Ignite Creation Date:
2025-12-24 @ 11:52 AM
Ignite Modification Date:
2026-01-26 @ 11:59 AM
Study NCT ID:
NCT02597361
Status:
COMPLETED
Last Update Posted:
2024-02-29
First Post:
2015-10-23
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome (ARCADE)
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D000094623', 'term': 'Ehlers-Danlos Syndrome, Type IV'}], 'ancestors': [{'id': 'D000784', 'term': 'Aortic Dissection'}, {'id': 'D000094665', 'term': 'Dissection, Blood Vessel'}, {'id': 'D000783', 'term': 'Aneurysm'}, {'id': 'D014652', 'term': 'Vascular Diseases'}, {'id': 'D002318', 'term': 'Cardiovascular Diseases'}, {'id': 'D004535', 'term': 'Ehlers-Danlos Syndrome'}, {'id': 'D020141', 'term': 'Hemostatic Disorders'}, {'id': 'D006474', 'term': 'Hemorrhagic Disorders'}, {'id': 'D006402', 'term': 'Hematologic Diseases'}, {'id': 'D006425', 'term': 'Hemic and Lymphatic Diseases'}, {'id': 'D012868', 'term': 'Skin Abnormalities'}, {'id': 'D000013', 'term': 'Congenital Abnormalities'}, {'id': 'D009358', 'term': 'Congenital, Hereditary, and Neonatal Diseases and Abnormalities'}, {'id': 'D012873', 'term': 'Skin Diseases, Genetic'}, {'id': 'D030342', 'term': 'Genetic Diseases, Inborn'}, {'id': 'D003095', 'term': 'Collagen Diseases'}, {'id': 'D003240', 'term': 'Connective Tissue Diseases'}, {'id': 'D017437', 'term': 'Skin and Connective Tissue Diseases'}, {'id': 'D012871', 'term': 'Skin Diseases'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D000077405', 'term': 'Irbesartan'}], 'ancestors': [{'id': 'D001713', 'term': 'Biphenyl Compounds'}, {'id': 'D001555', 'term': 'Benzene Derivatives'}, {'id': 'D006841', 'term': 'Hydrocarbons, Aromatic'}, {'id': 'D006844', 'term': 'Hydrocarbons, Cyclic'}, {'id': 'D006838', 'term': 'Hydrocarbons'}, {'id': 'D009930', 'term': 'Organic Chemicals'}, {'id': 'D013141', 'term': 'Spiro Compounds'}, {'id': 'D013777', 'term': 'Tetrazoles'}, {'id': 'D001393', 'term': 'Azoles'}, {'id': 'D006573', 'term': 'Heterocyclic Compounds, 1-Ring'}, {'id': 'D006571', 'term': 'Heterocyclic Compounds'}, {'id': 'D011083', 'term': 'Polycyclic Compounds'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE3'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'DOUBLE', 'whoMasked': ['PARTICIPANT', 'INVESTIGATOR']}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'PARALLEL'}, 'enrollmentInfo': {'type': 'ACTUAL', 'count': 61}}, 'statusModule': {'overallStatus': 'COMPLETED', 'startDateStruct': {'date': '2016-01', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2020-10', 'completionDateStruct': {'date': '2020-02-19', 'type': 'ACTUAL'}, 'lastUpdateSubmitDate': '2024-02-28', 'studyFirstSubmitDate': '2015-10-23', 'studyFirstSubmitQcDate': '2015-11-04', 'lastUpdatePostDateStruct': {'date': '2024-02-29', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2015-11-05', 'type': 'ESTIMATED'}, 'primaryCompletionDateStruct': {'date': '2020-02-19', 'type': 'ACTUAL'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Cardiovascular morbidity and mortality', 'timeFrame': '2 years', 'description': 'Total number of any non-fatal and fatal cardiovascular events or events related to vEDS'}, {'measure': 'Arterial lesions', 'timeFrame': '2 years', 'description': 'number and severity of arterial lesions detected by CTA'}], 'secondaryOutcomes': [{'measure': 'Rate of any symptomatic cardiovascular event', 'timeFrame': '2 years', 'description': 'CV death; any morbid and fatal events related to vEDS; Any non fatal CV event; Non-fatal stroke'}, {'measure': 'Occurrence of new asymptomatic arterial lesions (aneurysm, dissection), detected by a systematic CTA', 'timeFrame': '2 years', 'description': 'Arterial dissection/rupture/aneurysm in any vascular bed'}, {'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', 'description': 'Echo duplex ultrasound made at inclusion, 6, 12, 18 and 24 months'}, {'measure': 'Total number of arterial lesions worsened during follow-up', 'timeFrame': '2 years'}, {'measure': 'Changes in PWV (Pulse Wave Velocity)', 'timeFrame': '2 years', 'description': 'Applanation tonometry made at randomization visit, 6, 12, 18 and 24 months'}, {'measure': 'Changes in large arteries properties (diameter, wall stress, stiffness)', 'timeFrame': '2 years', 'description': 'Echotracking made at randomization visit, 6, 12, 18 and 24 months'}, {'measure': 'Decrease in office systolic/diastolic BP', 'timeFrame': '2 years', 'description': 'Vital signs (BP and HR) measured by automatic device at each visit'}, {'measure': 'Change in estimated glomerular filtration rate (MDRD)', 'timeFrame': '2 years', 'description': 'eGFR evaluated at each visit'}, {'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', 'description': 'Spot urine for drug determination (celiprolol and irbesartan urinary detection) made at randomization visit and 3, 12 and 24 months'}, {'measure': 'Quality of life', 'timeFrame': '2 years', 'description': 'SF36 and HADS questionnaires submitted to participants at randomization visit, 6, 12 and 24 months'}]}, 'oversightModule': {'oversightHasDmc': True}, 'conditionsModule': {'keywords': ['Ehlers-Danlos syndrome, vascular type', 'Type 2 Angiotensin Receptor Blockers'], 'conditions': ['Ehlers-Danlos Syndrome, Vascular Type']}, 'referencesModule': {'references': [{'pmid': '25758994', 'type': 'BACKGROUND', '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.'}, {'pmid': '23630948', 'type': 'RESULT', '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.'}, {'pmid': '20825986', 'type': 'RESULT', '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.'}, {'pmid': '39906986', 'type': 'DERIVED', 'citation': '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.'}]}, 'descriptionModule': {'briefSummary': '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.', 'detailedDescription': '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.\n\nThe 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.\n\nMethodology:\n\nMulticenter, double-blind, randomized (1:1), placebo-controlled, parallel group, study with blind endpoint evaluation in adult vEDS patients.\n\nMain criteria for inclusion:\n\nPatients 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.'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'maximumAge': '70 Years', 'minimumAge': '18 Years', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria:\n\n* Patients with genetically-proven vEDS (presence of a pathogenic mutation at the COL3A1 gene);\n* Age ≥18 years and \\<70 years;\n* Men and women with reliable contraception or negative beta-HCG at screening;\n* Celiprolol at the optimal tolerated dose since at least 12 weeks;\n* vEDS patient fully intolerant to celiprolol but not treated with any other drug active on the vascular system, except another beta-blocker;\n* No compelling indication for ARB therapy (renal infarction, hypertension, proteinuric nephropathy, chronic heart failure, myocardial infarction, stroke);\n* Estimated glomerular filtration rate (GFR) ≥ 30ml/min/1,73m2 (MDRD Formula);\n* Normal or clinically acceptable 12-lead ECG;\n* Written informed consent to participate in the study.\n\nExclusion Criteria:\n\nGeneral criteria\n\n* 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;\n* Participation in another interventional therapeutic study at the same time or within 3 months prior to the beginning of the present study;\n* Participant not affiliated to the French social security;\n* No written informed consent;\n* Severe contrast media allergy, not amenable to pre-treatment Medical and therapeutic criteria\n* History of previous symptomatic visceral complication (any CV event, pulmonary or digestive event) in the 3 months preceding the inclusion;\n* 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);\n* 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);\n* 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);\n* Known significant renal artery stenosis with evidence of renal ischemia (on Duplex ultrasound, CTA, or other exam);\n* Any concurrent life threatening condition other than vEDS with a life expectancy less than 2 years;\n* 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;\n* Any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety;\n* 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);\n* Women of child-bearing potential (WOCBP) without reliable contraception.'}, 'identificationModule': {'nctId': 'NCT02597361', 'acronym': 'ARCADE', 'briefTitle': 'Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome (ARCADE)', 'organization': {'class': 'OTHER', 'fullName': 'Assistance Publique - Hôpitaux de Paris'}, 'officialTitle': 'Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome: a Double Blind, Randomized, Placebo Controlled, Multicenter Trial.', 'orgStudyIdInfo': {'id': 'P140918'}, 'secondaryIdInfos': [{'id': '2015-001065-76', 'type': 'EUDRACT_NUMBER'}]}, 'armsInterventionsModule': {'armGroups': [{'type': 'ACTIVE_COMPARATOR', 'label': 'Irbesartan', 'description': '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.', 'interventionNames': ['Drug: Irbesartan']}, {'type': 'PLACEBO_COMPARATOR', 'label': 'Placebo', 'description': 'Placebo once or twice per day for 2 years.', 'interventionNames': ['Drug: Placebo']}], 'interventions': [{'name': 'Irbesartan', 'type': 'DRUG', 'description': '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', 'armGroupLabels': ['Irbesartan']}, {'name': 'Placebo', 'type': 'DRUG', 'description': 'Placebo o.d. to match 150mg or 300mg irbesartan tablets', 'armGroupLabels': ['Placebo']}]}, 'contactsLocationsModule': {'locations': [{'zip': '33075', 'city': 'Bordeaux', 'country': 'France', 'facility': 'CHU DE BORDEAUX - Hopital Saint Andre', 'geoPoint': {'lat': 44.84124, 'lon': -0.58046}}, {'zip': '69500', 'city': 'Bron', 'country': 'France', 'facility': 'CHU DE LYON - Hopital Femme Mere Enfant', 'geoPoint': {'lat': 45.73865, 'lon': 4.91303}}, {'zip': '14033', 'city': 'Caen', 'country': 'France', 'facility': 'CHU DE CAEN - Hopital Cote de Nacre', 'geoPoint': {'lat': 49.18585, 'lon': -0.35912}}, {'zip': '37044', 'city': 'Chambray-lès-Tours', 'country': 'France', 'facility': 'CHU DE TOURS - Hopital Trousseau', 'geoPoint': {'lat': 47.33537, 'lon': 0.70286}}, {'zip': '38043', 'city': 'Grenoble', 'country': 'France', 'facility': 'CHU DE GRENOBLE - Hopital Albert Michallon', 'geoPoint': {'lat': 45.17869, 'lon': 5.71479}}, {'zip': '38043', 'city': 'Grenoble', 'country': 'France', 'facility': 'CHU DE GRENOBLE - Hopital Couple Enfant', 'geoPoint': {'lat': 45.17869, 'lon': 5.71479}}, {'zip': '59000', 'city': 'Lille', 'country': 'France', 'facility': 'CHRU DE LILLE - Hopital Claude Huriez', 'geoPoint': {'lat': 50.63391, 'lon': 3.05512}}, {'zip': '69003', 'city': 'Lyon', 'country': 'France', 'facility': 'CHU DE LYON - Hopital Edouard Herriot', 'geoPoint': {'lat': 45.74906, 'lon': 4.84789}}, {'zip': '13385', 'city': 'Marseille', 'country': 'France', 'facility': 'AP-HM - Hopital de la Timone', 'geoPoint': {'lat': 43.29695, 'lon': 5.38107}}, {'zip': '34295', 'city': 'Montpellier', 'country': 'France', 'facility': 'CHU DE MONTPELLIER - Hopital Saint Eloi', 'geoPoint': {'lat': 43.61093, 'lon': 3.87635}}, {'zip': '44300', 'city': 'Nantes', 'country': 'France', 'facility': 'CHU DE NANTES - Hopital Hotel-Dieu', 'geoPoint': {'lat': 47.21725, 'lon': -1.55336}}, {'zip': '75015', 'city': 'Paris', 'country': 'France', 'facility': 'AP-HP - Hopital Europeen Georges-Pompidou', 'geoPoint': {'lat': 48.85341, 'lon': 2.3488}}, {'zip': '31059', 'city': 'Toulouse', 'country': 'France', 'facility': 'CHU DE TOULOUSE - Hopital Purpan', 'geoPoint': {'lat': 43.60426, 'lon': 1.44367}}, {'zip': '31059', 'city': 'Toulouse', 'country': 'France', 'facility': 'CHU DE TOULOUSE - Hopital Rangueil', 'geoPoint': {'lat': 43.60426, 'lon': 1.44367}}, {'zip': '54500', 'city': 'Vandœuvre-lès-Nancy', 'country': 'France', 'facility': 'CHRU DE NANCY - Institut Lorrain du Coeur et des Vaisseaux', 'geoPoint': {'lat': 48.66115, 'lon': 6.17114}}], 'overallOfficials': [{'name': 'Xavier JEUNEMAITRE, MD,PHD', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'AP-HP, INSERM'}]}, 'ipdSharingStatementModule': {'infoTypes': ['STUDY_PROTOCOL', 'SAP', 'ICF'], 'timeFrame': '3 years following publication. No end date', 'ipdSharing': 'YES', 'description': 'Individual participant data (IPD) that underlie results reported in publications after de-identification (text, tables, figures, and appendices).\n\nIPD detailed in the protocol of a planned meta-analysis could be shared.', 'accessCriteria': 'With whom? Qualified researchers who provide a methodologically sound proposal. Collaboration with the original team will be fostered.\n\nFor what types of analyses? To achieve aims in the approved proposal. Meta-analyses are encouraged.\n\nBy 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.\n\nProcessing of shared data must comply with European General Data Protection Regulation (GDPR).'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Assistance Publique - Hôpitaux de Paris', 'class': 'OTHER'}, 'collaborators': [{'name': 'Ministry of Health, France', 'class': 'OTHER_GOV'}], 'responsibleParty': {'type': 'SPONSOR'}}}}