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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by St. Michael's Hospital, Toronto
Sponsor:
Collaborators:
University of California, San Francisco
The Hospital for Sick Children
University of Toronto
Sunnybrook Health Sciences Centre
Ryerson University
Information provided by (Responsible Party):
St. Michael's Hospital, Toronto
ClinicalTrials.gov Identifier:
NCT01752049
First received: December 14, 2012
Last updated: February 12, 2014
Last verified: February 2014
  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 (HHT).
Drug: Topical timolol maleate
Drug: placebo saline drops

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Topical Anti-angiogenic Therapy for Telangiectasia in HHT: Proof of Concept

Resource links provided by NLM:


Further study details as provided by St. Michael's Hospital, Toronto:

Primary Outcome Measures:
  • Mean reduction in lesion area (compared with baseline measurement) of treated telangiectasia. [ Time Frame: 84 days ] [ Designated as safety issue: No ]
    Mean reduction in lesion area (compared with baseline measurement) of treated telangiectasia.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 2014
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Other Name: placebo saline drops

Detailed Description:

This is a small study of 10 patients from St. Michael's Hospital who have HHT and at least 5 typical telangiectaias.

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 eyedrop, that has been shown to reduce pressure in the eye and is commonly used for glaucoma.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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 3-5mm) on dorsum of hands (not including lesions on over inter-phalangeal joints)

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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01752049

Contacts
Contact: Myra E Slutsky, hon BA 416 864 6060 ext 2887 slutskym@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
Investigators
Principal Investigator: Marie E Faughnan, MD MSc FRCPC St. Michael's Hospital, Toronto
  More Information

No publications provided

Responsible Party: St. Michael's Hospital, Toronto
ClinicalTrials.gov Identifier: NCT01752049     History of Changes
Other Study ID Numbers: BVMC 6207
Study First Received: December 14, 2012
Last Updated: February 12, 2014
Health Authority: Canada: Health Canada

Keywords provided by St. Michael's Hospital, Toronto:
Hereditary Hemorrhagic Telangiectasia
Anti-angiogenic Therapy
vascular malformations

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

ClinicalTrials.gov processed this record on September 16, 2014