## Protocol Section
### Identification Module
**NCT ID:** NCT06414759

**Brief Title:** Efficacy and Safety of Combination Diuretic Therapy in Patients With Acute Decompensated Heart Failure and Volume Overload

**Official Title:** Efficacy and Safety of Combination Diuretic Therapy in Patients With Acute Decompensated Heart Failure and Volume Overload

#### Organization Study ID Info
**ID:** CL3575
#### Organization
**Class:** OTHER
**Full Name:** Cairo University
#### Secondary ID Infos
**Domain:** General Organization for Teaching Hospitals and Institutes (GOTHI)
**ID:** IHC00077
**Type:** REGISTRY
### Status Module
#### Completion Date
**Date:** 2025-03-30

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-16

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-13

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2024-12-30

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-05-22

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-16
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-08
**Study First Submit QC Date:** 2024-05-13
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER_GOV

**Name:** National Heart Institute, Egypt

#### Lead Sponsor

**Class:** OTHER

**Name:** Cairo University

#### Responsible Party

**Investigator Affiliation:** Misr International University

**Investigator Full Name:** Mohamed Ahmed Naguib Mohamed Abdelmoaty

**Investigator Title:** Teaching Assistant of Clinical Pharmacy

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** This study aims to compare two medications, acetazolamide and metolazone, along with loop diuretics, to see which one works better and is safer for patients with ADHF who have volume overload. By comparing these medications, we hope to learn which one can help these patients the most. This will help doctors choose the best treatment for patients with ADHF and volume overload.

### Conditions Module

**Conditions:**

- Acute Decompensated Heart Failure

- Volume Overload

- Edema

**Keywords:**

- ADHF

- Acute Decompensated Heart Failure

- AHF

- Acute Heart Failure

- Volume overload

- Edema

- Loop diuretics

- Fusrosemide

- Metolazone

- Acetazolamide

- Carbonic anhydrase inhibitor

- Thiazide like diuretics

- Thiazide diuretics

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** Prospective, randomized, single-blinded, controlled trial

##### Masking Info

**Masking:** SINGLE

**Who Masked:**

- PARTICIPANT

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 110

**Type:** ESTIMATED

**Phases:**

- PHASE4

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** First group (IV loop Diuretics + oral acetazolamide): patients will receive IV loop diuretic 2 times the outpatient oral (PO) daily dose, and oral loop diuretics will be stopped. In cases where the patient was not previously on oral diuretics, a starting dose of 40 mg of IV furosemide, IV bumetanide 1 mg or a bolus of 20 mg of IV torsemide can be utilized, together with acetazolamide: 500 mg PO once daily.

**Intervention Names:**

- Drug: Acetazolamide

- Drug: IV Loop Diuretics

**Label:** Group 1

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Second group (IV loop diuretics + oral metolazone): patients will receive IV loop diuretic approximately 2 times the outpatient oral daily dose, and oral loop diuretics will be stopped. In cases where the patient was not previously on oral diuretics, a starting dose of 40 mg of IV furosemide, IV bumetanide 1 mg or a bolus of 20 mg of IV torsemide can be utilized, together with metolazone: 5 mg PO once daily.

**Intervention Names:**

- Drug: Metolazone

- Drug: IV Loop Diuretics

**Label:** Group 2

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Group 1

**Description:** Acetazolamide is a medication that belongs to the class of carbonic anhydrase inhibitors. It acts by reducing the reabsorption of sodium in the proximal tubules of the kidneys. When combined with loop diuretics, acetazolamide has the potential to enhance the effectiveness of diuretic therapy, thus aiding in the process of decongestion.

It will be given 500mg orally, once daily.

**Name:** Acetazolamide

**Other Names:**

- Carbonic anhydrase inhibitor

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Group 2

**Description:** Metolazone is a medication with properties like thiazide diuretics, prescribed for the management of congestive heart failure and hypertension. Its mechanism of action involves blocking the transport of sodium across the epithelium of renal tubules, predominantly in the distal tubules.

It will be given 5mg orally, once daily.

**Name:** Metolazone

**Other Names:**

- Thiazide like diuretic

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Group 1

- Group 2

**Description:** IV loop diuretic 2 times the outpatient oral (PO) daily dose, and oral loop diuretics will be stopped. In cases where the patient was not previously on oral diuretics, a starting dose of 40 mg of IV furosemide, IV bumetanide 1 mg or a bolus of 20 mg of IV torsemide can be utilized.

**Name:** IV Loop Diuretics

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Total Urine output Volume

**Measure:** Urine Output

**Time Frame:** 48 Hours

#### Secondary Outcomes

**Description:** Urine output/40 mg furosemide equivalent

**Measure:** Diuretic Response

**Time Frame:** 48 Hours

**Description:** Change in Body Weight

**Measure:** Body Weight

**Time Frame:** 48 Hours

**Description:** Change in congestion score (Modified ADVOR Trial Congestion Score)

**Measure:** Congestion Score

**Time Frame:** 48 Hours

**Description:** Change in NT-Pro BNP/BNP levels

**Measure:** NT-proBNP/BNP

**Time Frame:** On admission and before discharge (up to 2 Weeks)

**Description:** Change in bicarbonate level from baseline \[ABG\]

**Measure:** Bicarbonate Level

**Time Frame:** 48 Hours

**Description:** Change in serum creatinine (SCr)

**Measure:** Serum Creatinine

**Time Frame:** 48 Hours

**Description:** Change in estimated glomerular filtration rate (eGFR) from baseline

**Measure:** eGFR

**Time Frame:** 48 Hours

**Description:** Change in systolic blood pressure (SBP) from baseline

**Measure:** Blood Pressure

**Time Frame:** 48 Hours

**Description:** Change in serum potassium from baseline

**Measure:** Serum Potassium

**Time Frame:** 48 Hours

**Description:** Both general ward and CCU

**Measure:** Length of Hospital Stay

**Time Frame:** Up to 2 weeks

**Description:** All-cause mortality and heart failure readmission during 3 months of follow-up

**Measure:** Mortality or HF Events

**Time Frame:** 3 Months

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Male or female patients with ages ≥ 18 years old, and less than 65 years old.
* For both elective and emergency hospital admissions, patients with a clinical diagnosis of ADHF must exhibit at least one clinical sign indicative of volume overload. These signs may include edema (score 2 or higher), ascites confirmed through echography, or pleural effusion confirmed by chest X-ray or echography or rales on auscultation, or jugular venous pressure greater than10 mm Hg.

Exclusion Criteria:

* Patient diagnosed with acute kidney injury upon hospital admission based on the presence of any of the following criteria: an increase in SCr by at least 0.3 mg/dL within 48 hours, an increase in SCr to at least 2 times the baseline value, known or presumed to have occurred within the prior 7 days, and a urine volume less than 0.5 ml/kg/hour for a duration of 6 hours.
* Patients with acute pulmonary edema caused by increased afterload and fluid redistribution to the lungs in the absence or with minimal fluid accumulation.
* Anticipated exposure to nephrotoxic agents (such as contrast dye) during hospitalization.
* Patients who exhibit anuria or are undergoing renal replacement therapy or ultrafiltration.
* Patients with eGFR less than 30 mL/min/1.73m² at the time of screening.
* Expected use of intravenous inotropes, vasopressors, or nitroprusside during the study.
* Prior cardiac transplantation and/or utilization of a ventricular assist device.
* Blood pressure below 90 mmHg or mean arterial pressure below 65 mmHg at the time of recruitment.
* Patients who are pregnant or breastfeeding.
* Administration of acetazolamide or metolazone within the one-month period preceding randomization.
* The usage of any diuretic agent during the treatment phase is not specified in the study protocol, except for mineralocorticoid receptor antagonists.

**Maximum Age:** 65 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** mohamed.naguib@miuegypt.edu.eg

**Name:** Mohamed AN Abdelmoaty, B.Sc. Pharmaceutical Sciences

**Phone:** +201146631157

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Giza

**Contacts:**

***Contact 1:***

- **Email:** mohamed.naguib@miuegypt.edu.eg

- **Name:** Mohamed AN Abdelmoaty, B.Sc. Pharmaceutical Sciences

- **Phone:** +201146631157

- **Role:** CONTACT

***Contact 2:***

- **Name:** Bassem Zarif, PhD, Cardiology

- **Phone:** +201223950548

- **Role:** CONTACT

***Contact 3:***

- **Name:** Mohamed AN Abdelmoaty, B.Sc. Pharmaceutical Sciences

- **Role:** PRINCIPAL_INVESTIGATOR

***Contact 4:***

- **Name:** Nirmeen Sabry, PhD, Clinical Pharmacy

- **Role:** PRINCIPAL_INVESTIGATOR

***Contact 5:***

- **Name:** Bassem Zarif, PhD, Cardiology

- **Role:** PRINCIPAL_INVESTIGATOR

***Contact 6:***

- **Name:** Sahar Atef, PhD, Clinical Pharmacy

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** Egypt

**Facility:** National Heart Institute

**State:** GZ

**Zip:** 3755204

### References Module

#### References

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**PMID:** 33983837

**Citation:** Hsiao R, Greenberg B. Contemporary Treatment of Acute Heart Failure. Prog Cardiovasc Dis. 2016 Jan-Feb;58(4):367-78. doi: 10.1016/j.pcad.2015.12.005. Epub 2016 Jan 5.

**PMID:** 26764279

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**PMID:** 21366472

**Citation:** Hoorn EJ, Ellison DH. Diuretic Resistance. Am J Kidney Dis. 2017 Jan;69(1):136-142. doi: 10.1053/j.ajkd.2016.08.027. Epub 2016 Nov 1.

**PMID:** 27814935

**Citation:** Suri SS, Pamboukian SV. Optimal diuretic strategies in heart failure. Ann Transl Med. 2021 Mar;9(6):517. doi: 10.21037/atm-20-4600.

**PMID:** 33850914

**Citation:** McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368. No abstract available. Erratum In: Eur Heart J. 2021 Oct 14;:

**PMID:** 34447992

**Citation:** Sica DA. Metolazone and its role in edema management. Congest Heart Fail. 2003 Mar-Apr;9(2):100-5. doi: 10.1111/j.1527-5299.2003.01907.x.

**PMID:** 12671341

**Citation:** Cox ZL, Hung R, Lenihan DJ, Testani JM. Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial. JACC Heart Fail. 2020 Mar;8(3):157-168. doi: 10.1016/j.jchf.2019.09.012. Epub 2019 Dec 11.

**PMID:** 31838029

**Citation:** Verbrugge FH, Dupont M, Bertrand PB, Nijst P, Penders J, Dens J, Verhaert D, Vandervoort P, Tang WH, Mullens W. Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. Acta Cardiol. 2015 Jun;70(3):265-73. doi: 10.1080/ac.70.3.3080630.

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**Citation:** Verbrugge FH, Martens P, Ameloot K, Haemels V, Penders J, Dupont M, Tang WHW, Droogne W, Mullens W. Acetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistance. Eur J Heart Fail. 2019 Nov;21(11):1415-1422. doi: 10.1002/ejhf.1478. Epub 2019 May 9.

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## Derived Section

### Condition Browse Module - Ancestors

- ID: D000006331

- Term: Heart Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M9421

- Name: Heart Failure

- Relevance: HIGH

- As Found: Heart Failure

- ID: M7657

- Name: Edema

- Relevance: LOW

- As Found: Unknown

- ID: M9419

- Name: Heart Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T170

- Name: Acute Graft Versus Host Disease

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000006333

- Term: Heart Failure

### Intervention Browse Module - Ancestors

- ID: D000045283

- Term: Natriuretic Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000000927

- Term: Anticonvulsants

- ID: D000004791

- Term: Enzyme Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000049990

- Term: Membrane Transport Modulators

- ID: D000000959

- Term: Antihypertensive Agents

- ID: D000049993

- Term: Sodium Chloride Symporter Inhibitors

### Intervention Browse Module - Browse Branches

- Abbrev: AnAg

- Name: Antihypertensive Agents

- Abbrev: NaAg

- Name: Natriuretic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: AntiConv

- Name: Anticonvulsants

### Intervention Browse Module - Browse Leaves

- ID: M11761

- Name: Metolazone

- Relevance: HIGH

- As Found: Endothelin

- ID: M2536

- Name: Acetazolamide

- Relevance: HIGH

- As Found: Pain Control

- ID: M7411

- Name: Diuretics

- Relevance: HIGH

- As Found: Hypoglycemia

- ID: M5515

- Name: Carbonic Anhydrase Inhibitors

- Relevance: HIGH

- As Found: Starts during

- ID: M1912

- Name: Torsemide

- Relevance: LOW

- As Found: Unknown

- ID: M8784

- Name: Furosemide

- Relevance: LOW

- As Found: Unknown

- ID: M5306

- Name: Bumetanide

- Relevance: LOW

- As Found: Unknown

- ID: M26153

- Name: Sodium Potassium Chloride Symporter Inhibitors

- Relevance: HIGH

- As Found: Duo

- ID: M4246

- Name: Anticonvulsants

- Relevance: LOW

- As Found: Unknown

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M4277

- Name: Antihypertensive Agents

- Relevance: LOW

- As Found: Unknown

- ID: M26152

- Name: Sodium Chloride Symporter Inhibitors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000008788

- Term: Metolazone

- ID: D000000086

- Term: Acetazolamide

- ID: D000004232

- Term: Diuretics

- ID: D000002257

- Term: Carbonic Anhydrase Inhibitors

- ID: D000049994

- Term: Sodium Potassium Chloride Symporter Inhibitors

### Misc Info Module

- Version Holder: 2024-05-31
