Prevention of Age-associated Cardiac and Vascular Dysfunction Through Nrf2 Signaling Using the Nutritional Supplement Sulforaphane

Study Design: We intend to include 200 individuals (100 men and 100 women, ≥60 years), with a diagnosis of heart failure with preserved ejection fraction (HFpEF) who are able to walk at least 500 feet, to participate in a randomized controlled, double blinded study, with Sulforaphane (SFN) or placebo treatment for 24 weeks. These potential subjects will be recruited in a randomized, controlled, double blinded pilot study comparing SFN to placebo. The study will be conducted at the Texas Tech University Health Sciences Center, and University Medical Center. The trial is approved by our local IRB (IRB NUMBER: L22-024, IRB APPROVAL DATE: 12/14/2021) and will be registered at clinicaltrials.gov. Well trained Nurses of Clinical Research Institute, TTUHSC will receive placebo and test compound from supplier and will dispense them to test subjects.

Sulforaphane and Placebo Information. Processed SFN-rich extract will be purchased from Nutramax Laboratories, Inc. 2208 Lakeside Blvd Edgewood, MD 21040. Caplets containing SFN-rich broccoli sprout extracts or placebo caplets containing microcrystalline cellulose will be obtained from from Nutramax Labs. Study medication will be dispensed in sealed bottles with instructions to keep them in a household freezer. The size of the caplet will be about the size of a 1000 mg Vit C pill (about 2 cm in length). The participants will be dosed, based on weight, in a double-blind fashion with identical appearing placebo or SFN caplets. Participants will be instructed to take a daily dose for 24 weeks based on the participants weight. Two caplets for individuals <100 lb., three caplets for individuals 100-200 lb. and four caplets for individuals >200 lb. SFN (Avmacol Extra Strength) or placebo will be prescribed by a study physician, and will be dispensed by the study coordinators at TTUHSC Lubbock. Pill counts will be conducted to demonstrate compliance.

The study medications will arrive pre-packaged and be stored in a refrigerator freezer in the TTUHSC Clinical Research Institute based on the manufacturer-based guidelines and dispensed to each participant at their baseline visit and at the 12 weeks visit. Patients will be expected to maintain at least an 80% adherence to the medication regimen, in the absence of prohibitive toxicity. Adherence will be monitored through pill counts. Subjects who do not meet 80% compliance when questioned with phone visits and at 12-week pill count, will be instructed on the importance of taking the pills as directed, but if they demonstrate less than 80% compliance on average for more than 2 in person and/or phone study visits, they will be withdrawn from the study, and we will not use their data. If side effects are noted, patient will be asked to notify the study team of the same and will be evaluated within a suitable time frame based on severity of side effects.

SFN is a safe natural isolate. The doses that are used in this study as described above (30mg/caplet) are considered adequate to maintain intended therapeutic drug levels, while maintaining a simple study design without significant concerns for drug toxicity. SFN has been used in several clinical trials from doses ranging from 2-200µmol/day for 2-28 weeks in 25-80 years old subjects without significant side-effect or toxicity (https://clinicaltrials.gov/ct2/results?term=sulforaphane\&Search=Search ).

Data Analysis and Statistical Considerations: Data will be analyzed using SPSS 21.0 (for Windows, SPSS Inc., Chicago, IL). Descriptive statistics and correlation analysis will be performed. All results will be expressed as mean±SE. The significance of difference in mean values between groups will be examined using analysis of variance (ANOVA) or, when the ANOVA assumptions are not fulfilled, using the Mann-Whitney (if two groups are to be compared) or Kruskal Wallis (if three or more groups are to be compared) non-parametric test. These tests will be followed by Tukey's HSD test for means or ranks if appropriate (SPSS 21.0). For evaluating changes in cardiac function and LV mass over time, a mixed-design ANOVA, implemented with generalized linear models, will be used. A value of P ≤ 0.05 will be considered statistically significant.