start date: January 2016
estimated completion: April 2020
last updated: July 10, 2018
phase of development:
Phase 3
size / enrollment: 108
study design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
study 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.
primary outcomes:
- Cardiovascular morbidity and mortality [ Time Frame:2 years ]
- Arterial lesions [ Time Frame:2 years ]
secondary outcomes:
- 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
- Occurrence of new asymptomatic arterial lesions (aneurysm [ Time Frame:2 years ] Arterial dissection/rupture/aneurysm in any vascular bed
- dissection) [ Time Frame:2 years ]
- detected by a systematic CTA [ Time Frame:2 years ]
- Time to first symptomatic clinical morbid and fatal events [ Time Frame:2 years ] Echo duplex ultrasound made at inclusion, 6, 12, 18 and 24 months
- Number of unplanned hospitalization for any vEDS related event [ Time Frame:2 years ]
- Total number of arterial lesions detected by vascular DUS [ Time Frame:2 years ] Applanation tonometry made at randomization visit, 6, 12, 18 and 24 months
- Total number of arterial lesions worsened during follow-up [ Time Frame:2 years ] Echotracking made at randomization visit, 6, 12, 18 and 24 months
- Changes in PWV (Pulse Wave Velocity) [ Time Frame:2 years ] Vital signs (BP and HR) measured by automatic device at each visit
- Changes in large arteries properties (diameter [ Time Frame:2 years ] eGFR evaluated at each visit
- wall stress [ Time Frame:2 years ]
- stiffness) [ Time Frame:2 years ] Morisky questionnaire at each visit and spot urine for drug determination (celiprolol and irbesartan urinary detection) made at randomization visit and 3, 12 and 24 months
- Decrease in office systolic/diastolic BP [ Time Frame:2 years ] SF36 and HADS questionnaires submitted to participants at randomization visit, 6, 12 and 24 months
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.
