Clinical trial NCT01848639: ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial
Official title: ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST), Phase III b
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: End Stage Renal Failure on Dialysis
Keywords: chronic kidney disease
end-stage renal disease
hemodialysis (ESRD)
cardiovascular morbimortality
aldosterone antagonist
spironolactone
Lead sponsor: University Hospital, Brest
Sponsor class: OTHER
Collaborators: name: Central Hospital, Nancy, France
name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2013-05-07
Enrollment: 823
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: * 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 25 months
Secondary outcomes:
measure: Determine the effects of spironolactone compared to placebo on the composite winratio endpoint
timeFrame: 24 months
measure: Determine the effects of spironolactone compared to placebo on the composite winratio endpoint
timeFrame: 24 months
measure: non-cardiovascular mortality rate
timeFrame: 24 months
measure: cumulative accident rates forming the primary endpoint
timeFrame: 24 months
measure: 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)
timeFrame: 24 months
measure: Incidence of procedures related to stenosis or vascular access thrombosis for hemodialysis (HD)
timeFrame: 24 months
measure: Incidence of coronary or peripheral revascularizations (including lower limb amputations)
timeFrame: 24 months
measure: Blood pressure (systolic and diastolic pressure)
timeFrame: 24 months
measure: Blood pressure's variability inter visit (systolic and diastolic pressure)
timeFrame: 24 months
measure: The occurrence of atrial fibrillation
timeFrame: 24 months
measure: Incidence of hyperkalemia> 6 mmol/l
timeFrame: 24 months
measure: Estimation of the effect of treatment on quality of life.
timeFrame: 24 months
measure: Estimation of the effect of treatment on quality of life.
timeFrame: 24 months
measure: Estimation of the effect of treatment on quality of life.
timeFrame: 24 months
Other outcomes:
measure: Ancillary study:establishment of a biological collection (serum bank and DNA biobank) for future biomarker studies
timeFrame: 24 months
measure: Ancillary study:morbimortality data
timeFrame: 3, 5 and 10 years of follow-up after the double-blind study
Locations:
city: Bruxelles
country: Belgium
facility: Hôpital Erasme- Bruxelles
city: Annonay
country: France
facility: CH Ardeche Nord
state: Ardeche
city: Amiens
country: France
facility: CHU Amiens
city: Avignon
country: France
facility: CH Avignon
city: Besançon
country: France
facility: CHU Besançon
city: Boulogne Sur Mer
country: France
facility: CH Boulogne Sur Mer
city: Brest
country: France
facility: CHRU Brest
city: Caen
country: France
facility: CHU Caen
city: Cahors
country: France
facility: CH Cahors
city: Chambéry
country: France
facility: CH Chambéry
city: Cherbourg
country: France
facility: CHPC Cherbourg
city: Colmar
country: France
facility: AURAL Colmar
city: Colmar
country: France
facility: Hopitaux Civils de Colmar
city: Créteil
country: France
facility: APHP Henri Mondor
city: Dijon
country: France
facility: CHU Dijon Hôpital du Bocage
city: Grenoble
country: France
facility: AGDUC Grenoble
city: Haguenau
country: France
facility: AURAL Haguenau
city: Haguenau
country: France
facility: CH Haguenau
city: La Roche Sur Yon
country: France
facility: La Roche Sur Yon
city: Lagny
country: France
facility: Polyclinique de Lagny
city: Lille
country: France
facility: Clinique Lille
city: Lille
country: France
facility: CHU Lille
city: Limoges
country: France
facility: ALURAD Limoges
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: CHU de Lyon
city: Lyon
country: France
facility: AURAL La Croix Rousse
city: Lyon
country: France
facility: CH St Joseph-St Luc
city: Lyon
country: France
facility: AURAL Lyon
city: Marseille
country: France
facility: Clinique Bouchard
city: Marseille
country: France
facility: Adpc Marseille
city: Marseille
country: France
facility: APHM Marseille
city: Metz
country: France
facility: Association de Metz
city: Metz
country: France
facility: ALTIR Metz
city: Metz
country: France
facility: CHR Metz-Thionville
city: Mulhouse
country: France
facility: AURAL Mulhouse
city: Mulhouse
country: France
facility: CH Mulhouse
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: CHU Nice
city: Nice
country: France
facility: Clinique St Georges
city: Paris
country: France
facility: AP-HP La Salpêtrière
city: Paris
country: France
facility: AURA Paris 14ème
city: Paris
country: France
facility: AURA Paris Plaisance
city: Paris
country: France
facility: Hôpital Tenon
city: Paris
country: France
facility: AP-HP Necker
city: Paris
country: France
facility: Institut Mutualiste Montsouris
city: Pierre-Bénite
country: France
facility: CHU Lyon Sud
city: Reims
country: France
facility: CHU de Reims
city: Reims
country: France
facility: ARPDD Reims
city: Rennes
country: France
facility: CHU Rennes
city: Reze
country: France
facility: ECHO Confluent
city: Roscoff
country: France
facility: Centre de Perharidy
city: Roubaix
country: France
facility: CH Roubaix
city: Saint Denis
country: France
facility: CHU de la Réunion Hôpital Félix Guyon
city: Saint Malo
country: France
facility: Aub Saint Malo
city: Saint-Malo
country: France
facility: Ch Saint Malo
city: St Brieuc
country: France
facility: CHG St Brieuc
city: Strasbourg
country: France
facility: AURAL St Anne (AURAL Strasbourg)
city: Strasbourg
country: France
facility: CHU Strasbourg
city: Strasbourg
country: France
facility: Clinique Sainte Anne
city: Strasbourg
country: France
facility: AURAL Strasbourg
city: Toulouse
country: France
facility: CHU Toulouse
city: Tours
country: France
facility: CHU Tours
city: Troyes
country: France
facility: CH Troyes
city: Valenciennes
country: France
facility: CH Valenciennes
city: Vandoeuvre les Nancy
country: France
facility: ALTIR Nancy
city: Vantoux
country: France
facility: Hôpitaux Privés de Metz- Hôpital Robert Schuman
city: Verdun
country: France
facility: CH Verdun
city: Vichy
country: France
facility: CH Vichy
city: Monaco
country: Monaco
facility: CH Princesse Grace
Study officials:
References:
citation: 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.