Sirolimus for Nosebleeds in HHT

Sirolimus for Nosebleeds in HHT: A Phase II Pilot Study

This pilot study is to determine the safety and efficacy of oral sirolimus (blood trough level 6-10ng/ml) in patients with HHT that are experiencing moderate or severe epistaxis. The effect of oral sirolimus on epistaxis will be compared to baseline using the Patient-Reported Outcome of cumulative weekly nose Bleeding Duration (PRO-CB). The PRO-CB association with biomarker variability over the duration of the study will be investigated. In the pilot study subjects will be treated with 2mg of sirolimus once daily to obtain a trough level of 6-10ng/ml for 3 months.

Study Overview

• Status: Completed
• Conditions: Epistaxis; Hereditary Hemorrhagic Telangiectasia; Nosebleeds
• Intervention / Treatment: Drug: Sirolimus

Detailed Description

The most common symptom of the hereditary hemorrhagic telangiectasia (HHT) disease is epistaxis. HHT is characterized by vascular (blood vessel) malformations, of the skin and mucus membranes of the nose (telangiectasia), gastrointestinal track, brain, lung and liver.

HHT is an autosomal dominant disease which is found in approximately 1 in 5000 individuals. Epistaxis affects 90% of adults with HHT, negatively affects quality of life and often causes anemia. Recent topical therapeutics trials have been negative and surgical therapies are invasive and offer only temporary benefit at best. Currently there are no highly-effective or approved systemic therapies for HHT-related epistaxis, but this is an area of active research and development. There is considerable in developing and identifying therapies that target the abnormal biology ad mechanisms in HHT, including antiangiogenic therapies, such as bevacizumab. Bevacizumab, however, is associated with significant toxicity, costly and administered intravenously.

Over the past few years, there has been considerable new evidence of the pathways involved in HHT disease and related potential therapeutic targets, including the mTOR pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K-Akt-mTOR and VEGFR2 pathways in endothelial cells. It was recently reported that the mTOR inhibitor, sirolimus, and the receptor tyrosine-kinase inhibitor, nintedanib, synergistically fully blocked, and also reversed, retinal AVMs, in the BMP9/10- immunoblocked neonatal mouse model of HHT. Subsequent unpublished preliminary data demonstrated that sirolimus was more effective than nintedanib at blocking anemia and bleeding in inducible ALK1 knockout HHT mice, and similarly effective to combined sirolimus-nintedanib. As such, sirolimus may provide therapeutic benefit for HHT patients. Human studies have shown "low-dose" sirolimus to be low risk and effective as a treatment for other vascular anomalies.

There is an urgent need for effective therapies for HHT and the chronic bleeding associated with the disease. Preliminary cellular and animal model data have identified sirolimus as a potential new pathway-based therapy in HHT. In addition, sirolimus is an interesting agent, as it is given orally and is available for repurposing. Data from other vascular malformations syndromes suggest that it can be effective in a "low-dose" range, reducing risk of toxicity, but there is only one published case report of sirolimus use in an HHT patient. This phase II pilot study will provide safety data as the primary outcome, and secondarily, efficacy data, outcome measure data and biological exploratory data, to support the planning of a future randomized and placebo -controlled clinical trial of sirolimus for epistaxis in HHT patients.

Sirolimus has been identified as a potential pathway-based therapy for HHT. Pre-clinical research has suggested that the pathogenesis of HHT is as a result of overactive mTOR and VEGFR2 pathway. Sirolimus has been found to work as an mTOR inhibitor to prevent the effects of overactive mTOR that results in arteriovenous malformations in a HHT. One clinical trial that used sirolimus to treat vascular anomalies, found that sirolimus was well tolerated and acted as an effective and safe treatment for most study participants.

Considerable experience using sirolimus in post-transplant patients and growing experience using sirolimus in patients with vascular anomalies exist. This pilot study will assess the safety and effectiveness of repurpose oral sirolimus, for epistaxis in patients with HHT.

It is hypothesized that oral sirolimus (blood trough level 6-10ng/ml) will be a safe and effective therapy for epistaxis in HHT patients.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age > 18 years
2. Clinical HHT diagnosis (8) or genetic diagnosis of HHT
3. Epistaxis at least 15 min per week.
4. COVID-19 Vaccine (2 doses)
5. Ability to give written informed consent, including compliance with the requirements of the study.

Exclusion Criteria:

1. Allergy/intolerance to the study drug or related agents
2. Unstable medical illness
3. Acute infection
4. Creatinine > ULN (upper limit of normal)
5. Liver transaminases (AST or ALT) >= 2x ULN
6. Women participant who are pregnant or breastfeeding or plan to become pregnant during the duration of the study
7. Women of childbearing potential not on effective contraception.
8. Male participants of reproductive potential whose female partners are of childbearing potential and are not planning to use highly effective contraceptive method
9. Immunocompromised
10. History of malignancy
11. Known untreated dyslipidemia (20% above the ULN of total cholesterol and triglycerides)
12. Specific contra-indications for study drug (detailed in the product monograph)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: All Participants; All participants received Sirolimus and were followed over the 9-month study period (3-month baseline, 3-month treatment period, 3-month follow up period). During 3-month treatment period, oral sirolimus was provided with a target blood trough of 6-10 ng/ml	Drug: Sirolimus; Oral sirolimus provided with starting dose of 2mg once daily, adjusted to maintain drug blood levels of 6-10 ng/ml (3-month course)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electrolytes	Number of participants with clinically significant abnormal electrolytes. Electrolytes include, Sodium, potassium, chloride, total CO2	9 months
Hemoglobin	Number of participants with clinically significant abnormal Hemoglobin	9 months
Renal Function	Number of participants with clinically significant abnormal urea and creatinine	9 months
Liver Function	Number of participants with clinically significant abnormal AST, ALT, and total bilirubin.	9 months
Change in Ferritin Levels	Number of participants with clinically significant abnormal ferritin levels	9 months
Blood Glucose Level	Number of participants with clinically significant abnormal glucose	9 months
Lipid Assessment	Number of participants with clinically significant abnormal total cholesterol and triglycerides	9 months
Total Number of Adverse Events (AEs)	Adverse events were monitored throughout the entire 9-month study period, including the 3-month baseline, 3-month treatment, and 3-month follow-up phases. However, only adverse events that occurred during the 3-month treatment period (i.e., when participants were actively receiving study drug) are reported here. This outcome measure is reporting the total number of adverse events across all participants that occurred during the 3-month treatment period. Adverse events were collected through patient self-reporting, clinical assessments at scheduled visits, and laboratory safety monitoring.	3 months
Total White Blood Cells	Number of participants with clinically significant abnormal total WBC	9 months
Red Blood Cells and Platelets	Number of participants with Clinically Significant RBCs and platelets	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Epistaxis Duration (PRO-CB)	Epistaxis was assessed using the Patient-Reported Outcome of Cumulative Weekly Nose Bleeding Duration (PRO-CB), collected via daily patient diary throughout the study (3-month baseline, 3-month treatment, and 3-month follow-up periods).	9 months
Exploratory Biomarker Analysis Related to Angiogenesis and Inflammation	Plasma samples were collected for future analysis of circulating biomarkers associated with angiogenesis and inflammation in HHT. The specific biomarker panel is to be finalized in collaboration with the HHT Study Team, and may include proteins such as ANG2, sICAM1, PIGF, TSP2, sVEGFR2, BMP9, IL-6, SDF1, sVCAM1, sVEGFR3, sCD73, sIL6R, TGF-β1, VEGF, sENG, OPN, TGF-β2, VEGF-C, GP130, PDGF-AA, sTGFβR3, VEGF-D, HGF, PDGF-BB, TIMP1, and sVEGFR1. Quantification methods (e.g., ELISA, multiplex immunoassay) and timepoints will be determined prior to analysiThis is an exploratory, post-treatment outcome measure and no data are yet available.s. This is an exploratory, post-treatment outcome measure and no data are yet available.	9 months
Change in Epistaxis Severity Score (ESS) at Treatment and Follow-up Periods Compared to Baseline	Epistaxis severity was measured using the Epistaxis Severity Score (ESS). ESS was administered at each clinic visit throughout the 9-month study period. However, only the ESS scores collected at Week 12 (end of baseline), Week 24 (end of treatment), and Week 36 (end of follow-up) were used for this outcome analysis. The ESS ranges from 0 to 10, with higher scores indicating more severe epistaxis.	9 months

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Collaborators: National Institutes of Health (NIH); University of California, San Francisco
• Investigators: Principal Investigator: Marie E Faughnan, MD MSc FRCPC, Unity Health Toronto

Publications and helpful links

General Publications

• Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, Kjeldsen AD, Plauchu H. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000 Mar 6;91(1):66-7. doi: 10.1002/(sici)1096-8628(20000306)91:13.0.co;2-p.
• Faughnan ME, Mager JJ, Hetts SW, Palda VA, Lang-Robertson K, Buscarini E, Deslandres E, Kasthuri RS, Lausman A, Poetker D, Ratjen F, Chesnutt MS, Clancy M, Whitehead KJ, Al-Samkari H, Chakinala M, Conrad M, Cortes D, Crocione C, Darling J, de Gussem E, Derksen C, Dupuis-Girod S, Foy P, Geisthoff U, Gossage JR, Hammill A, Heimdal K, Henderson K, Iyer VN, Kjeldsen AD, Komiyama M, Korenblatt K, McDonald J, McMahon J, McWilliams J, Meek ME, Mei-Zahav M, Olitsky S, Palmer S, Pantalone R, Piccirillo JF, Plahn B, Porteous MEM, Post MC, Radovanovic I, Rochon PJ, Rodriguez-Lopez J, Sabba C, Serra M, Shovlin C, Sprecher D, White AJ, Winship I, Zarrabeitia R. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med. 2020 Dec 15;173(12):989-1001. doi: 10.7326/M20-1443. Epub 2020 Sep 8.
• Merlo CA, Yin LX, Hoag JB, Mitchell SE, Reh DD. The effects of epistaxis on health-related quality of life in patients with hereditary hemorrhagic telangiectasia. Int Forum Allergy Rhinol. 2014 Nov;4(11):921-5. doi: 10.1002/alr.21374. Epub 2014 Aug 21.
• Whitehead KJ, Sautter NB, McWilliams JP, Chakinala MM, Merlo CA, Johnson MH, James M, Everett EM, Clancy MS, Faughnan ME, Oh SP, Olitsky SE, Pyeritz RE, Gossage JR. Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia: A Randomized Clinical Trial. JAMA. 2016 Sep 6;316(9):943-51. doi: 10.1001/jama.2016.11724.
• Sadick H, Naim R, Sadick M, Hormann K, Riedel F. Plasma level and tissue expression of angiogenic factors in patients with hereditary hemorrhagic telangiectasia. Int J Mol Med. 2005 Apr;15(4):591-6.
• Wetzel-Strong SE, Weinsheimer S, Nelson J, Pawlikowska L, Clark D, Starr MD, Liu Y, Kim H, Faughnan ME, Nixon AB, Marchuk DA. Pilot investigation of circulating angiogenic and inflammatory biomarkers associated with vascular malformations. Orphanet J Rare Dis. 2021 Sep 3;16(1):372. doi: 10.1186/s13023-021-02009-7.

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2022
• Primary Completion (Actual): December 2, 2024
• Study Completion (Actual): December 2, 2024

Study Registration Dates

• First Submitted: February 14, 2022
• First Submitted That Met QC Criteria: February 25, 2022
• First Posted (Actual): March 8, 2022

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: May 8, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Sirolimus; HHT; Hereditary Hemorrhagic Telangiectasia
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Respiratory Tract Diseases; Hemorrhage; Hematologic Diseases; Congenital Abnormalities; Nose Diseases; Otorhinolaryngologic Diseases; Signs and Symptoms, Respiratory; Cardiovascular Abnormalities; Hemostatic Disorders; Hemorrhagic Disorders; Vascular Malformations; Telangiectasis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hemic and Lymphatic Diseases; Epistaxis; Telangiectasia, Hereditary Hemorrhagic; Organic Chemicals; Macrolides; Lactones; Sirolimus
• Other Study ID Numbers: 200421448

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No