The Oxford Marfan Trial

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

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.

Study Overview

• Status: Unknown
• Conditions: Marfan Syndrome
• Intervention / Treatment: Drug: Irbesartan 150-300mg capsules daily for 6 months; Drug: Doxycycline placebo capsules daily for 6 months; Drug: Doxycycline 100-200mg capsules daily for 6 months; Drug: Irbesartan placebo capsules daily for 6 months

• Study Type: Interventional
• Enrollment (Anticipated): 56
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hayley Harvey; Email: hayley.harvey@cardiov.ox.ac.uk
• Study Contact Backup: Name: Alex Pitcher, MA (Oxon),DPhil, BM Mch, MRCP; Email: alex.pitcher@cardiov.ox.ac.uk

Study Locations

• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • Recruiting
      • John Radcliffe Hospital
      • Sub-Investigator: Edward Blair, MBChB MRCP
      • Sub-Investigator: Paul Wordsworth, MB FRCP
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • Recruiting
      • University of Oxford
      • 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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change (i.e. difference between first and last study visits) in aortic distensibility in the ascending aorta between allocation arms measured using CMR	0 months and 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
1. Change in aortic distensibility in the proximal and distal descending aorta between allocation arms measured using CMR	0 and 6 months
2. Change in aortic dimensions in the proximal and distal descending aorta	0 and 6 months
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	0 and 6 months
4. Change in peripheral (brachial) blood pressure between allocation arms measured using a calibrated, validated automated sphygmomanometer	0 and 6 months
5. Change in central blood pressure, and augmentation index between allocation arms measured by applanation tonometry and by oscillometric sphygmomanometry	0 and 6 months
6. Change in left ventricular volumes, mass and systolic function between allocation arms to placebo measured by CMR	0 and 6 months
7. Change in aortic pulse wave velocity between allocation arms measured by CMR	0 and 6 months
8. Change in carotid-femoral pulse wave velocity between allocation arms compared to placebo measured by applanation tonometry	0 and 6 months
9. Change in TGF-β level, or other biomarker, between allocation arms compared to placebo	0 and 6 months
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	0, 0.5 and 6 months
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	0-6 months

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Oxford University Hospitals NHS Trust
• Investigators: Principal Investigator: J Colin Forfar, BSc (hons), MA(Oxon), MD, PhD,, University of Oxford

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Anticipated): October 1, 2015
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: August 6, 2013
• First Submitted That Met QC Criteria: September 23, 2013
• First Posted (Estimate): September 24, 2013

Study Record Updates

• Last Update Posted (Estimate): June 9, 2015
• Last Update Submitted That Met QC Criteria: June 8, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Musculoskeletal Abnormalities; Abnormalities, Multiple; Bone Diseases, Developmental; Limb Deformities, Congenital; Syndrome; Marfan Syndrome; Arachnodactyly; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Antimalarials; Doxycycline; Irbesartan
• Other Study ID Numbers: 2010-023612-14