Epistaxis, Hereditary Hemorrhagic Telangiectasia (HHT)
Conditions
Keywords
Hereditary Hemorrhagic Telangiectasia, HHT, Epistaxis, Nosebleeds, Sirolimus, Rapamycin, Topical Sirolimus, Intranasal Therapy, Nasal Telangiectasia, Vascular Malformations, mTOR Inhibitor, Osler-Weber-Rendu Syndrome
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.
Detailed description
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.
Interventions
DRUGTopical 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: 10 mg/mL, Level 3: 20 mg/mL) as guided by the BOIN-AT design until the Maximum Tolerated Dose is identified.
Sponsors
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicities (DLTs) | From enrollment through the first 4 weeks of treatment for each cohort (the DLT evaluation window) | 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. |
| Number of participants with treatment-emergent adverse events (AEs) | From enrollment through end of treatment, typically at 12 weeks. | The aggregate count of participants experiencing AEs across the entire 12-week treatment period. |
| Severity of treatment-emergent adverse events, graded according to the NCI CTCAE v6.0. | From enrollment through the first 4 weeks of treatment for each cohort (the DLT evaluation window) | 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. |
| Whole blood sirolimus trough concentrations | Assessed at baseline, after 4 weeks of treatment, and at the end of treatment at 12 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
| Patient-reported frequency of epistaxis episodes | Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks. | Recorded as frequency of entries in the Cure HHT Diary and averaged over 28-day periods to supplement the ESS. |
| Patient-reported duration of epistaxis episodes | Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks. | Recorded via Cure HHT Diary on a six-tiered scale, with a minimum duration of \<1 minute and a maximum of \>60 minutes. |
| Patient-reported intensity of epistaxis episodes | Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks. | 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. |
| Patient-reported overall severity of epistaxis episodes | Recorded daily from beginning of screening period through end of treatment, typically at 12 weeks. | 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. |
| Clinical Global Impression - Severity (CGI-S) score, adapted for epistaxis | At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks). | 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. |
| Clinical Global Impression - Improvement (CGI-I) score, adapted for epistaxis. | Every 4 weeks during treatment, and at end of treatment (typically at 12 weeks) | 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. |
| Clinical Global Impression - Quality of Life (CGI-QoL) score, adapted for epistaxis. | At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks) | 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. |
| HHT-Specific Quality of Life (QoL) | At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks) | Participants will complete a 4-item, validated HHT-specific QoL questionnaire designed to assess the functional impact of HHT-related epistaxis. Each item is scored from 0 (never) to 4 (very often), yielding a total score ranging from 0 (no limitations) to 16 (severe limitations). Higher scores indicate more severe limitations of quality of life. |
| Modified QoL-HHT score | At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks) | The QoL-HHT is a 24-item, disease-specific questionnaire that quantifies multi-faceted impact of HHT on individual patient lives. Each statement is scored on a 5-point Likert scale ranging from 1 = "strongly disagree" to 5 = "strongly agree." Items are categorized into six validated domains: physical limitations (PL), social relationships (SR), concern about bleeding (CAB), relationship with the medical profession (RMP), experience of symptoms (ES), and concern about disease evolution (ED). This trial will use a modified 8-item QoL-HHT score by selecting specified items focused particularly on the overall burden of epistaxis in each participant's daily life, with higher scores indicating greater burden. |
| Satisfaction with Social Roles and Activities, measured by PROMIS® Short Form 8a v2.0 | At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks) | This is one of three short-form questionnaires from the NIH Patient-Reported Outcomes Measurement Information System (PROMIS®) which will be used to evaluate the impact of treatment on overall well-being and functioning. Each form yields a standardized T-score generated via the PROMIS® scoring engine, allowing comparison to a normative population (mean = 50, SD = 10). This 8-item measure evaluates satisfaction with social participation and daily responsibilities. Items include statements such as: "I am satisfied with my ability to do regular daily activities." Higher T-scores indicate greater satisfaction with social roles. |
| Depression, measured by PROMIS® Short Form 8b v1.0 | At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks) | This is one of three short-form questionnaires from the NIH Patient-Reported Outcomes Measurement Information System (PROMIS®) which will be used to evaluate the impact of treatment on overall well-being and functioning. Each form yields a standardized T-score generated via the PROMIS® scoring engine, allowing comparison to a normative population (mean = 50, SD = 10). This 8-item form assesses depressive symptoms experienced in the past 7 days, including feelings of sadness, hopelessness, and worthlessness. Higher T-scores indicate more severe depressive symptoms. |
| Fatigue, measured by PROMIS® Short Form 6a v1.0 | At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks) | This is one of three short-form questionnaires from the NIH Patient-Reported Outcomes Measurement Information System (PROMIS®) which will be usde to evaluate the impact of treatment on overall well-being and functioning. Each form yields a standardized T-score generated via the PROMIS® scoring engine, allowing comparison to a normative population (mean = 50, SD = 10). This 6-item questionnaire measures fatigue severity and its interference with physical and social functioning. Items include: "How fatigued were you on average?" Higher T-scores reflect more severe fatigue. |
| EQ-5D Visual Analogue Scale (EQ-VAS) | At baseline, initiation of treatment, every 4 weeks during treatment, and at end of treatment (typically at 12 weeks) | The EuroQol Visual Analogue Scale is a validated, standardized instrument developed by the EuroQol Group to capture a participant's self-rated health status. Participants indicate their current overall health on a vertical scale ranging from 0 ("worst imaginable health") to 100 ("best imaginable health"), generating a single index value of health-related quality of life. Higher scores indicate greater health-related quality of life. |
| Patient Satisfaction with Treatment | At end of treatment, typically at 12 weeks | Participants will be asked, "Overall, how satisfied are you with the ointment?", with answer choices ranging from 1 ("completely dissatisfied") to 7 ("completely satisfied"). Higher scores indicate greater satisfaction. |
| Perceived treatment benefit and satisfaction, measured by Modified TTAQ. | At end of treatment (typically at 12 weeks) | Topical Therapy Adherence Questionnaire (TTAQ) and companion Patient Preference Questionnaire (PPQ) were developed by Zschocke et al. to identify patient- and treatment-related factors that influence adherence to topical therapies. This trial uses a modified 19-item version of the TTAQ, focusing specifically on the Treatment Satisfaction and Benefits to Patient domains and curated to minimize respondent burden and align with the use of topical sirolimus in the nasal mucosa. Participants rate their agreement with each item on a 4-point Likert scale, ranging from 0 ("strongly disagree") to 3 ("strongly agree"), where higher scores indicate greater treatment satisfaction and benefit to patient. |
| Perceived treatment benefit and satisfaction, measured by Modified PPQ | At end of treatment (typically at 12 weeks) | The Topical Therapy Adherence Questionnaire (TTAQ) and companion Patient Preference Questionnaire (PPQ) were developed by Zschocke et al. to identify patient- and treatment-related factors that influence adherence to topical therapies. This trial uses a modified, 6-item version of the PPQ, focusing specifically on the Treatment Satisfaction and Benefits to Patient domains and curated to minimize respondent burden and align with our use of topical sirolimus in the nasal mucosa. Participants rate their agreement with each item on a 4-point Likert scale, ranging from 0 ("strongly disagree") to 3 ("strongly agree"), where higher scores indicate greater treatment satisfaction and benefit to patient. |
| Hematologic Support Score (HSS) | During screening and at end of treatment, typically at 12 weeks | The HSS is a composite measure that combines the assessment of red blood cell transfusion and iron infusion into a single endpoint, enabling evaluation over time. A higher number indicates greater transfusion/infusion burden. |
| Hematologic Impact Score (HIS) | During screening and at end of treatment, typically at 12 weeks | The HIS assesses the total hematologic impact over a reference time frame by accounting for changes in hemoglobin and HSS during that period (a higher number indicates greater improvement in hematologic status). |
| Mean change in hemoglobin concentration from baseline | During screening and at the end of treatment, typically at 12 weeks | Measured via standard automated complete blood count (CBC). |
| Mean change in hematocrit from baseline | During screening and at the end of treatment, typically at 12 weeks | Measured via standard automated complete blood count (CBC). |
| Mean change in mean corpuscular volume (MCV) from baseline | During screening and at the end of treatment, typically at 12 weeks | Measured via standard automated complete blood count (CBC). |
| Mean change in serum ferritin from baseline | During screening and at the end of treatment, typically at 12 weeks | Measured via standard iron panel. |
| Mean change in transferrin saturation from baseline | During screening and at the end of treatment, typically at 12 weeks | Measured via standard iron panel. |
| Number of red blood cell transfusions and parenteral iron administrations during treatment period | Assessed during screening and at end of treatment, typically at 12 weeks | Measured via patient reporting. |
| Endoscopic Disease Activity | Assessed during screening, after first 4 weeks of treatment (end of DLT evaluation period), and end of treatment (typically at 12 weeks) | Change in nasal telangiectasia severity, assessed by a modified HHT Endoscopy Score (HES). The HES is a clinician-administered scoring system used to assess the severity of nasal telangiectasias during endoscopic evaluation. For this study, five domains will be used: number of sites involved, vascular pattern, crusting, lesion location, and septal perforation. Each is scored from 0 to 3, with higher scores indicating more extensive disease. |
Countries
United States
Contacts
CONTACTJonathan B Overdevest, MD, PhD
Outcome results
None listed