Potassium Intake-response Trial to Control Hypertension

Study Overview
=================
Brief Summary
-----------------
The Potassium Intake-response Trial to Control Hypertension (PITCH) will test the intake-response relationship between potassium supplementation and blood pressure, which may inform clinical guidelines on the optimal level of potassium supplementation for blood pressure lowering among adults with stage 1 hypertension and dietary guidelines for population intake.

Detailed Description
-----------------
Hypertension is the leading preventable risk factor for cardiovascular disease (CVD) and all-cause mortality, and prevention and treatment of high blood pressure (BP), including stage 1 hypertension, is crucial for reducing the global burden of CVD. Nonpharmacological interventions, including dietary interventions, are recommended as the primary approach for prevention and treatment of hypertension in US adults. Observational epidemiological studies have reported an inverse association between dietary potassium intake and BP, and clinical trials have documented that potassium supplementation reduces BP. However, previous clinical trials of potassium supplementation and BP have been limited to comparing one single dose of potassium supplementation (mostly 60 mmol/day or 1173 mg/day) to placebo control. Therefore, the optimal level of dietary intake of potassium in the population is currently unknown. In 2019, the National Academies of Science, Engineering, and Medicine updated the Dietary Reference Intake (DRI) recommendations for potassium intake based on the most current evidence associating potassium intake with CVD outcomes, including BP. Limited evidence precluded the DRI Committee from establishing a Chronic Disease Risk Reduction Intake level. The specific goal of the proposed randomized controlled trial is to study the intake-response effect for 4 levels of potassium supplementation on BP among adults with untreated stage 1 hypertension. The investigators will test the primary hypothesis that compared with placebo (0 mmol/day potassium supplementation), there is a progressive relationship between increasing doses of oral potassium supplementation (30, 60, and 90 mmol/day or 1173, 2346, 3519 mg/day) and decreasing levels of 24-hour systolic BP from baseline to 12-weeks of follow-up. The investigators will also evaluate effects on daytime (awake) and nighttime (asleep) BP, office systolic and diastolic BP, sodium excretion, and effect mediation and moderation by age, sex, race, central adiposity, baseline urine excretion of sodium and potassium, and change in urine sodium. The results from the proposed trial will fill a critical knowledge gap and may identify the optimal level of potassium supplementation for BP lowering among adults with stage 1 hypertension. This information can be used to develop dietary guidelines for the prevention and treatment of hypertension and CVD.

Official Title
-----------------
Potassium Intake-response Trial to Control Hypertension

Conditions
-----------------
Blood Pressure

Intervention / Treatment
-----------------
* Dietary Supplement: Potassium Chloride
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men or women aged >18 years of any race/ethnicity Stage 1 hypertension at screening (untreated office systolic BP 130-139 and diastolic BP <90 mm Hg) Willing and able to provide informed consent Exclusion Criteria: Medical condition in which potassium supplementation is contraindicated: history of heart failure, myocardial infarction, stroke, cardiac arrythmia, chronic kidney disease or estimated glomerular filtration rate <60 ml/min/1.73 m^2, diabetes or non-fasting glucose >200 mg/dL, major depressive disorder (PHQ-9 score ≥15), psychosis, ulcer diseases including esophageal-gastric ulcer, malignancy in the past 5 years, liver disease, organ transplant, Addison's disease (adrenal insufficiency) Use of medications which may alter serum potassium levels or in which potassium supplementation is contraindicated: antihypertensive agents, antihistamines, antiparkinson agents, antimuscarinic agents, antipsychotics, muscle relaxants, systemic corticosteroids, or chronic use of non-steroidal anti-inflammatory drugs Serum potassium ≥5.0 mEq/L Serum bicarbonate <22 mEq/L Consumption of >85th percentile of usual potassium intake among US adults (>3,750 mg/day) For women, current pregnancy, breastfeeding, or plans to become pregnant during the study Consumption of ≥21 alcoholic beverages per week or consumption of ≥6 beverages per occasion Current or planned residence making it difficult to meet trial requirements or travel to the study site Current participation in another intervention or pharmaceutical trial Unable or unwilling to complete 24-hour BP or urinary sample collection Other concerns regarding ability to meet trial requirements, at the discretion of the investigators or staff

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible participants will be randomly assigned to placebo or 1 of 3 active intervention groups in a 1:1:1:1 ratio.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants randomized to the placebo arm will receive 1, 2, or 3 inert placebo tablets twice daily (i.e., 2, 4, or 6 tablets per day) for 12 weeks. | Other: Placebo<br>* Oral administration of inert placebo tablets<br>* Other names: Zeebo;|
| Active Comparator: Potassium Chloride 30 mmol per day<br>Participants randomized to the 30 mmol per day group will receive 1 potassium chloride tablet (15 mmol strength) twice daily (i.e., 2 tablets per day) for 12 weeks. | Dietary Supplement: Potassium Chloride<br>* Oral administration of potassium chloride tablets<br>* Other names: Klor-Con;|
| Active Comparator: Potassium Chloride 60 mmol per day<br>Participants randomized to the 60 mmol per day group will receive 2 potassium chloride tablets (15 mmol strength) twice daily (i.e., 4 tablets per day) for 12 weeks. | Dietary Supplement: Potassium Chloride<br>* Oral administration of potassium chloride tablets<br>* Other names: Klor-Con;|
| Active Comparator: Potassium Chloride 90 mmol per day<br>Participants randomized to the 90 mmol per day group will receive 3 potassium chloride tablets (15 mmol strength) twice daily (i.e., 6 tablets per day) for 12 weeks. | Dietary Supplement: Potassium Chloride<br>* Oral administration of potassium chloride tablets<br>* Other names: Klor-Con;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 24-hour systolic blood pressure (BP) from baseline to 12 weeks | Ambulatory blood pressure monitoring will be used to determine 24-hour systolic BP | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 24-hour diastolic blood pressure (BP) from baseline to 12 weeks | Ambulatory blood pressure monitoring will be used to determine 24-hour diastolic BP | 12 weeks | 
| Change in daytime (awake) systolic blood pressure (BP) from baseline to 12 weeks | Ambulatory blood pressure monitoring will be used to determine daytime BP | 12 weeks | 
| Change in daytime (awake) diastolic blood pressure (BP) from baseline to 12 weeks | Ambulatory blood pressure monitoring will be used to determine daytime BP | 12 weeks | 
| Change in nighttime (asleep) systolic blood pressure (BP) from baseline to 12 weeks | Ambulatory blood pressure monitoring will be used to determine nighttime BP | 12 weeks | 
| Change in nighttime (asleep) diastolic blood pressure (BP) from baseline to 12 weeks | Ambulatory blood pressure monitoring will be used to determine nighttime BP | 12 weeks | 
| Change in office systolic blood pressure (BP) from baseline to 12 weeks | An automated oscillometric device will be used to determine office BP based on the mean of 6 blood pressure values from two 12-week visits minus the mean of 6 values from 2 baseline visits | 12 weeks | 
| Change in office diastolic blood pressure (BP) from baseline to 12 weeks | An automated oscillometric device will be used to determine office BP based on the mean of 6 blood pressure values from two 12-week visits minus the mean of 6 values from 2 baseline visits | 12 weeks |