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Ehlers-Danlos Syndrome, Vascular TypePhase 3ARCADENCT02597361

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

A Phase 3 study testing Irbesartan in people with Ehlers-Danlos Syndrome, Vascular Type, run by Assistance Publique - Hôpitaux de Paris at 15 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
Ehlers-Danlos Syndrome, Vascular Type
What is being tested?
Irbesartan
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
61 participants
Where
15 sitesFrance
Study dates
Jan 2016to 19 Feb 2020
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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);
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  • 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.

Who cannot join

  • 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
Show all 16Show fewer
  • 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.

Trial locations and contacts

15 sites in 1 country.

15 sites in 1 country

France15 sites
  • CHU DE BORDEAUX - Hopital Saint Andre

    Bordeaux, 33075

  • CHU DE LYON - Hopital Femme Mere Enfant

    Bron, 69500

  • CHU DE CAEN - Hopital Cote de Nacre

    Caen, 14033

  • CHU DE TOURS - Hopital Trousseau

    Chambray-lès-Tours, 37044

  • CHU DE GRENOBLE - Hopital Albert Michallon

    Grenoble, 38043

  • CHU DE GRENOBLE - Hopital Couple Enfant

    Grenoble, 38043

  • CHRU DE LILLE - Hopital Claude Huriez

    Lille, 59000

  • CHU DE LYON - Hopital Edouard Herriot

    Lyon, 69003

  • AP-HM - Hopital de la Timone

    Marseille, 13385

  • CHU DE MONTPELLIER - Hopital Saint Eloi

    Montpellier, 34295

  • CHU DE NANTES - Hopital Hotel-Dieu

    Nantes, 44300

  • AP-HP - Hopital Europeen Georges-Pompidou

    Paris, 75015

  • CHU DE TOULOUSE - Hopital Purpan

    Toulouse, 31059

  • CHU DE TOULOUSE - Hopital Rangueil

    Toulouse, 31059

  • CHRU DE NANCY - Institut Lorrain du Coeur et des Vaisseaux

    Vandœuvre-lès-Nancy, 54500

Other trials in France

About this study

Official title: 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.

Read the 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.

Being tested
Irbesartan, Placebo
Keywords
Ehlers-Danlos syndrome, vascular type, Type 2 Angiotensin Receptor Blockers
Medical subject headings
Ehlers-Danlos Syndrome, Type IV

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IrbesartanDrug

    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

  • PlaceboDrug

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

Study groups in NCT02597361
Study groupRoleWhat they receive
IrbesartanActive comparatorIrbesartan: 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.
Receives: Drug: Irbesartan
PlaceboPlacebo comparatorPlacebo once or twice per day for 2 years.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Cardiovascular morbidity and mortality

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

    Measured: 2 years

  2. Arterial lesions

    number and severity of arterial lesions detected by CTA

    Measured: 2 years

Secondary outcomes (13)
  1. Rate of any symptomatic cardiovascular event

    CV death; any morbid and fatal events related to vEDS; Any non fatal CV event; Non-fatal stroke

    Measured: 2 years

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

    Arterial dissection/rupture/aneurysm in any vascular bed

    Measured: 2 years

  3. Time to first symptomatic clinical morbid and fatal events

    Measured: 2 years

  4. Number of unplanned hospitalization for any vEDS related event

    Measured: 2 years

  5. Total number of arterial lesions detected by vascular DUS

    Echo duplex ultrasound made at inclusion, 6, 12, 18 and 24 months

    Measured: 2 years

  6. Total number of arterial lesions worsened during follow-up

    Measured: 2 years

  7. Changes in PWV (Pulse Wave Velocity)

    Applanation tonometry made at randomization visit, 6, 12, 18 and 24 months

    Measured: 2 years

  8. Changes in large arteries properties (diameter, wall stress, stiffness)

    Echotracking made at randomization visit, 6, 12, 18 and 24 months

    Measured: 2 years

  9. Decrease in office systolic/diastolic BP

    Vital signs (BP and HR) measured by automatic device at each visit

    Measured: 2 years

  10. Change in estimated glomerular filtration rate (MDRD)

    eGFR evaluated at each visit

    Measured: 2 years

  11. Tolerability and safety of the irbesartan assessed by orthostatic hypotension, plasma creatinine, plasma K+ evaluated at each visit

    Measured: 2 years

  12. Compliance to treatment

    Spot urine for drug determination (celiprolol and irbesartan urinary detection) made at randomization visit and 3, 12 and 24 months

    Measured: 2 years

  13. Quality of life

    SF36 and HADS questionnaires submitted to participants at randomization visit, 6, 12 and 24 months

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Nov 2015 (estimated)
  2. Study startJan 2016
  3. Primary completion19 Feb 2020
  4. Study completion19 Feb 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
61 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02597361
Sponsor's protocol ID
P140918
Other IDs
2015-001065-76, 2015
Acronym
ARCADE
Status last verified
Oct 2020
First submitted
23 Oct 2015
Last updated
29 Feb 2024
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Yes: 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.

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.

    PubMed 25758994
  • 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.

    PubMed 23630948
  • 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.

    PubMed 20825986
  • 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.

    PubMed 39906986

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Irbesartan in people with Ehlers-Danlos Syndrome, Vascular Type, run by Assistance Publique - Hôpitaux de Paris at 15 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Cardiovascular morbidity and mortality (time frame: 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02597361, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Feb 2024.

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