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Trial registered on ANZCTR


Registration number
ACTRN12623000420640
Ethics application status
Approved
Date submitted
30/03/2023
Date registered
28/04/2023
Date last updated
1/09/2024
Date data sharing statement initially provided
28/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
The feasibility and pharmacokinetic study of using loading dose methotrexate in rheumatoid arthritis patients.
Scientific title
The Feasibility and Pharmacokinetics of Intensive Therapy for Rheumatoid Arthritis using Methotrexate Loading: A 6-week randomised clinical trial.
Secondary ID [1] 309000 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid arthritis 329038 0
Condition category
Condition code
Inflammatory and Immune System 326023 326023 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will receive triple disease-modifying antirheumatic drugs (DMARDs) therapy with the drugs that are standard-of-care at the Royal Adelaide Hospital (RAH) (hydroxychloroquine, sulfasalazine, methotrexate) – the decision to initiate this therapy is not a part of this study. The intervention arm will receive a higher initial dose of methotrexate (50 mg once weekly subcutaneously) + oral sulfasalazine + oral hydroxychloroquine for the first 3 weeks, followed by standard dosing of methotrexate (20mg once weekly orally) + oral sulfasalazine + oral hydroxychloroquine for the next 3 weeks.

The patient's adherence will be monitored through laboratory tests, patient's medical record and patient's self-reported adherence.
Intervention code [1] 325445 0
Treatment: Drugs
Comparator / control treatment
Active control: triple DMARD therapy, which consists of oral methotrexate 10mg once weekly for the first 2 weeks, followed by oral methotrexate 20mg once weekly + oral sulfasalazine + oral hydroxychloroquine for the next 4 weeks.

Our data will be compared to the historical data collected from the Early Arthritis Clinic cohort at Royal Adelaide Hospital between 1998 and 2023 who started on triple DMARD therapy (methotrexate + hydroxychloroquine + sulfasalazine).
Control group
Active

Outcomes
Primary outcome [1] 333876 0
Pharmacokinetic of methotrexate polyglutamate inside the red blood cell: the pharmacokinetic parameters for methotrexate polyglutamates inside red blood cell will be calculated via the Monolix software. The parameters for each polyglutamate (eg MTX-Glu1, MTX-Glu2 etc..) will be calculated individually, and also modelled together using multi-compartmental analysis. The parameters of interest will be steady state concentration, half-life, clearance, time to steady state (defined as 90% of the steady state concentration), area under the concentration time curve and time to detection of methotrexate polyglutamates in red blood cell.
Timepoint [1] 333876 0
The sample will only be drawn at one single timepoint for each week.

Baseline: The pre-dose blood sample will be drawn on the day of clinic visit within 30 mins of subcutaneous dosing or at least 6 hours before the oral dosing (depending on whether the patient is taking oral or subcutaneous methotrexate).

Week 1: The pre-dose blood sample will be drawn on the day of clinic visit within 30 mins of subcutaneous dosing or at least 6 hours before the oral dosing (depending on whether the patient is taking oral or subcutaneous methotrexate).

Week 2: The pre-dose blood sample will be drawn on the day of clinic visit within 30 mins of subcutaneous dosing or at least 6 hours before the oral dosing (depending on whether the patient is taking oral or subcutaneous methotrexate).

Week 3: The pre-dose blood sample will be drawn on the day of clinic visit within 30 mins of subcutaneous dosing or at least 6 hours before the oral dosing (depending on whether the patient is taking oral or subcutaneous methotrexate).

Week 6: The pre-dose blood sample will be drawn on the day of clinic visit within 30 mins of subcutaneous dosing or at least 6 hours before the oral dosing (depending on whether the patient is taking oral or subcutaneous methotrexate).
Primary outcome [2] 333877 0
Tolerance to, and safety of triple DMARD therapy that includes a methotrexate loading dose for initial treatment of RA.

The patients will be presented with a list of possible side effects (such as upper and lower GI, rash, shortness of breath etc.) in the Vital Activities and Lifestyle Index (VALI) Follow-up form. The patients will be asked to tick any side effect that they experienced with the dosing. Further assessment and review regarding the severity of side effect will be performed in the consultation process. The incidence and severity of Adverse Events (AEs)/Serious Adverse Events (SAEs) will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5).

Any change from baseline in physical examination findings, and from baseline in vital signs (Blood pressure and heart rate measured using a sphygmomanometer, respiratory rate using manual breath count and temperature by tympanic thermometer) will also be recorded.
Timepoint [2] 333877 0
Baseline, week 1, week 2, week 3 and week 6.

The adverse events, physical examinations and vital signs related to the loading dose of methotrexate will be assessed as they are reported or observed and reviewed at baseline (30mins post-dose), week 1 (pre-dose and 30mins post-dose), and week 2 (pre-dose and 30mins post-dose).

For the standard dosing of methotrexate, the adverse events, physical examinations and vital signs will be assessed as they are reported or observed and reviewed at week 1 (pre-dose), week 2 (pre-dose), week 3 (pre-dose) and week 6 (pre-dose).
Secondary outcome [1] 418612 0
The time to achieve low/minimal disease activity state as assessed using the Disease Activity Score 28-joint count (DAS28) to intensive triple DMARD therapy (i.e. that includes a loading dose of methotrexate) and compare this to the controls (this study combined with historical controls) that were treated with ‘standard’ triple DMARD therapy at the rheumatology clinic at the Central Adelaide Local Health Network (CALHN).
Timepoint [1] 418612 0
Baseline, week 1, week 2, week 3 and week 6 post-commencement of intervention.
Secondary outcome [2] 418613 0
The feasibility to implement the methotrexate loading dose regimen as assessed by study-specific questionnaires.

The recruitment capability will be assessed as a composite outcome. We will assess and report::
i) the number of potential participants,
ii) the number agreed to further contact/information about the study,
iii) the number who consented to participation.
iv) the recruitment rate and refusal rate for participation will be calculated.

We will also assess and report the participants' retention rate and adherence to the intervention protocol. The retention rate will be defined as the number of participants who were retained or kept after consenting to participate in the study. We will also report participants attendance rate with regard to receiving their scheduled methotrexate loading dose and their attendance to the scheduled blood sampling.
Timepoint [2] 418613 0
At the conclusion of the study.
Secondary outcome [3] 418647 0
The patients' attitude towards the methotrexate loading dose regimen as assessed by using the Beliefs about Medicines Questionnaire (BMQ).
Timepoint [3] 418647 0
Week 6 post-commencement of intervention.
Secondary outcome [4] 420604 0
The proportion of patients achieving low/minimal disease activity state as assessed using the Disease Activity Score 28-joint count (DAS28) to intensive triple DMARD therapy (i.e. that includes a loading dose of methotrexate) and compare this to the controls (this study combined with historical controls) that were treated with ‘standard’ triple DMARD therapy at the rheumatology clinic at the Central Adelaide Local Health Network (CALHN).
Timepoint [4] 420604 0
At the conclusion of the study.
Secondary outcome [5] 420849 0
Treatment Satisfaction Questionnaire for Medication Version 2 (TSQM-II)
Timepoint [5] 420849 0
Week 6 post-commencement of intervention.
Secondary outcome [6] 420850 0
Patients' attitude towards the methotrexate loading dose regimen as assessed by a study-specific questionnaire.
Timepoint [6] 420850 0
Week 6 post-commencement of intervention.

Eligibility
Key inclusion criteria
Patients attending the rheumatology clinic at the Central Adelaide Local Health Network (CALHN) who have active rheumatoid arthritis and for whom the decision has been made to commence methotrexate (and sulfasalazine and hydroxychloroquine) as triple DMARD therapy.
The decision to use methotrexate is not part of this trial. It will be made according to clinical need and according to our standardised inclusion criteria for commencement of methotrexate therapy. These include:
1) ALT < 2x ULN
2) Calculated Creatinine Clearance > 60 mL/min (Cockcroft-Gault)
3) Neutrophils within normal range
4) If a smoker, Pulmonary Function Tests will be conducted, and they must have FVC>70% predicted and DLCO> 60% predicted
5) At least 5 years since treatment for a malignancy (except non-melanoma skin cancers)
6) Not pregnant (test is done as standard prior to MTX commencement)
7) Able to read English and/or good communication skills.
8) Age greater than or equal to 18 years
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) BMI < 18 because sub-cutaneous injections of MTX will be used in the loading dose group. An upper BMI was discussed but there is no apparent reason for specifying an upper limit.
2) Age > 85 years

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 0
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
1.) Pharmacokinetic parameters for red and white cell methotrexate polyglutamates will be calculated via the Monolix software. The parameters for each polyglutamate (e.g. MTX-Glu1, MTX-Glu2 etc…) will be calculated individually, and also modelled together using multi-compartmental analysis. The parameters of interest will be steady state concentration, half-life, clearance, time to steady state (defined as 90% of the steady state concentration), area under the concentration time curve and time to detection of methotrexate polyglutamates in red and white blood cells. A comparison of the pattern of glutamation of methotrexate depending upon dosage strategy will also be made.

2.) Tolerance and safety (based on pathology tests) will be recorded for each group. The results will be descriptive.

3.) A Disease Activity Score 28 (DAS28) will be calculated for each participant. This is a well-recognised index that is used in clinical trials. The components of the DAS28 are tender and swollen joint counts for 28 joints, ESR or CRP, and patient global score.

4.) The proportion of participants achieving DAS28 <2.6 which is considered very low disease activity will be compared to the controls from this study and to historical controls (EART database ethics: R20120618) which are those treated with ‘standard’ triple DMARD therapy at the Early Arthritis Clinic at the Royal Adelaide Hospital.

5.) The analyses for the feasibility measures will be conducted using Microsoft Excel (Microsoft 365 MSO Version 2202 Build 16.0.14931.20116 64-bit) and SPSS Statistics version 22 for Windows (IBM Corporation, Armonk, NY, USA). Due to the small sample size in this study, it is assumed that the collected data will not be normally distributed, as such, we will report the median and interquartile range instead of mean and standard deviation. Descriptive statistics, such as medians, interquartile range, and frequencies will be used to describe the sample characteristics, participant retention rates, participant dropout rates, participant attendance rates, intervention duration and proportion of completed questionnaires.

6.) Differences in background demographic information between the loading dose group and standard dosing group will be tested using the Fisher's exact test for categorical variables. Continuous variables will be expressed as medians ± interquartile range and compared using the Mann Whitney U test.

6) The BMQ and TSQM-II questionnaire results will be reported via descriptive and statistical analysis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/05/2023
Actual
16/08/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
20
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 24053 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 39555 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 313213 0
Government body
Name [1] 313213 0
Central Adelaide Local Health Network Incorporated
Country [1] 313213 0
Australia
Primary sponsor type
Government body
Name
Central Adelaide Local Health Network Incorporated
Address
Port Rd Adelaide, SOUTH AUSTRALIA, 5000 Australia
Country
Australia
Secondary sponsor category [1] 314937 0
None
Name [1] 314937 0
None
Address [1] 314937 0
None
Country [1] 314937 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312444 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 312444 0
North Terrace, Adelaide, SA, 5000
Ethics committee country [1] 312444 0
Australia
Date submitted for ethics approval [1] 312444 0
31/10/2022
Approval date [1] 312444 0
15/12/2022
Ethics approval number [1] 312444 0
2022/HRE00249

Summary
Brief summary
Loading doses of methotrexate (where high dose methotrexate injection is given once weekly for three weeks at the start to control the disease activity of rheumatoid arthritis, followed by lower dose of oral methotrexate as maintenance) have been used sporadically by rheumatologists in practice, but the research evidence for the loading dose of methotrexate is limited. This study is aimed to investigate how the concentration of methotrexate and its active metabolites differ compared to the standard dose regimen. Also, this study is also aimed to assess the feasibility to implement this loading dose regimen in real life, and the patient's attitude towards this new dosing regimen.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124690 0
Prof Susanna Proudman
Address 124690 0
Rheumatology Unit, 8E303, level 8 Royal Adelaide Hospital North Terrace Adelaide SA 5000
Country 124690 0
Australia
Phone 124690 0
+61 0870742779
Fax 124690 0
Email 124690 0
[email protected]
Contact person for public queries
Name 124691 0
Michael Wiese
Address 124691 0
Level 5, Bradley Building, cnr North Terrace &, Morphett St, Adelaide SA 5000
Country 124691 0
Australia
Phone 124691 0
+61 8 8302 2312
Fax 124691 0
Email 124691 0
[email protected]
Contact person for scientific queries
Name 124692 0
Michael Wiese
Address 124692 0
Level 5, Bradley Building, cnr North Terrace &, Morphett St, Adelaide SA 5000
Country 124692 0
Australia
Phone 124692 0
+61 8 8302 2312
Fax 124692 0
Email 124692 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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No additional documents have been identified.