Topical Anti-angiogenic Therapy for Telangiectasia in HHT: Proof of Concept

Condition(s) targeted: Hereditary Hemorrhagic Telangiectasia (HHT).

Intervention: Topical timolol maleate (Drug); placebo saline drops (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: St. Michael's Hospital, Toronto

Official(s) and/or principal investigator(s):
Marie E Faughnan, MD MSc FRCPC, Principal Investigator, Affiliation: St. Michael's Hospital, Toronto

Overall contact:
Marie E Faughnan, MD MSc FRCPC, Phone: 416) 864-6060, Ext: 5412, Email: faughnanm@smh.ca

Hereditary hemorrhagic telangiectasia (HHT) is a hereditary vascular condition characterized by the development of abnormal connections between arteries and veins throughout the body, called vascular malformations. These abnormal blood vessels are referred to as arteriovenous malformations (AVM) if they are large and telangiectasias if they are small. Telangiectasias develop due to irregular growth of blood vessels. Anti-angiogenic therapy, such as the drug Apo-Timop, curbs the growth of new blood vessels. Apo-Timop is included in a class of medications called beta-blockers. Anti-angiogenic therapies exert their beneficial effects in a number of ways: by disabling the agents that activate and promote cell growth, or by directly blocking the growing blood vessel cells. The investigators think that anti-angiogenic therapy may lead to the shrinking of telangiectasia in people with HHT. The investigators hope that this study will provide us with proof of this concept and might lead to the development and study of anti-angiogenic therapies to help improve the lives of individuals with vascular malformations.

Official title: Topical Anti-angiogenic Therapy for Telangiectasia in HHT: Proof of Concept

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Mean reduction in lesion area (compared with baseline measurement) of treated telangiectasia.

Secondary outcome:

1. From Tissue: Descriptive changes in histopathology in baseline vs treated lesions, vessel density and distribution of capillaries, arterioles and venules.

2. From speckle variance OCT: Changes in lesion area, blood flow velocity and volume flow rates (treated vs baseline/ placebo).

3. Serum angiogenic markers (Aushon Blood-based Biomarkers in Clinical Research kit, analyzing 5- angiogenic biomarkers): Endoglin, BMP-9, VEGF+, TGF-beta1, TSP-1

4. Stability of area of untreated telangiectasias over the 84 day period (placebo group)

Detailed description: This is a small study of 10 patients from St. Michael's Hospital who have HHT and at least 5 typical telangiectasias. Patients who anticipate a major surgery during this study or are pregnant, breast feeding or on other beta blocker medication may not enroll in this study. This study lasts 12 weeks. During this time, subjects will apply a drop of either Apo-timop 0. 5% or a placebo solution to 4 telangiectasias twice daily. The active study medication is called Apo-Timop and is a clear liquid solution stored in a bottle. An eye dropper is used for application.

- Apo-timop will be applied to 3 telangiectasias and

- a placebo will be applied to one telangiectasia A placebo is an inactive substance,

with no active medication in it, and it looks the same as the real medication. There is no potential harm of receiving the placebo. It is necessary to use a placebo to make sure that the effect of Apo-timop can be determined without any bias. Subjects will receive four numbered bottles for every 28 day period as well as a photo which indicates which bottle is to be applied to which telangiectasia. Neither the subject nor the research staff will know which telangiectasia will receive the placebo. Apo-timop, is not part of the standard therapeutic regimen for HHT. It is a Health Canada approved medication which is applied as an eye drop, that has been shown to reduce pressure in the eye and is commonly used for glaucoma.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Definite clinical or genetic diagnosis of HHT 2. Known ENG or ALK1 mutation (personal or familial) 3. Age>=18 years 4. At least 5 typical (round/ovoid, not spider or linear) cutaneous telangiectasia (size range 2-5mm) on hands (not including lesions on over inter-phalangeal joints) or face Exclusion Criteria: 1. Contraindication to systemic beta-blocker (severe asthma, severe COPD, sinus bradycardia, 2nd or 3rd degree AV block, overt heart failure, hypotension, allergy/intolerance/ hypersensitivity to timolol) 2. Current treatment with systemic beta-blocker 3. Current participation in other therapeutic trial for HHT 4. Current pregnancy or breastfeeding.

Marie E Faughnan, MD MSc FRCPC, Phone: 416) 864-6060, Ext: 5412, Email: faughnanm@smh.ca

St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada; Recruiting
Marie E Faughnan, MD MSc FRCPC, Principal Investigator

Starting date: May 2013
Last updated: May 21, 2015