The Effect of Oral Nintedanib vs Placebo on Epistaxis in Hereditary Hemorrhagic Telangiectasia: The EPICURE Multicenter Randomized Double-Blind Trial

Academic Background

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare genetic disorder characterized by vascular malformations, particularly capillary dilatations. Epistaxis (nosebleeds) is the most common symptom in HHT patients, affecting over 90% of individuals. Epistaxis not only severely impacts patients’ quality of life but can also lead to iron deficiency anemia and even life-threatening conditions. Current treatments for HHT primarily include local moisturizing therapies, tranexamic acid, and ablative therapies. However, these methods have not shown significant long-term reduction in epistaxis. Additionally, ablative therapy may cause nasal septum perforation, increasing the frequency and severity of nosebleeds. For patients unresponsive to these treatments, systemic anti-angiogenic drugs such as bevacizumab may be an option, but their use is limited by administration routes, cost, and market authorization. Therefore, exploring other anti-angiogenic drugs for HHT is of great importance.

Nintedanib is an oral tyrosine kinase inhibitor (TKI) that inhibits growth factor receptors involved in angiogenesis, such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Studies have shown that nintedanib can prevent vascular pathologies and reduce gastrointestinal bleeding in HHT mouse models. Additionally, recent case reports have shown a significant decrease in the Epistaxis Severity Score (ESS) in HHT patients treated with nintedanib for pulmonary fibrosis. Thus, nintedanib may be an effective candidate for treating epistaxis in HHT patients.

Source of the Paper

This study was conducted by Ruben Hermann and colleagues from multiple hospitals and research institutions in France. The paper was published on December 1, 2024, in the journal Angiogenesis. The study was funded by the French National Research Program (PHRC 2018) and Boehringer Ingelheim.

Study Design and Methods

Study Design

This was a national, prospective, multicenter, phase II clinical trial using a randomized, double-blind, placebo-controlled parallel-group design to compare the efficacy of nintedanib versus placebo in HHT patients. The study consisted of a 12-week treatment period followed by a 12-week follow-up period. The study was approved by the French Research Ethics Committee and registered on ClinicalTrials.gov (NCT03954782).

Study Participants

The study enrolled patients aged 18 years and older with a confirmed clinical diagnosis of HHT and moderate to severe epistaxis, defined by an ESS score greater than 4. All patients were recruited from French HHT centers, and treatments were centralized in ten hospitals. Exclusion criteria included untreated pulmonary arteriovenous malformations, hemoptysis, hematuria, overt gastrointestinal bleeding or ulcers, cerebral arteriovenous malformations, liver disease or renal failure, active infections, known coronary artery disease or predisposition to thrombosis, use of certain medications (e.g., anticoagulants, antiplatelet drugs, other anti-angiogenic treatments), and unhealed wounds or recent surgery.

Randomization and Blinding

The randomization process was centralized, with a unique list generated using SAS® software by the Clinical Research Unit of the Hospices Civils de Lyon. Patients were randomly assigned to either the nintedanib or placebo group using an interactive web response system (IWRS) based on this list. Data management was performed using Ennov Clinical 7.1 (Clinsight) software.

Interventions

Patients in the nintedanib group received 150 mg of nintedanib orally twice daily, approximately 12 hours apart, for 12 weeks. The placebo group received soft gelatin capsules identical in appearance to nintedanib. In case of adverse reactions, treatment could be temporarily interrupted or the dose reduced to 100 mg twice daily. If adverse reactions persisted after dose reduction, treatment was discontinued.

Primary and Secondary Outcomes

The primary outcome was the proportion of patients achieving at least a 50% reduction in the mean monthly duration of epistaxis during the last 8 weeks of treatment compared to the 8 weeks before treatment. Secondary outcomes included monthly duration and frequency of epistaxis, hemoglobin levels, quality of life (assessed using the SF-36 questionnaire), and the number of red blood cell transfusions and iron infusions.

Results

Baseline Characteristics

A total of 60 patients were enrolled and randomized into the nintedanib and placebo groups, with 30 patients in each group. Baseline characteristics showed no significant differences between the two groups in terms of sex, age, gene mutations, nasal surgery history, nasal septum perforation, epistaxis duration and frequency, and hemoglobin levels.

Primary Outcome

In the intention-to-treat (ITT) population, 13 patients (43.3%) in the nintedanib group and 8 patients (26.7%) in the placebo group achieved the primary outcome (p = 0.28). Similar results were observed in the per-protocol (PP) analysis (12 patients, 42.9% in the nintedanib group vs. 8 patients, 28.6% in the placebo group, p = 0.40).

Secondary Outcomes

The nintedanib group showed a significant reduction in the median duration of epistaxis during treatment and follow-up (57% vs. 24%, p = 0.013) and a significant decrease in the monthly frequency of epistaxis (35% vs. 12%, p = 0.018). Additionally, the nintedanib group had a significant increase in hemoglobin levels (+18 g/L vs. -1 g/L, p = 0.02). However, there were no significant differences between the two groups in quality of life scores or the Epistaxis Severity Score (ESS).

Adverse Events

Adverse events were more common in the nintedanib group, with the most frequent being diarrhea, nausea, abdominal pain, and headaches. Two patients discontinued treatment due to severe adverse events (gastrointestinal bleeding and facial edema), and three patients had their dose reduced due to adverse reactions.

Discussion and Conclusion

The EPICURE trial is the first randomized clinical trial to evaluate the efficacy of nintedanib in HHT patients. Although the primary outcome did not reach statistical significance, the nintedanib group showed significant improvements in epistaxis duration and hemoglobin levels. These results support the efficacy of nintedanib in HHT patients and provide a basis for further research.

While adverse events were common in the nintedanib group, most patients were able to manage them through dose adjustments or temporary treatment interruptions. Compared to bevacizumab, nintedanib may serve as an alternative for certain patients, particularly those who are contraindicated, intolerant, or unresponsive to bevacizumab.

Highlights of the Study

1. First Randomized Clinical Trial: The EPICURE trial is the first randomized clinical trial to evaluate the efficacy of nintedanib in HHT patients.
2. Significant Improvements in Epistaxis and Hemoglobin Levels: Although the primary outcome was not statistically significant, the nintedanib group showed significant improvements in epistaxis duration and hemoglobin levels.
3. Manageable Safety Profile: Adverse events in the nintedanib group were common but manageable through dose adjustments or temporary treatment interruptions.

Significance of the Study

This study provides a new treatment option for HHT patients, particularly those who are unresponsive or intolerant to existing therapies. The significant efficacy and manageable adverse effects of nintedanib make it an important candidate for HHT treatment. Future research should further validate its long-term efficacy and safety and explore its potential in other angiogenesis-related diseases.