Clinical Trial: Efficacy of Thalidomide in the Treatment of Hereditary Hemorrhagic Telangiectasia

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: Efficacy of Thalidomide in the Treatment of Severe Recurrent Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)

Brief Summary: Hereditary hemorrhagic telangiectasia (HHT) (OMIM 187300 and 600376), also known as Rendu-Osler-Weber syndrome, is an autosomal dominant disease and has a prevalence between 1:5000 and 1:8000 in different populations. Clinically, the occurrence of mucocutaneous and gastrointestinal telangiectasias and of systemic arteriovenous malformations is commonly observed. Recurrent and severe epistaxis, due to the presence of telangiectasias in nasal mucosa, is the most common presentation of HHT, frequently leading to severe anemia requiring intravenous iron and blood transfusions. Although not life threatening, severe epistaxis has a great impact on quality of life in HHT patients and it represents the most important impediment in daily activities, that poses therapeutic challenge. Recently, angiogenesis has been implicated in the pathogenesis of HHT. Circulating concentrations of both TGF-beta and vascular endothelial growth factor (VEGF) are significantly elevated and therefore, anti-angiogenic substances may be effective in the treatment of vascular malformations in this disease. Thalidomide functions as a potent immunosuppressive and antiangiogenic agent. The aim of this study is to assess the clinical effects of thalidomide therapy on the severity of epistaxis in subjects with HHT who are refractory to standard therapies.

Detailed Summary:

In the management of HHT epistaxis, multiple approaches have been tried, including electrocautery, laser, embolization, arterial ligation, but all approaches are largely palliative with variable results, many requiring repeated interventions. Except for nasal closure, surgical options offer, at best, limited hemorrhage-free intervals, but no definitive results and all have side effects. Moreover, currently, there is no established medical treatment available for these patients. To limit blood loss, the few medical treatments used include manipulation of the coagulation and fibrinolytic pathways or topical applications of anti-inflammatory drugs. However, multiple lesions disseminated over the entire mucosal surface are common in affected individuals, making local treatment difficult. Re-bleeding consumes a disproportionate share of healthcare resources devoted to multiple admissions, repeated endoscopies and blood transfusions.

Recently, angiogenesis has been implicated in the pathogenesis of HHT. Circulating concentrations of both TGF-beta and vascular endothelial growth factor (VEGF) are significantly elevated and therefore, anti-angiogenic substances may be effective in the treatment of vascular malformations in this disease.

Thalidomide functions as a potent immunosuppressive and antiangiogenic agent by inhibiting the phagocytic ability of inflammatory cells and the production of cytokines, such as tumor necrosis factor-alpha (TNF-a). It has been shown to be effective in the treatment of inflammatory diseases, in conditions associated with human immunodeficiency virus (HIV) infection, and in various cancers. Bleeding inhibition has been observed in HHT patients who received thalidomide as an antiangiogenic cancer therapy. A recent paper has reported that thalidomide treatment induced vessel maturation in an experimenta
Sponsor: IRCCS Policlinico S. Matteo

Current Primary Outcome: Percentage of patients showing a decrease in the frequency, intensity and duration of epistaxis and in the blood transfusion requirement. [ Time Frame: up to 24 weeks ]

Cessation of nose bleeding will be defined as complete response. Reduction in the severity of any bleeding parameter less than complete response will represent partial response.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Size and number of telangiectasias evaluated by endoscopy of nasal mucosa (recording images of the size and localization of telangiectasias) [ Time Frame: up to 24 weeks ]
  • Minimum dose of the drug that reduces bleeding [ Time Frame: up to 24 weeks ]
  • Time to response [ Time Frame: up to 24 weeks ]
  • Time to relapse after the end of treatment [ Time Frame: up to 24 weeks after the end of treatment ]
  • Number of adverse events [ Time Frame: up to 1 year ]
  • Correlations between biological parameters, response to treatment and side effects profile [ Time Frame: up to 24 weeks ]
    • Correlations between the mutations that are responsible for HHT and response to treatment
    • Correlations between polymorphisms of CYP2C19 and response to treatment
    • Correlations between polymorphisms of CYP2C19 and side effects profile


Original Secondary Outcome: Same as current

Information By: IRCCS Policlinico S. Matteo

Dates:
Date Received: November 28, 2011
Date Started: November 2011
Date Completion: June 2016
Last Updated: February 27, 2016
Last Verified: August 2015