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

Sponsor

Northwestern University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05275907

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH), American Society for Transplantation (Other)

Enrollment

Location

Arms

34.7

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
High Blood Pressure Liver Transplant Renal Function Abnormal	Drug: Amlodipine Besylate Drug: Chlorthalidone	Phase 4

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

15 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Other

Official Title:

Pilot Study to Assess Blockade of Calcium Channels and Sodium Chloride Cotransporters for Physiologic Abnormalities in Liver Transplant Associated Hypertension

Actual Study Start Date :

Jul 12, 2022

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A first, then B 6 weeks of drug A followed by a 2-week washout period completed with 6 weeks of drug B	Drug: Amlodipine Besylate 10 mg capsule once daily for 6 weeks Drug: Chlorthalidone 25mg capsule once daily for 6 weeks
Active Comparator: B first, then A 6 weeks of drug B followed by a 2-week washout period completed with 6 weeks of drug A	Drug: Amlodipine Besylate 10 mg capsule once daily for 6 weeks Drug: Chlorthalidone 25mg capsule once daily for 6 weeks

Arm

Intervention/Treatment

Active Comparator: A first, then B

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

Drug: Amlodipine Besylate

10 mg capsule once daily for 6 weeks

Drug: Chlorthalidone

25mg capsule once daily for 6 weeks

Active Comparator: B first, then A

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

Drug: Amlodipine Besylate

10 mg capsule once daily for 6 weeks

Drug: Chlorthalidone

25mg capsule once daily for 6 weeks

Outcome Measures

Primary Outcome Measures

Change in central aortic pressure at 6 weeks of therapy compared to baseline values [Endpoints will be measured before the first dose of either amlodipine or chlorthalidone and at the end of each six-week double-blinded treatment period]
Carotid-femoral pulse wave velocity (PWV), the gold standard measure of large artery stiffness, will be measured using a SphygmoCor XCEL device (Atcor Medical).

Secondary Outcome Measures

Number of patients with improvement in diastolic function (E/e' ratio) [Endpoints will be measured before the first dose of either amlodipine or chlorthalidone and at the end of each six-week double-blinded treatment period]
We will perform comprehensive echo to assess diastolic function using E/e' ratio on all participants using a GE Vivid T8 ultrasound machine and a systematic echo protocol.
Number of patients with improvement in systolic function (absolute global longitudinal strain, %) [Endpoints will be measured before the first dose of either amlodipine or chlorthalidone and at the end of each six-week double-blinded treatment period]
We will perform comprehensive echo to assess systolic function using absolute global longitudinal strain (%) on all participants using a GE Vivid T8 ultrasound machine and a systematic echo protocol.
Change in Blood pressure [Endpoints will be measured before the first dose of either amlodipine or chlorthalidone and at the end of each six-week double-blinded treatment period]
24-hour ambulatory blood pressure (BP) monitoring will be performed in addition to office BP to determine Mean home systolic and diastolic BP, office systolic and diastolic BP and nocturnal BP readings
Change in Renal function [Endpoints will be measured before the first dose of either amlodipine or chlorthalidone and at the end of each six-week double-blinded treatment period]
Renal function will be primarily assessed by 24-hour creatinine clearance which is the most accurate measure of GFR after liver transplant.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 medical therapy (e.g., no change in current antihypertensive medications or immunosuppression for ≥ 30d)

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 < 4.0 mEq/L
Serum sodium < 135 mg/dL
Allergy to sulfa drugs
Steroid use > 5 mg/d
Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m2 or on dialysis
Pregnant women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611

Sponsors and Collaborators

Northwestern University
National Heart, Lung, and Blood Institute (NHLBI)
American Society for Transplantation

Investigators

Principal Investigator: Justin Boike, MD, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Justin Boike, Assistant Professor of Medicine-Gastroenterology & Hepatology and Preventive Medicine-Epidemiology, Northwestern University

ClinicalTrials.gov Identifier:

NCT05275907

Other Study ID Numbers:

STU00215781
1R56HL155093-01

First Posted:

Mar 11, 2022

Last Update Posted:

Jul 15, 2022

Last Verified:

Jul 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Yes

Keywords provided by Justin Boike, Assistant Professor of Medicine-Gastroenterology & Hepatology and Preventive Medicine-Epidemiology, Northwestern University

Additional relevant MeSH terms:

Hypertension

Amlodipine

Chlorthalidone

Study Results

No Results Posted as of Jul 15, 2022