Clinical trial NCT02597361: Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome (ARCADE)
Official title: Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome: a Double Blind, Randomized, Placebo Controlled, Multicenter Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ehlers-Danlos Syndrome, Vascular Type
Keywords: Ehlers-Danlos syndrome, vascular type
Type 2 Angiotensin Receptor Blockers
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2015-11-05
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to verify the hypothesis that patients with Vascular Ehlers Danlos syndrome (vEDS) should benefit of the blockade of angiotensin (Ang) II noxious effects on their vasculature affected by a defect in type III collagen in addition to the effects celiprolol. This randomized, double blind, placebo controlled trial compares the administration of the Ang II type I receptor blocker (ARB) - irbesartan- to placebo over a 2-year period in vEDS patients with the main objective to reduce the incidence of both symptomatic and asymptomatic vascular events.

Detailed description: vEDS is a rare life-threatening inherited condition due to mutations at the COL3A1 gene encoding the pro-alpha 1 chain of type III procollagen (OMIM #130050) with unpredictable and recurring arterial dissections/aneurysms starting in the early adulthood. The investigators have previously shown that a treatment with 200-400 mg per day of celiprolol, reduces both fatal and non-fatal vascular events in patients with vEDS. If tolerated, the treatment is now the standard treatment for vEDS. However, despite celiprolol , symptomatic and asymptomatic arterial events continue to occur in vEDS patients. Recent findings suggest a possible deleterious effect of endogenous Angiotensin II on medium size arteries in vEDS patients. The hypothesis of this study is that the blockade of endogenous Ang II will provide supplemental vascular protection and thus reduce recurrence of arterial events in vEDS patients.

The primary objective of this study is to determine in patients with molecularly proven vEDS, whether an Ang II receptor blocker, prescribed at an optimally tolerated dose combined with the reference celiprolol treatment, decreases the 24 months rate of both asymptomatic and symptomatic cardiovascular (CV) events when compared to placebo.

Methodology:

Multicenter, double-blind, randomized (1:1), placebo-controlled, parallel group, study with blind endpoint evaluation in adult vEDS patients.

Main criteria for inclusion:

Patients of both sexes aged 18 to 70 years with molecularly proven vEDS, not in an acute phase of the disease, with no contra-indication for taking an Ang II blocker.

Eligibility criteria: Inclusion Criteria:

* Patients with genetically-proven vEDS (presence of a pathogenic mutation at the COL3A1 gene);
* Age ≥18 years and \<70 years;
* Men and women with reliable contraception or negative beta-HCG at screening;
* Celiprolol at the optimal tolerated dose since at least 12 weeks;
* vEDS patient fully intolerant to celiprolol but not treated with any other drug active on the vascular system, except another beta-blocker;
* No compelling indication for ARB therapy (renal infarction, hypertension, proteinuric nephropathy, chronic heart failure, myocardial infarction, stroke);
* Estimated glomerular filtration rate (GFR) ≥ 30ml/min/1,73m2 (MDRD Formula);
* Normal or clinically acceptable 12-lead ECG;
* Written informed consent to participate in the study.

Exclusion Criteria:

General criteria

* Unlikely to co-operate in the study and/or poor compliance anticipated by the investigator, e.g., uncooperative attitude, inability to return for follow-up visit, and unlikelihood of completing the study;
* Participation in another interventional therapeutic study at the same time or within 3 months prior to the beginning of the present study;
* Participant not affiliated to the French social security;
* No written informed consent;
* Severe contrast media allergy, not amenable to pre-treatment Medical and therapeutic criteria
* History of previous symptomatic visceral complication (any CV event, pulmonary or digestive event) in the 3 months preceding the inclusion;
* Formal indication for an antihypertensive medication (office BP ≥140/90 mmHg on celiprolol on at least two separated visits, confirmed by daytime ambulatory BP or home BP ≥ 135/85 mmHg);
* Concomitant treatment with renin-angiotensin-aldosterone system blocking agents apart from the study drug, e.g. ACEI, ARB or aldosterone-antagonist or any renin inhibitor, if given for an elective indication (heart failure, renal infarction, chronic kidney disease, proteinuria, myocardial infarction, stroke);
* Any cardiac condition that justifies a specific medical care (i.e. second or third degree auriculo-ventricular block, potentially life threatening arrhythmia or other uncontrolled arrhythmia or persistent arrhythmia, clinically significant valvular heart disease);
* Known significant renal artery stenosis with evidence of renal ischemia (on Duplex ultrasound, CTA, or other exam);
* Any concurrent life threatening condition other than vEDS with a life expectancy less than 2 years;
* Likely allergy or hypersensitivity to irbesartan, based on known allergies to drugs of the same class, or which in the opinion of the investigator suggests an increased potential for an adverse hypersensitivity as well as known or suspected contraindications to the study drug;
* Any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety;
* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive Human Chorionic Gonadotropin (hCG) laboratory test (\>5 mIU/ml);
* Women of child-bearing potential (WOCBP) without reliable contraception.

Primary outcomes:
measure: Cardiovascular morbidity and mortality
timeFrame: 2 years
measure: Arterial lesions
timeFrame: 2 years
Secondary outcomes:
measure: Rate of any symptomatic cardiovascular event
timeFrame: 2 years
measure: Occurrence of new asymptomatic arterial lesions (aneurysm, dissection), detected by a systematic CTA
timeFrame: 2 years
measure: Time to first symptomatic clinical morbid and fatal events
timeFrame: 2 years
measure: Number of unplanned hospitalization for any vEDS related event
timeFrame: 2 years
measure: Total number of arterial lesions detected by vascular DUS
timeFrame: 2 years
measure: Total number of arterial lesions worsened during follow-up
timeFrame: 2 years
measure: Changes in PWV (Pulse Wave Velocity)
timeFrame: 2 years
measure: Changes in large arteries properties (diameter, wall stress, stiffness)
timeFrame: 2 years
measure: Decrease in office systolic/diastolic BP
timeFrame: 2 years
measure: Change in estimated glomerular filtration rate (MDRD)
timeFrame: 2 years
measure: Tolerability and safety of the irbesartan assessed by orthostatic hypotension, plasma creatinine, plasma K+ evaluated at each visit
timeFrame: 2 years
measure: Compliance to treatment
timeFrame: 2 years
measure: Quality of life
timeFrame: 2 years
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU DE BORDEAUX - Hopital Saint Andre
city: Bron
country: France
facility: CHU DE LYON - Hopital Femme Mere Enfant
city: Caen
country: France
facility: CHU DE CAEN - Hopital Cote de Nacre
city: Chambray-les-Tours
country: France
facility: CHU DE TOURS - Hopital Trousseau
city: Grenoble
country: France
facility: CHU DE GRENOBLE - Hopital Albert Michallon
city: Grenoble
country: France
facility: CHU DE GRENOBLE - Hopital Couple Enfant
city: Lille
country: France
facility: CHRU DE LILLE - Hopital Claude Huriez
city: Lyon
country: France
facility: CHU DE LYON - Hopital Edouard Herriot
city: Marseille
country: France
facility: AP-HM - Hopital de la Timone
city: Montpellier
country: France
facility: CHU DE MONTPELLIER - Hopital Saint Eloi
city: Nantes
country: France
facility: CHU DE NANTES - Hopital Hotel-Dieu
city: Paris
country: France
facility: AP-HP - Hopital Europeen Georges-Pompidou
city: Toulouse
country: France
facility: CHU DE TOULOUSE - Hopital Purpan
city: Toulouse
country: France
facility: CHU DE TOULOUSE - Hopital Rangueil
city: Vandoeuvre-les-Nancy
country: France
facility: CHRU DE NANCY - Institut Lorrain du Coeur et des Vaisseaux
Study officials:
affiliation: AP-HP, INSERM
name: Xavier JEUNEMAITRE, MD,PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Frank M, Albuisson J, Ranque B, Golmard L, Mazzella JM, Bal-Theoleyre L, Fauret AL, Mirault T, Denarie N, Mousseaux E, Boutouyrie P, Fiessinger JN, Emmerich J, Messas E, Jeunemaitre X. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome. Eur J Hum Genet. 2015 Dec;23(12):1657-64. doi: 10.1038/ejhg.2015.32. Epub 2015 Mar 11.
citation: Faugeroux J, Nematalla H, Li W, Clement M, Robidel E, Frank M, Curis E, Ait-Oufella H, Caligiuri G, Nicoletti A, Hagege A, Messas E, Bruneval P, Jeunemaitre X, Bergaya S. Angiotensin II promotes thoracic aortic dissections and ruptures in Col3a1 haploinsufficient mice. Hypertension. 2013 Jul;62(1):203-8. doi: 10.1161/HYPERTENSIONAHA.111.00974. Epub 2013 Apr 29.
citation: Ong KT, Perdu J, De Backer J, Bozec E, Collignon P, Emmerich J, Fauret AL, Fiessinger JN, Germain DP, Georgesco G, Hulot JS, De Paepe A, Plauchu H, Jeunemaitre X, Laurent S, Boutouyrie P. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet. 2010 Oct 30;376(9751):1476-84. doi: 10.1016/S0140-6736(10)60960-9. Epub 2010 Sep 7.