Clinical trial NCT05269849: Sirolimus for Nosebleeds in HHT
Official title: Low-dose Sirolimus for Nosebleeds in HHT: a Phase II Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hereditary Hemorrhagic Telangiectasia
Nosebleeds
Epistaxis
Keywords: Hereditary Hemorrhagic Telangiectasia
HHT
Sirolimus
Lead sponsor: Unity Health Toronto
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: University of California, San Francisco
First posted: 2022-03-08
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Electrolytes
timeFrame: 9 months
measure: Hematology
timeFrame: 9 months
measure: Renal function
timeFrame: 9 months
measure: Liver function
timeFrame: 9 months
measure: ferritin level
timeFrame: 9 months
measure: Blood glucose level
timeFrame: 9 months
measure: lipid assessment
timeFrame: 9 months
Secondary outcomes:
measure: Epistaxis
timeFrame: 9 months
measure: Biomarkers
timeFrame: 9 months
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
Study officials:
affiliation: Unity Health Toronto
name: Marie E Faughnan, MD MSc FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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citation: 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.
citation: 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.
citation: 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.
citation: 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.