Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome (ARCADE) (ARCADE)
Primary Purpose
Ehlers-Danlos Syndrome, Vascular Type
Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Irbesartan
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Ehlers-Danlos Syndrome, Vascular Type focused on measuring Ehlers-Danlos syndrome, vascular type, Type 2 Angiotensin Receptor Blockers
Eligibility 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.
Sites / Locations
- CHU DE BORDEAUX - Hopital Saint Andre
- CHU DE LYON - Hopital Femme Mere Enfant
- CHU DE CAEN - Hopital Cote de Nacre
- CHU DE TOURS - Hopital Trousseau
- CHU DE GRENOBLE - Hopital Albert Michallon
- CHU DE GRENOBLE - Hopital Couple Enfant
- CHRU DE LILLE - Hopital Claude Huriez
- CHU DE LYON - Hopital Edouard Herriot
- AP-HM - Hopital de la Timone
- CHU DE MONTPELLIER - Hopital Saint Eloi
- CHU DE NANTES - Hopital Hotel-Dieu
- AP-HP - Hopital Europeen Georges-Pompidou
- CHU DE TOULOUSE - Hopital Purpan
- CHU DE TOULOUSE - Hopital Rangueil
- CHRU DE NANCY - Institut Lorrain du Coeur et des Vaisseaux
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Irbesartan
Placebo
Arm 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.
Placebo once or twice per day for 2 years.
Outcomes
Primary Outcome Measures
Cardiovascular morbidity and mortality
Total number of any non-fatal and fatal cardiovascular events or events related to vEDS
Arterial lesions
number and severity of arterial lesions detected by CTA
Secondary Outcome Measures
Rate of any symptomatic cardiovascular event
CV death; any morbid and fatal events related to vEDS; Any non fatal CV event; Non-fatal stroke
Occurrence of new asymptomatic arterial lesions (aneurysm, dissection), detected by a systematic CTA
Arterial dissection/rupture/aneurysm in any vascular bed
Time to first symptomatic clinical morbid and fatal events
Number of unplanned hospitalization for any vEDS related event
Total number of arterial lesions detected by vascular DUS
Echo duplex ultrasound made at inclusion, 6, 12, 18 and 24 months
Total number of arterial lesions worsened during follow-up
Changes in PWV (Pulse Wave Velocity)
Applanation tonometry made at randomization visit, 6, 12, 18 and 24 months
Changes in large arteries properties (diameter, wall stress, stiffness)
Echotracking made at randomization visit, 6, 12, 18 and 24 months
Decrease in office systolic/diastolic BP
Vital signs (BP and HR) measured by automatic device at each visit
Change in estimated glomerular filtration rate (MDRD)
eGFR evaluated at each visit
Tolerability and safety of the irbesartan assessed by orthostatic hypotension, plasma creatinine, plasma K+ evaluated at each visit
Compliance to treatment
Spot urine for drug determination (celiprolol and irbesartan urinary detection) made at randomization visit and 3, 12 and 24 months
Quality of life
SF36 and HADS questionnaires submitted to participants at randomization visit, 6, 12 and 24 months
Full Information
NCT ID
NCT02597361
First Posted
October 23, 2015
Last Updated
November 2, 2020
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Ministry of Health, France
1. Study Identification
Unique Protocol Identification Number
NCT02597361
Brief Title
Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome (ARCADE)
Acronym
ARCADE
Official Title
Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome: a Double Blind, Randomized, Placebo Controlled, Multicenter Trial.
Study Type
Interventional
2. Study Status
Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
January 2016 (Actual)
Primary Completion Date
February 19, 2020 (Actual)
Study Completion Date
February 19, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Ministry of Health, France
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ehlers-Danlos Syndrome, Vascular Type
Keywords
Ehlers-Danlos syndrome, vascular type, Type 2 Angiotensin Receptor Blockers
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
61 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Irbesartan
Arm Type
Active Comparator
Arm 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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo once or twice per day for 2 years.
Intervention Type
Drug
Intervention Name(s)
Irbesartan
Intervention 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
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo o.d. to match 150mg or 300mg irbesartan tablets
Primary Outcome Measure Information:
Title
Cardiovascular morbidity and mortality
Description
Total number of any non-fatal and fatal cardiovascular events or events related to vEDS
Time Frame
2 years
Title
Arterial lesions
Description
number and severity of arterial lesions detected by CTA
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Rate of any symptomatic cardiovascular event
Description
CV death; any morbid and fatal events related to vEDS; Any non fatal CV event; Non-fatal stroke
Time Frame
2 years
Title
Occurrence of new asymptomatic arterial lesions (aneurysm, dissection), detected by a systematic CTA
Description
Arterial dissection/rupture/aneurysm in any vascular bed
Time Frame
2 years
Title
Time to first symptomatic clinical morbid and fatal events
Time Frame
2 years
Title
Number of unplanned hospitalization for any vEDS related event
Time Frame
2 years
Title
Total number of arterial lesions detected by vascular DUS
Description
Echo duplex ultrasound made at inclusion, 6, 12, 18 and 24 months
Time Frame
2 years
Title
Total number of arterial lesions worsened during follow-up
Time Frame
2 years
Title
Changes in PWV (Pulse Wave Velocity)
Description
Applanation tonometry made at randomization visit, 6, 12, 18 and 24 months
Time Frame
2 years
Title
Changes in large arteries properties (diameter, wall stress, stiffness)
Description
Echotracking made at randomization visit, 6, 12, 18 and 24 months
Time Frame
2 years
Title
Decrease in office systolic/diastolic BP
Description
Vital signs (BP and HR) measured by automatic device at each visit
Time Frame
2 years
Title
Change in estimated glomerular filtration rate (MDRD)
Description
eGFR evaluated at each visit
Time Frame
2 years
Title
Tolerability and safety of the irbesartan assessed by orthostatic hypotension, plasma creatinine, plasma K+ evaluated at each visit
Time Frame
2 years
Title
Compliance to treatment
Description
Spot urine for drug determination (celiprolol and irbesartan urinary detection) made at randomization visit and 3, 12 and 24 months
Time Frame
2 years
Title
Quality of life
Description
SF36 and HADS questionnaires submitted to participants at randomization visit, 6, 12 and 24 months
Time Frame
2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Xavier JEUNEMAITRE, MD,PHD
Organizational Affiliation
AP-HP, INSERM
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU DE BORDEAUX - Hopital Saint Andre
City
Bordeaux
ZIP/Postal Code
33075
Country
France
Facility Name
CHU DE LYON - Hopital Femme Mere Enfant
City
Bron
ZIP/Postal Code
69500
Country
France
Facility Name
CHU DE CAEN - Hopital Cote de Nacre
City
Caen
ZIP/Postal Code
14033
Country
France
Facility Name
CHU DE TOURS - Hopital Trousseau
City
Chambray-les-Tours
ZIP/Postal Code
37044
Country
France
Facility Name
CHU DE GRENOBLE - Hopital Albert Michallon
City
Grenoble
ZIP/Postal Code
38043
Country
France
Facility Name
CHU DE GRENOBLE - Hopital Couple Enfant
City
Grenoble
ZIP/Postal Code
38043
Country
France
Facility Name
CHRU DE LILLE - Hopital Claude Huriez
City
Lille
ZIP/Postal Code
59000
Country
France
Facility Name
CHU DE LYON - Hopital Edouard Herriot
City
Lyon
ZIP/Postal Code
69003
Country
France
Facility Name
AP-HM - Hopital de la Timone
City
Marseille
ZIP/Postal Code
13385
Country
France
Facility Name
CHU DE MONTPELLIER - Hopital Saint Eloi
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Name
CHU DE NANTES - Hopital Hotel-Dieu
City
Nantes
ZIP/Postal Code
44300
Country
France
Facility Name
AP-HP - Hopital Europeen Georges-Pompidou
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
CHU DE TOULOUSE - Hopital Purpan
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
CHU DE TOULOUSE - Hopital Rangueil
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
CHRU DE NANCY - Institut Lorrain du Coeur et des Vaisseaux
City
Vandoeuvre-les-Nancy
ZIP/Postal Code
54500
Country
France
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
25758994
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.
Results Reference
background
PubMed Identifier
23630948
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.
Results Reference
result
PubMed Identifier
20825986
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. Erratum In: Lancet. 2016 Aug 6;388(10044):564. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text.
Results Reference
result
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Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome (ARCADE)
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