Topical TOR-582 Treatment of Epistaxis in HHT

Phase 1Not Yet RecruitingNCT07667413

Columbia University27 enrolled

Overview

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.

This is a Phase I single-center trial evaluating the safety, tolerability, and clinical activity of TOR-582 in adults with HHT-associated epistaxis. The study will include a Phase 1a Dose-Finding study and a preliminary Proof-of-Concept protocol. The study will employ a Bayesian Optimal Interval (BOIN) dose-finding design with accelerated titration. Phase 1a will commence with topical administration of the TOR-582 compound in the nasal cavity, starting with a 1% dose (.2mL, dose level 2) delivered twice daily for a 12-week dosing period. Participants will complete a 1-week observational baseline period prior to initiation of treatment. The first 4 weeks of treatment will constitute the dose-limiting toxicity (DLT) evaluation period. Participants who complete the DLT evaluation period will continue treatment for an additional 8 weeks, for a total treatment duration of 12 weeks. The study will enroll up to 27 participants. Patients who fail to complete the dosing regimen for at least 80% of assigned dosages in their assigned cycle of treatment for reasons other than DLT will be excluded from DLT evaluation and may be replaced.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Interventions

Topical sirolimus ointmentDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

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

Whole blood sirolimus trough concentrations

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

Secondary Outcomes

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

Trends in the ESS at baseline and during and after treatment will quantify changes in bleeding burden. The ESS ranges from 0 to 10, with higher scores indicating greater severity.

Time frame: 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 as frequency of entries in the Cure HHT Diary and averaged over 28-day periods to supplement the ESS.

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

Patient-reported duration of epistaxis episodes

Recorded via Cure HHT Diary on a six-tiered scale, with a minimum duration of \<1 minute and a maximum of \>60 minutes.

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

Patient-reported intensity of epistaxis episodes

Recorded via Cure HHT Diary on a scale ranging from 1 ("spotting") to 6 ("gushing") and averaged over 28-day periods to supplement the ESS. Higher scores indicate greater intensity.

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

Patient-reported overall severity of epistaxis episodes

Recorded via Cure HHT Diary on a scale ranging from 1 to 10 and averaged over 28-day periods to supplement the ESS. Higher scores indicate greater overall severity.

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

Clinical Global Impression - Severity (CGI-S) score, adapted for epistaxis

The subjective assessment of nosebleed severity, as measured using adapted items from the Clinical Global Impression (CGI) scale. Participants will be asked: "Overall, how would you rate your nosebleeds now?", with response options ranging from 1 ("Excellent - no nosebleeds") to 6 ("Very Poor - nosebleeds are constant or severely disruptive"). Higher scores indicate greater severity.

Time frame: At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks).

Clinical Global Impression - Improvement (CGI-I) score, adapted for epistaxis.

Clinical Global Impression - Improvement (CGI-I) score, adapted for epistaxis. The subjective assessment of treatment-related change in nosebleed severity, as measured using adapted items from the Clinical Global Impression (CGI) scale. Participants will be asked: "Overall, how would you rate your nosebleeds since starting the treatment with this ointment?", with response options ranging from 1 ("much better") to 7 ("much worse"). Higher scores indicate less improvement.

Time frame: Every 4 weeks during treatment, and at end of treatment (typically at 12 weeks)

Clinical Global Impression - Quality of Life (CGI-QoL) score, adapted for epistaxis.

The subjective assessment of the impact of nosebleeds on quality of life, as measured using adapted items from the Clinical Global Impression (CGI) scale. Participants will be asked: "Overall, how would you rate how much your nosebleeds affect your overall quality of life?", with response options ranging from 1 ("not at all") to 6 ("extreme"). Higher scores indicate greater impact on quality of life.