Tacrolimus Crossover Trial for Hereditary Hemorrhagic Telangiectasia (HHT)

Tacrolimus Crossover Trial for Hereditary Hemorrhagic Telangiectasia (HHT)

Sponsors

Lead Sponsor: Unity Health Toronto

Collaborator: United States Department of Defense

Source Unity Health Toronto
Brief Summary

This study will investigate the effectiveness of oral low-dose tacrolimus for the treatment of recurrent nasal hemorrhage in HHT subjects. The primary outcome for the trials will be the reduction of epistaxis severity (minutes of bleeding per week). The biological outcomes of interest are the regression of vascular malformations as well as tissue and circulation biomarkers of the relevant mechanistic pathways. In this Phase II, randomized double-blind placebo-controlled crossover trial, the investigatrors estimate a sample size of 30 subjects with HHT, with moderate-severe recurrent epistaxis will be required. Subject will be treated with a 6-month course of tacrolimus twice daily or placebo twice daily.

Detailed Description

The aim is to study is to evaluate low-dose tacrolimus as a treatment for HHT with the proposed "HHT Clinical Trial Protocol". Rare disease presents a number of challenges in clinical trial design, including recruitment challenges, related power limitations and less knowledge about outcomes measurement. Considering these limitations, as well as the large variability in epistaxis measures across HHT patients, a crossover-trial design, with each subject receiving the study drug and placebo, and therefore serving as their own control, has been selected, including randomization and blinding, to limit bias in measuring this subjective outcome. This study will investigate tacrolimus, given its demonstrated anti-angiogenic and anti-inflammatory properties, as well as compelling effects in arteriovenous malformation (AVM) models. Specifically, tacrolimus has been shown to oppose the gene expression upregulation of the identified pro-angiogenic markers, thus resulting in anti-angiogenic effects. There are two mechanisms to this. Firstly, recent evidence has shown tacrolimus to be a potent ALK1 signaling mimetic at the transcriptional level. This is particularly significant given that the ALK1 pathway signaling is lost in HHT via the hallmark ACVRL1 and ENG genes. Independent of its effect on the ALK1 pathway, tacrolimus has been shown to be a potent inhibitor of VGEF signaling. As mentioned previously, the BMP9-ALK1-endoglin-Smad1/5/9 pathway in HHT, is a novel avenue of interest for treating hemorrhage in HHT and also regressing vascular malformations. Given the upstream inactivation of the ALK1 pathway, therapeutic potential via this pathway is dependent on Smad1/5/8 activation and signaling irrespective of the functional status of the corresponding ALK1 receptors. To this end, tacrolimus has been shown to activate Smad1/5/8 signaling in HHT patient-derived cells, thus confirming its therapeutic potential in HHT. Tacrolimus also has anti-inflammatory effects, via inhibition of pro-inflammatory cytokines, specifically IL2, which is associated with cytotoxic T cell proliferation and activation. Finally, recent evidence also demonstrated a reduction of vascular pathology in mouse models via tacrolimus administration. Tacrolimus also has the advantages of a proven safety track record for long-term use, given its long history in transplant medicine, and can be orally administered, making it more acceptable to patients. In addition to promising effects in laboratory-based studies, Canadian case study reported the regression of angiodysplasia and reduction of mucosal hemorrhage in a probable HHT patient who underwent liver transplantation following high-output cardiac failure and hepatic AVM development. A recent case report of treatment with oral low-dose -dose tacrolimus in an individual with HHT, found that tacrolimus dramatically improved epistaxis. Based on the evidence to date, the investigators hypothesize that oral low-dose tacrolimus will reduce nasal hemorrhage in HHT subjects, through anti-angiogenic and/or anti-inflammatory mechanisms, both of which have been implicated in HHT. This is a double-blind randomized placebo-controlled trial (N=30) of oral low-dose tacrolimus (0.025mg/kg/day and adjusted to maintain blood levels of 2-5ng/ml 6-month course) in HHT subjects with moderate-severe recurrent nasal hemorrhage. Drug dosing and safety monitoring will be tailored specifically to the agent studied. The primary outcome will be reduction of bleeding minutes per week. In addition, vascular malformation tissue (cutaneous) will be obtained pre and post-investigational product from some subject, and stained for inflammatory, angiogenic and BMP9-ALK1-endoglin- SMAD1/5/9 pathway markers. In addition, pre-excision, vascular malformations will be imaged with speckle variance optical coherence tomography (SVOCT), in vivo non-invasive micro-angiography, to measure lesion structure, vessel volume and vessel density, as previously described. Tissue and imaging may provide important insights into physiological mechanisms that explain clinical changes. If the drugs studied are effective at reducing nasal hemorrhage, this will have important clinical implications for HHT patients.

Overall Status Recruiting
Start Date 2020-10-20
Completion Date 2022-09-01
Primary Completion Date 2022-09-01
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
The change in epistaxis (nose bleeding) severity using low-dose Tacrolimus 96 weeks
Secondary Outcome
Measure Time Frame
Change in Epistaxis Severity Score (ESS) Baseline, Weeks; 12,18,24,30,36,42,48,60,66,72,78,84,96
Change in Chronic Bleeding Baseline, Weeks; 12,18,24,30,36,42,48,60,66,72,78,84,96
Micro-Imaging to measure regression of Vascular Malformations week 12, week 36, week 60, week 84
The use of Telangiectasia tissue sample to look at the mechanisms of action of Tacrolimus week 36, week 84
Change in Biomarkers Weeks: 12, 24, 36, 48, 60, 72, 84, 96
Enrollment 30
Condition
Intervention

Intervention Type: Drug

Intervention Name: Tacrolimus capsule (low-dose)

Description: low-dose Tacrolimus will be given for 6 months followed by a washout period for 6 months

Arm Group Label: Tacrolimus immediate-release capsules

Intervention Type: Drug

Intervention Name: Placebo

Description: Placebo will be given for 6 months followed by a washout period for 6 months

Arm Group Label: Placebo

Eligibility

Criteria:

Inclusion Criteria: 1. Age > 18 years 2. Clinical HHT diagnosis or personal genetic diagnosis of HHT 3. Epistaxis at least 15 min per week (mean for past month) 4. At least one telangiectasia (skin or mucosal) available for micro-imaging. 5. Ability to give written informed consent, including compliance with the requirements of the study. Exclusion Criteria: 1. Allergy/intolerance to the study drug or related agents 2. Unstable medical illness 3. Acute infection 4. Creatinine > ULN (upper limit of normal) 5. Liver transaminases (AST or ALT) >= 2x ULN 6. Women participant who are pregnant or breastfeeding or plan to become pregnant during the duration of the study 7. Women of childbearing potential not on effective contraception. Male participants of reproductive potential whose female partners are of childbearing potential and are not planning to use highly effective contraceptive method 8. BHCG level <6 IUL (re-test if 6-24 IU/L) 9. Specific contra-indications for study drug (detailed in the product monograph) 10. Abnormal ECG where the QTc >480msec

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Marie E Faughnan, MD,MSc,FRCPC Principal Investigator Unity Health Toronto
Overall Contact

Last Name: Dewi S Clark, BSc, MHSc

Phone: 416-864-6060

Phone Ext.: 42887

Email: [email protected]

Location
Facility: Status: Contact: Contact Backup: Investigator: St. Michael's Hospital Marie E Faughnan, MD MSc FRCP 416-864-6060 5412 [email protected] Marie E Faughnan, MD Principal Investigator
Location Countries

Canada

Verification Date

2020-11-01

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Tacrolimus immediate-release capsules

Type: Active Comparator

Description: subjects will be treated with a 6 months course of oral low-dose tacrolimus capsules to be taken twice daily starting dose of 0.025 mg/kg/day, adjusted to maintain drug blood levels of 2-5ng/ml

Label: Placebo

Type: Placebo Comparator

Description: Subjects will be given placebo oral capsules to be taken twice daily for 6 months.

Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Crossover Assignment

Intervention Model Description: Randomized Double-Blind Placebo-Controlled Crossover Trial

Primary Purpose: Treatment

Masking: Triple (Participant, Care Provider, Investigator)

Masking Description: Double- Blind

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