Efficacy of Nintedanib for Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) Patients

Hereditary hemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber disease, is a rare genetic disease with autosomal dominant transmission and a prevalence in the general population of 1/5'000 to 1/10'000. Genetic mutations in HHT affect the intracellular angiogenic signalling pathways (for example through the Vascular Endothelial Grow Factor [VEGF]) in endothelial cells. Clinically, HHT leads to arteriovenous malformations in various organs including the lung, brain, liver, digestive tract, skin, and nasal mucosa. More than 90% of HHT patients suffer from chronic nosebleeds called epistaxis, which may lead to severe iron deficiency, anemia requiring recurrent blood transfusions in 10-30%, emergency hospital admissions for acute and sometimes life-threatening bleeding, and moderate to severe reduction in quality of life in about 70%. Nintedanib, an antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis (IPF), also targets the VEGF receptor. The investigators hypothesize that nintedanib, acting by inhibition of the VEGF receptor, may reduce the duration and frequency of epistaxis in HHT patients.

This hypothesis will be studies in a phase II randomized controlled trial. The study design will be the following:

Pre-therapeutic observation period of 8 weeks followed by a 16-week interventional phase (nintedanib 150 mg once a day for 2 weeks, then twice a day for 14 weeks compared to a placebo at same regimen), and by an 8-week follow-up period to assess post-treatment effects and possible adverse events.

Number of randomized patients: up to 24 in each arm, to achieve at least 16 patients completing the entire study in each arm, with up to 8 drop-out in each arm allowed.

Patients will complete an epistaxis self-administered assessment grid daily since the screening visit, and an epistaxis severity score and a quality of life assessment at the end of weeks 8, 16, 20, 24 and 32.

Blood will be sampled at screening (= week 1), and at weeks 8, 12, 16, 20, 24 and 32 to assess hemoglobin and ferritin levels, and to monitor hepatic or renal functions for safety reasons.

Microphotography (dermoscopy) of selected cutaneous telangiectasia will be performed at visits 1, 6 and 7.

Prior to study initiation, the study protocol, the patient information form and consent form, as well as other study-specific documents will be submitted to the local ethics committee (CER-VD) and the Swiss national drug regulatory authority (Swissmedic) for approval. Any amendment to the protocol must be approved (if legally required) by these institutions.

Participants will be closely monitored for adverse events at each visit. Each participant will hold of an emergency card indicating his/her randomization number, the name and number of the study, the name of the PI, the possible Investigated Medical Product (IMP) i.e. nintedanib or placebo, and the emergency phone number. In case of serious adverse event (SAE), participants may call the emergency number. The call will be answered directly by the PI or a co-investigator.

Individual medical information obtained during the course of this study will be confidential and disclosure to third parties will be prohibited. Confidentiality will also be warranted by using coded subject identification in the computer files.

Only authorized staff of the research team, i.e. the sponsor-PI, investigators, and study nurse will be authorized to access participants data in a password-protected database. After database lock, the Sponsor-PI, investigators and statistician will be able to access the database for analysis. The database will be archived for ten years after study completion.