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

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ClinicalTrials.gov Identifier: NCT03953950
Recruitment Status : Not yet recruiting
First Posted : May 17, 2019
Last Update Posted : May 17, 2019
Sponsor:
Information provided by (Responsible Party):
Chidchanok Ruengorn, Chiang Mai University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
End Stage Renal Disease Peritoneal Dialysis Drug: Spironolactone Drug: Losartan Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: 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
Estimated Study Start Date : June 2019
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dialysis

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)




Primary Outcome Measures :
  1. Peritoneal dialysate effluent CA-125 [ Time Frame: 6 months ]
    Using a commercial microparticle enzyme-linked immunosorbent assay

  2. PET indices [ Time Frame: 6 months ]
    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).


Secondary Outcome Measures :
  1. Changes in dialysate adequacy by Weekly kt/V [ Time Frame: 6 months ]
  2. Changes in dialysate adequacy by weekly creatinine clearance [ Time Frame: 6 months ]
  3. Changes in serum albumin concentration [ Time Frame: 6 months ]
  4. Changes in serum potassium concentration [ Time Frame: 6 months ]
  5. Changes in waist circumference [ Time Frame: 6 months ]
  6. Changes in body mass index (BMI) [ Time Frame: 6 months ]
    Weight and height will be combined to report BMI in kg/m^2

  7. Changes in Nutritional status [ Time Frame: 6 months ]
    Using Subjective Global Assessment (SGA)

  8. Changes in Malnutrition-Inflammation Score (MIS) [ Time Frame: 6 months ]
  9. Changes in participant quality of life score [ Time Frame: 6 months ]
    Using Kidney Disease Quality of Life-36 (KDQOL-36 Version 1.3)

  10. Changes in health utility [ Time Frame: 6 months ]
    Using EuroQOL-5 dimension 5-level (EQ-5D-5L)

  11. Changes in disease-specific Thai quality of life score [ Time Frame: 6 months ]
    Using the 9-Thai Health status AssessmentInstrument (9-THAI) questionnaire

  12. Changes in participant well-being score [ Time Frame: 6 months ]
    Using the World Health Organization-Five (WHO-5) well-being index

  13. Number of participants with disability [ Time Frame: 6 months ]
    Using the Barthel activities daily life index


Other Outcome Measures:
  1. Changes in blood pressure [ Time Frame: 6 months ]
  2. Incidence of PD technique failure [ Time Frame: 6 months ]
  3. Incidence of PD-related infections [ Time Frame: 6 months ]
    Peritonitis or exit-site and tunnel infection

  4. Number of participants with investigational medicinal products-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 6 months ]
    Safety of investigational medicinal products related to potential harm (e.g. death, hospitalization, and emergency visit)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03953950


Locations
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Thailand
Pharmacoepidemiology and Statistics Research Center, Faculty of Pharmacy, Chiang Mai University
Chiang Mai, Thailand, 50200
Sponsors and Collaborators
Chiang Mai University

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Responsible Party: Chidchanok Ruengorn, Principal Investigator, Chiang Mai University
ClinicalTrials.gov Identifier: NCT03953950     History of Changes
Other Study ID Numbers: THOR Study Group
First Posted: May 17, 2019    Key Record Dates
Last Update Posted: May 17, 2019
Last Verified: May 2019

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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

Keywords provided by Chidchanok Ruengorn, Chiang Mai University:
Peritoneal Dialysis
Peritoneal Membrane
Spironolactone
Losartan
Renin-Angiotensin-Aldosterone System

Additional relevant MeSH terms:
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Kidney Failure, Chronic
Renal Insufficiency, Chronic
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Losartan
Spironolactone
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents