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Sponsor: Columbia University
Conditions: Hereditary Hemorrhagic Telangiectasia (HHT), Epistaxis
Interventions: Topical sirolimus ointment
Countries: United States
People with hereditary hemorrhagic telangiectasia (HHT) often experience frequent and severe nosebleeds that can disrupt daily life and lead to anemia, medical procedures, and reduced quality of life. This study is testing a new nasal ointment called TOR-582, which contains sirolimus, to determine whether it can be used safely when applied inside the nose. Adults with HHT and frequent nosebleeds will be invited to participate. Participants will first complete one week of observation without treatment, followed by up to 12 weeks of applying the study ointment inside each nostril twice daily. Different participants will receive different strengths of the ointment so researchers can identify the safest dose. During the study, participants will attend study visits, complete questionnaires about their nosebleeds and quality of life, keep a daily nosebleed diary, undergo nasal examinations, and have blood tests to monitor safety and medication levels. The information gained from this study will help determine whether this topical treatment can be safely studied further and will support the development of a new, less invasive option for managing nosebleeds in people with HHT.
Sex: ALL
Age: 18 Years to —
Healthy volunteers: No
Study type: INTERVENTIONAL
Inclusion Criteria:
1. Age 18 years or older at the time of consent.
2. Confirmed diagnosis of HHT, defined as meeting at least three of the four Curaçao criteria or preferably by genetic testing.
3. Moderate nasal epistaxis represented by an Epistaxis Severity Score (ESS) between 3 and 8 at screening, average NOSE-HHT score of 1.01-2, with a self-reported history of at least four spontaneous nosebleeds per week and a cumulative weekly bleeding duration of at least 60 minutes.
4. Stable nasal hygiene regimen and epistaxis-related medical management for at least 3 months prior to enrollment.
5. Stable epistaxis pattern for at least 3 months prior to enrollment
6. Adequate bone marrow function defined as:
1. Platelet count ≥ 100 × 10⁹/L (≥ 100,000/mm3)
2. WBC count ≥ 2.5 × 10⁹/L at screening (≥ 2,500/mm3)
3. Hgb ≥ 6g/dL with no transfusion in the prior 2 months
7. INR ≤ 1.4 and activated partial thromboplastin time (aPTT) within institutional normal limits.
8. Willingness to avoid initiation of other investigational or targeted therapeutic agents for epistaxis (including antiangiogenic or mTOR-modulating therapies) from the time of enrollment through study completion.
9. Female participants of childbearing potential must have a negative pregnancy test at screening and agree to use effective contraception during the study and for 28 days following the final dose.
10. Ability to comply with study procedures and follow-up visits, and capacity to provide written informed consent.
Exclusion Criteria:
1. Any medical contraindication to systemic sirolimus use.
2. Prior use of any mTOR inhibitor within the past 3 months.
3. Endoscopic evaluation of nasal cavity (HES-based)
1. Site: No numerical site exclusion
2. Pattern: AVM-type vascular pattern (HES pattern score = 2).
3. Crusting: Moderate to severe nasal crusting (HES crusting score ≥ 2).
4. Location: Telangiectasias isolated to the middle or posterior turbinates (HES location score ≥ 2).
5. Perforation: Presence of a nasal septal perforation
4. Surgical cautery or sclerotherapy within the past 3 months prior to enrollment
5. Vascular embolization of nasal vasculature within the past 3 months prior to enrollment
6. Clinically significant peripheral vascular disease or circulatory compromise.
7. Current use of strong CYP3A4 modulators, including inhibitors (e.g., ketoconazole, clarithromycin) or inducers (e.g., rifampin, phenytoin, carbamazepine, St. John's wort).
8. Use of anti-angiogenic therapies within 30 days prior to screening (e.g., bevacizumab, pazopanib, thalidomide, lenalidomide).
9. Use of illicit substances within the past 30 days, excluding marijuana.
10. Use of anticoagulant, antiplatelet, or fibrinolytic medications within the past 30 days, except for low-dose aspirin (81 mg or less).
11. Use of octreotide or systemic estrogen therapy within the past 30 days.
12. Clinical laboratory evaluation:
1. Renal dysfunction, defined as a serum creatinine level greater than 2.0 mg/dL.
2. Hepatic impairment, indicated by total bilirubin above 2.0 mg/dL (or above 4.0 mg/dL in patients with a known diagnosis of Gilbert's syndrome) or liver transaminases exceeding three times the upper limit of normal.
3. Known SMAD4 mutation with a history of significant gastrointestinal polyposis, unless colonoscopy within the past 18 months demonstrated either no polyps or ≤5 polyps judged to be clinically insignificant by a gastroenterologist.
13. History of unprovoked venous thromboembolism, confirmed by imaging.
14. Diagnosis of peripheral neuropathy as confirmed by neurologic evaluation.
15. Documented hyperproliferative anemia (myelodysplastic syndrome, aplastic anemia, etc.).
a. Current pregnancy or planned pregnancy within the next 6 months, or active breastfeeding.
16. Concurrent participation in another interventional research study.
17. Any condition, circumstance, language, or literacy limitation, that in the judgment of the investigator, would interfere with study participation or completion.- New York, New York, United States