Clinical trial NCT03397004: Doxycycline for Hereditary Hemorrhagic Telangiectasia
Official title: Doxycycline Crossover Trial for Hereditary Hemorrhagic Telangiectasia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hereditary Hemorrhagic Telangiectasia (HHT)
Keywords: Hereditary hemorrhagic telangiectasia
HHT
Doxycycline
Lead sponsor: Unity Health Toronto
Sponsor class: OTHER
Collaborators: name: Barrow Neurological Institute
name: Duke University
name: Feinstein Institute for Medical Research
name: University of Pittsburgh
name: Sunnybrook Health Sciences Centre
First posted: 2018-01-11
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This study will investigate the effectiveness of oral doxycycline for the treatment of recurrent nasal hemorrhage in Hereditary Hemorrhagic Telangiectasia (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. A Phase II, randomized double-blind placebo-controlled crossover trial. Approximately 30 subjects with HHT, with moderate-severe recurrent epistaxis will participate in the randomized double-blind placebo-controlled cross over trial. Subject will be treated with a 6-month course of doxycycline 100mg twice daily or placebo twice daily.

Detailed description: The aim is to study is to evaluate doxycycline 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 doxycycline, given its demonstrated anti-angiogenic and anti-inflammatory properties, as well as compelling effects in arteriovenous malformation (AVM) models. Doxycycline also has the advantages of a proven safety track record for long-term use, oral administration and low cost. Doxycycline suppresses vascular endothelial growth factor (VEGF)-induced cerebral matric metalloproteinase-9 (MMP-9) activity in vivo in the mouse model, and has anti-inflammatory effects as well, via inhibition of pro-inflammatory cytokines. In human brain vascular malformation tissue, there is evidence of increased expression of MMP-9 and VEGF and another tetracycline, minocycline, has attenuated brain hemorrhage in the mouse. Recently, a small retrospective case series reported sustained reduction in nasal hemorrhage in seven HHT patients treated with oral doxycycline. We hypothesize that oral doxycycline 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 doxycycline (100mg twice daily, 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-treatment, and stained for inflammatory, angiogenic and bone morphogenetic protein-9 (BMP9)-activin A receptor like type1(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. If the drugs studied are effective at reducing nasal hemorrhage, this will have important clinical implications for HHT patients, and the tissue and imaging may provide important insights into mechanisms.

Eligibility criteria: Inclusion Criteria:

* Age \>+ 18 years
* Clinical HHT diagnosis or genetic diagnosis of HHT
* Known personal or familial endoglin (ENG), ALK1 or SMAD4 mutation
* Epistaxis at least 15 min per week (mean for past month)
* At least two skin telangiectases

  * \>2mm diameter available for excisional biopsy,
  * at least two other telangiectases (skin or mucosal) available for micro-imaging
* Ability to give written informed consent

  * including compliance with the requirements of the study

Exclusion Criteria:

* Allergy/intolerance to the study drug or related agents
* Unstable medical illness
* Acute infection
* Creatinine \> upper limit of normal (ULN)
* Liver transaminases (AST or ALT) \>= 2x ULN
* Recent (within 2 month) use of study drug or other tetracycline agents
* Women who are pregnant
* Breastfeeding
* Plan to become pregnant during of the study
* Beta human chorionic gonadotropin (BHCG) level \<6 IUL (re-test if 6-24 IU/L)
* Specific contra-indications for study drug

Primary outcomes:
measure: The reduction in epistaxis (nose bleeding) severity over 96 weeks
timeFrame: daily for 96 weeks
Secondary outcomes:
measure: Change in epistaxis severity score (ESS)
timeFrame: baseline, week 12, week 24, week 36, week 48, week 60, week 72, week 84, week 96
measure: Measures related to chronic bleeding by a change from baseline
timeFrame: Baseline, week 12, week 18, week 24, week 30, week 36, week 42, week 48, week 60, week 66, week 72, week 78, week 84, week 96
measure: Regression of vascular malformations using Micro-imaging measures
timeFrame: week 12 (day 0), week 36, week 60, week 84
measure: Elucidate the mechanisms of action of doxycycline using tissue sample
timeFrame: week 36, week 84
measure: The measurement of a change in biomarkers
timeFrame: week 12 (day 0), week 24, week 36, week 48, week 60, week 72, week 84, week 96
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
Study officials:
affiliation: St. Michael's Hospital / The University of Toronto
name: Marie E Faughnan, MD MSc FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
citation: Thompson KP, Sykes J, Chandakkar P, Marambaud P, Vozoris NT, Marchuk DA, Faughnan ME. Randomized, double-blind, placebo-controlled, crossover trial of oral doxycycline for epistaxis in hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2022 Nov 7;17(1):405. doi: 10.1186/s13023-022-02539-8.