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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hereditary Hemorrhagic Telangiectasia	Drug: Topical timolol maleate; Drug: placebo saline drops	Not Applicable

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	10 participants
Allocation:	Randomized
Intervention Model:	Single Group Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Topical Anti-angiogenic Therapy for Telangiectasia in HHT: Proof of Concept
Study Start Date :	May 2013
Estimated Primary Completion Date :	June 2019
Estimated Study Completion Date :	June 2019

Arms and Interventions

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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 4 cutaneous telangiectasias per patient (timolol drops for 3 telangiectasia per patient and placebo drops to 1 telangiectasia per patient).; Other Name: 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 one cutaneous telangiectasias per patient.

Outcome Measures

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Primary Outcome Measures :

1. Mean reduction in lesion area (compared with baseline measurement) of treated telangiectasia. [ Time Frame: 84 days ]
   Mean reduction in lesion area (compared with baseline measurement) of treated telangiectasia.

Secondary Outcome Measures :

1. 1. From Tissue: Descriptive changes in histopathology in baseline vs treated lesions, vessel density and distribution of capillaries, arterioles and venules. [ Time Frame: 84 days ]
   1. From Tissue: Descriptive changes in histopathology in baseline vs treated lesions, vessel density and distribution of capillaries, arterioles and venules.
2. 2. From speckle variance OCT: Changes in lesion area, blood flow velocity and volume flow rates (treated vs baseline/ placebo). [ Time Frame: 84 days ]
   2. From speckle variance OCT: Changes in lesion area, blood flow velocity and volume flow rates (treated vs baseline/ placebo).
3. 3. Serum angiogenic markers (Aushon Blood-based Biomarkers in Clinical Research kit, analyzing 5- angiogenic biomarkers): Endoglin, BMP-9, VEGF+, TGF-beta1, TSP-1 [ Time Frame: at baseline and 84 days. ]
   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. 4. Stability of area of untreated telangiectasias over the 84 day period (placebo group) [ Time Frame: 84 days ]
   4. Stability of area of untreated telangiectasias over the 84 day period (placebo group)

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Marie E Faughnan, MD MSc FRCPC	416) 864-6060 ext 5412	faughnanm@smh.ca
Contact: Dewi Clark	416-8646060 ext 2887	clarkde@smh.ca

Locations

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

Sponsors and Collaborators

St. Michael's Hospital, Toronto

University of California, San Francisco

The Hospital for Sick Children

University of Toronto

Sunnybrook Health Sciences Centre

Ryerson University

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

Principal Investigator:	Marie E Faughnan, MD MSc FRCPC	St. Michael's Hospital, Toronto

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	St. Michael's Hospital, Toronto
ClinicalTrials.gov Identifier:	NCT01752049 History of Changes
Other Study ID Numbers:	BVMC 6207; 2U54NS065705-06 ( U.S. NIH Grant/Contract )
First Posted:	December 18, 2012
Last Update Posted:	May 18, 2017
Last Verified:	May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Keywords provided by St. Michael's Hospital, Toronto:

Hereditary Hemorrhagic Telangiectasia; Anti-angiogenic Therapy; vascular malformations; HHT

Additional relevant MeSH terms:

Vascular Malformations; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Vascular Diseases; Cardiovascular Diseases; Hemostatic Disorders; Hemorrhagic Disorders; Hematologic Diseases; Cardiovascular Abnormalities; Congenital Abnormalities; Timolol; Maleic acid; Angiogenesis Inhibitors	Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents; Enzyme Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antineoplastic Agents