Efficacy of Nintedanib in Reducing Epistaxis Duration in Hereditary Hemorrhagic Telangiectasia: A Phase II Randomized Controlled Trial

The primary objective of this Phase II randomized study is to evaluate whether the proportion of patients with **hereditary haemorrhagic telangiectasia** (HHT) experiencing a reduction of at least 30% in the duration of **epistaxis** after 16 weeks of treatment with **nintedanib** is significantly higher compared to those receiving a placebo. This objective is clinically relevant as it aims to determine the efficacy of nintedanib in reducing the burden of epistaxis, a common and debilitating symptom in HHT patients.

Secondary objectives include: - Assessing changes in epistaxis severity scores, quality of life, and biological values related to anemia in HHT patients under experimental treatment, with evaluations extending to two months post-follow-up to explore potential long-term effects. - Evaluating the long-term safety and tolerability of nintedanib, focusing on bleeding risks and the incidence of gastrointestinal, hepato-biliary, and renal side effects in HHT patients.

The clinical trial involves a total of **28 participants** diagnosed with **hereditary haemorrhagic telangiectasia**. The study population includes both male and female subjects, aged 18 years and older, who have provided signed informed consent. Participants were selected based on the presence of a pathogenic mutation in one of the HHT genes or meeting at least three out of four Curaçao clinical criteria. The trial specifically targets individuals experiencing moderate to serious epistaxis, as indicated by an Epistaxis Severity Score of 3 or higher. Participants must not have cerebral arteriovenous malformation, as confirmed by brain imaging. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is a **Phase II randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy of **nintedanib** in reducing the duration of epistaxis in patients with **hereditary haemorrhagic telangiectasia** (HHT). The primary objective is to determine if the proportion of HHT patients experiencing at least a 30% reduction in epistaxis duration after 16 weeks of treatment is significantly higher in the nintedanib group compared to the placebo group. The trial is expected to commence recruitment on May 1, 2025, and conclude by January 1, 2027, with a total treatment period of 16 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of HHT, age of 18 years or older, and moderate to severe epistaxis. The absence of cerebral arteriovenous malformation must be demonstrated through brain imaging. Following the screening, eligible participants will be randomized to receive either nintedanib or placebo. Study visits will occur at regular intervals to monitor safety, adherence, and efficacy, with the primary endpoint assessed at week 24. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted.

Participant involvement is expected to last approximately 24 weeks, including the screening period. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent prior to enrollment. The study will be conducted in accordance with Good Clinical Practice guidelines, ensuring the integrity and reliability of the data collected.

The clinical trial involves the administration of **nintedanib**, marketed under the name Ofev 150 mg soft capsules, as the experimental medication. Nintedanib is a chemical substance with the synonym BIBF 1120. The pharmaceutical form of the medication is a soft capsule, and it is administered orally. The dosage regimen consists of a maximum daily dose of 300 mg, with a total maximum dose of 31,500 mg over the course of the study. The treatment period is set for 16 weeks. The medication is manufactured by Boehringer Ingelheim International GmbH and is classified under the ATC code L01EX09. Participant compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **placebo** as a non-experimental treatment to serve as a comparator. The placebo is designed to match the experimental medication in appearance and administration route, ensuring blinding of the study. The primary objective of the trial is to evaluate the efficacy of nintedanib in reducing the duration of epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT) by at least 30% compared to baseline, over a 16-week period. The trial will assess whether the proportion of patients achieving this reduction is significantly higher in the nintedanib group compared to the placebo group.

The efficacy of nintedanib in the treatment of **hereditary haemorrhagic telangiectasia** (HHT) will be assessed in a Phase II randomized clinical trial. The primary endpoint for evaluating efficacy is the proportion of patients experiencing at least a 30% reduction in the duration of epistaxis after 16 weeks of treatment compared to baseline. This will be measured in both the nintedanib and placebo arms. The monthly epistaxis duration after 16 weeks is defined as the average duration during the last 12 weeks of treatment, specifically from weeks 12 to 24. Baseline epistaxis duration is defined as the average duration during the observation period from weeks 0 to 8.