Topical TOR-582 Treatment of Epistaxis in HHT
Trial statusNot yet recruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorColumbia University
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
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
Trial design
Design model
Sequential
Treatments tested in this trial
Topical sirolimus ointment
DrugThe 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.
Treatment groups
27 Participants
are divided into 3 treatment groupsGroup A: Dose Level 1 - 5 mg/mL (0.5%)Experimental treatment 1 intervention
Group B: Dose Level 2 - 10 mg/mL (1.0%)Experimental treatment 1 intervention
Group C: Dose Level 3 - 20 mg/mL (2.0%)Experimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
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)2
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.3
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)4
Whole blood sirolimus trough concentrations
Time frame
Assessed at baseline, after 4 weeks of treatment, and at the end of treatment at 12 weeksSecondary outcomes
1
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 weeks2
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.3
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.4
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.Sponsors and contacts
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Source ClinicalTrials.gov
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