Combined Treatment of Methotrexate + Glucocorticoids Versus Glucocorticoids Alone in Patients With PM and DM (Prometheus)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT00651040|
Recruitment Status : Completed
First Posted : April 2, 2008
Results First Posted : May 12, 2016
Last Update Posted : May 12, 2016
|First Submitted Date ICMJE||March 31, 2008|
|First Posted Date ICMJE||April 2, 2008|
|Results First Submitted Date ICMJE||October 29, 2015|
|Results First Posted Date ICMJE||May 12, 2016|
|Last Update Posted Date||May 12, 2016|
|Study Start Date ICMJE||May 2008|
|Actual Primary Completion Date||November 2014 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||The Primary Endpoint is the Total Dose of Glucocorticoids Administered Between Baseline and the End of Treatment. [ Time Frame: 1 year ]
The primary endpoint which has benn measured was the total dose of glucocorticoids administered between baseline and the end of treatment.
|Original Primary Outcome Measures ICMJE
||The primary endpoint that will be measured is the total dose of glucocorticoids administered between baseline and the end of treatment. [ Time Frame: 1 year and the 2. year follow up ]|
|Change History||Complete list of historical versions of study NCT00651040 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Assessment of Disease Activity and Damage,Muscle Strength and Endurance, Enzyme Levels, Glucocorticoid Side-effects, Dose, HAQ,SF-36, Treatment Failures [ Time Frame: 1 year ]|
|Original Secondary Outcome Measures ICMJE
||Assessment of Disease Activity and Damage,Muscle Strength and Endurance, Enzyme Levels, Glucocorticoid Side-effects, Dose, HAQ,SF-36, Treatment Failures [ Time Frame: 1 year and the 2. year follow up ]|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Combined Treatment of Methotrexate + Glucocorticoids Versus Glucocorticoids Alone in Patients With PM and DM|
|Official Title ICMJE||A Prospective, Randomised, Assessor-blind, Multicenter Study of Efficacy and Safety of Combined Treatment of Methotrexate + Glucocorticoids Versus Glucocorticoids Alone in Patients With Polymyositis and Dermatomyositis.|
Therapeutical trial in patients with idiopathic polymyositis (PM) and dermatomyositis (DM) is proposed. The study will investigate the safety and efficacy of combined methotrexate (MTX) + glucocorticoids (GC) treatment compared with GC alone.
This will be a randomised, open-label, assessor-blind, international multicenter trial, performed in several European centres interested in research on inflammatory myopathies (IIM).
A total number of 50 patients with PM/DM will be randomised into two groups (1: MTX+ GC and 2: GC only). Patients will be equally distributed between the two groups providing 25 patients per treatment arm. The randomisation will be based on random numbers generated by a computer program. After being enrolled in the study, the patients will receive 12 months of therapy followed by a 12-month follow-up period.
The primary endpoint is the total dose of GC ( in mg/kg weight), which will be administered for 12 months between baseline and the end of treatment.
There are several of secondary objectives, which will be pursued during and after the trial. Disease activity and damage will be prospectively assessed by tools for myositis disease activity (MYOACT and MITAX) and for myositis damage (MYODAM and MDI), global assessment of activity and damage by patients and by physician, muscle endurance, muscle strength by manual muscle testing, enzyme levels, GC related side effects, functional ability measured by HAQ, quality of life by SF-36, and number of patients with treatment failures. The other aims will also include (i) search for reliable prognostic parameters in the further prognosis of patients with PM/DM and (ii) studies on the pathogenic aspects of IIM. The investigations of serum, lymphocytes, muscle tissue and MRI will be organized. DNA and RNA will be stored for future genetic studies.
Patients with definite or probable PM or DM diagnosed according to diagnostic criteria will be enrolled. They will have disease activity that according to physician's own judgement requires high dose immunosuppressive treatment (based on clinical assessment of weakness, elevation of muscle enzymes and, if available, on magnetic resonance imaging findings). Patients should be previously untreated with the exception of GC treatment up to 8 weeks.
Patients with other than primary idiopathic PM or DM, such as drug-induced myositis, myositis in association with other connective tissue disease, inclusion body myositis, malignancy related myositis, and juvenile DM will be excluded.
All patients will start with prednisone 1 mg/kg/day and the dose will be tapered if patients meet definition of improvement, which has been proposed by IMACS group. MTX will be administered orally, once weekly, with a starting dose 10 mg. This will be increased gradually to 25 mg/week if tolerated by week 5. Patients will be first assessed after 2 weeks and than monthly for a period of 48 weeks. There will be a follow-up after a further 1 year in order to find out the impact of the early treatment on the long-term disease outcome.
All efficacy analyses will be performed using intention-to-treat population (ITT). In addition, the primary and secondary variables will be analysed using the per-protocol population, which will contain all patients in the ITT population, who also reached Week 48 without any major protocol violations. The safety population, which will contain any patient who received at least one dose of study drug, will be used for all safety analyses.
A prospective, randomized, assessor- blind, multicenter study of safety and efficacy of combined treatment of methotrexate and glucocorticoids versus glucocorticoids alone in patients with polymyositis and dermatomyositis
Tested investigational medicinal product: Methotrexate (Methotrexatum dinatricum 2,5 mg tbl.).
Mechanism of Action: Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate.
Comparator : Prednison (Prednisonum 20 mg tbl.)
Mechanism of Action: Glucocorticoids are naturally occurring hormones that prevent or suppress inflammation and immune responses when administered at pharmacological doses. At a molecular level, unbound glucocorticoids readily cross cell membranes and bind with high affinity to specific cytoplasmic receptors. This binding induces a response by modifying transcription and, ultimately protein synthesis to achieve the steroid's intended action. Such actions may include: inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, and suppression of humoral immune responses. Some of the net effects include reduction in edema or scar tissue, as well as a general suppression in immune response. The degree of clinical effect is normally related to the dose administered. The antiinflammatory actions of corticosteroids are thought to involve phospholipase A2 inhibitory proteins, collectively called lipocortins. Lipocortins, in turn, control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of the precursor molecule arachidonic acid. Likewise, the numerous adverse effects related to corticosteroid use are usually related to the dose administered and the duration of therapy.
Number of patients in the trial:
The aim of the study is to determine the safety and efficacy of adding methotrexate (MTX) to glucocorticoids (GC) compared with glucocorticoid treatment alone in patients with inflammatory myopathies.
The primary objective of the study is to determine the safety and efficacy of adding methotrexate (MTX) to glucocorticoids (GC) compared with glucocorticoid treatment alone in patients with inflammatory myopathies. The primary endpoint that will be measured is the total dose of glucocorticoids (in mg/kg weight) administered between baseline and the end of treatment.
The secondary objectives are:
Study of the pathogenic aspects of inflammatory myopathies. Therefore investigations of serum, lymphocytes, muscle tissue and MRI will be organized. DNA and RNA will be stored for future genetic studies.
This will be a randomized, assessor-blinded, multicenter, international study. After being enrolled in the study, the patients will receive 48 weeks of therapy followed by a 12-month follow-up period.
A total number of 50 patients with polymyositis/dermatomyositis are planned to be randomized. These will be equally distributed between the two groups providing 25 patients per treatment arm. Patients will be randomized on the basis of random numbers generated by a computer program.
Treatment of active polymyositis and dermatomyositis
Efficacy. The efficacy will be assessed by fulfillment of definition of improvement at every visit and treatment taper with glucocorticoids. Overall efficacy will be assessed by measurement of disease activity (MITAX, MYOACT), disease damage (MDI, MYODAM), global patient's and physician's assessments, manual muscle strength test, functional muscle test2, health assessment questionnaire (HAQ), and SF36.
The safety will be assessed at every visit by clinical and laboratory examinations. Specifically, clinical assessment will include physical examination, vital signs, muscle function index, manual muscle strength test, MYOACT, MITAX, MYODAM, MDI, HAQ and global assessment of activity and damage by physician and patient.
Laboratory assessments will include complete blood count, blood chemistry including SGOT (AST), SGPT (ALT), Na, K, creatinine, LDH, CK, CRP and urine pregnancy test if required by local practice.
In patients with pulmonary alveolitis or interstitial fibrosis at the start of the study - HRCT should be performed. If significant progress of pulmonary infiltrate will occur, this is considered to be treatment failure and patient will be treated according to standard approach.
Pulmonary toxicity from methotrexate can be suspected in patients with sudden onset of nonproductive cough with dyspnea. HRCT should be performed. If there are no other obvious reasons for these symptoms methotrexate should be discontinued.
If nausea after methotrexate occurs, try to divide the dose or give antinauseous drug. If there are still unacceptable gastrointestinal side effects, parenteral methotrexate administration can be considered.
Withdrawal from study.
Patients will be withdrawn from the study due to following reasons:
Treatment MTX will be administered orally (in case of oral intolerance intramusculary (i.m.)), once weekly for 48 weeks. There will be a clinically oriented dose escalation starting from 10 up to 20-25 mg of MTX. Five to ten mg of folic acid will be given 24 hours after each methotrexate dose.
Prednisone will be administered orally, initially at 1.0 mg/kg/day dosage and then tapered gradually equally in the two arms
Concomitant medication and treatment:
Recommended medication- Five to ten mg of folic acid will be given 24 hours after each methotrexate dose.
Prohibited medication: Other immunosuppressive agents are not allowed. All other medication is allowed at the discretion of the investigator.
Study flowchart Controls and visits will be organized: Day 0 (Baseline), in the 2.week, in the 1.,2., 3. 4., 5., 6., 7., 8., 9. 10. 11. and 12.month (Termination visit), than one year Follow-up
Summary statistics of the baseline characteristics will be tabulated by treatment group.
The main population for evaluation will be the ITT (intent- to-treat) population. Summary statistics (N, mean, standard deviation, median, minimum and maximum) will be presented for each treatment group by visit for the continuous variables. For the categorical variables N and % will be presented for each treatment group at endpoint.
A total number of 50 patients with polymyositis/dermatomyositis are planned to be randomized. These will be equally distributed between the two groups providing 25 patients per treatment arm. Two-sided tests at the 5% level of significance The primary endpoint that will be measured is the total dose of glucocorticoids (in mg/kg weight) administered between baseline and end of treatment.
Between treatment differences will be tested using parametric (t-test) and non-parametric tests (Mann-Whitney test).
The secondary efficacy variables are disease activity and damage measures, which will be assessed by myositis disease activity assessment tools (MYOACT and MITAX), myositis damage tools (MYODAM, MDI), and global assessment of activity and damage by patients and by physician The continuous secondary variables at endpoint will be tested for treatment differences using parametric (t-test, ANOVA) and non-parametric tests (Mann-Whitney test, Kruskal-Wallis ANOVA).
In the event that at the time of statistical analysis any of the model assumptions are not met data transformations or alternative methods of analysis will be performed as appropriate.
The categorical secondary efficacy variables will be tested for treatment differences using Fischer's exact test.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date ICMJE||November 2014|
|Actual Primary Completion Date||November 2014 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 80 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Czech Republic|
|Removed Location Countries|
|NCT Number ICMJE||NCT00651040|
|Other Study ID Numbers ICMJE||3401|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||Institute of Rheumatology, Prague|
|Study Sponsor ICMJE||Institute of Rheumatology, Prague|
|Collaborators ICMJE||Karolinska Institutet|
|PRS Account||Institute of Rheumatology, Prague|
|Verification Date||April 2016|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP