Topical TOR-582 Treatment of Epistaxis in HHT

NCT07667413 | Recruiting Phase 1 FDA Drug

• 1 other identifier: AAAV9649
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hereditary Hemorrhagic Telangiectasia (HHT); Epistaxis

Keywords

Hereditary Hemorrhagic Telangiectasia; HHT; Epistaxis; Nosebleeds; Sirolimus; Rapamycin; Topical Sirolimus; Intranasal Therapy; Nasal Telangiectasia; Vascular Malformations; mTOR Inhibitor; Osler-Weber-Rendu Syndrome

Outcome Measures

Primary Outcomes (4)

• Incidence of dose-limiting toxicities (DLTs)

  The occurrence of protocol-defined DLTs during the active treatment at each dose level, used to guide escalation/de-escalation decisions and determine the recommended Phase 1b dose. A DLT is defined as the occurrence of Grade 2 or higher AEs in greater than 25% of participants at a given dose level, or more than one Grade 3 or higher AE at any point in the trial.

  From enrollment through the first 4 weeks of treatment for each cohort (the DLT evaluation window)

• Number of participants with treatment-emergent adverse events (AEs)

  The aggregate count of participants experiencing AEs across the entire 12-week treatment period.

  From enrollment through end of treatment, typically at 12 weeks.

• Severity of treatment-emergent adverse events, graded according to the NCI CTCAE v6.0.

  The highest severity grade of clinical AEs experienced by each participant. The CTCAE scale ranges from Grade 1 (Mild) to Grade 5 (Death), where higher grades indicate greater clinical severity.

  From enrollment through the first 4 weeks of treatment for each cohort (the DLT evaluation window)

• Whole blood sirolimus trough concentrations

  Assessed at baseline, after 4 weeks of treatment, and at the end of treatment at 12 weeks

Secondary Outcomes (26)

• Epistaxis severity, measured by the Epistaxis Severity Score (ESS)

  Assessed at baseline, initiation of treatment, every 4 weeks during treatment, and at the end of treatment, typically at 12 weeks

• Patient-reported frequency of epistaxis episodes

  Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks.

• Patient-reported duration of epistaxis episodes

  Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks.

• Patient-reported intensity of epistaxis episodes

  Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks.

• Patient-reported overall severity of epistaxis episodes

  Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks.

Study Arms (3)

Dose Level 1 - 5 mg/mL (0.5%)

EXPERIMENTAL

Drug: Topical sirolimus ointment

Dose Level 2 - 10 mg/mL (1.0%)

EXPERIMENTAL

Drug: Topical sirolimus ointment

Dose Level 3 - 20 mg/mL (2.0%)

EXPERIMENTAL

Drug: Topical sirolimus ointment

Interventions

Topical sirolimus ointment DRUG

The active formulation of TOR-582 incorporates sirolimus at concentrations of 5 mg/mL (0.5%), 10 mg/mL (1.0%), and 20 mg/mL (2.0%) along with other active ingredients in an oil-based carrier ointment. Ointment will be applied intranasally twice daily in 0.2mL applications using TC5-R - Topi-CLICK Micro® 5 mL devices, which dispense metered 0.05 mL doses. Dose finding will begin at a dose of 10 mg/mL (1.0%). Doses will escalate sequentially across planned dose levels (Level 1: 5 mg/mL, Level 2: 10 mg/mL, Level 3: 20 mg/mL) as guided by the BOIN-AT design until the Maximum Tolerated Dose is identified.

Also known as: TOR-582

Dose Level 1 - 5 mg/mL (0.5%); Dose Level 2 - 10 mg/mL (1.0%); Dose Level 3 - 20 mg/mL (2.0%)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years or older at the time of consent.
• Confirmed diagnosis of HHT, defined as meeting at least three of the four Curaçao criteria or preferably by genetic testing.
• 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.
• Stable nasal hygiene regimen and epistaxis-related medical management for at least 3 months prior to enrollment.
• Stable epistaxis pattern for at least 3 months prior to enrollment
• Adequate bone marrow function defined as:
• Platelet count ≥ 100 × 10⁹/L (≥ 100,000/mm3)
• WBC count ≥ 2.5 × 10⁹/L at screening (≥ 2,500/mm3)
• Hgb ≥ 6g/dL with no transfusion in the prior 2 months
• INR ≤ 1.4 and activated partial thromboplastin time (aPTT) within institutional normal limits.
• 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.
• 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.
• Ability to comply with study procedures and follow-up visits, and capacity to provide written informed consent.

You may not qualify if:

• Any medical contraindication to systemic sirolimus use.
• Prior use of any mTOR inhibitor within the past 3 months.
• Endoscopic evaluation of nasal cavity (HES-based)
• Pattern: AVM-type vascular pattern (HES pattern score = 2).
• Crusting: Moderate to severe nasal crusting (HES crusting score ≥ 2).
• Location: Telangiectasias isolated to the middle or posterior turbinates (HES location score ≥ 2).
• Perforation: Presence of a nasal septal perforation
• Surgical cautery or sclerotherapy within the past 3 months prior to enrollment
• Vascular embolization of nasal vasculature within the past 3 months prior to enrollment
• Clinically significant peripheral vascular disease or circulatory compromise.
• Current use of strong CYP3A4 modulators, including inhibitors (e.g., ketoconazole, clarithromycin) or inducers (e.g., rifampin, phenytoin, carbamazepine, St. John's wort).
• Use of anti-angiogenic therapies within 30 days prior to screening (e.g., bevacizumab, pazopanib, thalidomide, lenalidomide).
• Use of illicit substances within the past 30 days, excluding marijuana.
• Use of anticoagulant, antiplatelet, or fibrinolytic medications within the past 30 days, except for low-dose aspirin (81 mg or less).
• Use of octreotide or systemic estrogen therapy within the past 30 days.

Sponsors & Collaborators

• Columbia University: lead

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

RECRUITING

MeSH Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic; Epistaxis; Vascular Malformations

Condition Hierarchy (Ancestors)

Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Telangiectasis; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nose Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms, Respiratory; Signs and Symptoms

Central Study Contacts

Jonathan B Overdevest, MD, PhD

CONTACT

212-305-6130; jo2566@cumc.columbia.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Otolaryngology Head and Neck Surgery

Model Details: This is an open-label, single-center, sequential dose-escalation Phase 1a study evaluating the safety, tolerability, and preliminary efficacy of intranasal topical sirolimus ointment in adults with hereditary hemorrhagic telangiectasia (HHT)-associated epistaxis. Participants will be enrolled into escalating dose cohorts and treated for up to 12 weeks with safety monitoring throughout the study period.

Study Record Dates

• First Submitted: June 18, 2026
• First Posted: June 25, 2026
• Study Start: July 1, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): May 1, 2027
• Last Updated: June 25, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)