Ignite Creation Date:
2024-05-05 @ 7:22 PM
Last Modification Date:
2024-10-26 @ 9:47 AM
Study NCT ID:
NCT00651040
Status:
COMPLETED
Last Update Posted:
2016-05-12
First Post:
2008-03-31
Brief Title:
Combined Treatment of Methotrexate Glucocorticoids Versus Glucocorticoids Alone in Patients With PM and DM
Sponsor:
Institute of Rheumatology Prague
Organization:
Institute of Rheumatology Prague
Study Overview
Official Title:
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
Status:
COMPLETED
Status Verified Date:
2016-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Prometheus
Brief Summary:
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 PMDM 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 mgkg 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 PMDM 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 physicians 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 mgkgday 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 mgweek 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
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 PMDM 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 mgkg 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 PMDM 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 physicians 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 mgkgday 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 mgweek 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
Detailed Description:
Clinical trial
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 25 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 steroids 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
Total 50
In this centre 10
Summary
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
1 PM and DM are usually treated with glucocorticoids and immunosuppressive drugs However such treatment has not yet been studied thoroughly and properly evaluated in a randomized controlled trial There are only few controlled studies of PMDM management and all of them have been performed in small groups of patients This will be the first randomized controlled trial with MTX
2 This clinical trial will assess efficacy MTX in patients with early PMDM
3 Also long- term effect of treatment MTX and glucocorticoids versus glucocorticoids will be evaluated
4 Inclusion criteria allow to follow up the consistent group of PMDM patients
5 In this trial the of newly developed tools for myositis disease activity will be used
6 The secondary objectives is to study pathogenic aspects of inflammatory myopathies
7 The serum DNA and RNA will be stored for future genetic studies and to study autoantibodies to search for prognostic markers
Objectives
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 mgkg weight administered between baseline and the end of treatment
The secondary objectives are
1 Assessment of disease activity and damage with the use of newly developed tools for myositis disease activity MYOACT and MITAX and myositis damage MYODAM and MDI as well as by global assessment of activity and damage by patients and by physician
2 Muscle strength by manual muscle testing
3 Muscle endurance
4 Muscle enzyme levels
5 Glucocorticoid related side-effects
6 Final glucocorticoid dose
7 Disability index by HAQ
8 Quality of life by SF-36
9 Number of patients with treatment failures
10 Search for reliable prognostic parameters in the further prognosis of patients with inflammatory myopathies
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
Study design
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 polymyositisdermatomyositis 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
Indication
Treatment of active polymyositis and dermatomyositis
Evaluations
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 patients and physicians assessments manual muscle strength test functional muscle test2 health assessment questionnaire HAQ and SF36
Safety
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
Patient selection
Inclusion criteria
1 Age between 18 - 80 years
2 Patients with definite or probable polymyositis or dermatomyositis diagnosed according to diagnostic criteria 9 10 Appendix 1
3 Physicians own judgment of the disease activity that requires high dose immunosuppressive treatment based on clinical assessment of weakness elevation of muscle enzymes and if available on magnetic resonance imaging findings
4 Previously untreated patients with the exception of glucocorticoid treatment up to 8 weeks
5 Signed informed consent
Exclusion criteria
1 Treatment with any immunosuppressive drug prior the study start
2 Treatment with glucocorticoids 20 mg of Prednisone or equivalent more than 8 weeks prior to study start
3 Drug induced myositis
4 Polymyositis and dermatomyositis in association with other connective tissue disease
5 Inclusion body myositis
6 Patients with immunodeficiency syndrome
7 Pregnancy and lactation
8 Fertile women not using adequate contraception during the study women planning to have children during the study course or 12 months after the end of the study
9 Malignancy
10 Juvenile dermatomyositis
11 Uncontrolled clinically significant hematological cardiovascular pulmonary endocrine metabolic gastrointestinal hepatic or renal disease which according to physicians consideration would interfere with high dose glucocorticoid and immunosuppressive treatment or would prevent to follow the treatment protocol
12 Severe infection
13 History of drug or alcohol abuse within the previous 6 months
14 Patients known to be HIV positive
15 Known hypersensitivity to methotrexate
Withdrawal from study
Patients will be withdrawn from the study due to following reasons
1 non-compliance with the study protocol
2 positive pregnancy for female patients test during the course of the study
3 if worsening occurs
4 use of prohibited concomitant treatment
5 any adverse event which in the investigators opinion may compromise health of a study subject
Treatment MTX will be administered orally in case of oral intolerance intramusculary im 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 10 mgkgday 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 2week in the 12 3 4 5 6 7 8 9 10 11 and 12month Termination visit than one year Follow-up
Statistics
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 polymyositisdermatomyositis 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 mgkg 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 Fischers exact test
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 25 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 steroids 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
Total 50
In this centre 10
Summary
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
1 PM and DM are usually treated with glucocorticoids and immunosuppressive drugs However such treatment has not yet been studied thoroughly and properly evaluated in a randomized controlled trial There are only few controlled studies of PMDM management and all of them have been performed in small groups of patients This will be the first randomized controlled trial with MTX
2 This clinical trial will assess efficacy MTX in patients with early PMDM
3 Also long- term effect of treatment MTX and glucocorticoids versus glucocorticoids will be evaluated
4 Inclusion criteria allow to follow up the consistent group of PMDM patients
5 In this trial the of newly developed tools for myositis disease activity will be used
6 The secondary objectives is to study pathogenic aspects of inflammatory myopathies
7 The serum DNA and RNA will be stored for future genetic studies and to study autoantibodies to search for prognostic markers
Objectives
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 mgkg weight administered between baseline and the end of treatment
The secondary objectives are
1 Assessment of disease activity and damage with the use of newly developed tools for myositis disease activity MYOACT and MITAX and myositis damage MYODAM and MDI as well as by global assessment of activity and damage by patients and by physician
2 Muscle strength by manual muscle testing
3 Muscle endurance
4 Muscle enzyme levels
5 Glucocorticoid related side-effects
6 Final glucocorticoid dose
7 Disability index by HAQ
8 Quality of life by SF-36
9 Number of patients with treatment failures
10 Search for reliable prognostic parameters in the further prognosis of patients with inflammatory myopathies
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
Study design
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 polymyositisdermatomyositis 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
Indication
Treatment of active polymyositis and dermatomyositis
Evaluations
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 patients and physicians assessments manual muscle strength test functional muscle test2 health assessment questionnaire HAQ and SF36
Safety
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
Patient selection
Inclusion criteria
1 Age between 18 - 80 years
2 Patients with definite or probable polymyositis or dermatomyositis diagnosed according to diagnostic criteria 9 10 Appendix 1
3 Physicians own judgment of the disease activity that requires high dose immunosuppressive treatment based on clinical assessment of weakness elevation of muscle enzymes and if available on magnetic resonance imaging findings
4 Previously untreated patients with the exception of glucocorticoid treatment up to 8 weeks
5 Signed informed consent
Exclusion criteria
1 Treatment with any immunosuppressive drug prior the study start
2 Treatment with glucocorticoids 20 mg of Prednisone or equivalent more than 8 weeks prior to study start
3 Drug induced myositis
4 Polymyositis and dermatomyositis in association with other connective tissue disease
5 Inclusion body myositis
6 Patients with immunodeficiency syndrome
7 Pregnancy and lactation
8 Fertile women not using adequate contraception during the study women planning to have children during the study course or 12 months after the end of the study
9 Malignancy
10 Juvenile dermatomyositis
11 Uncontrolled clinically significant hematological cardiovascular pulmonary endocrine metabolic gastrointestinal hepatic or renal disease which according to physicians consideration would interfere with high dose glucocorticoid and immunosuppressive treatment or would prevent to follow the treatment protocol
12 Severe infection
13 History of drug or alcohol abuse within the previous 6 months
14 Patients known to be HIV positive
15 Known hypersensitivity to methotrexate
Withdrawal from study
Patients will be withdrawn from the study due to following reasons
1 non-compliance with the study protocol
2 positive pregnancy for female patients test during the course of the study
3 if worsening occurs
4 use of prohibited concomitant treatment
5 any adverse event which in the investigators opinion may compromise health of a study subject
Treatment MTX will be administered orally in case of oral intolerance intramusculary im 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 10 mgkgday 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 2week in the 12 3 4 5 6 7 8 9 10 11 and 12month Termination visit than one year Follow-up
Statistics
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 polymyositisdermatomyositis 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 mgkg 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 Fischers exact test
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None