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

Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome: a Double Blind, Randomized, Placebo Controlled, Multicenter Trial.

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.

Study Overview

• Status: Completed
• Conditions: Ehlers-Danlos Syndrome, Vascular Type
• Intervention / Treatment: Drug: Irbesartan; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33075
    • CHU de Bordeaux - Hôpital Saint André
  • Bron, France, 69500
    • CHU de Lyon - Hopital Femme Mere Enfant
  • Caen, France, 14033
    • CHU de Caen - Hopital Cote de Nacre
  • Chambray-les-Tours, France, 37044
    • CHU de Tours - Hopital Trousseau
  • Grenoble, France, 38043
    • CHU de Grenoble - Hôpital Albert Michallon
  • Grenoble, France, 38043
    • CHU DE GRENOBLE - Hopital Couple Enfant
  • Lille, France, 59000
    • CHRU de Lille - Hopital Claude Huriez
  • Lyon, France, 69003
    • CHU de Lyon - Hopital Edouard Herriot
  • Marseille, France, 13385
    • AP-HM - Hôpital de la Timone
  • Montpellier, France, 34295
    • CHU De Montpellier - Hopital Saint Eloi
  • Nantes, France, 44300
    • CHU de Nantes - Hôpital Hôtel-Dieu
  • Paris, France, 75015
    • AP-HP - hôpital européen Georges-Pompidou
  • Toulouse, France, 31059
    • CHU de Toulouse - Hôpital Purpan
  • Toulouse, France, 31059
    • CHU de Toulouse - Hôpital Rangueil
  • Vandoeuvre-les-Nancy, France, 54500
    • CHRU DE NANCY - Institut Lorrain du Coeur et des Vaisseaux

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Irbesartan; 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; 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
Placebo Comparator: Placebo; Placebo once or twice per day for 2 years.	Drug: Placebo; Placebo o.d. to match 150mg or 300mg irbesartan tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of any symptomatic cardiovascular event	CV death; any morbid and fatal events related to vEDS; Any non fatal CV event; Non-fatal stroke	2 years
Occurrence of new asymptomatic arterial lesions (aneurysm, dissection), detected by a systematic CTA	Arterial dissection/rupture/aneurysm in any vascular bed	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	Echo duplex ultrasound made at inclusion, 6, 12, 18 and 24 months	2 years
Total number of arterial lesions worsened during follow-up		2 years
Changes in PWV (Pulse Wave Velocity)	Applanation tonometry made at randomization visit, 6, 12, 18 and 24 months	2 years
Changes in large arteries properties (diameter, wall stress, stiffness)	Echotracking made at randomization visit, 6, 12, 18 and 24 months	2 years
Decrease in office systolic/diastolic BP	Vital signs (BP and HR) measured by automatic device at each visit	2 years
Change in estimated glomerular filtration rate (MDRD)	eGFR evaluated at each visit	2 years
Tolerability and safety of the irbesartan assessed by orthostatic hypotension, plasma creatinine, plasma K+ evaluated at each visit		2 years
Compliance to treatment	Spot urine for drug determination (celiprolol and irbesartan urinary detection) made at randomization visit and 3, 12 and 24 months	2 years
Quality of life	SF36 and HADS questionnaires submitted to participants at randomization visit, 6, 12 and 24 months	2 years

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Ministry of Health, France
• Investigators: Principal Investigator: Xavier JEUNEMAITRE, MD,PHD, AP-HP, INSERM

Publications and helpful links

General Publications

• 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.
• 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.
• 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. Erratum In: Lancet. 2016 Aug 6;388(10044):564. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): February 19, 2020
• Study Completion (Actual): February 19, 2020

Study Registration Dates

• First Submitted: October 23, 2015
• First Submitted That Met QC Criteria: November 4, 2015
• First Posted (Estimated): November 5, 2015

Study Record Updates

• Last Update Posted (Actual): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Ehlers-Danlos syndrome, vascular type; Type 2 Angiotensin Receptor Blockers
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Disease; Congenital Abnormalities; Hematologic Diseases; Hemorrhagic Disorders; Genetic Diseases, Inborn; Connective Tissue Diseases; Hemostatic Disorders; Skin Diseases, Genetic; Skin Abnormalities; Aneurysm; Collagen Diseases; Dissection, Blood Vessel; Aortic Dissection; Syndrome; Ehlers-Danlos Syndrome; Ehlers-Danlos Syndrome, Type IV; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Irbesartan
• Other Study ID Numbers: P140918; 2015-001065-76 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Individual participant data (IPD) that underlie results reported in publications after de-identification (text, tables, figures, and appendices).

IPD detailed in the protocol of a planned meta-analysis could be shared.

• IPD Sharing Time Frame: 3 years following publication. No end date

IPD Sharing 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).

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF