Exploration of the effect of lactate administration after stroke in humans.

Zusammenfassung der Studie

This is a Phase IIA clinical study on ischemic stroke (AVC). The therapeutic intervention consists of a lactate infusion for 20 minutes. Preclinical studies show that lactate protects the brain after ischemic stroke. The primary objective is to assess whether lactate reaches the brain and alters the lactate concentration measured by magnetic resonance (MRS) in the center of the lesion, in the at-risk area around the lesion (penumbra), and in the other half of the brain. Other objectives include estimating the effect of lactate on the evolution of the penumbra via MRI (illustrating the size of the lesion and blood perfusion), neurological deficit, and cellular stress, reflected by the concentrations of a molecule (NAA) corresponding to neuronal well-being. We will select 30 patients (goal 10 per group) with occlusion of an artery supplying the brain, treated by mechanical thrombectomy (TEV, endovascular thrombectomy), without pharmacological thrombolysis, with moderate to severe neurological deficit, without significant prior disability, with no refusal of oral consent from the patient or relatives, and agreement from an independent physician. After a TEV, the patient is infused within 60 minutes with a solution containing either lactate or a control solution. Neither the patient nor the physicians know which solution is being administered. All measurements will be made at admission, after TEV and infusion, and after 24 hours, for both lactate and NAA in the 3 regions of interest. The temporal evolution of these measurements will be statistically evaluated. The total duration of the study is 3 months for each patient, and all will be followed up after 3 months for clinical control. The 3-month visit is part of routine care for patients who have suffered a stroke. The side effects of the treatment are known and minimal.

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Untersuchte Intervention

Lactate is an organic molecule, meaning it is natural. It is found in every cell of the body; it is on the skin, in sweat, and in saliva. It is harmless. Various preclinical studies have shown that lactate is protective after ischemic stroke, meaning caused by the blockage of an artery supplying the brain, by reducing the size of the lesion in the brain and improving neurological impairment. The intervention here aims to increase the lactate concentration in the blood to deliver lactate to the damaged brain, as described in preclinical studies, through a lactate solution infusion for 20 minutes. We will then examine, using magnetic resonance spectroscopy, whether the lactate molecule has entered the brain. Magnetic resonance spectroscopy consists of a short additional measurement period in the same machine as your diagnostic magnetic resonance imaging (MRI). This measurement allows us a non-invasive assessment of your brain's biochemistry, measuring not only lactate but also other substances formed by or necessary for brain metabolism. We will perform brain magnetic resonance spectroscopy in an MRI machine located in the emergency department of CHUV. The total duration of an MRS sequence is 6 minutes. A first measurement will be made upon your arrival at the emergency department, a second after the infusion, and a third one day later. PATIENT SELECTION We invite you to participate in this study if you are suffering from an acute stroke characterized by the blockage of one of the main arteries supplying the brain. Additionally, we only select patients treated by mechanical clot removal (called endovascular treatment, TEV). We ask for your oral consent as well as informed consent from the physician who is taking care of you in the emergency department and who is not participating in the study. Lactate has never been tested during strokes in humans. INTERVENTION After the endovascular treatment, in the recovery room, the study consists of infusing you for 20 minutes, after random allocation, with either lactate or a control solution, without medication, and then measuring the lactate concentration in different regions of the brain. To study the effect of the drug, it is important to compare with patients who do not receive it. Some of you, determined randomly, will therefore receive a control solution without medication. Neither the patients nor the physicians will know which solution was administered during the study. Lactate is administered at the same dose used in several preclinical studies in mice. This dosage has also been shown to be effective in studies in humans with an increase in blood lactate levels without complications. After the treatment, a second MRI with MRS is performed, and a third MRI/MRS will be performed at 24 hours. The MRI at 24 hours is part of the routine management of stroke, as described above. TEMPORAL SEQUENCE OF THE INTERVENTION 1. Admission to the emergency department 2. MRI, decision on endovascular treatment (TEV) alone 3. Selection, MRS spectroscopy 4. Endovascular treatment 5. Infusion of lactate or control solution without medication, randomly selected, no later than 1 hour after TEV 6. MRI-MRS after infusion 7. MRI-MRS after 24 hours 8. Clinical control at 3 months ADDITIONAL MEASUREMENTS IN THIS STUDY We will record your characteristics, your physiological and laboratory data at admission, your therapeutic interventions (mechanical thrombectomy, infusion of control or lactate solution) and your MRI characteristics at different times. All your data recorded during the study are routinely measured in the management of strokes (initial MRI and at 24 hours), except for the MRS, which is performed in the MRI, and the blood lactate level which are performed additionally for the needs of the study. The initial MRS and the one at 24 hours add only a few minutes to the routinely performed MRIs. You will be called for a follow-up at 3 months, as is the case for all patients who have suffered a stroke. DURATION OF THE STUDY AND RECRUITMENT For each enrolled patient, the total duration of the study (including recruitment, 20-minute treatment with measurement by MRI after administration and follow-up) is 3 months. New patients will be included over a period of 3 years.

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Untersuchte Krankheit(en)

Strokes (AVC) are a brain disease caused by the blockage of an artery that supplies blood to the brain or, much more rarely, by an intracerebral hemorrhage. The absence of blood supply, called ischemia, causes a lack of oxygen and glucose supply leading to brain suffering. Strokes are the leading cause of adult disability and the third leading cause of death worldwide. Significant advances in the management of ischemic stroke in recent years have improved the prognosis for many patients. These advances are primarily treatments that allow blocked arteries to be reopened, either by medication (thrombolysis) or with a mechanical instrument (thrombectomy). Despite the availability of these new treatments, more than three-quarters of patients in Switzerland cannot benefit from them, and among treated patients, a significant fraction retains significant disability and mortality remains high. For more than two decades, significant research efforts have aimed to develop other strategies to protect neurons (neuroprotection), targeting the mechanisms of cell death triggered by ischemia, studied in experimental models. Many approaches have effectively improved the outcomes of rodents after experimental ischemia, but to date, none have been applied to patients suffering from ischemic stroke.

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Sponsor

n/a

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Name der bewilligenden Ethikkommission (bei multizentrischen Studien nur die Leitkommission)

Ethikkommission Waadt

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Datum der Bewilligung durch die Ethikkommission

08.02.2021

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Ergebnisse der Studie