Efficacy and safety of intravenous bevacizumab on severe bleeding associated with hemorrhagic hereditary telangiectasia: A national, randomized multicenter trial.

BACKGROUND: Bevacizumab-a humanized monoclonal antibody-has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been conducted. METHODS: This study is a double-blind multicenter randomized phase 2 trial with a 1:1 active-treatment-to-placebo ratio. We included patients over the age of 18 with a confirmed diagnosis and the need for at least four red blood cell (RBC) units transfused in the 3 months before study enrollment. Bevacizumab was administered at a dose of 5 mg/kg every 14 days with a total of six injections. The primary efficacy criterion was a decrease of at least 50% in the cumulative number of RBC units transfused in a 3-month period before and after treatment. RESULTS: A total of 24 patients (12 in each group) were included and randomized at 4 different centers. In intention-to-treat analysis, 63.6% of patients (7/11) in the bevacizumab group versus 33.3% of patients (4/12) in the placebo group decreased the number of blood transfusions by at least 50% (p = 0.22). Hemoglobin levels significantly improved at 6 months in the bevacizumab versus placebo group (p = 0.02). The pharmacokinetics study revealed that patients with high exposure to bevacizumab had a significant decrease in RBC transfusions (p = 0.03). Fifty-nine adverse events were observed, 34 in the placebo arm versus 25 in the bevacizumab arm. CONCLUSION: Though the present trial was underpowered, patients with HHT receiving bevacizumab required numerically fewer red blood cell transfusions than those receiving placebo, particularly those with high exposure.

Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial.

Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks after the end of the treatment, the efficacy on the duration of nosebleeds of tacrolimus nasal ointment, administered for six weeks to patients with hereditary hemorrhagic telangiectasia complicated by nosebleeds, and we performed a prospective, multicenter, randomized, placebo-controlled, double-blinded, ratio 1:1 phase II study. Patients were recruited from three French Hereditary Hemorrhagic Telangiectasia (HHT) centers between May 2017 and August 2018, with a six-week follow-up, and we included people aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis (total duration > 30 min/6 weeks prior to inclusion). Tacrolimus ointment 0.1% was self-administered by the patients twice daily. About 0.1 g of product was to be administered in each nostril with a cotton swab. A total of 50 patients was randomized and treated. Mean epistaxis duration before and after treatment in the tacrolimus group were 324.64 and 249.14 min, respectively, and in the placebo group 224.69 and 188.14 min, respectively. Epistaxis duration improved in both groups, with no significant difference in our main objective comparing epistaxis before and after treatment (p = 0.77); however, there was a significant difference in evolution when comparing epistaxis before and during treatment (p = 0.04). Toxicity was low and no severe adverse events were reported. In conclusion, tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment. However, the good tolerance, associated with a significant improvement in epistaxis duration during treatment, encouraged us to perform a phase 3 trial on a larger patient population with a main outcome of epistaxis duration during treatment and a longer treatment time.

Efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. A double-blind, randomized, placebo-controlled trial.

Hereditary hemorrhagic telangiectasia is a rare vascular genetic disease. Epistaxis is the most frequent and disabling manifestation, and timolol appears to be a new therapeutic option as non-selective beta-blockers have in vitro and in vivo anti-angiogenic properties. Our main objective was to evaluate the efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. This study is a single-center, randomized, phase 2, double-blind placebo-controlled study with an allocation ratio of 1:1. It was proposed to patients with hereditary hemorrhagic telangiectasia monitored at the French Reference Center, and we included patients aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis. The treatment was self-administered by the patient with a posology of one spray (50 µL) of timolol 0.5% or placebo in each nostril twice a day for 28 consecutive days. The primary efficacy endpoint was mean monthly epistaxis duration, assessed by monitoring epistaxis grids. A total of 58 patients were randomized and treated. The baseline characteristics were similar in the 2 groups. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 26 patients receiving the drug in comparison with the placebo group (p = 0.54). Toxicity was low and no severe adverse events were reported. One limitation is that we included all HHT patients with nosebleeds and did not take into account history of nasal surgery or nasal crusts. Timolol, administered by nasal spray at a dose of 0.25 mg in each nostril twice a day for 28 consecutive days, did not improve epistaxis in patients with hereditary hemorrhagic telangiectasia at 4 months after the beginning of the treatment.