ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST)

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

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.

Study Overview

• Status: Completed
• Conditions: End Stage Renal Failure on Dialysis
• Intervention / Treatment: Drug: Spironolactone; Drug: Placebo

Detailed Description

• 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.

• Study Type: Interventional
• Enrollment (Actual): 823
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1070
    • Hôpital Erasme- Bruxelles
• France
  • Amiens, France, 80054
    • CHU Amiens
  • Avignon, France, 84000
    • Ch Avignon
  • Besançon, France, 25000
    • CHU Besançon
  • Boulogne Sur Mer, France, 62321
    • CH Boulogne sur Mer
  • Brest, France, 29609
    • CHRU Brest
  • Caen, France, 14033
    • CHU caen
  • Cahors, France, 46000
    • CH Cahors
  • Chambéry, France, 73000
    • CH Chambery
  • Cherbourg, France, 50100
    • CHPC Cherbourg
  • Colmar, France, 68000
    • AURAL Colmar
  • Colmar, France, 68024
    • Hopitaux Civils de Colmar
  • Créteil, France, 94010
    • APHP Henri Mondor
  • Dijon, France, 21079
    • CHU Dijon Hôpital du Bocage
  • Grenoble, France, 38043
    • AGDUC Grenoble
  • Haguenau, France, 67500
    • AURAL Haguenau
  • Haguenau, France, 67500
    • CH Haguenau
  • La Roche Sur Yon, France, 85000
    • La Roche sur Yon
  • Lagny, France, 77400
    • Polyclinique de Lagny
  • Lille, France, 59000
    • Clinique Lille
  • Lille, France, 59037
    • CHU Lille
  • Limoges, France, 87000
    • ALURAD Limoges
  • Limoges, France, 87042
    • CHU Limoges
  • Lyon, France, 69003
    • Chu de Lyon
  • Lyon, France, 69004
    • AURAL La Croix Rousse
  • Lyon, France, 69007
    • CH St Joseph-St Luc
  • Lyon, France, 69008
    • AURAL Lyon
  • Marseille, France, 13006
    • Clinique Bouchard
  • Marseille, France, 13009
    • Adpc Marseille
  • Marseille, France, 13385
    • APHM Marseille
  • Metz, France, 57000
    • Association de Metz
  • Metz, France, 58085
    • ALTIR Metz
  • Metz, France, 58085
    • CHR Metz-Thionville
  • Mulhouse, France, 68100
    • AURAL Mulhouse
  • Mulhouse, France, 68100
    • CH Mulhouse
  • Nancy, France, 54500
    • Chu Nancy
  • Nantes, France, 44093
    • CHU Nantes
  • Nice, France, 06002
    • CHU Nice
  • Nice, France, 06100
    • Clinique St Georges
  • Paris, France, 75013
    • AP-HP La Salpêtrière
  • Paris, France, 75014
    • AURA Paris 14ème
  • Paris, France, 75014
    • AURA Paris Plaisance
  • Paris, France, 75020
    • Hopital Tenon
  • Paris, France, 75743
    • AP-HP Necker
  • Paris, France
    • Institut Mutualiste Montsouris
  • Pierre-Bénite, France, 69495
    • CHU Lyon Sud
  • Reims, France, 51100
    • CHU de Reims
  • Reims, France, 51726
    • ARPDD Reims
  • Rennes, France, 35000
    • CHU Rennes
  • Reze, France, 44402
    • ECHO Confluent
  • Roscoff, France, 29260
    • Centre de Perharidy
  • Roubaix, France, 59056
    • CH Roubaix
  • Saint Denis, France, 97405
    • CHU de la Réunion Hôpital Félix Guyon
  • Saint Malo, France, 35400
    • Aub Saint Malo
  • Saint-Malo, France, 35403
    • CH Saint Malo
  • St Brieuc, France, 22000
    • CHG St Brieuc
  • Strasbourg, France, 67000
    • AURAL St Anne (AURAL Strasbourg)
  • Strasbourg, France, 67000
    • CHU Strasbourg
  • Strasbourg, France, 67000
    • Clinique Sainte Anne
  • Strasbourg, France, 67200
    • AURAL Strasbourg
  • Toulouse, France, 31059
    • CHU Toulouse
  • Tours, France, 37000
    • Chu Tours
  • Troyes, France, 10003
    • CH Troyes
  • Valenciennes, France, 59322
    • Ch Valenciennes
  • Vandoeuvre les Nancy, France, 54504
    • ALTIR Nancy
  • Vantoux, France, 57070
    • Hôpitaux Privés de Metz- Hôpital Robert Schuman
  • Verdun, France, 55107
    • CH Verdun
  • Vichy, France, 03201
    • CH Vichy
  • Ardeche
    • Annonay, Ardeche, France, 07100
      • CH Ardeche Nord
• Monaco
  • Monaco, Monaco
    • CH Princesse Grace

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Spironolactone; 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; 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.
Placebo Comparator: Placebo; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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
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
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
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

Other Outcome Measures

Outcome Measure	Time Frame
Ancillary study:morbimortality data	3, 5 and 10 years of follow-up after the double-blind study
Ancillary study:establishment of a biological collection (serum bank and DNA biobank) for future biomarker studies	24 months

Collaborators and Investigators

• Sponsor: University Hospital, Brest
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; Central Hospital, Nancy, France

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 (Actual): June 1, 2013
• Primary Completion (Actual): November 1, 2022
• Study Completion (Actual): November 1, 2022

Study Registration Dates

• First Submitted: May 3, 2013
• First Submitted That Met QC Criteria: May 3, 2013
• First Posted (Estimated): May 7, 2013

Study Record Updates

• Last Update Posted (Estimated): October 9, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: chronic kidney disease; end-stage renal disease; spironolactone; hemodialysis (ESRD); cardiovascular morbimortality; aldosterone antagonist
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease Attributes; Renal Insufficiency; Renal Insufficiency, Chronic; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Failure, Chronic; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: ALCHEMIST; RB 12-079 (Other Identifier: CHRU Brest)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Statistical Analysis Plan
• IPD Sharing Supporting Information Type: SAP

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