Effect of an energy-restricted Mediterranean diet, physical activity and behavioral intervention on the primary prevention of cardiovascular disease

Plain English Summary

Background and study aims
Predimed-plus is a study that will measure how successful an intensive weight-loss lifestyle intervention involving an energy-restricted (calorie controlled) Mediterranean diet (Mediet), promotion of physical activity and behavioral support (intervention group) is compared to a less intensive intervention (control group) also involving a Mediterranean diet but no energy restrictions and no lifestyle or physical activity programmes. The aim is to see whether the more intensive intervention is more likely to result in long-term weight-loss, a reduced risk of developing cardiovascular disease and a greater quality of life for older people with metabolic syndrome (the medical term for the combination of diabetes, high blood pressure and obesity) than when adopting the Mediterranean diet alone.

Who can participate?
Men aged 55 to 75 years and women aged 60-75 years with a body mass index (BMI) ≥27 to <40 kg/m2, no cardiovascular disease and with metabolic syndrome.

What does the study involve?
Participants are randomly allocated into one of two groups. The low-intensity intervention group are given a non-energy restricted Mediet. The intensive intervention group are given an energy-restricted Mediet, physical activity and behavioral support and weight loss goals. Changes in body weight or any instance of cardiovascular disease is recorded once a year, as well as other variables of lifestyle, educational achievement, history of illnesses, medication use, physical activity, dietary habits, and electrocardiography, blood pressure, and anthropometric measurements, neuropsychological and quality of life evaluations, and collection of fasting blood samples and morning spot urine.

What are the possible benefits and risks of participating?
Not provided at registration

Where is the study run from?
Human Nutrition Unit, University Hospital of Sant Joan de Reus, Department of Biochemistry and Biotechnology, Pere Virgili Institute for Health Research, Rovira i Virgili University, Reus, Spain (IP: Jordi Salas-Salvadó); Department of Preventive Medicine and Public Health, University of Navarra-Navarra Institute for Health Research (IdiSNA), Pamplona, Spain (IP: Miguel Ángel Martínez-González); Department of Preventive Medicine, University of Valencia, University Jaume I, Conselleria de Sanitat de la Generalitat Valenciana, Valencia, Spain (IP: Dolores Corella); Cardiovascular Risk and Nutrition Research Group, Servicio de Endocrinología, IMIM (Hospital del Mar Medical Research Institute), Barcelona. Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain (IP: Montse Fitó); Nutritional Epidemiology Unit, Miguel Hernandez University, ISABIAL-FISABIO, Alicante, Spain (IP: Jesús Vioque); Hospital Son Espases (HUSE) and Institute for Health Research Illes Balears (IdISBa), Palma de Mallorca, Spain (IP: Dora Romaguera); Department of Nutrition, Food Sciences, and Physiology, Center for Nutrition Research, University of Navarra, Pamplona, Spain (IP: J.Alfredo Martínez); Department School of Nursing, School of Health Sciences, University of Málaga-IBIMA, Málaga, Spain (IP: Julia Wärnberg); Lipids and Atherosclerosis Unit, Department of Internal Medicine, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain (IP: Jose lopez-Miranda); Department of Internal Medicine, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain (IP: Ramon Estruch); Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain (IP: Aurora Bueno-Cavanillas); OSI ARABA, University Hospital Araba, Vitoria, Spain (IP: Fernando Arós); Research Group on Community Nutrition & Oxidative Stress, University of Balearic Islands, Palma de Mallorca, Spain (IP: J.Antonio Tur); Virgen de la Victoria Hospital, University of Málaga, Málaga, Spain (IP: Francisco J. Tinahones); University of Las Palmas de Gran Canaria, Las Palmas, Spain (IP: Lluis Serra-Majem); Biomedicine Institute (IBIOMED); University of León, and Primary Health Care Management of León (Sacyl), León, Spain (IP: Vicente Martín);Department of Family Medicine, Research Unit, Distrito Sanitario Atención Primaria Sevilla, Sevilla, Spain (IP: José Lapetra); Department of Endocrinology, Foundation Jiménez-Díaz, Madrid, Spain (IP: Clotilde Vázquez); Lipids and Vascular Risk Unit, Internal Medicine, University Hospital of Bellvitge, Hospitalet de Llobregat, Barcelona, Spain (IP: Xavier Pintó); Department of Endocrinology, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain (IP: Josep Vidal); Nutritional Genomics and Epigenomics Group, Institute IMDEA-Food, CEI UAM+CSIC, Madrid, Spain (IP: Lidia Damiel); Division of Preventive Medicine, University of Jaén, Jaén, Spain (IP: Miguel Delgado-Rodríguez); Department of Endocrinology and Nutrition, Institute for Health Research Hospital Clínico San Carlos (IdISSC), Madrid, Spain (IP: Pilar Matias).

When is the study starting and how long is it expected to run for?
October 2013 to May 2020

Who is funding the study?
Carlos III Health Institute (several grants, Coordinator, jordi.salas@urv.cat), and the European Research Council (Advanced Research Grant to Miguel A. Martínez-Gonzlaéz, mamartinez#unav.es)

Who is the main contact?
1. Dr Jordi Salas-Salvadó
jordi.salas@urv.cat
2. Miguel A. Martínez-Gonzlaéz
mamartinez@unav.es

Trial website

http://www.predimedplus.com

Type

Scientific

Primary contact

Dr Jordi Salas-Salvadó

ORCID ID

http://orcid.org/0000-0003-2700-7459

Contact details

Human Nutrition Unit Universitat Rovira i Virgili. C/ Sant Llorenç 21/ Dpto Medicina Preventiva y Salud Pública / Universidad de Navarra. Irunlarrea 1 / Internal Medicine Department Hospital Clinic of Barcelona. Villarroel
170
jordi.salas@urv.cat/ mamartinez@unav.es / restruch@clinic.ub.es
Reus (Tarragona) / Pamplona / Barcelona
43201 / 31008 / 08036
Spain
+34 (0)977759313
jordi.salas@urv.cat

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

ERC 340918 & FIS PI13/00462

Scientific title

Cardiovascular effect of an intensive weight-loss lifestyle intervention based on an energy-restricted traditional Mediterranean diet (Mediet) together promotion of physical activity and behavioral support in comparison with a less intensive program using Mediet, but without energy restriction or other lifestyle changes: a randomized field trial

Acronym

PREDIMED-Plus

Study hypothesis

An intensive lifestyle intervention with an energy-restricted Mediet, promotion of physical activity, and behavioral support in comparison with Mediet alone, without other lifestyle changes, will reduce the risk of major cardiovascular outcomes (myocardial infarction, stroke, and cardiovascular mortality), be effective for weight loss and long-term weight-loss maintenance, and improve quality of life in older individuals with metabolic syndrome.

Ethics approval

Institutional Review Board of all participating centers

Study design

Randomized controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Prevention

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Cardiovascular disease

Intervention

Participants are randomly assigned into two equal groups:
1. Low-intensity intervention with a 14-item Mediet (with supplemental extra-virgin olive oil and tree nuts given at no cost for the participant) without energy-restriction, without weight loss goals and without a physical activity program.
2. Intensive intervention with an energy-restricted Mediet (with supplemental extra-virgin olive oil and tree nuts given at no cost for the participant) together with promotion of physical activity, behavioral support and weight loss goals.

All participants will follow a 4-week run-in period to ensure compliance with the protocol. If compliant, they will be randomly allocated to one of the 2 interventions.

Added 04/06/2018:
Each recruiting center randomly assigned candidates in a 1:1 ratio to either the intervention or the control group. Randomisation was performed using a centrally controlled, computer-generated random-number internet-based system with stratification by center, sex, and age categories (<65, 65-70, >70-years) and using blocks of 6 participants. Couples living in the same household who both met eligibility criteria were randomized together as clusters. Consequently the second member of each household was not individually randomised. In the specific cases of couples in which the spouse was recruited at different times, the last spouse entering the study was assigned (not randomised) to the same study arm than his/her partner.

Intervention type

Other

Phase

Not Applicable

Drug names

Primary outcome measure

Current primary outcome measures as of 04/06/2018:
1. A composite endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke
2. Changes in body weight
All participants are evaluated yearly for primary and secondary endpoints

Previous primary outcome measures:
1. A composite endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke
2. Changes of body weight
3. Changes in quality of life
All participants are evaluated yearly for primary and secondary endpoints

Secondary outcome measures

Current secondary outcome measures as of 04/06/2018:
Death of any cause, changes in waist circumference, and incidence of acute coronary syndrome (unstable angina), coronary revascularization (percutaneous or surgical), atrial fibrillation, peripheral artery disease, heart failure, type 2 diabetes mellitus and its complications, dementia, Parkinson disease, major unipolar depression, osteoporotic fractures, cholelithiasis or cholecystectomy, symptomatic gout, transient ischemic attack, cataract, venous thromboembolism or cancer (breast, prostate, lung, colorectal, or stomach).

Other intermediate outcomes are changes in:
1. Blood pressure
2. Fasting blood sugar
3. Serum lipid profile
4. Markers of inflammation
5. Other intermediate markers of cardiovascular risk
6. Overall diet and nutrient intake
7. Medication use
8. ECGs
9. Cognitive function, quality of life, and psychological and neuropsychological scores

All participants are evaluated yearly for primary and secondary endpoints

Previous secondary outcome measures:
Death of any cause and incidence of angina leading to a revascularization procedure, atrial fibrillation, peripheral artery disease, heart failure, diabetes mellitus and its complications, dementia, Parkinson disease, major unipolar depression, osteoporotic fractures, cholelithiasis or cholecystectomy, symptomatic gout or cancer (breast, prostate, lung, colorectal, or stomach).

Other intermediate outcomes are changes in:
1. Blood pressure
2. Fasting blood sugar
3. Serum lipid profile
4. Markers of inflammation
5. Other intermediate markers of cardiovascular risk
6. Overall diet and nutrient intake

All participants are evaluated yearly for primary and secondary endpoints

Overall trial start date

01/10/2013

Overall trial end date

01/05/2020

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Participants are community-dwelling high-risk people.
2. Men aged 55 to 75 years and women aged 60 to 75 years
3. Body mass index (BMI) between ≥ 27 y < 40 kg/m2
4. No cardiovascular disease (CVD) at enrolment
5. Who fulfil at least 3 of the criteria for the metabolic syndrome (Alberti et al., 2009). Diabetic participants will represent not more than 25% of the final sample.

Participant type

Patient

Age group

Senior

Gender

Both

Target number of participants

6000

Participant exclusion criteria

Current exclusion criteria as of 04/06/2018:
1. Illiteracy or inability/unwillingness to give written informed consent or communicate with study staff
2. Institutionalization (the participant is a permanent or long-stay resident in a nursing home)
3. Documented history of previous CVD, including angina; myocardial infarction; coronary revascularization procedures; stroke (either ischemic or haemorrhagic, including transient ischemic attacks); symptomatic peripheral artery disease; ventricular arrhythmia; uncontrolled atrial fibrillation; congestive heart failure (new york heart association class II or IV); hypertrophic cardiomyopathy; or history of aortic aneurysm
4. Active malignant cancer or history of malignancy within the last 5 years (with exception of non-melanoma skin cancer)
5. Impossibility to follow the recommended diet (for religious reasons, swallowing disorders, or other reasons) or to perform physical activity
6. A low predicted likelihood to change dietary habits according to the Prochaska and Diclemente stages of change model (Nigg et al., 1999)
7. Inability to follow the scheduled intervention visits (institutionalized individuals, lack of autonomy, unable to walk, lack of a stable address, travel plans, or other reason that render the subject unable to attend scheduled visits)
8. Body weight loss > 5 kg during the 6 months prior to the screening visit
9. Intention to undergo bariatric surgery in the next 6 months
10. History of very low-caloric diet during the 6 months prior to the screening visit
11. Prior bariatric surgery or indication and willingness to receive a surgical procedure for weight loss in the near future
12. History of inflammatory bowel disease or small bowel resection
13. Obesity of known endocrine origin (with the exception of treated hypothyroidism)
14. Food allergy to any Mediet component
15. Immunodeficiency or HIV-positive status
16. Liver cirrhosis or chronic renal failure
17. Serious psychiatric disorders: schizophrenia, bipolar disease, eating disorders, depression with hospitalization in past 6 months
18. Any severe co-morbid condition with less than 24-month life expectancy
19. Alcohol abuse or addition (total daily alcohol intake >50 g) or drug abuse within the past 6 months
20. History of major organ transplantation
21. Concurrent therapy with immunosuppressive drugs or cytotoxic agents
22. Current treatment with systemic corticosteroids
23. Current use of weight loss medication
24. Concurrent participation in another randomised clinical trial
25. Patients with an acute infection or inflammation (i.e., pneumonia) are allowed to participate in the study 3 months after resolution of their condition
26. Any other condition that may interfere with the completion of the study protocol

Previous exclusion criteria:
1. Unable or unwilling to give written informed consent or communicate with study staff
2. Documented history of previous CVD, including angina; myocardial infarction; coronary revascularization procedures; stroke (either ischemic or haemorrhagic, including transient ischemic attacks); symptomatic peripheral artery disease; ventricular arrhythmia; uncontrolled atrial fibrillation; congestive heart failure (new york heart association class II or IV); hypertrophic cardiomyopathy; or history of aortic aneurysm
3. Active malignant cancer or history of malignancy within the last 5 years (with exception of non-melanoma skin cancer)
4. Impossibility to follow the recommended diet (for religious reasons, swallowing disorders, or other reasons)
5. A low predicted likelihood to change dietary habits according to the Prochaska and Diclemente stages of change model (Nigg et al., 1999)
6. Inability to follow the scheduled intervention visits (institutionalized individuals, lack of autonomy, unable to walk, lack of a stable address, travel plans, or other reason that render the subject unable to attend scheduled visits)
7. Body weight loss > 5 kg during the 6 months prior to the screening visit
8. Intention to undergo bariatric surgery in the next 6 months
9. History of very low-caloric diet during the 6 months prior to the screening visit
10. Prior bariatric surgery or indication and willingness to receive a surgical procedure for weight loss in the near future
11. History of inflammatory bowel disease or small bowel resection
12. Obesity of known endocrine origin (with the exception of treated hypothyroidism)
13. Food allergy to any Mediet component
14. Immunodeficiency or HIV-positive status
15. Liver cirrhosis or chronic renal failure
16. Psychiatric disorders: schizophrenia, bipolar disease, eating disorders, depression with hospitalization in past 6 months
17. Any severe comorbid condition with less than 24-month life expectancy
18. Alcohol (total daily alcohol intake >50 g) or drug abuse within the past 6 months
19. History of major organ transplantation
20. Illiteracy
21. Concurrent therapy with immunosuppressive drugs or cytotoxic agents
22. Current treatment with systemic corticosteroids
23. Current use of weight loss medication
24. Concurrent participation in another randomised clinical trial
25. Patients with an acute infection or inflammation (i.e., pneumonia) are allowed to participate in the study 3 months after resolution of their condition
26. Any other condition that may interfere with the completion of the study protocol

Recruitment start date

05/09/2013

Recruitment end date

05/12/2016

Countries of recruitment

Spain

Trial participating centre

Human Nutrition Unit
University Hospital of Sant Joan de Reus Department of Biochemistry and Biotechnology Pere Virgili Institute for Health Research Rovira i Virgili University
Reus
-

Trial participating centre

Department of Preventive Medicine and Public Health
University of Navarra-Navarra Institute for Health Research (IdiSNA)
Pamplona
-

Trial participating centre

Department of Preventive Medicine
University of Valencia University Jaume I Conselleria de Sanitat de la Generalitat Valenciana
Valencia
-

Trial participating centre

Cardiovascular Risk and Nutrition Research Group
Servicio de Endocrinología, IMIM (Hospital del Mar Medical Research Institute)
Barcelona
-

Trial participating centre

Departament de Medicina
Universitat Autònoma de Barcelona
Barcelona
-

Trial participating centre

Nutritional Epidemiology Unit
Miguel Hernandez University ISABIAL-FISABIO
Alicante
-

Trial participating centre

Hospital Son Espases (HUSE) and Institute for Health Research Illes Balears (IdISBa)
Palma de Mallorca
-

Trial participating centre

Department of Nutrition, Food Sciences, and Physiology
Center for Nutrition Research University of Navarra
Pamplona
-

Trial participating centre

Department School of Nursing
School of Health Sciences University of Málaga-IBIMA
Málaga
-

Trial participating centre

Lipids and Atherosclerosis Unit
Department of Internal Medicine Maimonides Biomedical Research Institute of Cordoba (IMIBIC) Reina Sofia University Hospital University of Cordoba
Cordoba
-

Trial participating centre

Department of Internal Medicine
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Hospital Clínic University of Barcelona
Barcelona
-

Trial participating centre

Department of Preventive Medicine and Public Health
University of Granada
Granada
-

Trial participating centre

OSI ARABA, University Hospital Araba
Vitoria
-

Trial participating centre

Research Group on Community Nutrition & Oxidative Stress
University of Balearic Islands
Palma de Mallorca
-

Trial participating centre

Virgen de la Victoria Hospital
University of Málaga
Málaga
-

Trial participating centre

University of Las Palmas de Gran Canaria
Las Palmas
-

Trial participating centre

Biomedicine Institute (IBIOMED)
University of León Primary Health Care Management of León (Sacyl)
León
-

Trial participating centre

Department of Family Medicine
Research Unit Distrito Sanitario Atención Primaria Sevilla
Sevilla
-

Trial participating centre

Department of Endocrinology
Foundation Jiménez-Díaz
Madrid
-

Trial participating centre

Lipids and Vascular Risk Unit
Internal Medicine University Hospital of Bellvitge Hospitalet de Llobregat
Barcelona
-

Trial participating centre

Department of Endocrinology
IDIBAPS Hospital Clinic University of Barcelona
Barcelona
-

Trial participating centre

Nutritional Genomics and Epigenomics Group
Institute IMDEA-Food CEI UAM+CSIC
Madrid
-

Trial participating centre

Division of Preventive Medicine
University of Jaén
Jaén
-

Trial participating centre

Department of Endocrinology and Nutrition
Institute for Health Research Hospital Clínico San Carlos (IdISSC)
Madrid
-

Organisation

European Research Council (Belgium) / The Carlos III Health Institute (Instituto De Salud Carlos III) (Spain)

Sponsor details

Place Rogier 16
COV2 24/009 / C. Sinesio Delgado 4
Brussels / Madrid
Belgium / Spain
rtd-erc@ec.europa.eu / oficina.informacion@isciii.es
Brussels / Madrid
BE-1049 / ES 28
Belgium

Sponsor type

Other

Website

http://erc.europa.eu

Funder type

Research council

Funder name

European Research Council Advanced Research Grant (Grant Agreement No.: 340918) (Belgium)

Alternative name(s)

ERC

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

Funder name

Instituto de Salud Carlos III

Alternative name(s)

Institute of Health Carlos III, Carlos III Health Institute, ISCIII

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

Spain

Funder name

Ciberobn, Fis-Coordinated Grant PI13/00462, Rd 06/0045

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Basic results (scientific)

Publication list

Publication citations

04/06/2018: The following changes were made to the trial record: 1. The contact details, interventions, primary and secondary outcome measures, exclusion criteria and trial participating centres were updated. 2. The recruitment dates were added.