Salt Sensitivity Evaluation Via N-of-1 Trials (SENSE-Salt)

Study Title: Determining the Presence of Salt Sensitivity in Individuals With Elevated Blood Pressure Through Dietary Salt Interventions: A Series of N-of-1 Trials

Objective:

• Primary Objective: To assess whether there are differences in blood pressure responses between salt-sensitive and salt-resistant individuals.
• Exploratory Objectives: To explore the effects of different sodium-content diets on individual pulse, sleep, and mood; to evaluate whether a low-sodium diet increases the incidence of hypotension; and to identify metabolic differences associated with salt sensitivity.

Study Design: This study will utilize a two-phase N-of-1 randomized controlled trial design. It consists of the following phases:

• Salt Sensitivity Screening: Participants will undergo a 2-week dietary intervention (1 week of high-sodium diet: 200 mmol/day; 1 week of low-sodium diet: 85 mmol/day). Salt sensitivity will be determined by comparing changes in mean arterial pressure (MAP) between the high-sodium and low-sodium periods (△MAP). Individuals with △MAP ≥5 mmHg and in the upper 1/6 of the population will be classified as salt-sensitive (SS), while those with △MAP <5 mmHg and in the lower 1/6 will be classified as salt-resistant (SR).
• N-of-1 Trial: The identified salt-sensitive and salt-resistant individuals will undergo a 6-week N-of-1 trial, consisting of three cycles. Each cycle will last 2 weeks (1 week of high-sodium diet and 1 week of low-sodium diet). This design aims to assess individual blood pressure responses to changes in sodium intake.

Sample Size: A total of 72 participants will be recruited for the salt sensitivity screening, with an expected 24 participants proceeding to the N-of-1 trial.

Study Population: Healthy individuals aged 20-65 years, not on antihypertensive medication or with a stable regimen for at least 3 months, with systolic blood pressure between 110-159 mmHg and diastolic blood pressure between 70-99 mmHg, who are able to eat at the research center.

Primary Outcome: Reproducibility of salt sensitivity response classification. Secondary Outcomes:Changes in mean arterial pressure, systolic and diastolic blood pressure; exploratory outcomes such as sleep, mood, gut microbiome, and metabolomics; and safety outcomes including hypotension and hyponatremia.

Phase 1: Salt Sensitivity Screening

Inclusion:

• Signed informed consent for the salt sensitivity test.
• Systolic blood pressure between 110-159 mmHg and diastolic blood pressure between 70-99 mmHg.
• Not taking any antihypertensive medication, or have had a stable antihypertensive regimen for the past three months and agree not to adjust their medication during the study period.
• Able to comply with consuming the study-provided diet throughout the study period.

Exclusion:

• Special dietary requirements, such as allergies to common foods (e.g., eggs, seafood, peanuts), or conditions like asthma, irritable bowel syndrome, lactose intolerance, chronic kidney disease stage 4 or higher, history of gastrointestinal surgery, or special dietary needs due to other illnesses, surgery, or weight loss.
• Diagnosed with chronic diseases: any malignancy with a life expectancy of less than one year; chronic heart failure, severe depression or other mental disorders, long-term bedridden status, or mobility limitations.
• Experienced acute myocardial infarction or stroke within the past 6 months.
• Acute illnesses such as upper respiratory tract infection, fever, or severe diarrhea that have not yet resolved.
• Alcohol abuse.
• Pregnant or breastfeeding women, or women planning to become pregnant.
• Individuals who are deaf, mute, or have cognitive impairments that hinder communication.

Phase 2: N-of-1 Trial

Inclusion:

• Classified as salt-sensitive or salt-resistant through the Phase 1 screening:
• Salt-Sensitive (SS) Group: Participants with a change in mean arterial pressure (ΔMAP) ≥ 5 mmHg and in the upper 1/6 of the distribution of ΔMAP from the salt sensitivity test.
• Salt-Resistant (SR) Group: Participants with a change in mean arterial pressure (ΔMAP) < 5 mmHg and in the lower 1/6 of the distribution of ΔMAP from the salt sensitivity test.
• Signed informed consent for the n-of-1 trial.

Exclusion:

• Failed to complete the salt sensitivity test as required, or consumed less than 80% of the study-provided meals during the salt sensitivity test (i.e., fewer than 34 meals over 14 days).
• Experienced adverse events during the salt sensitivity test that, in the investigator's judgment, make it inappropriate to continue in the study.