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Trial registered on ANZCTR


Registration number
ACTRN12616001366448
Ethics application status
Approved
Date submitted
29/09/2016
Date registered
4/10/2016
Date last updated
4/10/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
The relationship between methotrexate drug and blood pressure in patients with rheumatoid arthritis
Scientific title
The relationship between methotrexate use and blood pressure and arterial function in the rheumatoid arthritis population
Secondary ID [1] 290238 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid Arthritis 300427 0
Blood pressure 300428 0
Arterial function 300429 0
Condition category
Condition code
Inflammatory and Immune System 300291 300291 0 0
Rheumatoid arthritis
Cardiovascular 300292 300292 0 0
Hypertension
Cardiovascular 300293 300293 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Condition and exposure:
This is an observational study conducted on rheumatoid arthritis (RA) population.
Participants were classified according to methotrexate (MTX) exposure into: currently taking MTX, and not taking MTX for at least 1 year (non-MTX) but they were on other anti-rheumatic medications. A third cohort of RA patient was those who were neither on MTX nor on any other medications. This group included those RA patients who were MTX naive (never treated) as well as those who had been exposed to MTX at some stage of their illness. Those started on MTX were considered on therapy until follow-up visit.
Duration of observation:
The study was taken place between April 2014 and December 2015. All participants were examined at baseline and then followed after 8 months.
Intervention code [1] 296018 0
Not applicable
Comparator / control treatment
Control group:
RA patients who were not taking MTX for at least 1 year
Control group
Active

Outcomes
Primary outcome [1] 299771 0
Clinic peripheral blood pressure was measured by an automatic monitor (AND automatic blood pressure monitor, model no.UA-767PC ).
Timepoint [1] 299771 0
Baseline, and at 8 months after the initial visit
Primary outcome [2] 299772 0
Ambulatory peripheral and central blood pressure were measured by the Mobil-O-Graph PWA monitor (IEM, Stolberg, Germany). Both peripheral and central blood pressure are a composite outcome.
Timepoint [2] 299772 0
Baseline and at 8 months after the initial visit
Primary outcome [3] 299782 0
Central blood pressure was measured at the clinic by the SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia).
Timepoint [3] 299782 0
Baseline and at 8 months after the initial visit
Secondary outcome [1] 328073 0
Inflammation and RA activity assessed by measuring inflammatory markers (CRP and ESR). This is a composite secondary outcome. Both markers were measured by serum essays at the SA pathology laboratory.
Timepoint [1] 328073 0
Baseline and at 8 months after the initial visit
Secondary outcome [2] 328074 0
Quality of life assessed using the Stanford Health Assessment Questionnaire
Timepoint [2] 328074 0
Baseline and at 8 months after the initial visit
Secondary outcome [3] 328075 0
Dietary intake over 12 months assessed by the Dietary Questionnaire for Epidemiological Studies Version 2 (DQES v2)
Timepoint [3] 328075 0
Baseline and at 8 months after the initial visit
Secondary outcome [4] 328076 0
The plasma concentration of asymmetric dimethylarginine (ADMA)
Timepoint [4] 328076 0
Baseline and at 8 months after the initial visit
Secondary outcome [5] 328077 0
Genetic polymorphisms of MTX ABCG2 gene were assessed by analyzing blood samples (white blood cells).
Timepoint [5] 328077 0
Baseline and at 8 months after the initial visit
Secondary outcome [6] 328078 0
The concentration of MTX was measured inside the red blood cells by using ion-pairing liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique.
Timepoint [6] 328078 0
Baseline and at 8 months after the initial visit
Secondary outcome [7] 328084 0
The level of Omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured by plasma assay. This is a composite outcome.
Timepoint [7] 328084 0
Baseline and at 8 months of the initial visit
Secondary outcome [8] 328101 0
Primary outcome:
Arterial function (augmentation index, AIx) was measured by the SphygmoCor at the clinic and it was monitored over 24-h by the Mobil-O-Graph PWA monitor.
Timepoint [8] 328101 0
Baseline and at 8 months after the initial visit
Secondary outcome [9] 328102 0
Primary outcome:
Arterial function (pulse wave velocity, PWV) was monitored over 24-h by the Mobil-O-Graph PWA monitor.
Timepoint [9] 328102 0
Baseline and at 8 months after the initial visit

Eligibility
Key inclusion criteria
Patients were included if:
1. Aged 18 years or older
2. Diagnosis of RA was made based on 1987 or 2010 American College of Rheumatology diagnostic criteria, and the rheumatologist diagnosis when the first date of fulfilling the diagnostic criteria was considered as RA incidence date
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
There were no exclusion criteria except if there was one of the following:
1. Sustained atrial fibrillation because arterial function cannot be examined
2. Active cancers as some anticancer drugs (including chemotherapy) induce endothelial dysfunction, which might affect the blood pressure and arterial function
3. Congestive heart failure (left ventricular diastolic dysfunction)
4. Cognitive impairment

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Sample size:
A sample size of 114 individuals was calculated to have 80% power (p­value of 0.05) to detect a significant difference of 10 mm Hg in SBP between MTX and non- MTX groups. This assumes a within group SBP SD of 20 mmHg. The following cohorts were formed based on their use of MTX i.e. approximately distributed:
1. Taking MTX drug (N=85 patients)
2. Not taking MTX drug (N= 26 patients)
3. Newly diagnosed with RA and not on MTX (N= 3)
Statistical analyses:
The STATA software version (13) was used. Statistical significance was defined as p-value< 0.05. Continues variables was tested for normal distribution and then presented as the mean +/- SD. On the other hand, non-continues variables were presented as frequencies and percentages. Since all outcomes were liner continues variables, liner regression was used to assess the effect of MTX exposure on the outcomes. Modelling was adjusted for wide range of potential confounders. Multiple regression analysis was used to assess effects of MTX dose and/or concentration over time. For the repeated measures, linear mixed models were used to model the individual variability in changes in BP with MTX treatment over time.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 6750 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 6751 0
Repatriation Hospital - Daw Park
Recruitment postcode(s) [1] 14395 0
5041 - Daw Park
Recruitment postcode(s) [2] 14394 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 294606 0
University
Name [1] 294606 0
Flinders University
Address [1] 294606 0
Department of Clinical Pharmacology
Flinders University and Flinders Medical Centre
Flinders Drive, Bedford Park, SA 5042
Country [1] 294606 0
Australia
Primary sponsor type
University
Name
Flinders University
Address
Department of Clinical Pharmacology
Flinders University and Flinders Medical Centre
Flinders Drive, Bedford Park, SA 5042
Australia
Country
Australia
Secondary sponsor category [1] 293470 0
None
Name [1] 293470 0
Address [1] 293470 0
Country [1] 293470 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296049 0
Southern Adelaide Clinical Human Research Ethics Committee (SAC HREC EC00188)
Ethics committee address [1] 296049 0
Flinders Medical Centre
The Flats G5 –Rooms 3 and 4
Flinders Drive
Bedford Park SA 5042
Ethics committee country [1] 296049 0
Australia
Date submitted for ethics approval [1] 296049 0
19/02/2014
Approval date [1] 296049 0
03/04/2014
Ethics approval number [1] 296049 0
76.14 - HREC/14/SAC/79

Summary
Brief summary
Rheumatoid arthritis (RA) is a chronic disabling autoimmune condition characterized by local and systemic inflammation, joint pain, stiffness and fatigue. RA patients also suffer from so-called ‘extra-articular’ manifestations, affecting several organs and systems such as the skin, eye, lung, heart, kidney, blood vessels, and bone marrow. Patients with RA and cardiovascular risk factors such as high blood pressure and diabetes are known to be at an increased risk of cardiovascular disease. Since cardiovascular disease is known to be an inflammatory condition, RA patients without cardiovascular risk factors may have an additional increased risk of developing cardiovascular disease. However, some evidence suggests that the use of methotrexate (MTX) drug, a traditional anti-inflammatory drug for use in RA patients, may lower the risk of cardiovascular disease. In order to establish whether MTX lowers specific risk factors for CVD in RA patients, any comparison of risk factors such as blood pressure and arterial function between patients receiving and not receiving MTX must take into account other factors that might influence these risk factors and which may be different between groups of patients receiving and not receiving MTX. These factors include the dose and concentration of MTX, levels of exercise, dietary nutrient intake, alcohol intake, and clinical and biological characteristics.
The main aim of our study is to examine whether taking MTX drug can improve blood pressure and arterial function in the RA. The novelty of our results will likely translate into a) substantial changes in clinical practice, in particular cardiovascular risk management in RA patients and, possibly, in the general population; b) high-impact research outputs in leading journals in rheumatology, cardiovascular medicine, pharmacology, molecular biology and chemistry; c) invitations to present data at key national and international meetings; and d) ongoing collaborations with the pharmacological industry in relation to the synthesis and further development of MTX analogues.
Trial website
Trial related presentations / publications
Baghdadi LR, Woodman RJ, Shanahan EM, Mangoni AA. Methotrexate, Blood Pressure and Arterial Wave Reflection in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/methotrexate-blood-pressure-and-arterial-wave-reflection-in-rheumatoid-arthritis
Public notes
Attachments [1] 1140 1140 0 0
Attachments [2] 1141 1141 0 0

Contacts
Principal investigator
Name 69342 0
Dr Leena Baghdadi
Address 69342 0
Department of Clinical Pharmacology
Flinders University and Flinders Medical Centre
Flinders Drive, Bedford Park, SA 5042
Australia
Country 69342 0
Australia
Phone 69342 0
+61431581783
Fax 69342 0
Email 69342 0
leena.baghdadi@flinders.edu.au
Contact person for public queries
Name 69343 0
Dr Leena Baghdadi
Address 69343 0
Department of Clinical Pharmacology
Flinders University and Flinders Medical Centre
Flinders Drive, Bedford Park, SA 5042
Australia
Country 69343 0
Australia
Phone 69343 0
+61431581783
Fax 69343 0
Email 69343 0
leena.baghdadi@flinders.edu.au
Contact person for scientific queries
Name 69344 0
Prof Arduino Mangoni
Address 69344 0
Department of Clinical Pharmacology
Flinders University and Flinders Medical Centre
Flinders Drive, Bedford Park, SA 5042
Australia
Country 69344 0
Australia
Phone 69344 0
+61 8 8204 7495
Fax 69344 0
Email 69344 0
arduino.mangoni@flinders.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary