Randomized, double-blind, placebo-controlled, crossover trial of oral doxycycline for epistaxis in hereditary hemorrhagic telangiectasia

K P Thompson, J Sykes, P Chandakkar, P Marambaud, N T Vozoris, D A Marchuk, M E Faughnan, K P Thompson, J Sykes, P Chandakkar, P Marambaud, N T Vozoris, D A Marchuk, M E Faughnan

Abstract

Background: Vascular malformations in hereditary hemorrhagic telangiectasia (HHT) lead to chronic recurrent bleeding, hemorrhage, stroke, heart failure, and liver disease. There is great interest in identifying novel therapies for epistaxis in HHT given its associated morbidity and impact on quality of life. We aimed to measure the effectiveness of oral doxycycline for the treatment of epistaxis and explore mechanisms of action on angiogenic, inflammatory and pathway markers in HHT using a randomized controlled trial.

Methods: 13 HHT patients with epistaxis were recruited from the Toronto HHT Center at St. Michael's Hospital. Recruitment was stopped early due to COVID-19-related limitations. The study duration was 24 months. Patients were randomly assigned to the treatment-first or placebo-first study arm. We compared the change in weekly epistaxis duration and frequency, biomarkers, blood measurements, and intravenous iron infusion and blood transfusion requirements between treatment and placebo.

Results: There was no significant difference in the change in weekly epistaxis duration (p = 0.136) or frequency (p = 0.261) between treatment and placebo. There was no significant difference in the levels of MMP-9, VEGF, ANG-2, IL-6 or ENG with treatment. Hemoglobin levels were significantly higher (p = 0.0499) during treatment. Ferritin levels were not significantly different between treatment and placebo. There was no significant difference in RBC transfusions between treatment periods (p = 0.299).

Conclusion: Overall, our study did not demonstrate effectiveness of doxycycline as a treatment for epistaxis in patients with HHT, though the study was underpowered. Secondary analyses provided new observations which may help guide future trials in HHT. Trial Registration ClinicalTrials.gov, NCT03397004. Registered 11 January 2018 - Prospectively registered, https://ichgcp.net/clinical-trials-registry/NCT03397004.

Keywords: Angiogenesis; Biomarkers; Doxycycline; Epistaxis; HHT; Hereditary hemorrhagic telangiectasia.

Conflict of interest statement

The authors have no relevant financial or non-financial interests to disclose.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Weekly epistaxis duration by treatment allocation. Shaded boxes represent periods of doxycycline treatment
Fig. 3
Fig. 3
Mean WED, hemoglobin level and RBC transfusions for individual patient responders. Horizontal tick marks represent mean WED for that month and error bars represent standard deviation of the mean. Hemoglobin levels are depicted by black circles and blood transfusions are indicated by an x, with each x representing 1 unit. In general, patients in Allocation B had more severe epistaxis than patients in Allocation A. The scale for mean WED was set to 87 min for Allocation A patients, except for Subject 1, who was a major outlier, with a maximum of 483 min. The scale for mean WED was set to 150 min for 5/6 Allocation B patients and 250 min for the remaining 1 patient
Fig. 4
Fig. 4
Mean WED, hemoglobin level and RBC transfusions for individual patient non-responders. Horizontal tick marks represent mean WED for that month and error bars represent standard deviation of the mean. Hemoglobin levels are depicted by black circles and blood transfusions are indicated by an x, with each x representing 1 unit. In general, patients in Allocation B had more severe epistaxis than patients in Allocation A. The scale for mean WED was set to 87 min for Allocation A patients, except for Subject 1, who was a major outlier, with a maximum of 483 min. The scale for mean WED was set to 150 min for 5/6 Allocation B patients and 250 min for the remaining 1 patient

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