Effect of Add-on Spironolactone to Losartan Versus Losartan Alone on Peritoneal Membrane Among Peritoneal Dialysis Patients (ESCAPE-PD)

Effect of Add-on Spironolactone to Losartan Versus Losartan Alone on Peritoneal Membrane Among Continuous Ambulatory Peritoneal Dialysis Patients: An Open-Label Randomized-Controlled Trial

The ESCAPE-PD (Effects of add-on SpironolaCtone to losartan versus Alone on Peritoneal mEmbrane among continuous ambulatory Peritoneal Dialysis patients) study is a randomized, open-label, single center, active-controlled clinical trial. Adults end-stage kidney disease patients 18 years or older undergoing continuous ambulatory peritoneal dialysis (CAPD) will be enrolled. A total 84 CAPD will be randomly assigned to either the combination of spironolactone and losartan (experimental arm) or losartan alone (control arm). The primary outcomes are the difference in peritoneal dialysate effluent cancer antigen-125 (CA-125) and peritoneal equilibration test (PET) indices (dialysate-to-plasma creatinine ratio, 4-hour ultrafiltration volume, and the concentration of glucose present in the solution at the start of the test). Secondary outcome measures include laboratory and mechanistic outcome measures, nutrition outcomes, health-related quality of life, physical function, clinical events, and safety profiles. Results will be disseminated to suggest a strategy to prevent the peritoneal membrane function among CAPD patients through peer-reviewed publications along with scientific meetings.

Study Overview

• Status: Unknown
• Conditions: Peritoneal Dialysis; End Stage Renal Disease
• Intervention / Treatment: Drug: Spironolactone; Drug: Losartan

Detailed Description

Peritoneal dialysis (PD) is one of the methods of renal replacement therapy (RRT) that can easily perform at home. The declared "PD first" policy from the National Health Security Office causes rapidly expansion of this group of patients. In the year 2013, the current study in Thailand showed that the patients enrolled for peritoneal dialysis accumulated for more than 15,000 people. It works continuously similar to the actual function of the kidneys in normal people. In addition, PD also helps to slow the decline of remaining kidney function (residual renal function), which is very important and affect in decreasing mortality rate in this group of patients. However, PD has several limitations such as complications from the infection and high failure rate associated with a dysfunction of the peritoneal membrane during long-term treatment. Approximately 4-12 percent of patients will have ultrafiltration failure and volume overload in the first couple of years of treatment and soar to 30-50 percent in patients treated for more than six years.

The causes of peritoneal membrane deterioration are exposure to incompatible dialysis solution with hyperosmolar glucose content, acidic pH, reactions to PD catheter material, uremia and peritonitis. The alterations of structural and functional of the peritoneal membrane after exposed to these several insults are epithelial-to-mesenchymal transition (EMT), and increase in peritoneal solute transport, which consequently leading to peritoneal dialysis failure. It has been already demonstrated that the local renin-angiotensin-aldosterone system (RAAS) plays a key role in this regulation by promoting the activation of neoangiogenesis and fibrotic pathways.

According to the pathophysiologic changes of the peritoneal membrane, Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) are adapted to be use in respect of membrane preserving agents. Many studies, both in human and animal models, demonstrate the protective effect against peritoneal membrane deterioration by inhibiting the formation of transforming growth factor beta1 (TGF-β1), vascular endothelial growth factor (VEGF), and decreasing progression rate of small to high transport membrane type. In fact, mineralocorticoid receptor antagonists (MRAs) seem to have higher efficacy than ACEIs/ARBs in some experimental models. The possible mechanism is the effects of mineralocorticoid receptor antagonists that not only inhibit the formation of TGF- β1 and VEGF, but also suppress intracellular Reactive Oxygen Species (ROS) generation, activation of extracellular signal-regulated kinase (ERK) 1/2, and p38 mitogen-activated protein kinase (MAPK), the substrates responsible for aldosterone induces alterations in cell phenotype. A prospective cohort study of 23 CAPD patients was conducted and evaluated the effect of spironolactone on peritoneal membrane. The result showed the possible benefit of spironolactone in slowing the decline of peritoneal function, suppressing the elevation of profibrotic markers, and increasing mesothelial cell mass.

As a result of the clinical practice, most of CAPD patients tend to receive ACEIs/ARBs as prescribe by the clinicians, in order to control blood pressure, raise serum potassium level, and others compelling indications. Thus, the concept of add-on MRAs to ACEIs/ARBs, desiring the synergistic effects of these 2 drugs group, for membrane preservation is challenge. Notwithstanding the fact that current evidence about the combination effects of ACEIs/ARBs with MRAs is limited in term of quality of the study, sample size, inadequate follow-up period, and poor sensitive parameter in assessing the structural and functional changes of the peritoneal membrane. Thereby, this study aims to evaluate the effect of add-on spironolactone to losartan versus losartan alone on membrane preservation in continuous ambulatory peritoneal dialysis patients.

• Study Type: Interventional
• Enrollment (Anticipated): 84
• Phase: Phase 4

Contacts and Locations

Study Locations

• Thailand
  • Chiang Mai, Thailand, 50200
    • Pharmacoepidemiology and Statistics Research Center, Faculty of Pharmacy, Chiang Mai University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years or older (both male and female patients)
• Incidence or prevalent end-stage kidney disease patients undergoing CAPD
• Had standard dialysis prescription for at least 30 days before screening
• History of hypertension
• Stable clinical condition without any inflammation at least 4 weeks prior to enrolment
• Had an ability to understand and willingness to sign an informed consent statement

Exclusion Criteria:

• Serum potassium concentration of ≥ 5.5 milliequivalent /liter
• History of severe or active cardiovascular and/or cerebrovascular disease
• History of renal artery stenosis
• Uncontrolled hypertension
• Contraindication to angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers or mineralocorticoid receptor antagonists
• Pregnancy
• Recent PD-related peritonitis or exit-site and tunnel infection (within 2 months of screening)
• Had planned to have kidney transplantation or transfer to other PD centers with 6 months
• Prognosis for survival less than 12 months
• Any conditions (both mental or physical) that would interfere with the participant's ability to comply with the study protocol
• Any disease of the abdominal wall, such as injury or surgery, burns, hernia, dermatitis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis or diverticulitis) that in the opinion of the Investigator would preclude the patient from being able to have PD
• Any intra-abdominal tumors or intestinal obstruction
• Current or recent (within 30 days) exposure to others investigational medicinal products

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination of spironolactone and losartan	Drug: Spironolactone; Spironolactone Starting dose: 25 mg/day Target dose: 100 mg/day Titration: every 1-2 weeks, based on BP (keep< 140/90 mmHg, but avoid hypotension <90/60 mmHg), and serum potassium level (<5.5 milliequivalent /liter); Drug: Losartan; Losartan Starting dose: 50 mg/day Target dose: 100 mg/day Titration: every 1-2 weeks, based on BP (keep< 140/90 mmHg, but avoid hypotension <90/60 mmHg), and serum potassium level (<5.5 milliequivalent /liter)
Active Comparator: Losartan Alone	Drug: Losartan; Losartan Starting dose: 50 mg/day Target dose: 100 mg/day Titration: every 1-2 weeks, based on BP (keep< 140/90 mmHg, but avoid hypotension <90/60 mmHg), and serum potassium level (<5.5 milliequivalent /liter)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peritoneal dialysate effluent CA-125	Using a commercial microparticle enzyme-linked immunosorbent assay	6 months
PET indices	PET indices including dialysate-to-plasma creatinine ratio [D/P Cr], 4-hour ultrafiltration (UF) volume, and the concentration of glucose present in the solution at the start of the test [D/D0]) measured using a modified PET method (performed using 2,000 mL of 2.5% glucose solution).	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in waist circumference		6 months
Changes in dialysate adequacy by Weekly kt/V		6 months
Changes in dialysate adequacy by weekly creatinine clearance		6 months
Changes in serum albumin concentration		6 months
Changes in serum potassium concentration		6 months
Changes in body mass index (BMI)	Weight and height will be combined to report BMI in kg/m^2	6 months
Changes in Nutritional status	Using Subjective Global Assessment (SGA)	6 months
Changes in Malnutrition-Inflammation Score (MIS)		6 months
Changes in participant quality of life score	Using Kidney Disease Quality of Life-36 (KDQOL-36 Version 1.3)	6 months
Changes in health utility	Using EuroQOL-5 dimension 5-level (EQ-5D-5L)	6 months
Changes in disease-specific Thai quality of life score	Using the 9-Thai Health status AssessmentInstrument (9-THAI) questionnaire	6 months
Changes in participant well-being score	Using the World Health Organization-Five (WHO-5) well-being index	6 months
Number of participants with disability	Using the Barthel activities daily life index	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in blood pressure		6 months
Incidence of PD technique failure		6 months
Incidence of PD-related infections	Peritonitis or exit-site and tunnel infection	6 months
Number of participants with investigational medicinal products-related adverse events as assessed by CTCAE v4.0	Safety of investigational medicinal products related to potential harm (e.g. death, hospitalization, and emergency visit)	6 months

Collaborators and Investigators

• Sponsor: Chiang Mai University

Publications and helpful links

General Publications

• Hasegawa T, Nishiwaki H, Ota E, Levack WM, Noma H. Aldosterone antagonists for people with chronic kidney disease requiring dialysis. Cochrane Database Syst Rev. 2021 Feb 15;2(2):CD013109. doi: 10.1002/14651858.CD013109.pub2.

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2019
• Primary Completion (Anticipated): September 1, 2020
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: April 20, 2019
• First Submitted That Met QC Criteria: May 15, 2019
• First Posted (Actual): May 17, 2019

Study Record Updates

• Last Update Posted (Actual): September 4, 2019
• Last Update Submitted That Met QC Criteria: August 30, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Peritoneal Dialysis; Spironolactone; Losartan; Renin-Angiotensin-Aldosterone System; Peritoneal Membrane
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Losartan; Spironolactone
• Other Study ID Numbers: THOR Study Group

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No