The purpose of this study is evaluate the effect and safety of the administration of a food supplement based on halophyte plant extracts versus placebo in the neurovascular healthy.

After being informed about the study and giving written informed consent, healthy volunteers (substudy A), patients with transient ischemic attack (TIA) or MINOR stroke (substudy B), patients with cerebral small vessel disease (substudy C) and patients who have suffered a non-disabling stroke and are going to receive carotid angioplasty and stenting (CAS) (substudy D) will be randomized in double-blind manner (participant and investigator) to take a food supplement based on halophyte plant extracts (1 g once a day) or placebo (once a day) for a treatment period of 3 months (substudy A), 11 months (substudy B), 1 year (substudy C) or 7-30 days (substudy D). Participants in substudy A will be twice as likely to be assigned to the experimental treatment as to placebo (2:1 ratio), while those in substudies B, C and D will be equally likely (1:1 ratio).

Substudy A:

• Inclusion Criteria:

  1. Patients ≥18 years old
  2. Possibility of analytical controls at the beginning/end of the study.
  3. Willingness and ability to give informed consent.

• Exclusion Criteria:

  1. Known neurovascular disease.
  2. Other chronic diseases for which the subject is taking medication on a regular basis.
  3. Hyperthyroidism according to the investigator's criteria.
  4. Volunteers taking vitamin or polyphenol-containing nutritional supplements in the 30 days prior to the screening visit (at the investigator's discretion).
  5. Severe illness with life expectancy of less than three months.
  6. Known allergies or intolerance to halophyte plants.
  7. Pregnant or lactating women.
  8. Presence of active neoplastic disease.
  9. Having participated in another clinical trial with medicinal products in the 30 days prior to the screening visit, or intending to do so during their participation in this study.
  10. Habitual consumption of halophyte plants.
  11. Patients who, at the investigator's discretion, are not able to comply with the study protocol.

Substudy B:

• Inclusion criteria:

  1. Patients ≥18 years old.
  2. Patients with typical symptoms lasting less than 24 hours seen at the HUVM classified as TIA or minor stroke (if Diffusion weighted imaging (DWI) positive on magnetic resonance imaging (MRI)) during the last year.
  3. Have a neuroimaging performed at the time of the acute episode that rules out other non-vascular lesions.
  4. Willingness and ability to give informed consent.

• Exclusion criteria:

  1. Patients taking vitamin or polyphenol-containing nutritional supplements in the 30 days prior to the screening visit (at the investigator's discretion).
  2. Having participated in another clinical trial with medicinal products in the 30 days prior to the screening visit, or intending to do so during their participation in this study.
  3. Hyperthyroidism at the investigator's discretion.
  4. Dysphagia that prevents the intake of the study treatment.
  5. Patients dependent for basic activities of daily living (mRS >3) or with severe disease with life expectancy of less than 12 months.
  6. Known allergies or intolerance to halophyte plants.
  7. Habitual consumption of halophyte plants.
  8. Pregnant or lactating women.
  9. Presence of active neoplastic disease.
  10. Patients who, at the investigator's discretion, are unable to comply with the study protocol.

Substudy C:

• Inclusion criteria:

  1. Patients ≥18 years of age.
  2. Lacunar syndrome with acute ischaemic lesion on neuroimaging of less than 1.5 cm maximum diameter.
  3. Willingness and ability to give informed consent.

• Exclusion criteria:

  1. Patients taking vitamin or polyphenol-containing nutritional supplements in the 30 days prior to the screening visit (at the investigator's discretion).
  2. Hyperthyroidism at the investigator's discretion.
  3. Claustrophobia or morbid obesity (IMT >40) precluding performance of MRI 3 Tesla.
  4. Patients dependent for basic activities of daily living (mRS >3) or with severe disease with an expected life expectancy of less than 12 months.
  5. Dysphagia that prevents the intake of the study treatment.
  6. Known allergies or intolerances to halophyte plants.
  7. Pregnant or breastfeeding women.
  8. Presence of active neoplastic disease.
  9. Having participated in another clinical trial with medicinal products in the 30 days prior to the screening visit, or intending to do so during their participation in this study.
  10. Habitual consumption of halophyte plants.
  11. Patients who, at the investigator's discretion, are not able to comply with the study protocol.

Substudy D:

• Inclusion criteria:

  1. Patient with carotid stenosis that warrants treatment in one of the following cases:

     • Symptomatic carotid stenosis >50% with stroke within 6 months prior to inclusion and not disabling at the time of inclusion.
     • Asymptomatic carotid stenosis >70% provided some of the following criteria are met:

     I. Presence of silent stroke on neuroimaging.

     II. Stenosis with progression (>20%).

     III. Soft or ulcerated (unstable) plaque.

     IV. Occlusion of contralateral internal carotid artery (ICA).

     V. Impaired haemodynamic reserve.

  2. Receive carotid angioplasty and stenting (CAS) of said artery within a maximum of one month after inclusion and with a minimum of one week of taking the treatment from inclusion to intervention.

  3. Be able to orally take the dietary supplement/placebo from the event until just prior to the intervention.

  4. Patients ≥18 years.

  5. Willingness and ability to give informed consent.

• Exclusion criteria:

  1. Patients taking vitamin or polyphenol-containing nutritional supplements in the 30 days prior to the screening visit (at the investigator's discretion).
  2. Hyperthyroidism at the investigator's discretion.
  3. Claustrophobia or morbid obesity preventing the performance of MRI 1.5 Tesla.
  4. Severe disease with expected life expectancy of less than one month.
  5. Dysphagia preventing the intake of the study treatment.
  6. Known allergies or intolerance to halophyte plants.
  7. Pregnant or lactating women.
  8. Presence of active neoplastic disease.
  9. Having participated in another clinical trial with medicinal products in the 30 days prior to the screening visit, or intending to do so during their participation in this study.
  10. Habitual consumption of halophyte plants.
  11. Patients who, at the investigator's discretion, are not able to comply with the study protocol.

Analyzed data will be published as a whole

The BIO-DIS company in Seville prepared the extract/placebo bottles for each study arm by assigning them a unique coding for each participant that does not distinguish between extract and placebo. This coding is then the participant's study code. Treatment bottles were prepared and coded according to the ratio of dietary supplement/placebo (1:1 for Branch B, C and D and 2:1 for Branch A) and the number of participants in each branch.

The list indicating which treatment (supplement/placebo) each coding corresponds to will be kept at the Hospital Universtario Virgen Macarena (HUVM) Pharmacy Service for the duration of the study. The blind will only be disclosed in the event of an adverse event (AE) that requires it and/or after completion of the analysis of the main end-points of each arm in a blinded manner.