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Trial record 2 of 12 for:    Recruiting, Not yet recruiting, Available Studies | Ehlers-Danlos syndrome

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

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ClinicalTrials.gov Identifier: NCT02597361
Recruitment Status : Recruiting
First Posted : November 5, 2015
Last Update Posted : July 10, 2018
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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.

Condition or disease Intervention/treatment Phase
Ehlers-Danlos Syndrome, Vascular Type Drug: Irbesartan Drug: Placebo Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome: a Double Blind, Randomized, Placebo Controlled, Multicenter Trial.
Actual Study Start Date : January 2016
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2020


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




Primary Outcome Measures :
  1. Cardiovascular morbidity and mortality [ Time Frame: 2 years ]
    Total number of any non-fatal and fatal cardiovascular events or events related to vEDS

  2. Arterial lesions [ Time Frame: 2 years ]
    number and severity of arterial lesions detected by CTA


Secondary Outcome Measures :
  1. Rate of any symptomatic cardiovascular event [ Time Frame: 2 years ]
    CV death; any morbid and fatal events related to vEDS; Any non fatal CV event; Non-fatal stroke

  2. Occurrence of new asymptomatic arterial lesions (aneurysm, dissection), detected by a systematic CTA [ Time Frame: 2 years ]
    Arterial dissection/rupture/aneurysm in any vascular bed

  3. Time to first symptomatic clinical morbid and fatal events [ Time Frame: 2 years ]
  4. Number of unplanned hospitalization for any vEDS related event [ Time Frame: 2 years ]
  5. Total number of arterial lesions detected by vascular DUS [ Time Frame: 2 years ]
    Echo duplex ultrasound made at inclusion, 6, 12, 18 and 24 months

  6. Total number of arterial lesions worsened during follow-up [ Time Frame: 2 years ]
  7. Changes in PWV (Pulse Wave Velocity) [ Time Frame: 2 years ]
    Applanation tonometry made at randomization visit, 6, 12, 18 and 24 months

  8. Changes in large arteries properties (diameter, wall stress, stiffness) [ Time Frame: 2 years ]
    Echotracking made at randomization visit, 6, 12, 18 and 24 months

  9. Decrease in office systolic/diastolic BP [ Time Frame: 2 years ]
    Vital signs (BP and HR) measured by automatic device at each visit

  10. Change in estimated glomerular filtration rate (MDRD) [ Time Frame: 2 years ]
    eGFR evaluated at each visit

  11. Tolerability and safety of the irbesartan assessed by orthostatic hypotension, plasma creatinine, plasma K+ evaluated at each visit [ Time Frame: 2 years ]
  12. Compliance to treatment [ Time Frame: 2 years ]
    Spot urine for drug determination (celiprolol and irbesartan urinary detection) made at randomization visit and 3, 12 and 24 months

  13. Quality of life [ Time Frame: 2 years ]
    SF36 and HADS questionnaires submitted to participants at randomization visit, 6, 12 and 24 months



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02597361


Contacts
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Contact: Xavier JEUNEMAITRE, MD,PHD +33 1 56 09 38 80 xavier.jeunemaitre@aphp.fr
Contact: Michael FRANK, MD +33 1 56 09 50 40 michael.frank@aphp.fr

Locations
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France
CHU DE BORDEAUX - Hopital Saint Andre Recruiting
Bordeaux, France, 33075
Contact: Joel CONSTANS, MD,PHD    +33 5 56 79 57 16    joel.constans@chu-bordeaux.fr   
CHU DE LYON - Hopital Femme Mere Enfant Recruiting
Bron, France, 69500
Contact: Sophie DUPUIS-GIROD, MD,PHD    +33 4 27 85 65 24    sophie.dupuis-girod@chu-lyon.fr   
CHU DE CAEN - Hopital Cote de Nacre Recruiting
Caen, France, 14033
Contact: Damien LANEELLE, MD,PHD    +33 2 31 06 53 27    laneelle-d@chu-caen.fr   
CHU DE TOURS - Hopital Trousseau Not yet recruiting
Chambray-les-Tours, France, 37044
Contact: Gabriela GEORGESCOU, MD    +33 2 47 47 46 25    g.georgescou@chu-tours.fr   
CHU DE GRENOBLE - Hopital Albert Michallon Recruiting
Grenoble, France, 38043
Contact: Christophe SEINTURIER, MD,PHD    +33 4 76 76 89 60    cseinturier@chu-grenoble.fr   
CHU DE GRENOBLE - Hopital Couple Enfant Not yet recruiting
Grenoble, France, 38043
Contact: Pierre-Simon JOUK, MD,PHD    +33 7 76 76 72 85    psjouk@chu-grenoble.fr   
CHRU DE LILLE - Hopital Claude Huriez Recruiting
Lille, France, 59000
Contact: Marc LAMBERT, MD    +33 3 20 44 42 96    marc.lambert@chru-lille.fr   
CHU DE LYON - Hopital Edouard Herriot Not yet recruiting
Lyon, France, 69003
Contact: Jacques NINET, MD,PHD    +33 4 72 11 75 71    jacques.ninet@chu-lyon.fr   
AP-HM - Hopital de la Timone Recruiting
Marseille, France, 13385
Contact: Laurence BAL-THEOLEYRE, MD    +33 4 91 38 81 20    laurence.bal@ap-hm.fr   
CHU DE MONTPELLIER - Hopital Saint Eloi Recruiting
Montpellier, France, 34295
Contact: Isabelle QUERE, MD,PHD    +33 67 33 70 25    i-quere@chu-montpellier.fr   
CHU DE NANTES - Hopital Hotel-Dieu Not yet recruiting
Nantes, France, 44300
Contact: Marc-Antoine PISTORIUS, MD    +33 2 40 08 33 34    marc.pistorius@chu-nantes.fr   
AP-HP - Hopital Europeen Georges-Pompidou Recruiting
Paris, France, 75015
Contact: Xavier JEUNEMAITRE, MD,PHD    +33 1 56 09 38 80    xavier.jeunemaitre@aphp.fr   
Contact: Michael FRANK, MD    +33 1 56 09 50 40    michael.frank@aphp.fr   
CHU DE TOULOUSE - Hopital Purpan Not yet recruiting
Toulouse, France, 31059
Contact: Sophie JULIA, MD    +33 5 61 77 90 55    julia.s@chu-toulouse.fr   
CHU DE TOULOUSE - Hopital Rangueil Recruiting
Toulouse, France, 31059
Contact: Alessandra BURA-RIVIERE, MD,PHD    +33 5 61 32 24 38    bura-riviere.a@chu-toulouse.fr   
CHRU DE NANCY - Institut Lorrain du Coeur et des Vaisseaux Recruiting
Vandoeuvre-les-Nancy, France, 54500
Contact: Denis WAHL, MD,PHD    +33 3 83 15 36 14    d.wahl@chu.nancy.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Ministry of Health, France
Investigators
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Principal Investigator: Xavier JEUNEMAITRE, MD,PHD AP-HP, INSERM

Publications of Results:
Other Publications:
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02597361     History of Changes
Other Study ID Numbers: P140918
2015-001065-76 ( EudraCT Number )
First Posted: November 5, 2015    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Ehlers-Danlos syndrome, vascular type
Type 2 Angiotensin Receptor Blockers
Additional relevant MeSH terms:
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Ehlers-Danlos Syndrome
Syndrome
Disease
Pathologic Processes
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Hemorrhagic Disorders
Hematologic Diseases
Skin Abnormalities
Congenital Abnormalities
Skin Diseases, Genetic
Genetic Diseases, Inborn
Collagen Diseases
Connective Tissue Diseases
Skin Diseases
Irbesartan
Angiotensin II
Giapreza
Angiotensinogen
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Vasoconstrictor Agents
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors