Topical TOR-582 Treatment of Epistaxis in HHT

Официальное название

A Phase I Trial of TOR-582, a Topical Sirolimus-based Treatment for Epistaxis in Adults With Hereditary Hemorrhagic Telangiectasia

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Topical sirolimus ointment
  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:

Первичные конечные точки

• Incidence of dose-limiting toxicities (DLTs) [Срок оценки: 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) [Срок оценки: From enrollment through end of treatment, typically at 12 weeks.]
• Severity of treatment-emergent adverse events, graded according to the NCI CTCAE v6.0. [Срок оценки: From enrollment through the first 4 weeks of treatment for each cohort (the DLT evaluation window)]
• Whole blood sirolimus trough concentrations [Срок оценки: Assessed at baseline, after 4 weeks of treatment, and at the end of treatment at 12 weeks]

Вторичные конечные точки (12)

• Epistaxis severity, measured by the Epistaxis Severity Score (ESS) [Срок оценки: 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 [Срок оценки: Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks.]
• Patient-reported duration of epistaxis episodes [Срок оценки: Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks.]
• Patient-reported intensity of epistaxis episodes [Срок оценки: Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks.]
• Patient-reported overall severity of epistaxis episodes [Срок оценки: 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 [Срок оценки: 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. [Срок оценки: 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. [Срок оценки: At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks)]
• HHT-Specific Quality of Life (QoL) [Срок оценки: At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks)]
• Modified QoL-HHT score [Срок оценки: At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks)]
• Satisfaction with Social Roles and Activities, measured by PROMIS® Short Form 8a v2.0 [Срок оценки: At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks)]
• Depression, measured by PROMIS® Short Form 8b v1.0 [Срок оценки: At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks)]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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)

• Site: No numerical site exclusion
• 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.
• Clinical laboratory evaluation:

• Renal dysfunction, defined as a serum creatinine level greater than 2.0 mg/dL.
• 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.
• 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.
• History of unprovoked venous thromboembolism, confirmed by imaging.
• Diagnosis of peripheral neuropathy as confirmed by neurologic evaluation.
• Documented hyperproliferative anemia (myelodysplastic syndrome, aplastic anemia, etc.).

a. Current pregnancy or planned pregnancy within the next 6 months, or active breastfeeding.

• Concurrent participation in another interventional research study.
• Any condition, circumstance, language, or literacy limitation, that in the judgment of the investigator, would interfere with study participation or completion.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Columbia University Irving Medical Center — New York

Идентификаторы

NCT: NCT07667413 · AAAV9649

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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