Parrado         
Sub-Investigator: Alfredo Pereira         
CS Tomiño Recruiting
Tomiño, Pontevedra, Spain, 36200
Contact: Evangelina Filloy, MD    34-986-623411   
Principal Investigator: Evangelina Filloy, MD         
Sub-Investigator: Adolfo T Perez, MD         
Sub-Investigator: Nieves Turienzo, MD         
Sub-Investigator: Dolores Cardalda         
Sub-Investigator: Jose C Varela         
Sub-Investigator: Francisca Vazquez         
Bioengineering & Chronobilogy Labs., University of Vigo Recruiting
Vigo, Pontevedra, Spain, 36200
Contact: Ramon C Hermida, PhD    34986812148   
Contact: Diana E Ayala, MD, PhD    34986812148   
Principal Investigator: Ramon C Hermida, PhD         
Principal Investigator: Diana E Ayala, MD, PhD         
Sub-Investigator: Artemio Mojon, PhD         
Sub-Investigator: Jose R Fernandez, PhD         
Sub-Investigator: Ignacio Alonso, PhD         
Sub-Investigator: Maria J Fontao         
Sub-Investigator: Rita Soler         
Sub-Investigator: Susana Serrano         
CS Calle Cuba Recruiting
Vigo, Pontevedra, Spain, 36202
Contact: Felisa Dominguez, MD    34986416226   
Principal Investigator: Felisa Dominguez, MD         
CS A Doblada Recruiting
Vigo, Pontevedra, Spain, 36205
Contact: Teresa Rios, MD    34986275121   
Principal Investigator: Teresa Rios, MD         
CS Coia Recruiting
Vigo, Pontevedra, Spain, 36209
Contact: Peregrina Eiroa, MD    34986209282   
Principal Investigator: Peregrina Eiroa, MD         
Sub-Investigator: Jesus C Nieto, MD         
CS Sardoma Recruiting
Vigo, Pontevedra, Spain, 36214
Contact: Manuel Dominguez, MD, PhD    34986416324   
Principal Investigator: Manuel Dominguez, MD, PhD         
CS Teis Recruiting
Vigo, Pontevedra, Spain, 36216
Contact: Pedro A Callejas, MD    34986374229   
Principal Investigator: Pedro A Callejas, MD         
CS Vilaboa Recruiting
Vilaboa, Pontevedra, Spain, 36141
Contact: Sonia M Gomara, MD    34986679229   
Principal Investigator: Sonia M Gomara, MD         
Sub-Investigator: Julio J Alvarez, MD         
Sub-Investigator: Margarita Estevez         
Sub-Investigator: Maria C Ferreira         
CS San Roque Recruiting
Vilagarcía De Arousa, Pontevedra, Spain, 36600
Contact: Envira Sineiro, MD    34986507448   
Principal Investigator: Elvira Sineiro, MD         
Sub-Investigator: Margarita Alvariño         
Sub-Investigator: Luis M Fontenla         
Sub-Investigator: Margarita Fraga, MD         
Sub-Investigator: Barbara Llovo         
Sub-Investigator: Rita Martinez         
Sub-Investigator: Santiago Santidrian, MD         
CS Fingoi Recruiting
Lugo, Spain, 27002
Contact: Carmen Castiñeira, MD    34982251035   
Principal Investigator: Carmen Castiñeira, MD         
Sub-Investigator: Maria C Aguado         
Sub-Investigator: Carmen Costa         
Sub-Investigator: Domingo D Garcia, MD         
Sub-Investigator: Bernardino Pardo, MD         
Sub-Investigator: Enrique J Vazquez, MD         
Complexo Hospitalario Universitario de Ourense Recruiting
Orense, Spain, 32005
Contact: Alfonso Otero, MD, PhD    34988385625   
Principal Investigator: Alfonso Otero, MD, PhD         
CS Lerez Recruiting
Pontevedra, Spain, 36156
Contact: Ana Moya, MD    34986871496   
Principal Investigator: Ana Moya, MD         
Sub-Investigator: Andres Ruiz, MD         
Sub-Investigator: Aurelia Constenla         
Sub-Investigator: Maria I Franco         
Sponsors and Collaborators
University of Vigo
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Study Director: Ramon C Hermida, PhD University of Vigo

Additional Information:
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Responsible Party: Ramon C. Hermida, Professor, University of Vigo Identifier: NCT00725127     History of Changes
Other Study ID Numbers: CARING-2008/1
First Posted: July 30, 2008    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Ramon C. Hermida, University of Vigo:
Primary prevention
Impaired fasting glucose
Type 2 diabetes
Total mortality
Myocardial infarction
Angina pectoris
Chronic kidney disease
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors