ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial

Study Overview
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Brief Summary
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This study is designed to etablish the effects of spironolactone in comparison to placebo on the composite endpoint of nonfatal Myocardial Infarction (MI) and acute coronary syndrome, hospitalization for heart failure, nonfatal stroke or cardiovascular-induced death. The primary endpoint will be the time to onset of the first incident.

Detailed Description
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During a run-in period : Spironolactone will be initially administered per os at a 25 mg dose per two days in practice after the session, three times per week Patients will be randomized (spironolactone vs. placebo) and titrated over one month to a maximum single dose of 25 mg/d However if kalemia is greater than or equal to 5.5 mmol / l twice on this run-in period or on the day of randomization, patient won't be randomized. A pre-specified algorithm for the management of the risk of incident hyperkalemia will be followed, including dose adjustment, temporary cessation of study treatment, in addition to usual dietary measures and the use of chelating resins and low-potassium dialysis baths Patients will be followed for a mean of 2 years.

Official Title
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ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST), Phase III b

Conditions
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End Stage Renal Failure on Dialysis

Intervention / Treatment
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* Drug: Spironolactone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent. Adult men and women on HD for at least 45 days for ESRD regardless of the etiology including diabetes, with at least 3 HD sessions per week Presenting at least one of the follow comorbidities, cardiovascular abnormalities or CV risk factors: Left ventricular hypertrophy defined by left ventricular mass > 130 g/m2 in men and 100 g/m2 in women (echocardiography) OR Cornell (RaVL + SV3) >28 mm in men, > 20 mm in women(ECG) OR left ventricular ejection fraction < 40% OR large QRS > 0.14 sec OR Left bundle branch block (ECG) measured during the twelve months preceding inclusion; diabetes; OR history of cardiovascular disease: coronary artery disease, symptomatic lower limb peripheral arterial disease, carotid or renal artery stenosis > 50%, stroke, hospitalization for heart failure, permanent atrial fibrillation (AF), oral anticoagulant treatment for AF, valvular heart prosthesis, OR CRP > 5 mg/l for 3 months without infectious or neoplastic disease documented in progress Exclusion Criteria: history of hypersensitivity to spironolactone or galactose intolerance the Lapp lactase deficiency or malabsorption of glucose or galactose hyperkalemia > 5.5 mmol/l during the two weeks prior to enrolment history of unscheduled hemodialysis for hyperkalemia during the last six months hospitalization for hyperkalemia during the last six months patients with imperative indication of a combination of ACEI and sartan or renin inhibitor (each being authorized separately), NSAIDS, Cox-2 inhibitors kidney transplant scheduled within the year symptomatic interdialytic hypotension acute systemic disease uncompensated hypothyroidism acute hyperthyroidism any prior or concomitant clinical condition compromising the inclusion, in the discretion of the investigator cardiac transplant severe uncontrolled arrhythmia stroke within 3 months prior to enrolment acute coronary syndrome in the previous month inclusion recent (1 month) or planned coronary revascularization by angioplasty recent (3 months) or planned cardiovascular surgery (excluding HD vascular access) non menopausal women or without effective contraceptive methods pregnancy, breastfeeding or planning a pregnancy within 2 years non compliance protected adult SBP > 200 mmHg and/or DBP > 110 mmHg Concomitant treatment can not be stopped by another potassium-sparing diuretic, a potassium supplements, AINS or Cox 2 inhibitors

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Spironolactone<br>After a month in run-in period under 25 mg per 2 days of spironolactone administered per os in practice after dialysis session three times a week, patients will be randomized to spironolactone. The dose should be increased to 25 mg once daily and could be adjusted in using an algorithm used in the EPHESUS and EMPHASIS-HF trials. | Drug: Spironolactone<br>* After a month in run-in period under 25 mg per 2 days of spironolactone administered per os in practice after dialysis session three times a week, patients will be randomized to spironolactone. The dose should be increased to 25 mg once daily and could be adjusted in using an algorithm used in the EPHESUS and EMPHASIS-HF trials.<br>|
| Placebo Comparator: Placebo<br>After a month in run-in period under 25 mg per 2 days of spironolactone administered per os in practice after dialysis session three times a week, patients will be randomized to placebo. The dose should be increased to 25 mg once daily and could be adjusted in using an algorithm used in the EPHESUS and EMPHASIS-HF trials. | Drug: Placebo<br>* After a month in run-in period under 25 mg per 2 days of spironolactone administered per os in practice after dialysis session three times a week, patients will be randomized to placebo. The dose should be increased to 25 mg once daily and could be adjusted in using an algorithm used in the EPHESUS and EMPHASIS-HF trials.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time to onset of the first incident :non-fatal MI or acute coronary syndrome or hospitalization for heart failure or nonfatal stroke or cardiovascular (CV) death |  | 25 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the effects of spironolactone compared to placebo on the composite winratio endpoint | Following a hierarchical strategy of statistical tests including the primary endpoint. Composite winratio endpoint of: all-cause mortality at 2 years according to the Finkelstein and Schoenfeld method. | 24 months | 
| Determine the effects of spironolactone compared to placebo on the composite winratio endpoint | Following a hierarchical strategy of statistical tests including the primary endpoint. Composite winratio endpoint of: time until a cardiovascular event (hospitalization for heart failure, or non-fatal myocardial infarction, or acute coronary syndrome or non-fatal stroke) at 2 years according to the Finkelstein and Schoenfeld method. | 24 months | 
| non-cardiovascular mortality rate | Additional secondary objectives will be considered in the context of hypothesis generation | 24 months | 
| cumulative accident rates forming the primary endpoint | Additional secondary objectives will be considered in the context of hypothesis generation | 24 months | 
| The time of survival without a major CV event (non fatal MI, acute coronary syndrome, hospitalization for heart failure, non-fatal stroke, cardiac arrest resuscitation) | Additional secondary objectives will be considered in the context of hypothesis generation | 24 months | 
| Incidence of procedures related to stenosis or vascular access thrombosis for hemodialysis (HD) | Additional secondary objectives will be considered in the context of hypothesis generation | 24 months | 
| Incidence of coronary or peripheral revascularizations (including lower limb amputations) | Additional secondary objectives will be considered in the context of hypothesis generation | 24 months | 
| Blood pressure (systolic and diastolic pressure) | Additional secondary objectives will be considered in the context of hypothesis generation | 24 months | 
| Blood pressure's variability inter visit (systolic and diastolic pressure) | Additional secondary objectives will be considered in the context of hypothesis generation | 24 months | 
| The occurrence of atrial fibrillation | Additional secondary objectives will be considered in the context of hypothesis generation | 24 months | 
| Incidence of hyperkalemia> 6 mmol/l | Additional secondary objectives will be considered in the context of hypothesis generation | 24 months | 
| Estimation of the effect of treatment on quality of life. | KDQoL questionnaire ; minimum value = 0 ; maximum value = 100 ; higher score means a better outcome | 24 months | 
| Estimation of the effect of treatment on quality of life. | Minnesota questionnaire ; minimum value = 0 ; maximum value = 100 ; higher score means a better outcome | 24 months | 
| Estimation of the effect of treatment on quality of life. | SF36 questionnaire ; minimum value = 0 ; maximum value = 100 ; higher score means a better outcome | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic kidney disease, end-stage renal disease, hemodialysis (ESRD), cardiovascular morbimortality, aldosterone antagonist, spironolactone