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

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.

Study Overview

• Status: Completed
• Conditions: Hereditary Hemorrhagic Telangiectasia
• Intervention / Treatment: Drug: Topical timolol maleate; Drug: placebo saline drops

Detailed Description

This is a small study of 5 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 (84 days). 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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

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. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Topical timolol maleate; Drug: • Topical timolol maleate 0.5% drops; Topical timolol maleate 0.5% drops; Applied twice daily for 12 weeks (84 days) or until disappearance of lesions; Study drops will be applied to 3 cutaneous telangiectasias per patient telangiectasia per patient).	Drug: Topical timolol maleate; Topical timolol maleate 0.5% drops; Applied twice daily for 12 weeks (84 days) or until disappearance of lesions; Study drops will be applied to 3 cutaneous telangiectasias per patient; Other Names: Topical timolol maleate 0.5% drops
Placebo Comparator: Placebo; placebo saline drops -Applied twice daily for 12 weeks (84 days) or until disappearance of lesions to one cutaneous telangiectasias per patient.	Drug: placebo saline drops; Applied twice daily for 12 weeks (84 days) or until disappearance of lesions to 1 cutaneous telangiectasias per patient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Lesion Area of Treated Telangiectasia.	Change in lesion area (compared with baseline measurement) of treated telangiectasia.	84 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Descriptive Changes in Histopathology in Baseline vs Treated Lesions	84 days
Serum Angiogenic Markers	84 days
Stability of Area of Untreated Telangiectasias Over the 84 Day Period	84 days
Blood Flow Velocity and Volume Flow Rates	84 days

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Collaborators: The Hospital for Sick Children; Sunnybrook Health Sciences Centre; National Institute of Neurological Disorders and Stroke (NINDS); University of California, San Francisco; University of Toronto; Toronto Metropolitan University
• Investigators: Principal Investigator: Marie E Faughnan, MD MSc FRCPC, Unity Health Toronto

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): August 30, 2019
• Study Completion (Actual): August 30, 2019

Study Registration Dates

• First Submitted: December 14, 2012
• First Submitted That Met QC Criteria: December 17, 2012
• First Posted (Estimated): December 18, 2012

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: August 24, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: HHT; Hereditary Hemorrhagic Telangiectasia; Anti-angiogenic Therapy; vascular malformations
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Congenital Abnormalities; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Cardiovascular Abnormalities; Vascular Malformations; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Enzyme Inhibitors; Timolol; Maleic acid
• Other Study ID Numbers: BVMC 6207; 2U54NS065705-06 (U.S. NIH Grant/Contract)

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