Doxycycline for Hereditary Hemorrhagic Telangiectasia

The aim is to study is to evaluate doxycycline as a treatment for HHT with the proposed "HHT Clinical Trial Protocol". Rare disease presents a number of challenges in clinical trial design, including recruitment challenges, related power limitations and less knowledge about outcomes measurement. Considering these limitations, as well as the large variability in epistaxis measures across HHT patients, a crossover-trial design, with each subject receiving the study drug and placebo, and therefore serving as their own control, has been selected, including randomization and blinding, to limit bias in measuring this subjective outcome.

This study will investigate doxycycline, given its demonstrated anti-angiogenic and anti-inflammatory properties, as well as compelling effects in arteriovenous malformation (AVM) models. Doxycycline also has the advantages of a proven safety track record for long-term use, oral administration and low cost. Doxycycline suppresses vascular endothelial growth factor (VEGF)-induced cerebral matric metalloproteinase-9 (MMP-9) activity in vivo in the mouse model, and has anti-inflammatory effects as well, via inhibition of pro-inflammatory cytokines. In human brain vascular malformation tissue, there is evidence of increased expression of MMP-9 and VEGF and another tetracycline, minocycline, has attenuated brain hemorrhage in the mouse. Recently, a small retrospective case series reported sustained reduction in nasal hemorrhage in seven HHT patients treated with oral doxycycline. We hypothesize that oral doxycycline will reduce nasal hemorrhage in HHT subjects, through anti-angiogenic and/or anti-inflammatory mechanisms, both of which have been implicated in HHT.

This is a double-blind randomized placebo-controlled trial (N=30) of oral doxycycline (100mg twice daily, 6-month course) in HHT subjects with moderate-severe recurrent nasal hemorrhage. Drug dosing and safety monitoring will be tailored specifically to the agent studied. The primary outcome will be reduction of bleeding minutes per week. In addition, vascular malformation tissue (cutaneous) will be obtained pre and post-treatment, and stained for inflammatory, angiogenic and bone morphogenetic protein-9 (BMP9)-activin A receptor like type1(ALK1)-endoglin- Smad1/5/9 pathway markers. In addition, pre-excision, vascular malformations will be imaged with speckle variance optical coherence tomography (SVOCT), in vivo non-invasive micro-angiography to measure lesion structure, vessel volume and vessel density, as previously described. If the drugs studied are effective at reducing nasal hemorrhage, this will have important clinical implications for HHT patients, and the tissue and imaging may provide important insights into mechanisms.

Inclusion criteria

• Age >+ 18 years
• Clinical HHT diagnosis or genetic diagnosis of HHT
• Known personal or familial endoglin (ENG), ALK1 or SMAD4 mutation
• Epistaxis at least 15 min per week (mean for past month)
• At least two skin telangiectases

• >2mm diameter available for excisional biopsy,
• at least two other telangiectases (skin or mucosal) available for micro-imaging
• Ability to give written informed consent

• including compliance with the requirements of the study

Exclusion criteria

• Allergy/intolerance to the study drug or related agents
• Unstable medical illness
• Acute infection
• Creatinine > upper limit of normal (ULN)
• Liver transaminases (AST or ALT) >= 2x ULN
• Recent (within 2 month) use of study drug or other tetracycline agents
• Women who are pregnant
• Breastfeeding
• Plan to become pregnant during of the study
• Beta human chorionic gonadotropin (BHCG) level <6 IUL (re-test if 6-24 IU/L)
• Specific contra-indications for study drug