TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial

Study design

Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a parallel-design, randomised, double-blind, placebo-controlled trial to assess whether treatment with telmisartan for 2 years will reduce the rate of AAA expansion. The TEDY trial plans to enrol 300 participants with small AAA, defined by a maximum orthogonal infra-renal aortic diameter of ≥35 and ≤49 mm on computed tomographic angiography (CTA) or ultrasound. In order to explicitly assess the impact of AT1 blockade on AAA expansion, TEDY will only include individuals who have no current or planned usage of AT1 blockers or ACE inhibitors. TEDY will not include individuals with an existing indication for AAA repair (according to the treating physician) or expectation that this will be revised within one year. Furthermore, participants will only be included if they have a high likelihood of treatment compliance for 24 months according to their supervising physician. Additional exclusion criteria include contraindications to telmisartan and previous abdominal aortic surgery. A full list of inclusion and exclusion criteria is given in Table 1.

Randomisation and follow-up

The overall design of the TEDY trial is shown in Fig. 1. At the initial visit, individuals will be considered for inclusion in the trial (Table 1) and if eligible, informed consent will be sought. Individuals will undergo a short health survey, clinical examination by a medical officer, resting brachial blood pressure, resting ankle-brachial index, and collection of fasting blood samples for analysis of lipid profile, blood glucose, inflammatory markers, AAA biomarkers, liver function and renal function. An additional blood sample will be stored for future genetic, protein and lipidomic analyses. A baseline CTA and ultrasound will be obtained for detailed measurements of the AAA.

Eligible participants who have provided written informed consent will return for a randomisation visit, during which they will be allocated to either telmisartan (40 mg od daily) or matching placebo (once daily) for 24 months. Patients will be randomised by a blinded health professional through the secure trial website, coordinated by an independent trial centre. Treatment allocation will be determined by a computer-generated random number sequence that is stratified by study site and initial aortic diameter (35 to 39 mm, 40 to 44 mm, and 45 to 49 mm). Random number sequences will correspond to serial numbers on concealed study packaging. Only the trial drug centre and the Data and Safety Monitoring Board (DSMB) will know the identity of pre-packaged drugs. The Stanford study centre will utilize an independent randomization procedure implemented locally, whereby ID numbers are randomly allocated to the two study groups using randomization software (www.tufts.edu/~gdallal/randomize.htm). The resultant randomization key will be provided to the on-site pharmacy, which dispenses study medication to participants according to the condition assignment prescribed by the key.

Following randomisation, participants will receive their allocated study medication and subsequent instruction on the dosing regimen. Individuals will be contacted by phone 2 weeks after randomisation and asked about adherence to study treatment and known medication side effects. Phone consultations will be repeated at 9, 15 and 21 months. Follow-up visits will occur at 3, 6, 12, 18 and 24 months, during which the occurrence of trial endpoints and adverse events will be appraised. Participants will receive ongoing health questionnaires, clinical examination, blood tests and imaging according to Table 2. All participants, including those in whom allocated medication is discontinued, will be invited to follow up for the duration of the study in the absence of AAA repair. Final follow-up will occur at 24 months after randomisation, at which point the participant will discontinue the prescribed medication.

Endpoints

The trial primary endpoint will be the difference in AAA growth between the intervention and control groups over 24 months. AAA growth will be assessed by 1) maximum infra-renal aortic volume on CTA, 2) maximum orthogonal diameter on CTA, and 3) maximum diameter on ultrasound. Infra-renal aortic volume can be measured in a reproducible way and changes in it appear to provide a more sensitive means to assess AAA growth [49]. It is expected that a number of participants may not receive a CTA at 24 months due to drop-out, for example due to requirement for AAA surgery. We therefore have also included ultrasound measured AAA growth as a primary endpoint since ultrasound assessments will be performed every 6 months.

CTA will be obtained at entry, 12 and 24 months depending on local ethics guidelines (CTA at entry and 24 months only for Stanford and Leiden study centres). Assessment of infra-renal aortic volume will be performed according to a previously established protocol at the main study centre (mean inter-observer coefficient of variation = 2.7 %) [49]. The total volume of the infra-renal aorta, including the aortic wall and lumen, will be estimated using a semi-automated program that we have previously established to be reproducible [49]. In short, axial regions of interest are drawn around the aorta from the slice inferior to the origin of the lowest renal artery to the slice superior to the bifurcation of the aorta. The areas of these regions of interest are summated using CT analysis software to yield an overall volume. The maximum orthogonal AAA diameter on CTA is a measurement of infra-renal aortic diameter perpendicular to the lumen, devised to avoid over-estimation of tortuous AAAs. We have previously reported a reproducible protocol to measure orthogonal aortic diameter (mean inter-observer coefficient of variation = 3.5 %) [50]. Initially, seeds are placed in the centre of the infra-renal aorta from the renal arteries to the aortic bifurcation. Curved multi-planar reconstruction is then used to reconstruct the aorta perpendicular to its axis. The reconstructed aorta is subsequently scouted to find the region of maximum diameter, taking many measurements. The largest diameter is taken to be the maximum orthogonal diameter.

Ultrasound measurements will be undertaken at entry, 6, 12, 18 and 24 months. Maximum anteroposterior and transverse infra-renal aortic diameter will be measured by experienced sonographers using a 3.75-MHz transducer and ultrasound machines present in vascular laboratories of each centre. Diameters will be measured in the plane of the aorta with callipers placed on the outer part of the aortic wall. The largest external anterior-posterior and transverse AAA diameters will be recorded. The location at which the maximum diameter is measured will always be within the infra-renal aorta but will be selected based on the maximum diameter not particular location within this artery segment. The intra-observer reproducibility of ultrasound measurements has been assessed at major participating centres and shown to be good (coefficient of repeatability ≤1.6 mm for four reporting centres) [18, 31]. Central analysis of both CTA and ultrasound images will be performed at the study centre.

Secondary endpoints include change in resting brachial blood pressure, AAA biomarker profile, and health-related quality of life. Resting brachial blood pressure will be measured at entry, 3, 6, 12, 18 and 24 months. Three blood pressure measurements will be recorded at 3-minute intervals, with the average blood pressure used as the representative value. Blood will be taken at entry, 6, 12, 18 and 24 months to assess changes in circulating AAA biomarkers. The AAA biomarker panel will include OPN, OPG, D-dimer, TGF-β1 and MMP-9, and will be measured centrally. These circulating proteins have been selected based on extensive evidence suggesting that they have a central role in AAA pathology [39, 51]. Health-related quality of life will be assessed by the Short Form-36 (SF-36) questionnaire collected at entry, 12 and 24 months. The SF-36 has previously been validated for use in elderly patients with vascular disease [52, 53].

Additional outcome data recorded will include requirement for AAA repair surgery as determined by the treating vascular surgeon, AAA rupture, all-cause mortality, acute cardiovascular events, withdrawal from study medication, drug safety and changes in background medication. Medication compliance will be assessed by hand-counting of pills during scheduled visits.

Sample size and power calculations

At present there is insufficient preliminary data demonstrating an accurate effect size of AT1 blockers on AAA growth. In line with other AAA drug trials, we estimated our sample size based on a clinically relevant reduction of 30 % in annual AAA growth [18]. Given local AAA growth rates (mean = 1.20 mm/y, standard deviation = 1.16) applicable to the study population, we calculated an effect size d = 0.36 [54]. Accordingly, based on t-test analysis, this study requires 126 participants per group (252 in total, power = 80 %, α = 0.05) to detect the hypothesised reductions in AAA growth. Taking into account a 24-month drop-out rate of approximately 20 %, we plan to recruit 300 patients.

Study organization

The TEDY trial has been developed through an international collaboration of experts in AAA biology, clinical management of AAA, aortic imaging and drug trials. TEDY is a multi-centre study conducted from major vascular centres in Australia, The Netherlands and the USA. The study steering committee comprises senior vascular investigators from the centres involved and experts in drug trials and data analysis (Appendix). This will be the main policy and decision-making committee for the study and will meet by teleconference. Currently, there are nine study centres in total, seven in Australia, one in Leiden, Netherlands, and one in Stanford, California, USA. The Stanford study centre is sponsored by Medtronic Inc. (Santa Rosa, CA) and will utilise independent randomisation, medication concealment and imaging analysis. The core imaging and biomarker laboratories are located at the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, James Cook University, Townsville Australia, and the Veteran’s Administration Palo Alto Health Care System, USA. The web-based randomisation database will be managed by the Monash Clinical Trials Centre, Melbourne Australia, with an independent randomisation centre at Stanford University. The Baker IDI Heart and Diabetes Institute will coordinate medication concealment and packaging for Australian centres. The Leiden study centre will coordinate medication concealment locally for convenience. An independent DSMB will review all adverse events and conduct an interim analysis.

Data handling

Trial documentation including design, eligibility criteria, protocols and case report forms (CRF) will be shared electronically with participating study centres. The online clinical trial portal will house the central web-based randomisation system (https://ccre.med.monash.edu.au/TedyRand/). Data recorded on printed CRFs will be faxed or scanned to the trial coordinating centre where it will be entered centrally and examined for data quality. All participating centres have received local ethics approval and the study is being conducted in accordance with the Declaration of Helsinki. The TEDY trial is registered at www.anzctr.org.au: ACTRN12611000931976. The Stanford arm of the trial is registered at www.clinicaltrials.gov ID: NCT01683084.

Safety

Previous large randomised control trials have shown telmisartan to have a good safety record [55, 56]. The TRANSCEND trial demonstrated negligible side effects for telmisartan (80 mg od daily) in approximately 6,000 individuals with cardiovascular disease [55]. These findings suggest that telmisartan (40 mg od daily) should be well tolerated by the majority of patients eligible for the TEDY trial. Participant safety will be assessed on all visits and phone calls. Detailed safety assessment will occur at 3, 12 and 24 months and will involve a targeted medical history, physical examination of heart rate and brachial blood pressure, laboratory parameters including serum chemistry (liver function tests, glucose, creatinine, sodium, potassium, chloride) and haematology (haemoglobin, differential white blood cell count and platelet count), and adverse event reporting via report forms provided to study centres. Participant safety will also be assessed by phone calls occurring at 2 weeks, 9 months, 15 months and 21 months. Adverse events may comprise shortness of breath, wheeze, rash, dizziness and fatigue. Possible side effects of the medication include back pain, diarrhoea, respiratory tract infection and sinus inflammation. In line with other medication trials, serious adverse events (SAEs) will be defined as death, requirement for in-patient hospital treatment and persistent or significant disability.

The DSMB will consist of an independent epidemiologist, vascular surgeon and statistician; and will meet to assess all adverse events. In particular, the DSMB will concentrate on AAA-related events such as sudden death due to AAA rupture, as well as adverse events related to study medication. Expected AAA rupture rates for small AAAs are approximately 1 to 2 % per year based on published data [9, 10]. Rupture rates greater than this will be considered to be a cause for concern. In this instance consideration will be given to assessment of all other outcome data from the study. AAA growth will be compared between placebo and telmisartan groups using this data. The final decision to stop the study will take into account AAA ruptures, AAA growth data and any other serious complications. Following their assessment, the DSMB would report their recommendation to the steering committee. One formal interim analysis will be undertaken when 60 % of participants have been followed-up for 24 months. Based on all available data at the time of the interim analysis, the difference in growth at 24 months of follow-up will be estimated and tested.

Statistical analysis

The principal analysis of primary and secondary endpoints will be based on intention to treat at the time of randomisation. All patients who meet the eligibility criteria, provide written informed consent and are enrolled in the study will be included in the primary analysis, regardless of adherence to treatment medication. The efficiency of randomisation will be assessed by comparing the distribution of recognized determinants of AAA progression and also background medication use prior to the study between the treatment and control groups.

The primary efficacy parameter is the between treatment groups difference in mean growth in AAA over 2 years as estimated by the maximum AAA volume on CTA, maximum orthogonal diameter on CTA, and maximum diameter on ultrasound. If there were to be no drop-outs, the observed mean progression over 2 years would be compared and tested using a two-sample t-test. However, it is expected that a non-negligible proportion of patients will drop out before 2 years due to aneurysm repair. Aneurysm growth will therefore be analysed by a linear mixed model, specifying zero difference between treatment groups at baseline. The model will have up to 11 repeated dependent measurements: three CTA volume measurements, three CTA diameter measurements, and five ultrasound measurements.

The fixed part of the model will contain the following covariates: Time for CTA measurements as a categorical, time for ultrasound measurements as a categorical, treatment, interaction between treatment and CTA time, and interaction between treatment and ultrasound time. The covariance part of the model will constitute a linear covariance matrix containing the following parameters: Variance of CTA measurements, variance of ultrasound measurements and covariance parameters. Without reference to the fixed part of the model, the goodness of fit of the assumed covariance model will be investigated. If necessary, the model will be extended with additional terms. The analysis will be performed using the PROC MIXED procedure on SAS (Cary, North Carolina), which is capable of fitting arbitrary linear covariance matrices. The main null hypothesis that will be tested is based on the treatment effect as estimated by this model at 24 months on CTA and ultrasound measurements.

It is possible that participants randomised to telmisartan may have a small reduction in blood pressure. In the event that the control group are more frequently receiving other blood pressure modifying medications at the completion of the trial, post-hoc analyses will be conducted with appropriate adjustment for these confounding factors.

The stopping boundaries are based on the alpha and beta spending function theory and the stopping rule preserves the overall probability of 0.05 of rejecting the null hypothesis in favour of telmisartan while the null hypothesis is true [57]. The stopping rule is flexible in the sense that the actual time of the interim analyses may deviate from the scheduled time and that more interim analyses may be inserted. The stopping rule is designed using SAS PROC SEQDESIGN. We have chosen a gamma cumulative spending function with gamma parameter equal to −5 for alpha and −7 for beta. These choices lead to conservative stopping boundaries, such that the trial will stop for superiority only if the evidence for a favourable telmisartan effect is very strong and the trial will stop for futility only if the interim analysis suggests it very unlikely that a significant telmisartan effect will be found at the end of the trial. At the interim analysis, the trial will stop for superiority if the one-sided P value in favour of telmisartan is smaller than 0.0032. The trial will stop for futility if the one-sided P value is larger than 0.5.