Impact of Controlling Vascular Risk Factors on the Progression of Alzheimer's Disease (COVARAD)

Three quarters of patients with Alzheimer's disease have at least one vascular risk factor (VRF). Vascular brain lesions are present in most Alzheimer's patients (especially older ones). This cerebrovascular disease potentiates Alzheimer's lesions in early-stage disease. Many research studies have shown that VRFs are also risk factors for Alzheimer's disease; this is true for arterial hypertension and dyslipidaemia in particular and, to a lesser extent, diabetes and cardiopathy. Moreover, recent drug trials (SYST-EUR, PROGRESS and HOPE) have indicated that antihypertensive medications can prevent the appearance of dementia (and notably Alzheimer's disease) in over-60 hypertensive subjects. An observational study of 233 Alzheimer's patients with an average follow-up period of 4 years has shown that the annual decline in the Mini-Mental State Examination (MMSE) score was lower in patients in whom all the VRFs were being treated than in patients in whom no VRFs were being treated (1.5 ± 2.5 points versus 2.5 ± 2 points, respectively; p<0.04).1 However, it is not currently known whether optimal treatment of VRFs can influence the progression and prognosis of Alzheimer's disease. Answering this question could have a significant impact on public health.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease; Cardiovascular Risk Factors
• Intervention / Treatment: Other: standard care; Other: optimal care of VRF

Detailed Description

It is not currently known whether the optimum treatment of VRFs influences the progression and prognosis of Alzheimer's disease. Our starting hypothesis is that VRF control in Alzheimer's patients is associated with slower cognitive decline, less intense loss of personnel independence and fewer adverse events over the course of the disease (cardiovascular or cerebrovascular events, behavioural disorders, caregiver burden, hospitalization and death).

COVARAD study is a randomized, controlled, multicentre study comparing 2 VRF care strategies in mild-to-moderate (MMSE > 18) Alzheimer's disease patients with at least one VRF. The objective of this work is to evaluate the effect of "optimal" care strategy, in strict compliance with the French HAS guidelines concerning targets for blood pressure, glycaemia and blood lipid levels, on the cognitive function in mild-to-moderate Alzheimer's patients (MMSE score > 18), in comparison with a control group (i.e. receiving standard care from a primary care physician). The study test the hypothesis whereby "optimal" care of the 3 main modifiable VRFs is associated with slower cognitive decline in Alzheimer's disease patients (evaluated on the ADAS-cog score), when compared with standard care and to compare the MMSE, MoCA and VADAS-cog scores, mood and behaviour (MADRS and NPI), loss of independence (ADCS-ADL), the occurrence of cardiovascular or cerebrovascular events, the number and length of hospitalisations, caregiver burden (on the Zarit scale), institutionalization and survival in the two groups (i.e. depending whether VRFs are managed optimally or not).

This study could influence clinical practice. If VRF control does have an influence on the progression of Alzheimer's disease, an information campaign could modify practice and have a significant impact on public health.

An independent Data and Safety Monitoring Board will be set up to monitor the diabetic patients, in view of the risks related to "optimal" care (ACCOR and ADVANCE studies). Nevertheless, the risk of adverse events will be limited by raising the threshold value for glycated haemoglobin to 8%.

• Study Type: Interventional
• Enrollment (Actual): 304
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • CHU Amiens Picardie
  • Arras, France
    • CH ARRAS
  • Boulogne-sur-Mer, France
    • CH Boulogne
  • Béthune, France
    • Centre Hospitalier Bethune Beuvry
  • Calais, France
    • Ch Calais -
  • Denain, France
    • CH de DENAIN
  • Douai, France
    • CH de DOUAI
  • Dunkerque, France
    • Ch Dunkerque
  • Le Quesnoy, France
    • CH Le Quesnoy
  • Lens, France
    • Ch Dr.Schaffner de Lens
  • Lille, France, 59037
    • CMRR Lille hopital Roger Salengro
  • Lille, France, 59037
    • Hôpital des Bâteliers, CHU
  • Lomme, France
    • CH Saint-Philibert, GHICL
  • Paris, France
    • Hu Paris Centre Site Broca Aphp - Paris
  • Roubaix, France
    • CH de Roubaix
  • Rouen, France
    • CHU Rouen
  • Saint-Omer, France
    • Ch Region de St-Omer
  • Seclin, France
    • Groupe Hospitalier Seclin Carvin -
  • Talence, France, 33404
    • Chu de Bordeaux - Talence
  • Tourcoing, France
    • Ch Tourcoing
  • Valenciennes, France
    • Ch Valenciennes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

• Subjects aged 60 or over
• Subjects with Alzheimer's disease, according to the NINCDS/ADRDA diagnostic criteria 71
• MMSE > 18
• Subjects with at least one VRF (whether treated or not): arterial hypertension (defined as SBP/DBP ≥ 140/90 mmHg in at least three different consultations or, for ambulatory measurements, > 130/80 mmHg with a Holter recorder or > 135/85 mmHg with a self-measurement device), type 2 diabetes (defined as a glycaemia value over 1.26 g/l (7 mmol/l) after an 8-hour fast (confirmed on two occasions), dyslipidaemia (defined as an LDL cholesterol level > 1.6 g/l or 1.3 or 1 g/l, depending on the patient's risk level)
• Subjects having agreed to participate in the study (provision of informed consent).
• Subjects accompanied by a person likely to provide information on the patient (during the visit or over the phone).

Exclusion criteria

• Any other disease that might interfere with the evaluation of cognitive disorders.
• No formal education or a poor understanding of French (interfering with administration of the neuropsychological tests).
• Major physical problems likely to interfere with administration of the tests (poor eyesight, hearing, etc.).
• Non-Alzheimer's dementia (isolated vascular dementia, Lewy body dementia, frontotemporal dementia, etc.)
• Psychotropic drugs likely to modify the patient's non-stabilized cognitive state.
• Patients with a history of cardiovascular events can be included (randomization will be balanced in terms of this criterion).
• Participation in a therapeutic clinical trial during the study period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: standard care; Follow up with city doctor with recommendation HAS French guidelines	Other: standard care; AD patients will be followed with the city doctor and the letter t will be send for remember French HAS guidelines
Experimental: optimal care of VRF; Monitoring according to the strict recommendations of the HAS French guidelines	Other: optimal care of VRF; VRF of AD patients will be treated optimally in strict compliance with the French HAS guidelines concerning targets for blood pressure, glycaemia and blood lipid levels, in accordance with standardized therapeutic regimens.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
ADAS-Cog	18 months

Secondary Outcome Measures

Outcome Measure	Time Frame
MMSE	18 months
MoCA	18 months
VADAS-Cog	18 months
Trail Making Test	18 months
ADL-ADCS	18 months
IADL	18 months
MADRS	18 months
NPI	18 months
Zarit Inventory of Burden	18 months

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Collaborators: Ministry of Health, France
• Investigators: Study Director: Florence PASQUIER, MD, Univ Lille Nord de France, clinique neurologique, Centre Mémoire de Ressources et de Recherche - CHRU Lille; Principal Investigator: Marie-Anne MACKOWIAK, MD, Univ Lille Nord de France, clinique neurologique, Centre Mémoire de Ressources et de Recherche - CHRU Lille; Principal Investigator: Didier HANNEQUIN, MD, CHU Rouen; Principal Investigator: Olivier GODEFROY, MD, CHU Amiens; Principal Investigator: Muriel RAINFRAY, MD, CHU Bordeaux

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2010
• Primary Completion (Actual): May 1, 2022
• Study Completion (Actual): May 1, 2022

Study Registration Dates

• First Submitted: August 23, 2011
• First Submitted That Met QC Criteria: August 23, 2011
• First Posted (Estimate): August 25, 2011

Study Record Updates

• Last Update Posted (Actual): May 24, 2022
• Last Update Submitted That Met QC Criteria: May 23, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Alzheimer's disease; cardiovascular risk factors
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: 2008_28/0914; 2009-A00269-48 (Other Identifier: ID-RCB number, ANSM); PHRC 2008/1925 (Other Identifier: DGOS, Ministry of Health, France); B90419-40 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No