## Protocol Section
### Identification Module
**NCT ID:** NCT06431919

**Acronym:** CIRROSTAT

**Brief Title:** Carvedilol + Simvastatin vs. Carvedilol Alone for Chronic Liver Disease and Cirrhotic Cardiomyopathy and Its Impact on Hepatic Decompensation and Survival; a Double-blind Randomized Controlled Trial

**Official Title:** Carvedilol + Simvastatin vs. Carvedilol Alone for Chronic Liver Disease and Cirrhotic Cardiomyopathy and Its Impact on Hepatic Decompensation and Survival; a Double-blind Randomized Controlled Trial

#### Organization Study ID Info
**ID:** PGI/HEP/000214
#### Organization
**Class:** OTHER
**Full Name:** Post Graduate Institute of Medical Education and Research, Chandigarh
### Status Module
#### Completion Date
**Date:** 2027-08

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-29

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-22

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2025-08

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-08

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-29
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-22
**Study First Submit QC Date:** 2024-05-22
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER_GOV

**Name:** Indian Council of Medical Research

#### Lead Sponsor

**Class:** OTHER

**Name:** Post Graduate Institute of Medical Education and Research, Chandigarh

#### Responsible Party

**Investigator Affiliation:** Post Graduate Institute of Medical Education and Research, Chandigarh

**Investigator Full Name:** Madhumita Premkumar

**Investigator Title:** ASSOCIATE PROFESSOR

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Cirrhosis and portal hypertension are associated with a hyperdynamic circulation and decompensation events, including development of ascites, variceal bleeding, acute kidney injury, and susceptibility to infections.

Rationale:

Cirrhosis and portal hypertension are associated with a hyperdynamic circulation and decompensation events, including ascites, variceal bleeding, acute kidney injury, and susceptibility to infections. CCM, present in 30-70% of patients, is characterized by structural and functional abnormalities in the heart, and is associated with progression of cirrhosis, impaired quality of life and poor survival. Statins play a crucial role in reducing proatherogenic LDL cholesterol levels, making them a cornerstone in managing diabetes and cardiovascular diseases (CVDs) with the aim of decreasing or reversing atherosclerosis. This trial aims to evaluate the impact and safety of simvastatin in cirrhotic cardiomyopathy.

Novelty: Simvastatin might be of special value in diastolic dysfunction through its hemodynamic and functional effects on LV remodeling and improve portal hemodynamics through the pleotropic effects of lipophilic statins.

Objectives:

The primary objective is to assess the combined effects of carvedilol and simvastatin in managing CCM vs carvedilol alone for a composite outcome to prevent decompensation and reduce all-cause mortality. We will comprehensively evaluate cardiac function, decompensation events and survival based on impact of simvastatin over the standard betablocker carvedilol.

Methods:

This is double-blinded randomized placebo-controlled trial involving patients diagnosed with CCM. Clinical data, including cardiac imaging, cardiac biomarkers, and survival outcomes, will be assessed for either group.

Expected Outcome:

We anticipate that the synergistic use of simvastatin and carvedilol will effectively reduce portal pressure, improve portal haemodynamic, and enhance cardiac remodelling. Successful reversal of LVDD can potentially prevent clinical events such as ascites, encephalopathy, and acute kidney injury (AKI).

**Detailed Description:** Cirrhotic cardiomyopathy (CCM) in chronic liver disease is seen as a blunted contractile responsiveness to stress, and/or altered diastolic relaxation with electrophysiological abnormalities, in absence of known cardiac disease(1, 6). Cirrhosis induces systemic inflammation, and oxidative stress leading to cardiac structural remodeling, including fibrosis, hypertrophy, and chamber dilation. CCM is associated with risk of LVDD which further lead to hepatorenal syndrome (HRS)(7), septic shock. (8) and peri transplant cardiac complications.(9) Autonomic dysfunction, and neurohormonal imbalances, cardiac arrhythmias, overt heart failure are common features of CCM in advanced liver disease. Efforts to ameliorate the abnormalities associated with CCM are crucial and necessitate a significant evidence-based therapeutic intervention. We have tested the use of carvedilol in this population and found that it causes an improvement in survival.

CCM can be managed by reducing preload (though nitrates), and by ameliorating neurohormonal activation. Lowering the heart rate to 55-65 beats per minute (bpm), as done with β-blockers, is likely to help by improving myocardial oxygen demand and coronary perfusion time with independent effects on portal hypertension, and heart failure(10, 11) β-blockers may reduce myocardial contractility and patients with cirrhosis have low tolerance to β-blocker dosages required to achieve a THR of 55-65 bpm. Ivabradine is useful in a subset with baseline tachycardia but does not offer survival benefit over carvedilol alone. Therefore, there is a great need to evaluate other agents that can achieve improvement in CCM related complications in cirrhosis.

* Furthermore, β-blockers might diminish myocardial contractility, and patients with cirrhosis may struggle to tolerate β-blocker doses necessary for attaining a target heart rate (THR) of 55-65 bpm. Hence, there's a critical necessity to assess alternative agents capable of ameliorating complications associated with cirrhotic cardiomyopathy (CCM).
* Early interventions to avert cardiovascular morbidity will prove to be cost effective in managing outcome, as they avert high cost of managing the public health burden of all-cause mortality in cirrhosis.
* Cardiovascular complications stand as the primary cause of mortality post-liver transplantation (LT), underscoring the need for thorough evaluation before LT.
* This study will systematically screen participants for coronary artery disease as an integral part of its screening process.
* Statins, particularly simvastatin, exert a favorable impact on vascular reactivity especially in cirrhosis. Simvastatin increases the production of nitric oxide(NO), leading to increased hepatic blood flow and reduced sinusoidal resistance, particularly upon short-term exposure. resistance (8).
* Kaplan et al showed extended exposure to simvastatin (1 month regimen, comprising 20 mg/day for the initial 15 days followed by 40 mg/day for the subsequent 15 days) resulted in a significant decrease in hepatic venous portal pressure as compared to control placebo. Additionally, this prolonged regimen exhibited improvements in hepatocyte metabolic function.(9).
* Simvastatin has an acceptable adverse event profile in decompensated Child B patients (10, 11). There is no high-quality evidence specifically evaluating the role of simvastatin in cirrhotic cardiomyopathy, although there are data to suggest its efficacy in portal hypertension. The proposed project covers an area of overlap between cardiovascular and liver disease outcomes, which reflect as decompensation events, worsening in liver severity scores and all-cause mortality.

### Conditions Module

**Conditions:**

- Decompensated Cirrhosis

- Cirrhotic Cardiomyopathy

- Cirrhosis, Liver

- Left Ventricular Diastolic Dysfunction

- Acute Kidney Injury

**Keywords:**

- Decompensated Cirrhosis

- Cirrhotic Cardiomyopathy

- Left ventricular diastolic dysfunction

- Acute kidney injury

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** QUADRUPLE

**Masking Description:** Double-blind randomized controlled trial

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 260

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** * Simvastatin fixed dose of 20 mg per day
* Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate
* Standard Medical Therapy

**Intervention Names:**

- Drug: Simvastatin 20mg

- Drug: Carvedilol 3.125 mg

**Label:** Experimental: Simvastatin + Carvedilol-arm

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** * Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate
* Standard Medical Therapy

**Intervention Names:**

- Drug: Carvedilol 3.125 mg

**Label:** Active Comparator: Carvedilol arm

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Experimental: Simvastatin + Carvedilol-arm

**Description:** Simvastatin fixed dose of 20 mg per day

**Name:** Simvastatin 20mg

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Active Comparator: Carvedilol arm

- Experimental: Simvastatin + Carvedilol-arm

**Description:** Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate

**Name:** Carvedilol 3.125 mg

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** The primary outcome measure is defined as a composite end point of acute decompensation event (acute variceal bleeding, new ascites or recurrence of previously controlled ascites, episode of hepatic encephalopathy or acute kidney injury) OR all-cause death in patients with cirrhosis and cirrhotic cardiomyopathy

**Measure:** Time to acute decompensation event

**Time Frame:** 1 Year

#### Secondary Outcomes

**Measure:** All-cause Mortality

**Time Frame:** From enrollment until 1 year of follow up

**Measure:** New decompensation event

**Time Frame:** 1 Year

**Measure:** Improvement in CCM parameters (left ventricular diastolic function) in either arm based on Echocardiography and Cardiac Imaging

**Time Frame:** 1 Year

**Measure:** Episodes warranting hospitalization

**Time Frame:** 1 Year

**Description:** ELISA or autoanalyzer will be performed for qunatification

**Measure:** Serum level of BNP and other cardiac and inflammatory biomarkers

**Time Frame:** 1 Year

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Age range of 18-65 years
* Compensated cirrhosis, as diagnosed by histology or clinical, laboratory and USG findings,
* CCM (with EF\>50%) on 2D echocardiography with TDI
* Written informed consent.

Exclusion Criteria:

* Age \>65 years
* Serum Creatinine\>2 mg/dl
* Patient previously treated with statin (one month before the study)
* Contraindications to statins
* Advanced Cirrhosis (CTP score\>9)
* Coronary artery disease
* Sick sinus syndrome/ Pacemaker, valvular heart disease
* Cardiac rhythm disorder, Peripartum cardiomyopathy
* Portopulmonary hypertension/ hepatopulmonary syndrome
* Transjugular intrahepatic portosystemic shunt (TIPS) insertion
* Hepatocellular carcinoma
* Pregnancy or lactation
* Patients with HIV or retroviral therapy
* Anemia Hb \< 8gm/dl in females, and \< 9 gm/dl in males
* Acute variceal bleeding in last 6 months.
* Need for medications, metabolized by CYP3A4(such as amlodipine, verapamil, fenofibrate azole antibiotics, protease inhibitors etc.)

**Maximum Age:** 65 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** drmadhumitap@gmail.com

**Name:** Dr Madhumita Premkumar, DM

**Phone:** 7087003409

**Role:** CONTACT

#### Overall Officials

**Official 1:**

**Affiliation:** PGIMER

**Name:** Dr Madhumita Premkumar, DM

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000004066

- Term: Digestive System Diseases

- ID: D000010335

- Term: Pathologic Processes

- ID: D000006331

- Term: Heart Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

- ID: D000051437

- Term: Renal Insufficiency

- ID: D000007674

- Term: Kidney Diseases

- ID: D000014570

- Term: Urologic Diseases

- ID: D000052776

- Term: Female Urogenital Diseases

- ID: D000005261

- Term: Female Urogenital Diseases and Pregnancy Complications

- ID: D000091642

- Term: Urogenital Diseases

- ID: D000052801

- Term: Male Urogenital Diseases

- ID: D000018754

- Term: Ventricular Dysfunction

### Condition Browse Module - Browse Branches

- Abbrev: BC06

- Name: Digestive System Diseases

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: BXS

- Name: Urinary Tract, Sexual Organs, and Pregnancy Conditions

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M11103

- Name: Liver Cirrhosis

- Relevance: HIGH

- As Found: Cirrhosis

- ID: M11107

- Name: Liver Diseases

- Relevance: HIGH

- As Found: Liver Disease

- ID: M12154

- Name: Cardiomyopathies

- Relevance: HIGH

- As Found: Cardiomyopathy

- ID: M28998

- Name: Acute Kidney Injury

- Relevance: HIGH

- As Found: Acute Kidney Injury

- ID: M20591

- Name: Ventricular Dysfunction, Left

- Relevance: HIGH

- As Found: Left Ventricular Diastolic Dysfunction

- ID: M20824

- Name: Ventricular Dysfunction

- Relevance: LOW

- As Found: Unknown

- ID: M8485

- Name: Fibrosis

- Relevance: HIGH

- As Found: Cirrhosis

- ID: M8883

- Name: Gastrointestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M7255

- Name: Digestive System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M9419

- Name: Heart Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M26718

- Name: Renal Insufficiency

- Relevance: LOW

- As Found: Unknown

- ID: M10698

- Name: Kidney Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M17319

- Name: Urologic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M2875

- Name: Urogenital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M27093

- Name: Female Urogenital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14127

- Name: Pregnancy Complications

- Relevance: LOW

- As Found: Unknown

- ID: M8399

- Name: Female Urogenital Diseases and Pregnancy Complications

- Relevance: LOW

- As Found: Unknown

- ID: M27095

- Name: Male Urogenital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T1303

- Name: Chronic Graft Versus Host Disease

- Relevance: LOW

- As Found: Unknown

- ID: T170

- Name: Acute Graft Versus Host Disease

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000008107

- Term: Liver Diseases

- ID: D000008103

- Term: Liver Cirrhosis

- ID: D000058186

- Term: Acute Kidney Injury

- ID: D000009202

- Term: Cardiomyopathies

- ID: D000018487

- Term: Ventricular Dysfunction, Left

- ID: D000005355

- Term: Fibrosis

### Intervention Browse Module - Ancestors

- ID: D000000924

- Term: Anticholesteremic Agents

- ID: D000000960

- Term: Hypolipidemic Agents

- ID: D000000963

- Term: Antimetabolites

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000057847

- Term: Lipid Regulating Agents

- ID: D000019161

- Term: Hydroxymethylglutaryl-CoA Reductase Inhibitors

- ID: D000004791

- Term: Enzyme Inhibitors

- ID: D000000319

- Term: Adrenergic beta-Antagonists

- ID: D000018674

- Term: Adrenergic Antagonists

- ID: D000018663

- Term: Adrenergic Agents

- ID: D000018377

- Term: Neurotransmitter Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000000959

- Term: Antihypertensive Agents

- ID: D000000975

- Term: Antioxidants

- ID: D000020011

- Term: Protective Agents

- ID: D000002121

- Term: Calcium Channel Blockers

- ID: D000049990

- Term: Membrane Transport Modulators

- ID: D000077264

- Term: Calcium-Regulating Hormones and Agents

- ID: D000014665

- Term: Vasodilator Agents

- ID: D000058668

- Term: Adrenergic alpha-1 Receptor Antagonists

- ID: D000000317

- Term: Adrenergic alpha-Antagonists

### Intervention Browse Module - Browse Branches

- Abbrev: AnAg

- Name: Antihypertensive Agents

- Abbrev: ChanBlk

- Name: Channel Blockers

- Abbrev: VaDiAg

- Name: Vasodilator Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Lipd

- Name: Lipid Regulating Agents

- Abbrev: Hemat

- Name: Hematinics

- Abbrev: BDCA

- Name: Bone Density Conservation Agents

### Intervention Browse Module - Browse Leaves

- ID: M1718

- Name: Carvedilol

- Relevance: HIGH

- As Found: Day 5

- ID: M21713

- Name: Simvastatin

- Relevance: HIGH

- As Found: Being

- ID: M11110

- Name: Liver Extracts

- Relevance: LOW

- As Found: Unknown

- ID: M4243

- Name: Anticholesteremic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4278

- Name: Hypolipidemic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4281

- Name: Antimetabolites

- Relevance: LOW

- As Found: Unknown

- ID: M28883

- Name: Lipid Regulating Agents

- Relevance: LOW

- As Found: Unknown

- ID: M21155

- Name: Hydroxymethylglutaryl-CoA Reductase Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M3671

- Name: Adrenergic beta-Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M20746

- Name: Adrenergic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M20755

- Name: Adrenergic Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M20504

- Name: Neurotransmitter Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4277

- Name: Antihypertensive Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4292

- Name: Antioxidants

- Relevance: LOW

- As Found: Unknown

- ID: M21869

- Name: Protective Agents

- Relevance: LOW

- As Found: Unknown

- ID: M5381

- Name: Calcium

- Relevance: LOW

- As Found: Unknown

- ID: M5384

- Name: Calcium Channel Blockers

- Relevance: LOW

- As Found: Unknown

- ID: M5398

- Name: Calcium, Dietary

- Relevance: LOW

- As Found: Unknown

- ID: M9789

- Name: Hormones

- Relevance: LOW

- As Found: Unknown

- ID: M17412

- Name: Vasodilator Agents

- Relevance: LOW

- As Found: Unknown

- ID: M29194

- Name: Adrenergic alpha-1 Receptor Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M3669

- Name: Adrenergic alpha-Antagonists

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000077261

- Term: Carvedilol

- ID: D000019821

- Term: Simvastatin

### Misc Info Module

- Version Holder: 2024-05-31
