ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial

End Stage Renal Failure on Dialysis Clinical Trial

— ALCHEMIST  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01848639
• Other study ID #: ALCHEMIST
• Secondary ID: RB 12-079
• Status: Completed
• Phase: Phase 3
• Start date: June 2013
• Est. completion date: November 2022

Study information

• Verified date: October 2023
• Source: University Hospital, Brest
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 823
• Est. completion date: November 2022
• Est. primary completion date: November 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• End Stage Renal Failure on Dialysis
• Kidney Failure, Chronic

Intervention

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
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.

Locations

Country	Name	City	State
Belgium	Hôpital Erasme- Bruxelles	Bruxelles
France	CHU Amiens	Amiens
France	CH Ardeche Nord	Annonay	Ardeche
France	CH Avignon	Avignon
France	CHU Besançon	Besançon
France	CH Boulogne Sur Mer	Boulogne Sur Mer
France	CHRU Brest	Brest
France	CHU Caen	Caen
France	CH Cahors	Cahors
France	CH Chambéry	Chambéry
France	CHPC Cherbourg	Cherbourg
France	AURAL Colmar	Colmar
France	Hopitaux Civils de Colmar	Colmar
France	APHP Henri Mondor	Créteil
France	CHU Dijon Hôpital du Bocage	Dijon
France	AGDUC Grenoble	Grenoble
France	AURAL Haguenau	Haguenau
France	CH Haguenau	Haguenau
France	La Roche Sur Yon	La Roche Sur Yon
France	Polyclinique de Lagny	Lagny
France	CHU Lille	Lille
France	Clinique Lille	Lille
France	ALURAD Limoges	Limoges
France	CHU Limoges	Limoges
France	AURAL La Croix Rousse	Lyon
France	AURAL Lyon	Lyon
France	CH St Joseph-St Luc	Lyon
France	CHU de Lyon	Lyon
France	Adpc Marseille	Marseille
France	APHM Marseille	Marseille
France	Clinique Bouchard	Marseille
France	ALTIR Metz	Metz
France	Association de Metz	Metz
France	CHR Metz-Thionville	Metz
France	AURAL Mulhouse	Mulhouse
France	CH Mulhouse	Mulhouse
France	CHU Nancy	Nancy
France	CHU Nantes	Nantes
France	CHU Nice	Nice
France	Clinique St Georges	Nice
France	AP-HP La Salpêtrière	Paris
France	AP-HP Necker	Paris
France	AURA Paris 14ème	Paris
France	AURA Paris Plaisance	Paris
France	Hôpital Tenon	Paris
France	Institut Mutualiste Montsouris	Paris
France	CHU Lyon Sud	Pierre-Bénite
France	ARPDD Reims	Reims
France	CHU de Reims	Reims
France	CHU Rennes	Rennes
France	ECHO Confluent	Reze
France	Centre de Perharidy	Roscoff
France	CH Roubaix	Roubaix
France	CHU de la Réunion Hôpital Félix Guyon	Saint Denis
France	Aub Saint Malo	Saint Malo
France	Ch Saint Malo	Saint-Malo
France	CHG St Brieuc	St Brieuc
France	AURAL St Anne (AURAL Strasbourg)	Strasbourg
France	AURAL Strasbourg	Strasbourg
France	CHU Strasbourg	Strasbourg
France	Clinique Sainte Anne	Strasbourg
France	CHU Toulouse	Toulouse
France	CHU Tours	Tours
France	CH Troyes	Troyes
France	CH Valenciennes	Valenciennes
France	ALTIR Nancy	Vandoeuvre les Nancy
France	Hôpitaux Privés de Metz- Hôpital Robert Schuman	Vantoux
France	CH Verdun	Verdun
France	CH Vichy	Vichy
Monaco	CH Princesse Grace	Monaco

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital, Brest	Central Hospital, Nancy, France, Institut National de la Santé Et de la Recherche Médicale, France

Countries where clinical trial is conducted

Belgium,  France,  Monaco, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ancillary study:establishment of a biological collection (serum bank and DNA biobank) for future biomarker studies		24 months
Other	Ancillary study:morbimortality data		3, 5 and 10 years of follow-up after the double-blind study
Primary	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	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
Secondary	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
Secondary	non-cardiovascular mortality rate	Additional secondary objectives will be considered in the context of hypothesis generation	24 months
Secondary	cumulative accident rates forming the primary endpoint	Additional secondary objectives will be considered in the context of hypothesis generation	24 months
Secondary	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
Secondary	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
Secondary	Incidence of coronary or peripheral revascularizations (including lower limb amputations)	Additional secondary objectives will be considered in the context of hypothesis generation	24 months
Secondary	Blood pressure (systolic and diastolic pressure)	Additional secondary objectives will be considered in the context of hypothesis generation	24 months
Secondary	Blood pressure's variability inter visit (systolic and diastolic pressure)	Additional secondary objectives will be considered in the context of hypothesis generation	24 months
Secondary	The occurrence of atrial fibrillation	Additional secondary objectives will be considered in the context of hypothesis generation	24 months
Secondary	Incidence of hyperkalemia> 6 mmol/l	Additional secondary objectives will be considered in the context of hypothesis generation	24 months
Secondary	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
Secondary	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
Secondary	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