Selenium Intervention Registry Randomized Trial in Heart Failure (SIRI-HF)

Heart failure is a serious condition in which the heart is unable to pump blood effectively, and it remains a leading cause of hospitalization and death worldwide despite advances in treatment.

Selenium is an essential micronutrient that plays an important role in cellular energy production, antioxidant defense, and overall cardiovascular function. Low selenium levels are common among patients with heart failure in Northern Europe, and observational studies have shown that selenium deficiency is associated with an increased risk of hospitalization and death. In cases of severe deficiency, such as in Keshan disease, heart dysfunction can be reversed with selenium supplementation, suggesting a potential causal relationship.

However, it is not yet known whether selenium supplementation can improve clinical outcomes in patients with heart failure when added to standard medical therapy.

The SIRI-HF trial is a randomized, placebo-controlled study designed to evaluate whether daily supplementation with 200 micrograms of selenium, in addition to guideline-directed medical therapy, improves outcomes in patients with heart failure.

The primary endpoint is a composite of recurrent heart failure hospitalizations and cardiovascular death. Secondary endpoints include all-cause mortality, changes in symptoms and functional status, and safety outcomes.

This study will include patients from Sweden and Norway and aims to determine whether correcting selenium deficiency can improve prognosis in heart failure.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Cognitive Functioning; Selenium; Selenium Supplementation; Heart Failure and Reduced Ejection Fraction; Heart Failure and Mildly Reduced Ejection Fraction; Heart Failure and Preserved Ejection Fraction
• Intervention / Treatment: Dietary supplement: Selenium Supplement; Dietary supplement: Placebo

Detailed Description

Heart failure (HF) is a complex, systemic syndrome characterized not only by impaired cardiac function but also by metabolic, inflammatory, and neurohormonal disturbances. Despite advances in guideline-directed medical therapy, patients with HF continue to experience high rates of hospitalization and mortality, highlighting the need for additional therapeutic strategies.

Selenium is an essential trace element incorporated into selenoproteins that play key roles in redox regulation, mitochondrial function, immune modulation, and thyroid hormone metabolism. Observational data from European populations, where dietary selenium intake is relatively low, have demonstrated associations between low selenium status and increased risk of incident HF, impaired functional capacity, reduced quality of life, and higher mortality. Mechanistically, selenium deficiency may contribute to impaired mitochondrial oxidative phosphorylation, increased oxidative stress, and cardiomyocyte dysfunction.

While prior randomized studies of selenium supplementation have yielded mixed results, these have largely been conducted in populations with adequate baseline selenium levels or have not specifically targeted patients with HF. Smaller studies and subgroup analyses suggest potential benefits on cardiac function and clinical outcomes, but definitive evidence is lacking.

The SIRI-HF trial is designed to address this evidence gap using a pragmatic, registry-based randomized clinical trial (RRCT) design. The study is embedded within established national heart failure registries in Sweden (SwedeHF) and Norway (NHFR), enabling large-scale recruitment and efficient long-term follow-up through linkage with national healthcare and administrative registries. This approach allows for comprehensive capture of clinical events, including hospitalizations and mortality, in a real-world setting.

A total of 4,326 adult patients with a diagnosis of heart failure will be randomized in a 1:1 ratio to receive either oral selenium supplementation (200 µg daily) or matching placebo, in addition to standard care. The trial is double-blind, with participants, investigators, and outcome assessors masked to treatment allocation. Recruitment is planned over approximately four years, with follow-up extending up to five years depending on enrollment timing.

The study is conducted using a largely remote design. Eligible patients are identified through registry data and invited to participate via digital or postal consent procedures. Study treatment is distributed directly to participants, and follow-up includes periodic electronic questionnaires assessing symptoms, adherence, and quality of life. Clinical outcomes are ascertained through linkage with national registries, minimizing the need for in-person visits and reducing loss to follow-up.

The primary endpoint is the total number of heart failure hospitalizations and cardiovascular deaths, analyzed as recurrent events over the follow-up period. Secondary endpoints include time-to-event outcomes such as first heart failure hospitalization or cardiovascular death, as well as individual components including cardiovascular mortality and all-cause mortality. Additional exploratory outcomes include broader cardiovascular events, unscheduled hospitalizations, incident dementia, and changes in patient-reported health status measured by the Kansas City Cardiomyopathy Questionnaire.

A predefined mechanistic sub-study will be conducted in a subset of participants to evaluate the effects of selenium supplementation on cardiac structure and function, biomarkers, functional capacity, and biochemical measures of selenium status.

The registry-based design, large sample size, and integration with national health data systems are expected to provide robust and generalizable evidence regarding the effect of selenium supplementation on clinically relevant outcomes in patients with heart failure.

• Study Type: Interventional
• Enrollment (Estimated): 4326
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Martin Magnusson, Professor; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se

Study Locations

• Norway
  • Oslo, Norway
    • Recruiting
    • Oslo University Hospital
    • Contact: Peder Langeland Myhre, Professor; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se
• Sweden
  • Gothenburg, Sweden
    • Recruiting
    • Sahlgrenska University Hospital Östra
    • Contact: Erik, Thunström; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se
  • Gothenburg, Sweden
    • Recruiting
    • Sahlgrenska
    • Contact: Charlotta Ljungman; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se
  • Jönköping, Sweden
    • Recruiting
    • Ryhov Hospital
    • Contact: Patric Karlström; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se
  • Linköping, Sweden
    • Recruiting
    • Linköping University Hospital
    • Contact: Peter Wodlin; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se
  • Lund, Sweden
    • Recruiting
    • Skånes University Hospital
    • Contact: Gustav Smith, Professor; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se
  • Stockholm, Sweden
    • Recruiting
    • Karolinska University Hospital
    • Contact: Camilla Hage, Ass. professor; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se
  • Umeå, Sweden
    • Recruiting
    • Norrlands University Hospital
    • Contact: Therese Andersson; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se
  • Uppsala, Sweden
    • Recruiting
    • Akademiska University hospital
    • Contact: Christina Christersson; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se
  • Örebro, Sweden
    • Recruiting
    • Orebro University Hospital
    • Contact: Barna Szabo; Phone Number: +46186119515; Email: siri_hf@ucr.uu.se
  • Skåne County
    • Malmo, Skåne County, Sweden
      • Recruiting
      • Skånes University Hospital
      • Principal Investigator: Martin Magnusson, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

To be considered for inclusion in this study, patients must meet all of the following eligibility requirements:

• 18 years of age
• primary discharge diagnosis of HF coded as ICD-10: I50, as recorded in The SwedeHF registry
• be able to provide documented informed consent by signing and dating the designated consent form.

Exclusion Criteria:

• Not suitable in the opinion of the Investigator (for example due to severe or terminal comorbidity with poor prognosis, or characteristics, pregnancy etc.) that may interfere with adherence to trial protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Selenium 200mcg daily in addition to GDMT	Dietary supplement: Selenium Supplement; Selenium will be provided as the Bio-SelenoPrecise supplement. Each Bio-SelenoPrecise tablet contains 200 μg of selenium in the form of the yeast-based compound SelenoPrecise yeast. The tablets also include excipients such as microcrystalline cellulose, dicalcium phosphate, crosscarmellose sodium, silica, magnesium stearate, and is coated with hydroxypropyl methylcellulose
Placebo Comparator: Placebo in addition to GDMT	Dietary supplement: Placebo; Placebo tablet identical to active comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of HF hospitalizations and/or CV mortality in heart failure patients.	The primary objective is to assess whether supplementation with selenium compared to placebo reduces the number of HF hospitalizations and/or CV mortality in HF patients.	Recruitment over 4 years, followed by an additional year of observation, resulting in an average follow-up of 3 years, with an adaptive component allowing for an interim analysis to evaluate accrued data and adjust the study duration if necessary

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of major adverse cardiovascular events	- Major adverse CV events (MACE), defined as a combination of hospitalization for HF, stroke, acute myocardial infarction, or CV death.	Recruitment over 4 years, followed by an additional year of observation, resulting in an average follow-up of 3 years, with an adaptive component allowing for an interim analysis to evaluate accrued data and adjust study duration if necessary.
Time to a composite event of first hospitalization for HF or CV death	Secondary objectives of the study are (i) time to a composite event of first hospitalization for HF or CV death, both defined as in the primary endpoint,	Recruitment over 4 years, followed by an additional year of observation, resulting in an average follow-up of 3 years, with an adaptive component allowing for an interim analysis to evaluate accrued data and adjust the study duration if necessary

Collaborators and Investigators

• Sponsor: Skane University Hospital
• Collaborators: Uppsala Clinical Research Center, Sweden

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2026
• Primary Completion (Estimated): March 1, 2030
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: April 7, 2026
• First Submitted That Met QC Criteria: April 15, 2026
• First Posted (Actual): April 22, 2026

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: heart failure; selenium; RRCT; SIRI-HF
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Heart Failure, Diastolic; Heart Failure, Systolic
• Other Study ID Numbers: Dnr 2025-02943-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No