ALCHEMIST: ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial

Sponsor

University Hospital, Brest (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01848639

Collaborator

Central Hospital, Nancy, France (Other), Institut National de la Santé Et de la Recherche Médicale, France (Other)

825

Enrollment

Locations

Arms

112

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
End Stage Renal Failure on Dialysis	Drug: Spironolactone Drug: Placebo	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

825 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 1, 2013

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

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.

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

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

Outcome Measures

Primary Outcome Measures

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

The cumulate rate of non fatal MI or acute coronary syndrome, hospitalization for heart failure, nonfatal stroke or CV death [25 months]
The time to onset of death from i) any cause and ii) from a CV event and iii) from a non CV cause [25 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) [25 months]
Incidence of procedures related to stenosis or vascular access thrombosis for hemodialysis (HD) [25 months]
Incidence of coronary or peripheral revascularizations (including lower limb amputations) [25 months]
Blood pressure and its inter visit variability [25 months]
The occurrence of atrial fibrillation [25 months]
Incidence of hyperkalemia> 6 mmol/l [25 months]
Estimation of the effect of treatment on quality of life. [25 months]

Other Outcome Measures

Ancillary study:establishment of a biological collection (serum bank and DNA biobank) for future biomarker studies [25 months]
Ancillary study:morbimortality data [3, 5 and 10 years of follow-up after the double-blind study]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hôpital Erasme- Bruxelles	Bruxelles		Belgium	1070
2	CH Ardeche Nord	Annonay	Ardeche	France	07100
3	CHU Amiens	Amiens		France	80054
4	CH Avignon	Avignon		France	84000
5	CHU Besançon	Besançon		France	25000
6	CH Boulogne Sur Mer	Boulogne Sur Mer		France	62321
7	CHRU Brest	Brest		France	29609
8	CHU Caen	Caen		France	14033
9	CH Cahors	Cahors		France	46000
10	CH Chambéry	Chambéry		France	73000
11	CHPC Cherbourg	Cherbourg		France	50100
12	AURAL Colmar	Colmar		France	68000
13	Hopitaux Civils de Colmar	Colmar		France	68024
14	APHP Henri Mondor	Créteil		France	94010
15	CHU Dijon Hôpital du Bocage	Dijon		France	21079
16	AGDUC Grenoble	Grenoble		France	38043
17	AURAL Haguenau	Haguenau		France	67500
18	CH Haguenau	Haguenau		France	67500
19	La Roche Sur Yon	La Roche Sur Yon		France	85000
20	Polyclinique de Lagny	Lagny		France	77400
21	Clinique Lille	Lille		France	59000
22	CHU Lille	Lille		France	59037
23	ALURAD Limoges	Limoges		France	87000
24	CHU Limoges	Limoges		France	87042
25	CHU de Lyon	Lyon		France	69003
26	AURAL La Croix Rousse	Lyon		France	69004
27	CH St Joseph-St Luc	Lyon		France	69007
28	AURAL Lyon	Lyon		France	69008
29	Clinique Bouchard	Marseille		France	13006
30	Adpc Marseille	Marseille		France	13009
31	APHM Marseille	Marseille		France	13385
32	Association de Metz	Metz		France	57000
33	ALTIR Metz	Metz		France	58085
34	CHR Metz-Thionville	Metz		France	58085
35	AURAL Mulhouse	Mulhouse		France	68100
36	CH Mulhouse	Mulhouse		France	68100
37	CHU Nancy	Nancy		France	54500
38	CHU Nantes	Nantes		France	44093
39	CHU Nice	Nice		France	06002
40	Clinique St Georges	Nice		France	06100
41	AP-HP La Salpêtrière	Paris		France	75013
42	AURA Paris 14ème	Paris		France	75014
43	AURA Paris Plaisance	Paris		France	75014
44	Hôpital Tenon	Paris		France	75020
45	AP-HP Necker	Paris		France	75743
46	Institut Mutualiste Montsouris	Paris		France
47	CHU Lyon Sud	Pierre-Bénite		France	69495
48	CHU de Reims	Reims		France	51100
49	ARPDD Reims	Reims		France	51726
50	CHU Rennes	Rennes		France	35000
51	ECHO Confluent	Reze		France	44402
52	Centre de Perharidy	Roscoff		France	29260
53	CH Roubaix	Roubaix		France	59056
54	CHU de la Réunion Hôpital Félix Guyon	Saint Denis		France	97405
55	Aub Saint Malo	Saint Malo		France	35400
56	Ch Saint Malo	Saint-Malo		France	35403
57	CHG St Brieuc	St Brieuc		France	22000
58	AURAL St Anne (AURAL Strasbourg)	Strasbourg		France	67000
59	CHU Strasbourg	Strasbourg		France	67000
60	AURAL Strasbourg	Strasbourg		France	67200
61	CHU Toulouse	Toulouse		France	31059
62	CHU Tours	Tours		France	37000
63	CH Troyes	Troyes		France	10003
64	CH Valenciennes	Valenciennes		France	59322
65	ALTIR Nancy	Vandoeuvre les Nancy		France	54504
66	Hôpitaux Privés de Metz- Hôpital Robert Schuman	Vantoux		France	57070
67	CH Verdun	Verdun		France	55107
68	CH Vichy	Vichy		France	03201
69	CH Princesse Grace	Monaco		Monaco