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

NCT05275907 | Withdrawn Phase 4 DMC FDA Drug

• 2 other identifiers: STU002157811R56HL155093-01
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

High Blood Pressure; Liver Transplant; Renal Function Abnormal

Keywords

liver transplant; hypertension; cardiac function; kidney function; treatment

Outcome Measures

Primary Outcomes (1)

• Change in central aortic pressure at 6 weeks of therapy compared to baseline values

  Carotid-femoral pulse wave velocity (PWV), the gold standard measure of large artery stiffness, will be measured using a SphygmoCor XCEL device (Atcor Medical).

  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

Secondary Outcomes (4)

• 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

• 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

• 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

• 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

Study Arms (2)

A first, then B

ACTIVE COMPARATOR

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

Drug: Amlodipine Besylate; Drug: Chlorthalidone

B first, then A

ACTIVE COMPARATOR

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

Drug: Amlodipine Besylate; Drug: Chlorthalidone

Interventions

Amlodipine Besylate DRUG

10 mg capsule once daily for 6 weeks

A first, then B; B first, then A

Chlorthalidone DRUG

25mg capsule once daily for 6 weeks

A first, then B; B first, then A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

Related Publications (11)

• Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-e248. doi: 10.1016/j.jacc.2017.11.006. Epub 2017 Nov 13. No abstract available.

  PMID: 29146535 BACKGROUND

• ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97. doi: 10.1001/jama.288.23.2981.

  PMID: 12479763 BACKGROUND

• Wright JT Jr, Dunn JK, Cutler JA, Davis BR, Cushman WC, Ford CE, Haywood LJ, Leenen FH, Margolis KL, Papademetriou V, Probstfield JL, Whelton PK, Habib GB; ALLHAT Collaborative Research Group. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005 Apr 6;293(13):1595-608. doi: 10.1001/jama.293.13.1595.

  PMID: 15811979 BACKGROUND

• Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005 Sep 10-16;366(9489):895-906. doi: 10.1016/S0140-6736(05)67185-1.

  PMID: 16154016 BACKGROUND

• Luscher TF, Yang Z, Kiowski W, Linder L, Dohi Y, Diederich D. Endothelin-induced vasoconstriction and calcium antagonists. J Hum Hypertens. 1992 Dec;6 Suppl 2:S3-8.

  PMID: 1289511 BACKGROUND

• Neal DA, Brown MJ, Wilkinson IB, Byrne CD, Alexander GJ. Hemodynamic effects of amlodipine, bisoprolol, and lisinopril in hypertensive patients after liver transplantation. Transplantation. 2004 Mar 15;77(5):748-50. doi: 10.1097/01.tp.0000116418.78963.dc.

  PMID: 15021839 BACKGROUND

• Levitsky J, O'Leary JG, Asrani S, Sharma P, Fung J, Wiseman A, Niemann CU. Protecting the Kidney in Liver Transplant Recipients: Practice-Based Recommendations From the American Society of Transplantation Liver and Intestine Community of Practice. Am J Transplant. 2016 Sep;16(9):2532-44. doi: 10.1111/ajt.13765. Epub 2016 Apr 22.

  PMID: 26932352 BACKGROUND

• Moes AD, Hesselink DA, van den Meiracker AH, Zietse R, Hoorn EJ. Chlorthalidone Versus Amlodipine for Hypertension in Kidney Transplant Recipients Treated With Tacrolimus: A Randomized Crossover Trial. Am J Kidney Dis. 2017 Jun;69(6):796-804. doi: 10.1053/j.ajkd.2016.12.017. Epub 2017 Mar 1.

  PMID: 28259499 BACKGROUND

• Olde Engberink RH, Frenkel WJ, van den Bogaard B, Brewster LM, Vogt L, van den Born BJ. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. Hypertension. 2015 May;65(5):1033-40. doi: 10.1161/HYPERTENSIONAHA.114.05122. Epub 2015 Mar 2.

  PMID: 25733241 BACKGROUND

• Kwon BJ, Jang SW, Choi KY, Kim DB, Cho EJ, Ihm SH, Youn HJ, Kim JH. Comparison of the efficacy between hydrochlorothiazide and chlorthalidone on central aortic pressure when added on to candesartan in treatment-naive patients of hypertension. Hypertens Res. 2013 Jan;36(1):79-84. doi: 10.1038/hr.2012.143. Epub 2012 Oct 4.

  PMID: 23034468 BACKGROUND

• Pareek A, Messerli FH, Saravia G, Mehta RT. Interamerican Society of Cardiology (IASC) position statement: Chlorthalidone vs. thiazide-type diuretics. Int J Cardiol Hypertens. 2020 Sep 19;7:100054. doi: 10.1016/j.ijchy.2020.100054. eCollection 2020 Dec.

  PMID: 33447776 BACKGROUND

MeSH Terms

Conditions

Hypertension

Interventions

Amlodipine; Chlorthalidone

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Benzophenones; Phthalimides; Imides; Ketones; Sulfones; Sulfur Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Dempsey Hughes, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine-Gastroenterology & Hepatology

Study Record Dates

• First Submitted: November 17, 2021
• First Posted: March 11, 2022
• Study Start: July 12, 2022
• Primary Completion: October 2, 2023
• Study Completion: October 4, 2023
• Last Updated: October 13, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Following publication with no end date.
• Access Criteria: Any purpose.

Locations

US (1)