Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome (ARCADE)

NCT02597361 | Completed Phase 3 DMC

• 2 other identifiers: P1409182015-001065-76
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 15

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.

Conditions

Ehlers-Danlos Syndrome, Vascular Type

Keywords

Ehlers-Danlos syndrome, vascular type; Type 2 Angiotensin Receptor Blockers

Outcome Measures

Primary Outcomes (2)

• Cardiovascular morbidity and mortality

  Total number of any non-fatal and fatal cardiovascular events or events related to vEDS

  2 years

• Arterial lesions

  number and severity of arterial lesions detected by CTA

  2 years

Secondary Outcomes (13)

• Rate of any symptomatic cardiovascular event

  2 years

• Occurrence of new asymptomatic arterial lesions (aneurysm, dissection), detected by a systematic CTA

  2 years

• Time to first symptomatic clinical morbid and fatal events

  2 years

• Number of unplanned hospitalization for any vEDS related event

  2 years

• Total number of arterial lesions detected by vascular DUS

  2 years

Study Arms (2)

Irbesartan

ACTIVE COMPARATOR

Irbesartan: 150 or 300 mg o.d. for 2 years.The up-titration of irbesartan from 150 mg to 300 mg o.d. occurs during the first 8 weeks following randomization and will be driven by clinical, hemodynamic and biological (plasma creatinine and K) tolerability.

Drug: Irbesartan

Placebo

PLACEBO COMPARATOR

Placebo once or twice per day for 2 years.

Drug: Placebo

Interventions

Irbesartan DRUG

Irbesartan: 150 or 300 mg o.d. The up-titration of irbesartan from 150 mg to 300 mg o.d. occur during the first 8 weeks following randomization

Irbesartan

Placebo DRUG

Placebo o.d. to match 150mg or 300mg irbesartan tablets

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Ministry of Health, France: collaborator

Study Sites (15)

CHU DE BORDEAUX - Hopital Saint Andre

Bordeaux, 33075, France

Location

CHU DE LYON - Hopital Femme Mere Enfant

Bron, 69500, France

Location

CHU DE CAEN - Hopital Cote de Nacre

Caen, 14033, France

Location

CHU DE TOURS - Hopital Trousseau

Chambray-lès-Tours, 37044, France

Location

CHU DE GRENOBLE - Hopital Albert Michallon

Grenoble, 38043, France

Location

CHU DE GRENOBLE - Hopital Couple Enfant

Grenoble, 38043, France

Location

CHRU DE LILLE - Hopital Claude Huriez

Lille, 59000, France

Location

CHU DE LYON - Hopital Edouard Herriot

Lyon, 69003, France

Location

AP-HM - Hopital de la Timone

Marseille, 13385, France

Location

CHU DE MONTPELLIER - Hopital Saint Eloi

Montpellier, 34295, France

Location

CHU DE NANTES - Hopital Hotel-Dieu

Nantes, 44300, France

Location

AP-HP - Hopital Europeen Georges-Pompidou

Paris, 75015, France

Location

CHU DE TOULOUSE - Hopital Purpan

Toulouse, 31059, France

Location

CHU DE TOULOUSE - Hopital Rangueil

Toulouse, 31059, France

Location

CHRU DE NANCY - Institut Lorrain du Coeur et des Vaisseaux

Vandœuvre-lès-Nancy, 54500, France

Location

Related Publications (4)

• 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.

  PMID: 25758994 BACKGROUND

• 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.

  PMID: 23630948 RESULT

• 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.

  PMID: 20825986 RESULT

• Jeunemaitre X, Mousseaux E, Frank M, Adham S, Pitocco F, Billon C, Ben Yakhlef M, El Hachmi M, Bura-Riviere A, Lapebie FX, Le Hello C, Laneelle D, Seinturier C, Dieterich K, Lambert M, Dupuis-Girod S, Zuily S, Bal-Theoleyre L, Boulon C, Henneton P, Lu E, Denarie N, Boutouyrie P, Mirault T, Chatellier G, Azizi M. Efficacy of Irbesartan in Celiprolol-Treated Patients With Vascular Ehlers-Danlos Syndrome. Circulation. 2025 Mar 11;151(10):686-695. doi: 10.1161/CIRCULATIONAHA.124.072849. Epub 2025 Feb 5.

  PMID: 39906986 DERIVED

MeSH Terms

Conditions

Ehlers-Danlos Syndrome, Type IV

Interventions

Irbesartan

Condition Hierarchy (Ancestors)

Aortic Dissection; Dissection, Blood Vessel; Aneurysm; Vascular Diseases; Cardiovascular Diseases; Ehlers-Danlos Syndrome; Hemostatic Disorders; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Skin Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases, Genetic; Genetic Diseases, Inborn; Collagen Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Spiro Compounds; Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Polycyclic Compounds

Study Officials

• Xavier JEUNEMAITRE, MD,PHD

  AP-HP, INSERM

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 23, 2015
• First Posted: November 5, 2015
• Study Start: January 1, 2016
• Primary Completion: February 19, 2020
• Study Completion: February 19, 2020
• Last Updated: February 29, 2024

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: 3 years following publication. No end date
• Access Criteria: With whom? Qualified researchers who provide a methodologically sound proposal. Collaboration with the original team will be fostered. For what types of analyses? To achieve aims in the approved proposal. Meta-analyses are encouraged. By what mechanism will data be made available? Data sharing must be accepted by the sponsor and the principal investigator (PI) based on scientific project and scientific involvement of the PI team. Proposals should be directed to xavier.jeunemaitre@aphp.fr. Teams wishing obtain IPD must meet the sponsor and IP team to present scientific (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory data access agreement. Processing of shared data must comply with European General Data Protection Regulation (GDPR).

Locations

FR (15)