Topical Anti-angiogenic Therapy for Telangiectasia in HHT: Proof of Concept
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Purpose
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 | Intervention |
|---|---|
| Hereditary Hemorrhagic Telangiectasia | Drug: Topical timolol maleate Drug: placebo saline drops |
| Study Type: | Interventional |
| Study Design: | 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 |
- 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.
- 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. 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. 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. 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)
| Estimated Enrollment: | 10 |
| Study Start Date: | May 2013 |
| Estimated Study Completion Date: | June 2019 |
| Estimated Primary Completion Date: | June 2019 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Topical timolol maleate
Drug: • Topical timolol maleate 0.5% drops
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Drug: Topical timolol maleate
Other Name: Topical timolol maleate 0.5% drops
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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.
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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.
Eligibility
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Senior) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Definite clinical or genetic diagnosis of HHT
- Known ENG or ALK1 mutation (personal or familial)
- Age>=18 years
- 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:
- 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)
- Current treatment with systemic beta-blocker
- Current participation in other therapeutic trial for HHT
- Current pregnancy or breastfeeding.
Contacts and Locations
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01752049
| 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 |
| Canada, Ontario | |
| St. Michael's Hospital | Recruiting |
| Toronto, Ontario, Canada, M5B 1W8 | |
| Principal Investigator: Marie E Faughnan, MD MSc FRCPC | |
| Principal Investigator: | Marie E Faughnan, MD MSc FRCPC | St. Michael's Hospital, Toronto |
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 Submitted: | December 14, 2012 |
| 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:
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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 |