Hereditary Hemorrhagic Telangiectasia
Conditions
Keywords
Hereditary Hemorrhagic Telangiectasia, Anti-angiogenic Therapy, vascular malformations, HHT
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.
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.
Interventions
* 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
DRUGplacebo saline drops
Applied twice daily for 12 weeks (84 days) or until disappearance of lesions to 1 cutaneous telangiectasias per patient.
Sponsors
University of California, San Francisco
The Hospital for Sick Children
University of Toronto
Sunnybrook Health Sciences Centre
Toronto Metropolitan University
National Institute of Neurological Disorders and Stroke (NINDS)
Unity Health Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Lesion Area of Treated Telangiectasia. | 84 days | Change in lesion area (compared with baseline measurement) of treated telangiectasia. |
Secondary
| 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 |
Countries
Canada
Participant flow
Recruitment details
Each Participant received both treatment and placebo
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants 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).
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). | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment Canada | 5 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 1 / 5 | 1 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Change in Lesion Area of Treated Telangiectasia.
Change in lesion area (compared with baseline measurement) of treated telangiectasia.
Time frame: 84 days
Population: 5 participants enrolled, each participant have Hereditary Hemorrhagic Telangiectasia (HHT) and have at least 5 typical telangiectasias on their hands or face.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Topical Timolol Maleate | Change in Lesion Area of Treated Telangiectasia. | -6 mm^2 | Standard Deviation 11 |
| Placebo | Change in Lesion Area of Treated Telangiectasia. | -8 mm^2 | Standard Deviation 17 |
Secondary
Blood Flow Velocity and Volume Flow Rates
Time frame: 84 days
Population: No data collected
Secondary
Descriptive Changes in Histopathology in Baseline vs Treated Lesions
Time frame: 84 days
Population: No data collected
Secondary
Serum Angiogenic Markers
Time frame: 84 days
Population: No data collected
Secondary
Stability of Area of Untreated Telangiectasias Over the 84 Day Period
Time frame: 84 days
Population: No data collected