## Protocol Section
### Identification Module
**NCT ID:** NCT06434025

**Acronym:** COMBINED-HF

**Brief Title:** IV Iron and SGLT2 Inhibitor on Ventricular Function and Myocardial Iron Content in Heart Failure With Iron Deficiency

**Official Title:** Effect of Combination of Intravenous Iron and SGLT2 Inhibitor on Ventricular Function and Myocardial Iron Content in Patients With Heart Failure and Iron Deficiency.

#### Organization Study ID Info
**ID:** 78861724.0.0000.5327
#### Organization
**Class:** OTHER
**Full Name:** Hospital de Clinicas de Porto Alegre
#### Secondary ID Infos
**Domain:** AGH-Use HCPA
**ID:** 2023-0428
**Type:** OTHER
### Status Module
#### Completion Date
**Date:** 2026-11-24

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-30

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-23

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-05-24

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-05-24

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-30
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-23
**Study First Submit QC Date:** 2024-05-23
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** Vifor Pharma

#### Lead Sponsor

**Class:** OTHER

**Name:** Hospital de Clinicas de Porto Alegre

#### Responsible Party

**Investigator Affiliation:** Hospital de Clinicas de Porto Alegre

**Investigator Full Name:** Luis Beck Da Silva Neto

**Investigator Title:** Professor of Medicine

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** Background. Treatment with intravenous iron has been shown to improve symptoms, functional capacity, and quality of life in patients with heart failure with reduced ejection fraction (HFrEF) and iron deﬁciency. However, the mechanisms underlying these beneﬁcial eﬀects remain unknown. SGLT2i seem to alter hematocrit and other hematological markers or iron content.

This study aims to measure cardiac magnetic resonance changes in myocardial iron content and in left ventricular function after administration of intravenous iron with and without the concomitant use of SGLT2 inhibitor in patients with HFrEF and iron deﬁciency.

**Detailed Description:** Background. Treatment with intravenous iron has been shown to improve symptoms, functional capacity, and quality of life in patients with heart failure with reduced ejection fraction (HFrEF) and iron deﬁciency. However, the mechanisms underlying these beneﬁcial eﬀects remain unknown. SGLT2i seem to alter hematocrit and other hematological markers or iron content. This study aims to measure cardiac magnetic resonance changes in myocardial iron content after administration of intravenous iron and to assess changes in left ventricular function in patients with HFrEF and iron deﬁciency.

Methods. Ninety-nine outpatient with symptomatic HFrEF, left ventricular ejection fraction (LVEF) \<40%, SGLT2i naive, and iron deﬁciency will be assigned, to receive intravenous iron + SGLT2i; or intravenous iron + placebo of SGLT2i; or placebo of both therapies for 30 days. Myocardial iron will be evaluated by T2-star (T2\*) cardiac magnetic resonance (CMR) sequencing before intravenous iron infusion. After 30 days, all patients will be reassessed by T2\* CMR sequencing. The primary endpoint will be changes in LVEF and myocardial iron content at 30 days. Secondary endpoints will include correlations of these changes with myocardial iron content, functional capacity, quality of life, and cardiac biomarkers.

Conclusions. This study will determine the eﬀect of ferric carboxymaltose and its combination with SGLT2i on LVEF and its relationship with measures of myocardial iron content, functional capacity, and biomarkers in HFrEF and iron deﬁciency.

### Conditions Module

**Conditions:**

- Heart Failure, Systolic

- Iron Deficiencies

**Keywords:**

- heart failure

- iron deficiency

- SGLT2 inhibitor

- intravenous iron

- clinical trial

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** HFrEF, LVEF \<40%, SGLT2i naive, and iron deﬁciency. Assigned to receive:

1. intravenous iron + SGLT2i;
2. intravenous iron + placebo of SGLT2i;
3. placebo of both therapies.

##### Masking Info

**Masking:** TRIPLE

**Who Masked:**

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 99

**Type:** ESTIMATED

**Phases:**

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Patients will receive 2 vials of ferric carboxymaltose 500 mg (Ferinject® 500 mg, CSL-Vifor) IV, once; and Dapagliflozin 10 mg PO, OD, for 30 days.

**Intervention Names:**

- Drug: Iron Carboxymaltose

**Label:** IV iron + SGLT2 inhibitor

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Patients will receive 2 vials of ferric carboxymaltose 500 mg (Ferinject® 500 mg, CSL-Vifor) IV, once; and placebo PO, OD, for 30 days.

**Intervention Names:**

- Drug: Iron Carboxymaltose

**Label:** IV iron + placebo of SGLT2 inhibitor

**Type:** ACTIVE_COMPARATOR

#### Arm Group 3

**Description:** Patients will receive 2 vials of placebo IV, once; and placebo PO, OD, for 30 days.

**Intervention Names:**

- Drug: Iron Carboxymaltose

**Label:** Placebo of IV iron and placebo of SGLT2 inhibitor

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- IV iron + SGLT2 inhibitor

- IV iron + placebo of SGLT2 inhibitor

- Placebo of IV iron and placebo of SGLT2 inhibitor

**Description:** Combination of Iron Carboxymaltose and Dapagliflozin

**Name:** Iron Carboxymaltose

**Other Names:**

- Dapagliflozin

**Type:** DRUG

### Outcomes Module

#### Other Outcomes

**Description:** distance walked in six minute walk test

**Measure:** six minute walk test (6MWT)

**Time Frame:** 30 days

**Description:** NT-terminal pro-B-type natriuretic peptide (NT-proBNP) levels

**Measure:** NT-proBNP

**Time Frame:** 30 days

**Description:** Quality of life assessed by the Minnesota Living with Heart Failure Questionnaire

**Measure:** MLHFQ

**Time Frame:** 30 days

**Description:** Serum Hepcidin levels

**Measure:** Hepcidin

**Time Frame:** 30 days

**Description:** Reticulocyte hemoglobin content

**Measure:** Reticulocyte hemoglobin content

**Time Frame:** 30 days

**Description:** Transferrin soluble receptors

**Measure:** Transferrin soluble receptors

**Time Frame:** 30 days

**Description:** Glomerular filtration rate

**Measure:** Glomerular filtration rate

**Time Frame:** 30 days

#### Primary Outcomes

**Description:** LVEF assessed by Cardiac Magnetic Ressonance

**Measure:** left ventricular function assessed (LVEF) by CMR.

**Time Frame:** 30 days

#### Secondary Outcomes

**Description:** Myocardial iron content assessed by T2\* CMR

**Measure:** Myocardial iron content assessed by T2* CMR

**Time Frame:** 30 days

**Description:** myocardial strain assessed by T2\* CMR

**Measure:** myocardial strain assessed by T2* CMR

**Time Frame:** 30 days

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Age 18 years or over;
2. Ejection fraction (EF) ≤40%, estimated by color Doppler echocardiography or CMR or radionuclide ventriculography;
3. Serum ferritin \<100 µg/L or serum ferritin between 100 and 299 µg/L and transferrin saturation \<20%;
4. Serum hemoglobin between 9.5 and 13.5 mg/dL;
5. Patients must be SGLT2 naive;
6. Informed consent form (ICF) signed.

Exclusion Criteria:

1. Kidney disease requiring dialysis or chronic kidney disease not requiring dialysis with an estimated glomerular ﬁltration rate \<30 mL/min/1.73 m2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation;
2. Severe primary valve disease;
3. Acute coronary syndrome requiring cardiac surgery or coronary artery bypass surgery in the past 3 months;
4. Patients already being treated for some type of non-iron deﬁciency anemia;
5. Blood transfusion within 30 days prior to CMR examination;
6. Patients with a pacemaker, cardiac resynchronization therapy, or implantable defibrillator;
7. Diagnosis of hemochromatosis.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** lbneto@hcpa.edu.br

**Name:** LUIS BECK DA SILVA, MD ScD

**Phone:** 55 51 997330870

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Porto Alegre

**Contacts:**

***Contact 1:***

- **Email:** apbsilveira@hcpa.edu.br

- **Name:** Ana Paula Silveira, BMD

- **Phone:** 55 51 33596223

- **Role:** CONTACT

***Contact 2:***

- **Email:** mraymundo@hcpa.edu.br

- **Name:** Marcia Raymundo

- **Phone:** 55 51 33596224

- **Role:** CONTACT

**Country:** Brazil

**Facility:** Hospital de Clínicas de Porto Alegre

**State:** RS

**Zip:** 90450120

#### Overall Officials

**Official 1:**

**Affiliation:** Hospital de Clinicas de Porto Alegre

**Name:** LUIS BECK DA SILVA, MD ScD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000006331

- Term: Heart Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

- ID: D000019189

- Term: Iron Metabolism Disorders

- ID: D000008659

- Term: Metabolic Diseases

- ID: D000000747

- Term: Anemia, Hypochromic

- ID: D000000740

- Term: Anemia

- ID: D000006402

- Term: Hematologic Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC15

- Name: Blood and Lymph Conditions

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: BC23

- Name: Symptoms and General Pathology

### Condition Browse Module - Browse Leaves

- ID: M20857

- Name: Anemia, Iron-Deficiency

- Relevance: HIGH

- As Found: Iron Deficiency

- ID: M2781

- Name: Iron Deficiencies

- Relevance: HIGH

- As Found: Iron Deficiency

- ID: M9421

- Name: Heart Failure

- Relevance: HIGH

- As Found: Heart Failure

- ID: M27579

- Name: Heart Failure, Systolic

- Relevance: HIGH

- As Found: Heart Failure, Systolic

- ID: M27583

- Name: Systolic Murmurs

- Relevance: LOW

- As Found: Unknown

- ID: M4070

- Name: Anemia

- Relevance: LOW

- As Found: Unknown

- ID: M9419

- Name: Heart Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M11639

- Name: Metabolic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M21177

- Name: Iron Metabolism Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M4077

- Name: Anemia, Hypochromic

- Relevance: LOW

- As Found: Unknown

- ID: M9490

- Name: Hematologic Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000006333

- Term: Heart Failure

- ID: D000054143

- Term: Heart Failure, Systolic

- ID: D000018798

- Term: Anemia, Iron-Deficiency

- ID: D000090463

- Term: Iron Deficiencies

### Intervention Browse Module - Ancestors

- ID: D000077203

- Term: Sodium-Glucose Transporter 2 Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000007004

- Term: Hypoglycemic Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: Hypo

- Name: Hypoglycemic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Micro

- Name: Micronutrients

### Intervention Browse Module - Browse Leaves

- ID: M348449

- Name: Dapagliflozin

- Relevance: HIGH

- As Found: COPD

- ID: M10533

- Name: Iron

- Relevance: LOW

- As Found: Unknown

- ID: M1691

- Name: Sodium-Glucose Transporter 2 Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M10054

- Name: Hypoglycemic Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000529054

- Term: Dapagliflozin

### Misc Info Module

- Version Holder: 2024-05-31
