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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome: a Double Blind, Randomized, Placebo Controlled, Multicenter Trial.

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 Summary:

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.


Sponsor: Assistance Publique - Hôpitaux de Paris

Current Primary Outcome:

  • Cardiovascular morbidity and mortality [ Time Frame: 2 years ]
    Total number of any non-fatal and fatal cardiovascular events or events related to vEDS
  • Arterial lesions [ Time Frame: 2 years ]
    number and severity of arterial lesions detected by CTA


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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, dissection), detected by a systematic CTA [ Time Frame: 2 years ]
    Arterial dissection/rupture/aneurysm in any vascular bed
  • Time to first symptomatic clinical morbid and fatal events [ Time Frame: 2 years ]
  • 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 ]
    Echo duplex ultrasound made at inclusion, 6, 12, 18 and 24 months
  • Total number of arterial lesions worsened during follow-up [ Time Frame: 2 years ]
  • Changes in PWV (Pulse Wave Velocity) [ Time Frame: 2 years ]
    Applanation tonometry made at randomization visit, 6, 12, 18 and 24 months
  • Changes in large arteries properties (diameter, wall stress, stiffness) [ Time Frame: 2 years ]
    Echotracking made at randomization visit, 6, 12, 18 and 24 months
  • Decrease in office systolic/diastolic BP [ Time Frame: 2 years ]
    Vital signs (BP and HR) measured by automatic device at each visit
  • Change in estimated glomerular filtration rate (MDRD) [ Time Frame: 2 years ]
    eGFR evaluated at each visit
  • Tolerability and safety of the irbesartan assessed by orthostatic hypotension, plasma creatinine, plasma K+ evaluated at each visit [ Time Frame: 2 years ]
  • Compliance to treatment [ 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
  • Quality of life [ Time Frame: 2 years ]
    SF36 and HADS questionnaires submitted to participants at randomization visit, 6, 12 and 24 months


Original Secondary Outcome: Same as current

Information By: Assistance Publique - Hôpitaux de Paris

Dates:
Date Received: October 23, 2015
Date Started: January 2016
Date Completion: April 2020
Last Updated: September 1, 2016
Last Verified: August 2016