Hereditary Hemorrhagic Telangiectasia (HHT)Phase 2HHTNCT03397004
Doxycycline for Hereditary Hemorrhagic Telangiectasia
A Phase 2 study testing Doxycycline Hyclate in people with Hereditary Hemorrhagic Telangiectasia (HHT), run by Unity Health Toronto at 1 site in Canada.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hereditary Hemorrhagic Telangiectasia (HHT)
- What is being tested?
- Doxycycline Hyclate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 13 participants
- Where
- 1 siteCanada
- Study dates
- 12 Sep 2018to 1 Mar 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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,
Show all 9Show fewer
- 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
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Doxycycline Crossover Trial for Hereditary Hemorrhagic Telangiectasia
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.
Read the 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.
- Being tested
- Doxycycline Hyclate, Placebo
- Keywords
- Hereditary hemorrhagic telangiectasia, HHT, Doxycycline
- Medical subject headings
- Telangiectasia, Hereditary Hemorrhagic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Doxycycline HyclateDrug
Also called capsule
Doxycycline will be given for 6 months, followed by a washout period for 6 months (pre or post a crossover intervention)
PlaceboDrug
Also called capsule
Placebo will be given for 6 months, followed by a washout period for 6 months (pre or post a crossover intervention)
| Study group | Role | What they receive |
|---|---|---|
| doxycycline Hyclate | Active comparator | subjects will be treated with a 6-month course of doxycycline oral capsule at a dose of 100mg twice daily Receives: Drug: Doxycycline Hyclate |
| Placebo | Placebo comparator | subjects will be given a placebo oral capsule twice daily for 6-months Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
The reduction in epistaxis (nose bleeding) severity over 96 weeks
Participants will be asked to maintain a daily diary for the duration of the study (96 weeks). Participants will record all epistaxis events daily, noting the duration in minutes and whether or not there was gushing during each nosebleed. The change in epistaxis severity will be measured from a sum of duration of all bleeding events each week, as measured from the participant daily diary.
Measured: daily for 96 weeks
Secondary outcomes (5)
Change in epistaxis severity score (ESS)
The epistaxis severity score is a six item questionnaire used to calculate a severity of HHT related nose bleeding. Each question is pertaining to the subject's typical symptoms within the last 3 months period. The first three questions are related to frequency, duration and intensity. The forth question whether or not medical attention was sought for nose bleeding. The remaining two questions are related to the presence of anemia and the need for blood transfusion due to nose bleeding. The resulting epistaxis severity score vary between; none 0-1, mild bleeding >1-4, moderate bleeding >4-7 and >7-10 for severe bleeding.
Measured: baseline, week 12, week 24, week 36, week 48, week 60, week 72, week 84, week 96
Measures related to chronic bleeding by a change from baseline
Blood samples will be taken to measure change in chronic bleeding by looking at the hemoglobin, ferritin and iron saturation level. Samples will be taken prior to investigational product for a baseline value. This will be followed by measurements every six weeks during the periods of investigational product for comparative analysis.
Measured: 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
Regression of vascular malformations using Micro-imaging measures
Telangiectases will be micro-imaged using an established medical imaging technique speckle variance optical coherence tomography (SVOCT). The micro-imaging will be used for vasculature measurements. The SVOCT will measure the telangiectasia lesion area, volume, and density, lesion flow velocity and volume flow rate. Structural images will be generated. Imaging will be performed at four time points throughout the duration of the study.
Measured: week 12 (day 0), week 36, week 60, week 84
Elucidate the mechanisms of action of doxycycline using tissue sample
A punch biopsy of one cutaneous telangiectasia will be performed at two time points during the study. The biopsy tissue sample will be taken at the end of each 6 month active comparator (drug) or placebo treatment. The tissue will be analyze for lesion vessel density, distribution of vessel types (capillary, venule, arteriole) and for insights into mechanisms. Further investigation will include staining for inflammatory, angiogenesis and BMP9-ALK1-endoglin-Smad1/5/9 pathway markers (VEGF, MMP-9, cyclooxygenase-2 (COX-2), Endoglin, ALK1).
Measured: week 36, week 84
The measurement of a change in biomarkers
Serum, plasma levels will be measured for inflammatory, angiogenic, and BMP9-ALK1-endoglin-Smad1/5/9 pathway (VEGF, MMP-9, Thrombospondin-2, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), endothelin). Biomarker samples will be collected every 3-months. This will allow each subject to also provide their own controls for each treated case. The change in biomarkers will be analyzed.
Measured: week 12 (day 0), week 24, week 36, week 48, week 60, week 72, week 84, week 96
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jan 2018
- Study start12 Sep 2018
- Primary completion18 Feb 2021
- Study completion1 Mar 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hereditary Hemorrhagic Telangiectasia (HHT)Studies of the same condition, open and under way.
- More trials run by Unity Health TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Unity Health Toronto
- Sponsor type
- University, hospital or other
- Collaborators
- Barrow Neurological Institute, Duke University, Feinstein Institute for Medical Research, University of Pittsburgh, Sunnybrook Health Sciences Centre
- Responsible party
- Sponsor
- Investigators
- Marie E Faughnan, MD MSc FRCPC, Principal investigator, St. Michael's Hospital / The University of Toronto
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03397004
- Sponsor's protocol ID
- 160517448
- Other IDs
- Award Number W81XWH-17-1-0429
- Acronym
- HHT
- Status last verified
- Mar 2025
- First submitted
- 21 Nov 2017
- Last updated
- 1 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 36344987
Study at a glance
From the registry record, last updated by the sponsor on 1 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Doxycycline Crossover Trial for Hereditary Hemorrhagic Telangiectasia
- ClinicalTrials.gov ID
- NCT03397004
- Acronym / sponsor ID
- HHT / 160517448
- Keywords
- Hereditary hemorrhagic telangiectasia, HHT, Doxycycline
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Unity Health TorontoUniversity, hospital or other
- Collaborators
- Barrow Neurological Institute, Duke University, Feinstein Institute for Medical Research, University of Pittsburgh, Sunnybrook Health Sciences Centre
- Study start
- 12 Sep 2018 (actual)
- Primary completion
- 18 Feb 2021 (actual)
- Study completion
- 1 Mar 2021 (actual)
- First posted
- 11 Jan 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| doxycycline Hyclate | Active comparator | Drug: Doxycycline Hyclatesubjects will be treated with a 6-month course of doxycycline oral capsule at a dose of 100mg twice daily |
| Placebo | Placebo comparator | Drug: Placebosubjects will be given a placebo oral capsule twice daily for 6-months |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Doxycycline HyclateAlso: capsuleDoxycycline will be given for 6 months, followed by a washout period for 6 months (pre or post a crossover intervention) | Drug | doxycycline Hyclate |
| PlaceboAlso: capsulePlacebo will be given for 6 months, followed by a washout period for 6 months (pre or post a crossover intervention) | Drug | Placebo |
Primary outcome
The reduction in epistaxis (nose bleeding) severity over 96 weeks
Time frame: daily for 96 weeks
Participants will be asked to maintain a daily diary for the duration of the study (96 weeks). Participants will record all epistaxis events daily, noting the duration in minutes and whether or not there was gushing during each nosebleed. The change in epistaxis severity will be measured from a sum of duration of all bleeding events each week, as measured from the participant daily diary.
5 secondary outcomes
Change in epistaxis severity score (ESS)
Time frame: baseline, week 12, week 24, week 36, week 48, week 60, week 72, week 84, week 96
Measures related to chronic bleeding by a change from baseline
Time frame: 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
Regression of vascular malformations using Micro-imaging measures
Time frame: week 12 (day 0), week 36, week 60, week 84
Elucidate the mechanisms of action of doxycycline using tissue sample
Time frame: week 36, week 84
The measurement of a change in biomarkers
Time frame: week 12 (day 0), week 24, week 36, week 48, week 60, week 72, week 84, week 96
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Apr 2025.
- Derived from this study: PubMed 36344987Thompson 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marie E Faughnan, MD MSc FRCPC principal investigator
St. Michael's Hospital / The University of Toronto
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Doxycycline Hyclate in people with Hereditary Hemorrhagic Telangiectasia (HHT), run by Unity Health Toronto at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The reduction in epistaxis (nose bleeding) severity over 96 weeks (time frame: daily for 96 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03397004, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Apr 2025; AzTrials last refreshed its copy on 3 Nov 2026.