The Oxford Marfan Trial
Primary Purpose
Marfan Syndrome
Status
Unknown status
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Irbesartan 150-300mg capsules daily for 6 months
Doxycycline 100-200mg capsules daily for 6 months
Doxycycline placebo capsules daily for 6 months
Irbesartan placebo capsules daily for 6 months
Sponsored by
About this trial
This is an interventional treatment trial for Marfan Syndrome
Eligibility Criteria
Inclusion Criteria:
- Male or female, aged 13 years or above at last birthday (note that there is no upper age limit for inclusion in this trial)
- For those aged greater than or equal to 16 years of age at the time of enrolment, participant is willing and, in the opinion of the investigator, able to give informed consent for participation in the trial
- For those aged 13-15 at the time of enrolment, participant is willing and, in the opinion of the investigator, able to give informed assent, and parent/guardian is willing and able to give informed consent for participation in the trial.
- Weight ≥ 50kg
- Diagnosed with Marfan syndrome according to the revised Ghent criteria 1996
- Dilated aorta (BSA-adjusted aortic root z-score ≥2 at the aortic sinuses of Valsalva, using the method of Roman et al, or an absolute aortic root dimension >4.0cm at the sinuses of Valsalva measured using either echocardiography or CMR)
- If the participant is a female of child-bearing potential, they are willing to ensure effective contraception as defined in the contraception policy
- If the participant is taking β-blocker therapy, they are willing to stop taking these one week prior to each CMR scan
- Willing and, in the investigator's opinion, able to comply with all trial requirements
- Willing to allow his or her General Practitioner and if appropriate, Consultant, to be informed of his or her participation in the trial and of any clinical findings or issues which may arise
Exclusion Criteria:
- Female who is pregnant
- Female who is planning pregnancy within 6 months of enrolment
- Female who is breast feeding
- Previous aortic dissection
- Previous aortic surgery
- Bicuspid or unicuspid aortic valve
- Scheduled elective cardiac or aortic surgery within 6 months of enrolment
- Definite diagnosis of Loeys-Dietz or Shpritzen-Goldberg syndrome
- Known bilateral renal artery stenosis or renal artery stenosis to a single functioning kidney
- History of idiopathic intracranial hypertension
- Exposure to angiotensin receptor antagonists, angiotensin converting enzyme inhibitors, or medications containing these compounds in the 3 months prior to enrolment in the trial
- Absolute indication for angiotensin receptor antagonists, angiotensin converting enzyme inhibitors, doxycycline or other antibiotics of the tetracycline class at enrolment
- Taking β-blocker therapy for an indication other than the Marfan syndrome
- Participant has participated in another research study involving an investigational medicinal product or device in the 3 months prior to enrolment
- Renal impairment of a moderate or severe degree (eGFR <60 mls/min/1.73m2)
- Hyperkalaemia (>5.1 mmol/L)
- Significant hepatic impairment (ALT or AST >3 times upper limit of normal)
- History of allergic reaction or any other clinically significant intolerance to irbesartan or its constituents; other angiotensin receptor blockers / antagonists; angiotensin converting enzyme inhibitors, doxycycline or its constituents, or placebo medications or its constituents
- Contra-indications to MRI (e.g. implantable cardiac electronic device, claustrophobia, intracranial aneurysm clips and metallic ocular foreign bodies etc.)
- Participant currently required to take or likely to be required to start, in the 6 months following enrolment, a medicinal product which is known or suspected to interact, to a clinically significant extent, with irbesartan including: potassium supplementation, potassium sparing diuretics, lithium, regular use of antacids containing aluminium magnesium hydroxide
- Participant currently required to take or likely to be required to start, in the 6 months following enrolment, a medicinal product which is known or suspected to interact, to a clinically significant extent, with doxycycline including ergotamine and methysergide. This includes drugs known to induce the cytochrome P450 system to a clinically significant extent, including but not limited to, carbamazepine, phenytoin, rifampicin, griseofulvin, barbiturates or sulphonylureas.
- Alcohol dependence
- Any other significant disease, disorder or circumstance (e.g. terminal illness), which, in the opinion of the Investigator, may either put the participant at risk in the trial, or may introduce significant bias to the trial, or may affect the participant's ability to participate in the trial
Sites / Locations
- John Radcliffe HospitalRecruiting
- University of OxfordRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Placebo Comparator
Arm Label
Irbesartan 150-300mg (and doxycycline placebo)
Doxycycline 100-200mg (and irbesartan placebo)
Irbesartan 150-300mg and doxycycline 100-200mg
irbesartan and doxycycline placebo
Arm Description
Irbesartan 150-300mg capsules daily for 6 months Doxycycline placebo capsules daily for 6 months
Doxycycline 100-200mg capsules daily for 6 months Irbesartan placebo capsules daily for 6 months
Irbesartan 150-300mg capsules daily for 6 months Doxycycline 100-200mg capsules daily for 6 months
Irbesartan placebo capsules daily for 6 months Doxycycline placebo capsules daily for 6 months
Outcomes
Primary Outcome Measures
Change (i.e. difference between first and last study visits) in aortic distensibility in the ascending aorta between allocation arms measured using CMR
Secondary Outcome Measures
1. Change in aortic distensibility in the proximal and distal descending aorta between allocation arms measured using CMR
2. Change in aortic dimensions in the proximal and distal descending aorta
3. Change in mean and peak axial and mean and peak circumferential aortic wall shear stress between allocation arms estimated by CMR using a 4D flow sequence
4. Change in peripheral (brachial) blood pressure between allocation arms measured using a calibrated, validated automated sphygmomanometer
5. Change in central blood pressure, and augmentation index between allocation arms measured by applanation tonometry and by oscillometric sphygmomanometry
6. Change in left ventricular volumes, mass and systolic function between allocation arms to placebo measured by CMR
7. Change in aortic pulse wave velocity between allocation arms measured by CMR
8. Change in carotid-femoral pulse wave velocity between allocation arms compared to placebo measured by applanation tonometry
9. Change in TGF-β level, or other biomarker, between allocation arms compared to placebo
10. Tolerability and safety of irbesartan and doxycycline, assessed by incidence of adverse reactions and change in health status score, using the SF-36 questionnaire
11. Document the frequency of aortic dissection, death from cardiovascular causes, or need for aortic root or valve surgery (if any) in each allocation arm
Full Information
NCT ID
NCT01949233
First Posted
August 6, 2013
Last Updated
June 8, 2015
Sponsor
University of Oxford
Collaborators
Oxford University Hospitals NHS Trust
1. Study Identification
Unique Protocol Identification Number
NCT01949233
Brief Title
The Oxford Marfan Trial
Official Title
A Randomised, Double-blind, Placebo-controlled Pilot Trial of Irbesartan, Doxycycline and a Combination on Markers of Vascular Dysfunction in the Marfan Syndrome, Using Cardiovascular Magnetic Resonance Imaging
Study Type
Interventional
2. Study Status
Record Verification Date
June 2015
Overall Recruitment Status
Unknown status
Study Start Date
October 2013 (undefined)
Primary Completion Date
October 2015 (Anticipated)
Study Completion Date
December 2017 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Oxford
Collaborators
Oxford University Hospitals NHS Trust
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The primary objective of the trial is to estimate the effects of allocation to irbesartan, or doxycycline, or a combination of both irbesartan and doxycycline, compared with placebo, on measures of elastic function of the aorta in people with the Marfan syndrome and enlargement of the aorta.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Marfan Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
56 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Irbesartan 150-300mg (and doxycycline placebo)
Arm Type
Experimental
Arm Description
Irbesartan 150-300mg capsules daily for 6 months Doxycycline placebo capsules daily for 6 months
Arm Title
Doxycycline 100-200mg (and irbesartan placebo)
Arm Type
Experimental
Arm Description
Doxycycline 100-200mg capsules daily for 6 months Irbesartan placebo capsules daily for 6 months
Arm Title
Irbesartan 150-300mg and doxycycline 100-200mg
Arm Type
Experimental
Arm Description
Irbesartan 150-300mg capsules daily for 6 months Doxycycline 100-200mg capsules daily for 6 months
Arm Title
irbesartan and doxycycline placebo
Arm Type
Placebo Comparator
Arm Description
Irbesartan placebo capsules daily for 6 months Doxycycline placebo capsules daily for 6 months
Intervention Type
Drug
Intervention Name(s)
Irbesartan 150-300mg capsules daily for 6 months
Intervention Type
Drug
Intervention Name(s)
Doxycycline 100-200mg capsules daily for 6 months
Intervention Type
Drug
Intervention Name(s)
Doxycycline placebo capsules daily for 6 months
Intervention Type
Drug
Intervention Name(s)
Irbesartan placebo capsules daily for 6 months
Primary Outcome Measure Information:
Title
Change (i.e. difference between first and last study visits) in aortic distensibility in the ascending aorta between allocation arms measured using CMR
Time Frame
0 months and 6 months
Secondary Outcome Measure Information:
Title
1. Change in aortic distensibility in the proximal and distal descending aorta between allocation arms measured using CMR
Time Frame
0 and 6 months
Title
2. Change in aortic dimensions in the proximal and distal descending aorta
Time Frame
0 and 6 months
Title
3. Change in mean and peak axial and mean and peak circumferential aortic wall shear stress between allocation arms estimated by CMR using a 4D flow sequence
Time Frame
0 and 6 months
Title
4. Change in peripheral (brachial) blood pressure between allocation arms measured using a calibrated, validated automated sphygmomanometer
Time Frame
0 and 6 months
Title
5. Change in central blood pressure, and augmentation index between allocation arms measured by applanation tonometry and by oscillometric sphygmomanometry
Time Frame
0 and 6 months
Title
6. Change in left ventricular volumes, mass and systolic function between allocation arms to placebo measured by CMR
Time Frame
0 and 6 months
Title
7. Change in aortic pulse wave velocity between allocation arms measured by CMR
Time Frame
0 and 6 months
Title
8. Change in carotid-femoral pulse wave velocity between allocation arms compared to placebo measured by applanation tonometry
Time Frame
0 and 6 months
Title
9. Change in TGF-β level, or other biomarker, between allocation arms compared to placebo
Time Frame
0 and 6 months
Title
10. Tolerability and safety of irbesartan and doxycycline, assessed by incidence of adverse reactions and change in health status score, using the SF-36 questionnaire
Time Frame
0, 0.5 and 6 months
Title
11. Document the frequency of aortic dissection, death from cardiovascular causes, or need for aortic root or valve surgery (if any) in each allocation arm
Time Frame
0-6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
13 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female, aged 13 years or above at last birthday (note that there is no upper age limit for inclusion in this trial)
For those aged greater than or equal to 16 years of age at the time of enrolment, participant is willing and, in the opinion of the investigator, able to give informed consent for participation in the trial
For those aged 13-15 at the time of enrolment, participant is willing and, in the opinion of the investigator, able to give informed assent, and parent/guardian is willing and able to give informed consent for participation in the trial.
Weight ≥ 50kg
Diagnosed with Marfan syndrome according to the revised Ghent criteria 1996
Dilated aorta (BSA-adjusted aortic root z-score ≥2 at the aortic sinuses of Valsalva, using the method of Roman et al, or an absolute aortic root dimension >4.0cm at the sinuses of Valsalva measured using either echocardiography or CMR)
If the participant is a female of child-bearing potential, they are willing to ensure effective contraception as defined in the contraception policy
If the participant is taking β-blocker therapy, they are willing to stop taking these one week prior to each CMR scan
Willing and, in the investigator's opinion, able to comply with all trial requirements
Willing to allow his or her General Practitioner and if appropriate, Consultant, to be informed of his or her participation in the trial and of any clinical findings or issues which may arise
Exclusion Criteria:
Female who is pregnant
Female who is planning pregnancy within 6 months of enrolment
Female who is breast feeding
Previous aortic dissection
Previous aortic surgery
Bicuspid or unicuspid aortic valve
Scheduled elective cardiac or aortic surgery within 6 months of enrolment
Definite diagnosis of Loeys-Dietz or Shpritzen-Goldberg syndrome
Known bilateral renal artery stenosis or renal artery stenosis to a single functioning kidney
History of idiopathic intracranial hypertension
Exposure to angiotensin receptor antagonists, angiotensin converting enzyme inhibitors, or medications containing these compounds in the 3 months prior to enrolment in the trial
Absolute indication for angiotensin receptor antagonists, angiotensin converting enzyme inhibitors, doxycycline or other antibiotics of the tetracycline class at enrolment
Taking β-blocker therapy for an indication other than the Marfan syndrome
Participant has participated in another research study involving an investigational medicinal product or device in the 3 months prior to enrolment
Renal impairment of a moderate or severe degree (eGFR <60 mls/min/1.73m2)
Hyperkalaemia (>5.1 mmol/L)
Significant hepatic impairment (ALT or AST >3 times upper limit of normal)
History of allergic reaction or any other clinically significant intolerance to irbesartan or its constituents; other angiotensin receptor blockers / antagonists; angiotensin converting enzyme inhibitors, doxycycline or its constituents, or placebo medications or its constituents
Contra-indications to MRI (e.g. implantable cardiac electronic device, claustrophobia, intracranial aneurysm clips and metallic ocular foreign bodies etc.)
Participant currently required to take or likely to be required to start, in the 6 months following enrolment, a medicinal product which is known or suspected to interact, to a clinically significant extent, with irbesartan including: potassium supplementation, potassium sparing diuretics, lithium, regular use of antacids containing aluminium magnesium hydroxide
Participant currently required to take or likely to be required to start, in the 6 months following enrolment, a medicinal product which is known or suspected to interact, to a clinically significant extent, with doxycycline including ergotamine and methysergide. This includes drugs known to induce the cytochrome P450 system to a clinically significant extent, including but not limited to, carbamazepine, phenytoin, rifampicin, griseofulvin, barbiturates or sulphonylureas.
Alcohol dependence
Any other significant disease, disorder or circumstance (e.g. terminal illness), which, in the opinion of the Investigator, may either put the participant at risk in the trial, or may introduce significant bias to the trial, or may affect the participant's ability to participate in the trial
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hayley Harvey
Email
hayley.harvey@cardiov.ox.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Alex Pitcher, MA (Oxon),DPhil, BM Mch, MRCP
Email
alex.pitcher@cardiov.ox.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
J Colin Forfar, BSc (hons), MA(Oxon), MD, PhD,
Organizational Affiliation
University of Oxford
Official's Role
Principal Investigator
Facility Information:
Facility Name
John Radcliffe Hospital
City
Oxford
State/Province
Oxfordshire
ZIP/Postal Code
OX3 9DU
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Edward Blair, MBChB MRCP
First Name & Middle Initial & Last Name & Degree
Paul Wordsworth, MB FRCP
Facility Name
University of Oxford
City
Oxford
State/Province
Oxfordshire
ZIP/Postal Code
OX3 9DU
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alex Pitcher, DPhil, MA, BM BCh, MRCP
First Name & Middle Initial & Last Name & Degree
Andrew Lewis, MB BS MRes MRCP
First Name & Middle Initial & Last Name & Degree
Hayley Harvey
First Name & Middle Initial & Last Name & Degree
Stefan Neubauer, MD FRCP FACC FMedSci
First Name & Middle Initial & Last Name & Degree
Paul Leeson
First Name & Middle Initial & Last Name & Degree
Jacqueline Birks
12. IPD Sharing Statement
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The Oxford Marfan Trial
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