Mechanism of Hypertension Treatments in Liver Transplant Recipients (BLOCK LTR-HTN)

NCT ID: NCT05275907

Last Updated: 2023-10-13

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-07-12
• Study Completion Date: 2023-10-04

Brief Summary

Liver transplantation is a high risk, high-cost intervention that extends life in over 8,000 patients in the US each year. Of those that receive transplants, 1 in 3 will have a complication related to their heart after transplant. Research has been done to attempt to reduce the risk of these complications from occurring. High blood pressure, otherwise known as "hypertension," is an important risk factor for heart complications. Hypertension is found in 92% of liver transplant recipients within 6 years of their procedure. However, using data from our transplant patients at Northwestern we recently showed that having a normal blood pressure in the first year following liver transplant lowered the risk of heart complications and the risk of death by over half. However, there are no studies investigating the best medications to lower blood pressure in liver transplant recipients.

There are several types of medications that can be used to treat high blood pressure. Currently, most transplant providers use a class of medications called calcium channel blockers as the first medications for hypertension in liver transplant patients. However, there is little data to support this recommendation. There is some new evidence suggesting that another class of medications, called thiazide-like diuretics, might be beneficial to lower blood pressure in liver transplant recipients. The current study will use two different medications: the calcium channel blocker called amlodipine besylate (at dose of 10mg) and the thiazide-like diuretic known as chlorthalidone (25mg). Both medications are taken once per day by mouth and are FDA approved for the treatment of high blood pressure in the general population.

The main purpose of this study is to determine how well these two medications lower blood pressure and how they may improve markers of heart function and kidney function in liver transplant recipients. The long-term goal of this research is to improve heart outcomes in those that have undergone liver transplant by addressing risk factors that can be modified, including blood pressure. This study will help determine the size of the needed group for further studies to ensure proper investigation of which of these two medications may most benefit liver transplant patients.

Detailed Description

The study will involve a randomized crossover trial of two medications: amlodipine besylate 10mg and chlorthalidone 25mg daily by mouth. Amlodipine was selected as the dihydropyridine calcium channel blocker (CCB) due to extensive trial evidence demonstrating its efficacy in hypertension (HTN) in the general population and established safety and efficacy for calcineurin inhibitor (CNI)-induce HTN in kidney transplant recipients. Chlorthalidone was chosen amongst other thiazides due to its favorable safety profile, superior effectiveness in reducing cardiovascular events (CVEs) in the general population, stronger reduction in central pressure, and prior evidence of efficacy in kidney transplant recipients with CNI-induced HTN. Dosing for either medication was determined based on the median and maximum recommended doses for each medication when used for the treatment of stage II HTN BP ≥140/≥90 and previous trial evidence demonstrating similar blood pressure-lowering effects of amlodipine and chlorthalidone at these doses. We recognize that several prior studies have used a starting dose of chlorthalidone 12.5mg; however, this dose is no longer available in the U.S. and tablets are not scored to allow for accurate trial dosing. We specifically selected a relatively short duration of follow up (six weeks per intervention) due to several factors, including 1) the time to peak hemodynamic effects and durations of action of the trial interventions, balanced with 2) optimizing adherence to the study protocols to be able to measure key mechanistic factors, and 3) minimizing dropout. Given the well-described half-life elimination of the two medications, we do not anticipate issues with crossover effects in the second phase outcome assessments occurring six weeks following the washout period. Nonetheless, exploratory analyses will account for potential period or crossover effects using mixed effects models.

Conditions

High Blood Pressure; Liver Transplant; Renal Function Abnormal

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: TRIPLE

Study Groups

A first, then B

6 weeks of drug A followed by a 2-week washout period completed with 6 weeks of drug B

Group Type: ACTIVE_COMPARATOR

Amlodipine Besylate

Intervention Type: DRUG

10 mg capsule once daily for 6 weeks

Chlorthalidone

Intervention Type: DRUG

25mg capsule once daily for 6 weeks

B first, then A

6 weeks of drug B followed by a 2-week washout period completed with 6 weeks of drug A

Group Type: ACTIVE_COMPARATOR

Amlodipine Besylate

Intervention Type: DRUG

10 mg capsule once daily for 6 weeks

Chlorthalidone

Intervention Type: DRUG

25mg capsule once daily for 6 weeks

Interventions

Amlodipine Besylate

10 mg capsule once daily for 6 weeks

Intervention Type: DRUG

Chlorthalidone

25mg capsule once daily for 6 weeks

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Liver transplant alone recipient
• At least 90 days from transplant
• Average daytime systolic blood pressure (SBP)>140mmHG with 24h ambulatory blood pressure monitoring. Patients will be enrolled in 24h ambulatory blood pressure monitoring (ABPM) if they have hypertension (HTN) defined by diagnostic codes, treatment with antihypertensive medications for ≥ 2 months, and a history of office blood pressure readings ≥140/90 mmHg at two separate office visits.
• Stable antihypertensive medical therapy (e.g., no change in current antihypertensive medications within 30d of screening)
• No acute cellular rejection within 30d of screening

Exclusion Criteria

• Contraindication to withholding calcium channel blockers (CCB) or beta-blocker (e.g., atrial fibrillation/flutter)
• Treatment with other diuretics that cannot be held
• Acute coronary syndrome or revascularization within 60d
• Serum potassium < 3.5 mEq/L
• Serum sodium < 135 mg/dL
• Allergy to sulfa drugs
• Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m2 or on dialysis
• Pregnant women

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

American Society for Transplantation

UNKNOWN

Sponsor Role: collaborator

Northwestern University

OTHER

Sponsor Role: lead

Responsible Party

Dempsey Hughes

Assistant Professor of Medicine-Gastroenterology & Hepatology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Dempsey Hughes, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Locations

Northwestern University

Chicago, Illinois, United States

Countries

United States

References

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Other Identifiers

1R56HL155093-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STU00215781

Identifier Type: -

Identifier Source: org_study_id