The purpose of the study is to test the hypothesis of slowing the progression of White Matter Lesions (WML) by lowering blood pressure (BP) in patients with cognitive complaints and a moderate to high grade of WML on brain MRI.
SCIENTIFIC BACKGROUND: White Matter Lesions (WML) are cerebrovascular abnormalities discovered on MRI that are associated with an increased risk of dementia. High blood pressure (BP) is a major risk factor for WML. WML are therefore key lesions in the causal chain linking vascular factors and dementia, particularly Alzheimer's disease.
However, it has not been shown that lowering BP could limit the progression of the WML in people with cognitive impairment.
OBJECTIVES: To test the hypothesis of slowing progression of WML by lowering BP in patients with memory complaints with a moderate to high grade of WML on brain MRI.
STUDY DESIGN: PROBE (Prospective randomized open blinded end-point) trial. Blind reading of both MRI for every patient in each group. After stratified randomization on age, sex and center, patients will be assigned to two strategies:
- Reinforced Group (RG): enhanced strategy aiming at a systolic BP <135 mmHg;
- Usual Group (UG): usual strategy based on the usual routine care.
SAMPLE SIZE: 820 patients will be enrolled (410 in each arm) in 25 Memory Resources and Research Center (CMRR) with access to 1.5 T or more MRI.
CONDUCT OF THE STUDY:
Duration of the inclusion period: 23 months and 2 weeks. Patient participation duration: 36 months +/- 2 weeks Total study duration: 5 years. Clinical and para-clinical evaluation: MRI as part of research at the beginning of the study and before the end of the study at 36 months (primary endpoint); Clinical evaluation of neuropsychological tests at the beginning of the study and yearly ; walking speed measurement single leg stance balance test ; repeated BP measurements; monitoring of neurological signs and symptoms; blood test at the beginning of the study (electrolytes, lipid profiles, fasting blood glucose, if not existing) MRI if not existing (- 5 years) for validation of the inclusion criterion and performed in the ordinary course.
- Blood pressure lowering algorithm Other
Other Names: enhanced strategy Intervention Desc: The treatments used in the "enhanced strategy" arm are those proposed by national (HAS2013, SFHTA2013) and international (ESH 2013) recommendations, according to their Marketing Authorization and Summary of Product Characteristics : Diuretics, beta-blockers, Angiotensin Converting Enzyme inhibitors, Angiotensin Receptor Blockers, Calcium Channel Blockers Throughout the study, choice of drugs in each therapeutic class is left on the investigator's initiative. All drugs of these classes may be used , no specific drug is tested in this study. ARM 1: Kind: Experimental Label: blood pressure lowering algorithm Description: enhanced strategy aiming to reduce systolic blood pressure to <135 mmHg
- Usual strategy Other
Intervention Desc: The implementation of antihypertensive therapy the current recommendations to reach the blood pressure target in usual care. Throughout the study, choice of drugs in each therapeutic class is left on the investigator's initiative. Combinations of different pharmacological classes can be tested in order to find the most effective and best tolerated combinations. ARM 1: Kind: Experimental Label: usual strategy Description: usual strategy based on the usual care of routine care
- Allocation: Randomized
- Masking: Open Label
- Purpose: Prevention
- Endpoint: Efficacy Study
- Intervention: Parallel Assignment
|Type||Measure||Time Frame||Safety Issue|
|Primary||The main criterion is based on the quantitative assessment of White Matter Lesions (WML) volumes at the beginning and at the end of the study for each patient and each arm of the trial. The WML volume from the final MRI is compared to that of the initial||36 months||No|
|Secondary||Imaging criteria : changes in the number of large or confluent WML||36 months||No|
|Secondary||Imaging criteria : changes in the volume of WML depending on their location (periventricular and deep white matter)||36 months||No|
|Secondary||Imaging criteria : changes in the number of silent infarctus||36 months||No|
|Secondary||Imaging criteria : changes in the number of microbleeds||36 months||No|
|Secondary||Imaging criteria : evolution of brain volumes (gray matter, white matter, CSF, and regional volumes including hippocampus)||36 months||No|
|Secondary||Clinical criteria: clinical criteria (changes in neuropsychological tests||36 months||No|
|Secondary||Clinical criteria: changes inwalking speed||36 months||No|
|Secondary||Clinical criteria: number of incident cases of dementia||36 months||No|
|Secondary||Number of incident cases of vascular events validated by an expert committee||36 months||No|
|Secondary||Clinical criteria: total mortality by cause||36 months||No|