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出境医 / 临床实验 / Vitamin D and Hereditary Haemorrhagic Telangiectasia

Vitamin D and Hereditary Haemorrhagic Telangiectasia

Study Description
Brief Summary:
The study aims to assess whether supplementing vitamin D in patients diagnosed with Hereditary Haemorrhagic Telangiectasia (HHT) will decrease the frequency and severity of nosebleeds these patients experience. It is hypothesized that the larger the dose of daily vitamin D given to the patients, the less frequent and less severe the nosebleeds will be.

Condition or disease Intervention/treatment Phase
Hereditary Haemorrhagic Telangiectasia Drug: Vit D Drug: Placebo Oral Tablet Phase 2

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients included in the study will be randomized. Block randomization will be utilized to ensure an equal number of experimental and control patients are in each arm. A closed envelope system will be used to randomize participants within each arm.
Masking: Double (Participant, Investigator)
Masking Description: The study is double blinded, the investigators and the patients throughout the data collection and data analysis period will not be aware of the vitamin D dosage given.
Primary Purpose: Treatment
Official Title: Vitamin D Supplementation and Reduction of Severity and Frequency of Epistaxis in Hereditary Haemorrhagic Telangiectasia
Actual Study Start Date : July 16, 2018
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : September 1, 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: 1000 IU Vitamin D Drug: Vit D
Patients will take an oral vitamin D supplement once a day for 6 months.
Experimental: 4000 IU Vitamin D Drug: Vit D
Patients will take an oral vitamin D supplement once a day for 6 months.
Placebo Comparator: Placebo Drug: Placebo Oral Tablet
Patients will take a placebo oral tablet once a day for 6 months.
Outcome Measures
Primary Outcome Measures :
  1. Change in Epistaxis Severity Score [ Time Frame: Baseline, 3 months, and 6 months ]

    A questionnaire that will be given to the patients at each visit which is a major predictor of quality of life in HHT patients.

    The score includes six independent predictors of self-described epistaxis severity. The responses will then be weighted by respective coefficients and these added together to give a raw ESS, which will then be divided by the range of the raw score (2.71) and multiplied by 10 to give normalized ESS within the range of 0 to 10 (no epistaxis to severe epistaxis).



Secondary Outcome Measures :
  1. Change in Modified Lund-Kennedy Score [ Time Frame: Baseline, 3 months, and 6 months ]
    The score is an objective measure based on Endoscopic sinonasal mucosal inflammation. The score is determined from a range of 0-12 with higher numbers indicating worse inflammation. Endoscopy will determine the density and location of telangiectasias, vascular morphology or patterns, relative percentage of arteriovenous malformations (AVMs), degree of crusting, septal perforation and site.


Eligibility Criteria
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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 19 years or older
  • Definite diagnosis of HHT using the Curacao criteria;
  • HHT patients already on Vitamin D supplementation (these patients will still be included since the study is examining mega-doses specifically)

Exclusion Criteria:

  • Patients with sinonasal tumours;
  • Patients with bleeding disorders;
  • Patients with serum levels of 250 or more ng/ml of vitamin D before or during the study supplementation (considered to be toxic levels)
  • Patients who are unable to speak English;
  • Patients who live outside B.C.
Contacts and Locations

Contacts
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Contact: Amin Javer, MD FRCSCFARS 6048069926 sinusdoc@me.com
Contact: India Dhillon, BSc 6048069926 idhillon3@providencehealth.bc.ca

Locations
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Canada, British Columbia
E.N.T Clinic, St. Paul's Hospital Recruiting
Vancouver, British Columbia, Canada, V6Z 1Y6
Contact: India Dhillon, BSc    604-806-9926    idhillon3@providencehealth.bc.ca   
Principal Investigator: Amin R Javer, MD FRCSCFARS         
Sponsors and Collaborators
St. Paul's Hospital, Canada
Tracking Information
First Submitted Date  ICMJE May 24, 2019
First Posted Date  ICMJE June 11, 2019
Last Update Posted Date June 11, 2019
Actual Study Start Date  ICMJE July 16, 2018
Estimated Primary Completion Date July 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 7, 2019) 		Change in Epistaxis Severity Score [ Time Frame: Baseline, 3 months, and 6 months ]
A questionnaire that will be given to the patients at each visit which is a major predictor of quality of life in HHT patients. The score includes six independent predictors of self-described epistaxis severity. The responses will then be weighted by respective coefficients and these added together to give a raw ESS, which will then be divided by the range of the raw score (2.71) and multiplied by 10 to give normalized ESS within the range of 0 to 10 (no epistaxis to severe epistaxis).
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2019) 		Change in Modified Lund-Kennedy Score [ Time Frame: Baseline, 3 months, and 6 months ]
The score is an objective measure based on Endoscopic sinonasal mucosal inflammation. The score is determined from a range of 0-12 with higher numbers indicating worse inflammation. Endoscopy will determine the density and location of telangiectasias, vascular morphology or patterns, relative percentage of arteriovenous malformations (AVMs), degree of crusting, septal perforation and site.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Vitamin D and Hereditary Haemorrhagic Telangiectasia
Official Title  ICMJE Vitamin D Supplementation and Reduction of Severity and Frequency of Epistaxis in Hereditary Haemorrhagic Telangiectasia
Brief Summary The study aims to assess whether supplementing vitamin D in patients diagnosed with Hereditary Haemorrhagic Telangiectasia (HHT) will decrease the frequency and severity of nosebleeds these patients experience. It is hypothesized that the larger the dose of daily vitamin D given to the patients, the less frequent and less severe the nosebleeds will be.
Detailed Description

  1. Purpose:

    The focus of the study is to determine if supplementing vitamin D in patients diagnosed with HHT will reduce the frequency and severity of epistaxis episodes.

  2. Hypothesis:

    For patients diagnosed with HHT, daily vitamin D supplementation will reduce the frequency and severity of epistaxis. Additionally, there will be a greater reduction in epistaxis frequency and severity the larger the dose of daily vitamin D supplemented

  3. Justification:

    Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant inherited disorder of the fibrovascular tissue that causes malformation of capillaries (called "telangiectases") and/or larger blood vessels (called "arteriovenous malformations") throughout the body. The formation of these lesions ultimately result in patients experiencing increased tendency for bleeding. These lesions may present in varying locations systemically, however recurrent and severe epistaxis is the most common presentation of HHT.

    Various medical and surgical treatments exist for management of HHT patients which are aimed at decreasing the frequency and severity of epistaxis episodes. These therapies include: humidification, nasal lubrication, nasal hot saline irrigation, intranasal packing, oestrogen ointment, tranexamic acid, bevacizumab systemic/topically applied, use of propranolol to lower blood pressure, electrocautery and YAG laser. Although all these various options are available, there currently is no consensus toward an optimal solution. Treatment can become especially difficult due to progressive anaemia or when anticoagulant or anti-thrombotic therapy becomes necessary. Therefore, there is a need for establishment of a safe and effective therapy.

    It has been suggested that vitamin D plays a role in cardiovascular health. Vitamin D plays a key role in establishing the integrity of blood vessels as it has been shown to provide protection of the vascular wall as well has having minor anticoagulation effects. As well, observational retrospective studies have found an association between vitamin D levels and epistaxis bleeding time and severity in HHT patients, with higher serum vitamin D levels being associated with decrease epistaxis bleeding time and severity. Despite evidence of positive effect of vitamin D on HHT, currently no prospective study has been done.

  4. Objectives:

    Primary Objective To determine if vitamin D supplementation with 1000 IU or 4000 IU will reduce the frequency and severity of epistaxis in HHT patients.

    Secondary Objective To determine the adequate dosage of vitamin D supplementation required to reduce frequency and severity of epistaxis in HHT patients.

  5. Research Method

The proposed study is a prospective double-blinded, placebo controlled, randomized control trial.

All the St. Paul's Sinus Centre patients willing to participate in the study will be invited for screening. Currently, the clinic has ~60 patients with HHT; therefore the investigators hope to enrol ~20 patients in each of the three study arms.

Consenting patient will be randomized to ensure equal number of experimental and control patients are in each arm. A closed envelop system will be used to randomize participants within each arm. Patients diagnosed with HHT who are not taking vitamin D supplementation at the time of recruitment will be randomized into one of the following three groups:

  1. 1000 IU/day vitamin D,
  2. 4000 IU/day vitamin D, or
  3. Placebo control Patients who are already taking vitamin D at the time of recruitment will be asked to stop taking the current dose of vitamin D and will be randomized into either the 1000 IU or 4000 IU arm of the study. Patients previously taking Vitamin D will not participate as placebo controls.

Upon enrolment in the study, demographic data will be obtained, including age, gender, and ethnicity. Patient's will also have baseline blood work drawn, standard of care, (full hematological profile, ferritin, aPTT, INR, serum vitamin D, IgE) and be asked to fill out a questionnaire to provide a baseline Epistaxis Severity Score (ESS). This questionnaire is routinely used to assess quality of life in HHT patients and includes six independent predictors of self-described epistaxis severity. Baseline nasal endoscopic scoring will also be performed by endoscopic imaging of the nasal cavity.

The patients will be instructed on dosing of vitamin D supplementation. Patients will continue daily supplementation for three months until the first follow up visit. At the first follow-up visit patients will again have blood work drawn, be asked to fill out the ESS questionnaire, and receive nasal endoscopic scoring.

The last follow-up visit will be at six months and a repeat of the same procedures/tests will be carried out.

6. Statistical Analysis:

The primary outcome of this study will be the Epistaxis Severity Score (ESS), which is obtained from patient questionnaires. The secondary outcome will be the Nasal Endoscopic Score. The difference in the ESS and endoscopic score before and after supplementation within and between groups will be analyzed using paired and unpaired students t-tests based on the variance results.

Descriptive statistics (mean, median, SD) will be used to describe demographic and hematological data collected.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Patients included in the study will be randomized. Block randomization will be utilized to ensure an equal number of experimental and control patients are in each arm. A closed envelope system will be used to randomize participants within each arm.
Masking: Double (Participant, Investigator)
Masking Description:
The study is double blinded, the investigators and the patients throughout the data collection and data analysis period will not be aware of the vitamin D dosage given.
Primary Purpose: Treatment
Condition  ICMJE Hereditary Haemorrhagic Telangiectasia
Intervention  ICMJE
  • Drug: Vit D
    Patients will take an oral vitamin D supplement once a day for 6 months.
  • Drug: Placebo Oral Tablet
    Patients will take a placebo oral tablet once a day for 6 months.
Study Arms  ICMJE
  • Experimental: 1000 IU Vitamin D
    Intervention: Drug: Vit D
  • Experimental: 4000 IU Vitamin D
    Intervention: Drug: Vit D
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo Oral Tablet
Publications *
  • Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet. 2009 Jul;17(7):860-71. doi: 10.1038/ejhg.2009.35. Epub 2009 Apr 1. Review.
  • Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, Kjeldsen AD, Plauchu H. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000 Mar 6;91(1):66-7.
  • Hoag JB, Terry P, Mitchell S, Reh D, Merlo CA. An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope. 2010 Apr;120(4):838-43. doi: 10.1002/lary.20818.
  • Chamali B, Finnamore H, Manning R, Laffan MA, Hickson M, Whelan K, Shovlin CL. Dietary supplement use and nosebleeds in hereditary haemorrhagic telangiectasia - an observational study. Intractable Rare Dis Res. 2016 May;5(2):109-13. doi: 10.5582/irdr.2016.01019.
  • Plauchu H, de Chadarévian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet. 1989 Mar;32(3):291-7.
  • Al Mheid I, Patel R, Murrow J, Morris A, Rahman A, Fike L, Kavtaradze N, Uphoff I, Hooper C, Tangpricha V, Alexander RW, Brigham K, Quyyumi AA. Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans. J Am Coll Cardiol. 2011 Jul 5;58(2):186-92. doi: 10.1016/j.jacc.2011.02.051.
  • Min B. Effects of vitamin d on blood pressure and endothelial function. Korean J Physiol Pharmacol. 2013 Oct;17(5):385-92. doi: 10.4196/kjpp.2013.17.5.385. Epub 2013 Oct 17. Review.
  • Weber LM, McDonald J, Whitehead K. Vitamin D levels are associated with epistaxis severity and bleeding duration in hereditary hemorrhagic telangiectasia. Biomark Med. 2018 Apr;12(4):365-371. doi: 10.2217/bmm-2017-0229. Epub 2018 Mar 14.
  • Geisthoff UW, Nguyen HL, Röth A, Seyfert U. How to manage patients with hereditary haemorrhagic telangiectasia. Br J Haematol. 2015 Nov;171(4):443-52. doi: 10.1111/bjh.13606. Epub 2015 Jul 23. Review.
  • McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med. 2011 Jul;13(7):607-16. doi: 10.1097/GIM.0b013e3182136d32. Review.
  • Reh DD, Yin LX, Laaeq K, Merlo CA. A new endoscopic staging system for hereditary hemorrhagic telangiectasia. Int Forum Allergy Rhinol. 2014 Aug;4(8):635-9. doi: 10.1002/alr.21339. Epub 2014 Apr 29.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: June 7, 2019) 		60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2020
Estimated Primary Completion Date July 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 19 years or older
  • Definite diagnosis of HHT using the Curacao criteria;
  • HHT patients already on Vitamin D supplementation (these patients will still be included since the study is examining mega-doses specifically)

Exclusion Criteria:

  • Patients with sinonasal tumours;
  • Patients with bleeding disorders;
  • Patients with serum levels of 250 or more ng/ml of vitamin D before or during the study supplementation (considered to be toxic levels)
  • Patients who are unable to speak English;
  • Patients who live outside B.C.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03981562
Other Study ID Numbers  ICMJE H18-01337
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: All IPD that underlie results in a publication will be available to other researchers.
Responsible Party Amin Javer, St. Paul's Hospital, Canada
Study Sponsor  ICMJE St. Paul's Hospital, Canada
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account St. Paul's Hospital, Canada
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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