The Oxford Marfan Trial

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by University of Oxford
Sponsor:
Collaborator:
Oxford University Hospitals NHS Trust
Information provided by (Responsible Party):
University of Oxford
ClinicalTrials.gov Identifier:
NCT01949233
First received: August 6, 2013
Last updated: March 6, 2014
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Marfan Syndrome
Drug: Irbesartan 150-300mg capsules daily for 6 months
Drug: Doxycycline 100-200mg capsules daily for 6 months
Drug: Doxycycline placebo capsules daily for 6 months
Drug: Irbesartan placebo capsules daily for 6 months
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University of Oxford:

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 [ Time Frame: 0 months and 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 1. Change in aortic distensibility in the proximal and distal descending aorta between allocation arms measured using CMR [ Time Frame: 0 and 6 months ] [ Designated as safety issue: No ]
  • 2. Change in aortic dimensions in the proximal and distal descending aorta [ Time Frame: 0 and 6 months ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 4. Change in peripheral (brachial) blood pressure between allocation arms measured using a calibrated, validated automated sphygmomanometer [ Time Frame: 0 and 6 months ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 6. Change in left ventricular volumes, mass and systolic function between allocation arms to placebo measured by CMR [ Time Frame: 0 and 6 months ] [ Designated as safety issue: No ]
  • 7. Change in aortic pulse wave velocity between allocation arms measured by CMR [ Time Frame: 0 and 6 months ] [ Designated as safety issue: No ]
  • 8. Change in carotid-femoral pulse wave velocity between allocation arms compared to placebo measured by applanation tonometry [ Time Frame: 0 and 6 months ] [ Designated as safety issue: No ]
  • 9. Change in TGF-β level, or other biomarker, between allocation arms compared to placebo [ Time Frame: 0 and 6 months ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 56
Study Start Date: October 2013
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Irbesartan 150-300mg (and doxycycline placebo)
Irbesartan 150-300mg capsules daily for 6 months Doxycycline placebo capsules daily for 6 months
Drug: Irbesartan 150-300mg capsules daily for 6 months Drug: Doxycycline placebo capsules daily for 6 months
Experimental: Doxycycline 100-200mg (and irbesartan placebo)
Doxycycline 100-200mg capsules daily for 6 months Irbesartan placebo capsules daily for 6 months
Drug: Doxycycline 100-200mg capsules daily for 6 months Drug: Irbesartan placebo capsules daily for 6 months
Experimental: Irbesartan 150-300mg and doxycycline 100-200mg
Irbesartan 150-300mg capsules daily for 6 months Doxycycline 100-200mg capsules daily for 6 months
Drug: Irbesartan 150-300mg capsules daily for 6 months Drug: Doxycycline 100-200mg capsules daily for 6 months
Placebo Comparator: irbesartan and doxycycline placebo
Irbesartan placebo capsules daily for 6 months Doxycycline placebo capsules daily for 6 months
Drug: Doxycycline placebo capsules daily for 6 months Drug: Irbesartan placebo capsules daily for 6 months

  Eligibility

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01949233

Contacts
Contact: Hayley Harvey hayley.harvey@cardiov.ox.ac.uk
Contact: Alex Pitcher, MA (Oxon),DPhil, BM Mch, MRCP alex.pitcher@cardiov.ox.ac.uk

Locations
United Kingdom
John Radcliffe Hospital Recruiting
Oxford, Oxfordshire, United Kingdom, OX3 9DU
Sub-Investigator: Edward Blair, MBChB MRCP         
Sub-Investigator: Paul Wordsworth, MB FRCP         
University of Oxford Recruiting
Oxford, Oxfordshire, United Kingdom, OX3 9DU
Sub-Investigator: Alex Pitcher, DPhil, MA, BM BCh, MRCP         
Sub-Investigator: Andrew Lewis, MB BS MRes MRCP         
Sub-Investigator: Hayley Harvey         
Sub-Investigator: Stefan Neubauer, MD FRCP FACC FMedSci         
Sub-Investigator: Paul Leeson         
Sub-Investigator: Jacqueline Birks         
Sponsors and Collaborators
University of Oxford
Oxford University Hospitals NHS Trust
Investigators
Principal Investigator: J Colin Forfar, BSc (hons), MA(Oxon), MD, PhD, University of Oxford
  More Information

No publications provided

Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT01949233     History of Changes
Other Study ID Numbers: 2010-023612-14
Study First Received: August 6, 2013
Last Updated: March 6, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Arachnodactyly
Marfan Syndrome
Syndrome
Abnormalities, Multiple
Bone Diseases
Bone Diseases, Developmental
Cardiovascular Abnormalities
Cardiovascular Diseases
Congenital Abnormalities
Connective Tissue Diseases
Disease
Genetic Diseases, Inborn
Heart Defects, Congenital
Heart Diseases
Limb Deformities, Congenital
Musculoskeletal Abnormalities
Musculoskeletal Diseases
Pathologic Processes
Doxycycline
Irbesartan
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Anti-Bacterial Agents
Anti-Infective Agents
Antihypertensive Agents
Antimalarials
Antiparasitic Agents
Antiprotozoal Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on October 29, 2014