PRINTOJDMTR: Five-year Actively Controlled Clinical Trial in New Onset Juvenile Dermatomyositis

• Sponsor: Istituto Giannina Gaslini (Other)
• Overall Status: Completed
• CT.gov ID: NCT00323960
• Collaborator: Pediatric Rheumatology International Trials Organization (Other)
• Enrollment: 139
• Location: 1
• Arms: 3
• Actual Duration (Months): 114
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This is a 5-year project, involving 185 partners from 46 countries ((110 in 21 European Union (EU) States and 75 in 25 extra-EU States)), with a randomised clinical trials (RCT) in juvenile dermatomyositis (JDM): 5-year phase III single-blind, RCT in children with newly diagnosed JDM: prednisone (PDN) versus PDN plus methotrexate (MTX) versus PDN plus Cyclosporine A. The trial is aimed to find out the treatment regimen associated with the lowest occurrence of flare and the lowest drug related toxicity

Condition or Disease	Intervention/Treatment	Phase
Juvenile Dermatomyositis	Drug: 3 MPDN pulse + PDN; Drug: 3 MPDN pulse + PDN + CSA; Drug: 3 MPDN pulse + PDN + MTX	Phase 3

Detailed Description

Scientific objectives: The proposed project is aimed to improve treatment approaches for rare, severe and disabling paediatric rheumatic diseases (PRD). This goal will be achieved by the Paediatric Rheumatology International Trials Organisation (PRINTO) an international network whose main function is to provide a scientific base for current PRD treatments for which no evidence based data exist in the literature, and for drugs for which there is no support from industries.

This is a 5-year project, involving 46 countries (110 in 21 EU States and 75 in 25 extra-EU States), with a randomised clinical trials (RCT) in juvenile dermatomyositis (JDM): 5-year phase III single-blind, RCT in children with newly diagnosed JDM: prednisone (PDN) versus PDN plus methotrexate (MTX) versus PDN plus Cyclosporine A (CsA). The trial is aimed to find out the treatment regimen associated with the lowest occurrence of flare and the lowest drug related toxicity. The retention on treatment will be used as main measure of effectiveness.

Methodology: The present protocol is the natural follow up of previous work conducted by PRINTO. In particular the RCT foreseen in this protocol is modelled after the successful completion of an early phase trial with MTX in juvenile idiopathic arthritis, and will use validated JDM outcome measures for the evaluation of response to therapy.

It is the basic premise of this protocol that, without i) the involvement of the international paediatric rheumatology community, ii) the innovative type of mechanism described herein, these studies would never be conducted.

Objectives. The goals of the current protocol is therefore the natural follow-up of the objectives achieved with the previous grants and, in particular, of projects designed to discern new models for the successful conduct of clinical trials in children with rare diseases, and to develop standardized and validated measures for the evaluation of response to therapy in JDM.

The proposed trial in JDM (prednisone [PDN] versus PDN plus methotrexate [MTX] versus PDN plus cyclosporine [CsA]), should serve as a model for the successful running of early phase clinical trials for severe and disabling rare diseases of childhood.

The ultimate aim of these trials is to provide evidence-based information about the clinical utility of drugs in the management of rare paediatric conditions.

Study Design

• Study Type: Interventional
• Actual Enrollment: 139 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Five-year Single-blind, Phase III Effectiveness Randomised Actively Controlled Clinical Trial in New Onset Juvenile Dermatomyositis: Prednisone Versus Prednisone Plus Cyclosporine a Versus Prednisone Plus Methotrexate
• Actual Study Start Date: May 31, 2006
• Actual Primary Completion Date: May 12, 2011
• Actual Study Completion Date: Nov 29, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Methylprednisolone pulse (MPDN)+PDN+CSA MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A	Drug: 3 MPDN pulse + PDN + CSA; 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Cyclosporine 5 mg/Kg/day in 2 oral doses
Active Comparator: MPDN+PDN+MTX MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate	Drug: 3 MPDN pulse + PDN + MTX; 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Methotrexate 15-20 mg/m2 once per week. Patients treated with MTX will receive concomitant folic or folinic acid according to the attending physician decision.
Active Comparator: MPDN+PDN MPDN= methylprednisolone PDN= prednisone or equivalent	Drug: 3 MPDN pulse + PDN; 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years.

Outcome Measures

Primary Outcome Measures

1. Responder Status Defined as 20% Improvement in at Least 3 Core Set Variables With no More Than 1 of the Remaining Variables, (Muscle Strength Excluded), Worsened by > 30%. [6 months]

   The PRINTO Juvenile Dermatomyositis (JDM) core set variables are: muscle strength by the mean of the Childhood Myositis Assessment Scale (CMAS); physician's global assessment of disease activity on a 10 cm Visual Analogue Scale (VAS); global disease activity assessment by the mean of the Disease Activity Index (DAS); parent's/patient's global assessment of overall well-being on a 10 cm VAS; functional ability assessment by the mean of the Childhood Health Assessment Questionnaire (CHAQ) health-related quality of life assessment.

2. Time to Clinical Remission [60 months]

   Clinical remission is defined as the status of inactive disease for at least 6 continuous months defined as normal muscle strength (CMAS equal to 52) and physician global assessment of disease activity equal to 0.

Secondary Outcome Measures

1. Time to Major Therapeutic Changes [60 months]

   Time to major therapeutic changes is defined as the addition of CSA or MTX or any other disease-modifying antirheumatic drug (DMARS) in any of the 3 groups or discontinuation of assigned therapy for any reason including adverse events. Retention on treatment was used as main measure of effectiveness.

2. Time to Prednisone, or Equivalent, Discontinuation [60 months]

   Prednisone or equivalent glucocorticoid discontinuation is defined as the complete discontinuation of glucocorticoids

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria. Each patient must meet all the following criteria in order to participate in this trial:

1. Newly diagnosed and untreated children (only treatment with 1 NSAID is allowed and/or prednisone >1 mg/kg/day for no more than 1 month from diagnosis) with probable or definite diagnosis of JDM according to published (12;13). If a muscle biopsy will be performed (optional) it will be read by the pathologists of the participating centres (light and immunofluorescence). Slides of paraffin-embedded sections from all patients will be re-viewed by a blinded myopathologist at PRINTO.

2. Age at enrolment ≤ 18 years.

3. Female of child-bearing potential must have a negative pregnancy test at the beginning of the trial, and then every 3 months. If sexually active, they must agree to use adequate contraception, throughout study participation, and must have no intention of conceiving during the course of the study. Post-pubertal males must have no plans to father a child during the study and agree to use adequate birth control methods if sexually active.

4. Ability to comply with the entire study procedures, ability to communicate meaningfully with the investigational staff, competence to give written informed consent; to be applied to the parents and/or patients, as appropriate

5. Duly executed, written, informed consent obtained from the parents/patient.

Exclusion Criteria. Any of the following will exclude a patient from this trial:

1. Neutrophil count <1,500/mm3 and/or platelet count <50,000/mm3

2. Demonstration of cutaneous or gastrointestinal ulceration of JDM related pulmonary disease or cardiomyopathy at the time of diagnosis.

3. History of poor compliance.

4. Evidence of current use of alcohol or illicit drugs abuse.

5. Live vaccines not allowed during the entire duration of the trial.

Dropout Criteria. Patients will be considered "treatment failures", and dropped from the trial but included in efficacy analysis, if any of the following will occur during the active period of the trial.

1. Non compliance with study medication administration

2. Enrolment in other therapeutic trials.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Istituto Giannina Gaslini	Genoa		Italy	16147

Sponsors and Collaborators

• Istituto Giannina Gaslini
• Pediatric Rheumatology International Trials Organization

Investigators

• Principal Investigator: Nicolino Ruperto, MD, MPH, Istituto Giannina Gaslini _ PRINTO Senior Scientist
• Study Chair: Alberto Martini, MD, Prof., Istituto Giannina Gaslini_PRINTO Chairman

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Web site of the international network who is conducting the trial
• Web site for families in 50 different languages with information about the pediatric rheumatic diseases

Publications

• Al-Mayouf S, Al-Mazyed A, Bahabri S. Efficacy of early treatment of severe juvenile dermatomyositis with intravenous methylprednisolone and methotrexate. Clin Rheumatol. 2000;19(2):138-41.
• Heckmatt J, Hasson N, Saunders C, Thompson N, Peters AM, Cambridge G, Rose M, Hyde SA, Dubowitz V. Cyclosporin in juvenile dermatomyositis. Lancet. 1989 May 13;1(8646):1063-6.
• Miller LC, Sisson BA, Tucker LB, DeNardo BA, Schaller JG. Methotrexate treatment of recalcitrant childhood dermatomyositis. Arthritis Rheum. 1992 Oct;35(10):1143-9.
• Pistoia V, Buoncompagni A, Scribanis R, Fasce L, Alpigiani G, Cordone G, Ferrarini M, Borrone C, Cottafava F. Cyclosporin A in the treatment of juvenile chronic arthritis and childhood polymyositis-dermatomyositis. Results of a preliminary study. Clin Exp Rheumatol. 1993 Mar-Apr;11(2):203-8.

• Responsible Party: Nicolino Ruperto, MD, MPH, Senior Scientist of PRINTO, Istituto Giannina Gaslini
• ClinicalTrials.gov Identifier: NCT00323960
• Other Study ID Numbers: IGG-PRINTO-002; AIFA; Myositis Association
• First Posted: May 10, 2006
• Last Update Posted: Mar 16, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Nicolino Ruperto, MD, MPH, Senior Scientist of PRINTO, Istituto Giannina Gaslini: Juvenile dermatomyositis; randomised actively controlled clinical trial; prednisone; cyclosporine; methotrexate; effectiveness
• Additional relevant MeSH terms: Dermatomyositis

Study Results

Participant Flow

Arm/Group Title	Methylprednisolone Pulse+Prednisone	Methylprednisolone Pulse+Prednisone+Cyclosporine A	Methylprednisolone Pulses+Prednisone+Methotrexate
Arm/Group Description	Group 1 received 3 pulses of methylprednisolone and has been randomized to prednisone or equivalent	Group 2 received 3 pulses of methylprednisolone and has been randomized to prednisone or equivalent plus cyclosporine A	Group 3 received 3 pulses of methylprednisolone and has been randomized to prednisone or equivalent plus methotrexate
Period Title: Overall Study
STARTED	47	46	46
COMPLETED	47	46	46
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	MPDN+PDN	MPDN+PDN+CSA	MPDN+PDN+MTX	Total
Arm/Group Description	MPDN+PDN MPDN= methylprednisolone PDN= prednisone or equivalent 3 MPDN pulse + PDN: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years.	MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A 3 MPDN pulse + PDN + CSA: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Cyclosporine 5 mg/Kg/day in 2 oral doses	MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate 3 MPDN pulse + PDN + MTX: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Methotrexate 15-20 mg/m2 once per week. Patients treated with MTX will receive concomitant folic or folinic acid according to the attending physician decision.	Total of all reporting groups
Overall Participants	47	46	46	139
Age (Count of Participants)
<=18 years	47 100%	46 100%	46 100%	139 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	7.2	8.9	7.1	7.5
Sex: Female, Male (Count of Participants)
Female	26 55.3%	26 56.5%	30 65.2%	82 59%
Male	21 44.7%	20 43.5%	16 34.8%	57 41%
Region of Enrollment (participants) [Number]
Italy	11 23.4%	13 28.3%	10 21.7%	34 24.5%
Algeria	1 2.1%	0 0%	0 0%	1 0.7%
Argentina	11 23.4%	2 4.3%	2 4.3%	15 10.8%
Austria	1 2.1%	0 0%	0 0%	1 0.7%
Belgium	3 6.4%	0 0%	3 6.5%	6 4.3%
Brazil	4 8.5%	6 13%	3 6.5%	13 9.4%
Colombia	1 2.1%	0 0%	0 0%	1 0.7%
Czech Republic	1 2.1%	1 2.2%	0 0%	2 1.4%
Denmark	0 0%	2 4.3%	0 0%	2 1.4%
France	3 6.4%	10 21.7%	11 23.9%	24 17.3%
Germany	2 4.3%	0 0%	1 2.2%	3 2.2%
Greece	0 0%	1 2.2%	1 2.2%	2 1.4%
Israel	0 0%	0 0%	1 2.2%	1 0.7%
Latvia	0 0%	0 0%	1 2.2%	1 0.7%
Mexico	0 0%	3 6.5%	3 6.5%	6 4.3%
Netherlands	1 2.1%	1 2.2%	2 4.3%	4 2.9%
Norway	2 4.3%	0 0%	0 0%	2 1.4%
Serbia	1 2.1%	0 0%	0 0%	1 0.7%
Slovakia	0 0%	2 4.3%	0 0%	2 1.4%
Slovenia	1 2.1%	2 4.3%	1 2.2%	4 2.9%
Spain	0 0%	1 2.2%	0 0%	1 0.7%
Sweden	2 4.3%	1 2.2%	2 4.3%	5 3.6%
United Kingdom	1 2.1%	0 0%	1 2.2%	2 1.4%
United States	0 0%	0 0%	1 2.2%	1 0.7%
Venezuela	1 2.1%	1 2.2%	3 6.5%	5 3.6%
disease duration (months) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [months]	2.6	2.7	2.8	2.8

Outcome Measures

1. Primary Outcome

Title	Responder Status Defined as 20% Improvement in at Least 3 Core Set Variables With no More Than 1 of the Remaining Variables, (Muscle Strength Excluded), Worsened by > 30%.
Description	The PRINTO Juvenile Dermatomyositis (JDM) core set variables are: muscle strength by the mean of the Childhood Myositis Assessment Scale (CMAS); physician's global assessment of disease activity on a 10 cm Visual Analogue Scale (VAS); global disease activity assessment by the mean of the Disease Activity Index (DAS); parent's/patient's global assessment of overall well-being on a 10 cm VAS; functional ability assessment by the mean of the Childhood Health Assessment Questionnaire (CHAQ) health-related quality of life assessment.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Comparison between group 2 (PDN+CSA) and 3 (PDN+MTX) combined versus group 1 (PDN)

Arm/Group Title	Group 1 (MPDN+PDN)	Group 2 (MPDN+PDN+CSA)	Group 3 (MPDN+PDN+MTX)
Arm/Group Description	MPDN+PDN MPDN= methylprednisolone PDN= prednisone or equivalent 3 MPDN pulse + PDN: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years.	MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A 3 MPDN pulse + PDN + CSA: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Cyclosporine 5 mg/Kg/day in 2 oral doses	MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate 3 MPDN pulse + PDN + MTX: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Methotrexate 15-20 mg/m2 once per week. Patients treated with MTX will receive concomitant folic or folinic acid according to the attending physician decision.
Measure Participants	47	46	46
Count of Participants [Participants]	24 51.1%	32 69.6%	33 71.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1 (MPDN+PDN), Group 2 (MPDN+PDN+CSA), Group 3 (MPDN+PDN+MTX)
	Comments	We calculated that a sample size of 40 patients would be needed in each study group (total 120 patients) to have 80% power for comparison of combination treatments (prednisone plus methotrexate or prednisone plus ciclosporin) with the reference treatment (prednisone alone).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0228
	Comments	For multiple hypothesis testing, we used Bonferroni's correction (with n=3 posterior comparisons).
	Method	Chi-squared
	Comments	To assess proportions we used the χ² test or Fisher's exact test

2. Primary Outcome

Title	Time to Clinical Remission
Description	Clinical remission is defined as the status of inactive disease for at least 6 continuous months defined as normal muscle strength (CMAS equal to 52) and physician global assessment of disease activity equal to 0.
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 (MPDN+PDN)	Group 2 (MPDN+PDN+CSA)	Group 3 (MPDN+PDN+MTX)
Arm/Group Description	MPDN+PDN MPDN= methylprednisolone PDN= prednisone or equivalent 3 MPDN pulse + PDN: 3 methylprednisolone pulses (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years.	MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A 3 MPDN pulse + PDN + CSA: 3 methylprednisolone pulses (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Cyclosporine 5 mg/Kg/day in 2 oral doses	MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate 3 MPDN pulse + PDN + MTX: 3 methylprednisolone pulses (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Methotrexate 15-20 mg/m2 once per week. Patients treated with MTX will receive concomitant folic or folinic acid according to the attending physician decision.
Measure Participants	47	46	46
Number (95% Confidence Interval) [events per 1000 persons-time]	5.99	4.95	13.39

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1 (MPDN+PDN), Group 2 (MPDN+PDN+CSA), Group 3 (MPDN+PDN+MTX)
	Comments	We used the Kaplan-Meier method to produce survival curves (groups 1 and 2 versus group 3) and compared them with the Log-Rank test. We judged a p value less than 0·05 significant. We reported in the table the incidence rates with 95% confidence intervals of the 3 groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Relative risk
	Estimated Value	2.45
	Confidence Interval	(2-Sided) 95%; 1.2 to 5.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	RR related to prednisone plus methotrexate arm (group 3) versus prednisone alone (group 1) and prednisone plus ciclosporin (group 2).

3. Secondary Outcome

Title	Time to Major Therapeutic Changes
Description	Time to major therapeutic changes is defined as the addition of CSA or MTX or any other disease-modifying antirheumatic drug (DMARS) in any of the 3 groups or discontinuation of assigned therapy for any reason including adverse events. Retention on treatment was used as main measure of effectiveness.
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 (MPDN+PDN)	Group 2 (MPDN+PDN+CSA)	Group 3 (MPDN+PDN+MTX)
Arm/Group Description	MPDN+PDN MPDN= methylprednisolone PDN= prednisone or equivalent 3 MPDN pulse + PDN: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years.	MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A 3 MPDN pulse + PDN + CSA: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Cyclosporine 5 mg/Kg/day in 2 oral doses	MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate 3 MPDN pulse + PDN + MTX: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Methotrexate 15-20 mg/m2 once per week. Patients treated with MTX will receive concomitant folic or folinic acid according to the attending physician decision.
Measure Participants	47	46	46
Number (95% Confidence Interval) [events per 1000 persons-time]	30.52	17.52	13.92

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1 (MPDN+PDN), Group 2 (MPDN+PDN+CSA), Group 3 (MPDN+PDN+MTX)
	Comments	We used the Kaplan-Meier method to produce survival curves (group 1 versus groups 2 and 3) and compared them with the Log-Rank test. We judged a p value less than 0·05 significant. We reported in the table the incidence rates with 95% confidence intervals of the 3 groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Relative risk
	Estimated Value	1.95
	Confidence Interval	(2-Sided) 95%; 1.2 to 3.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	RR related to prednisone alone (group 1) versus prednisone plus ciclosporin (group 2) and prednisone plus methotrexate arm (group 3).

4. Secondary Outcome

Title	Time to Prednisone, or Equivalent, Discontinuation
Description	Prednisone or equivalent glucocorticoid discontinuation is defined as the complete discontinuation of glucocorticoids
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 (MPDN+PDN)	Group 2 (MPDN+PDN+CSA)	Group 3 (MPDN+PDN+MTX)
Arm/Group Description	MPDN+PDN MPDN= methylprednisolone PDN= prednisone or equivalent 3 MPDN pulse + PDN: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years.	MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A 3 MPDN pulse + PDN + CSA: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Cyclosporine 5 mg/Kg/day in 2 oral doses	MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate 3 MPDN pulse + PDN + MTX: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Methotrexate 15-20 mg/m2 once per week. Patients treated with MTX will receive concomitant folic or folinic acid according to the attending physician decision.
Measure Participants	47	46	46
Number (95% Confidence Interval) [events per 1000 persons-time]	15.91	27.82	24.42

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1 (MPDN+PDN), Group 2 (MPDN+PDN+CSA), Group 3 (MPDN+PDN+MTX)
	Comments	We used the Kaplan-Meier method to produce survival curves (groups 2 and 3 versus group 1) and compared them with the Log-Rank test. We judged a p value less than 0·05 significant. We reported in the table the incidence rates with 95% confidence intervals of the 3 groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Relative risk
	Estimated Value	1.65
	Confidence Interval	(2-Sided) 95%; 1.24 to 2.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	RR related to prednisone+methotrexate arm or prednisone+ciclosporin versus prednisone alone.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group 1 (MPDN+PDN), Group 2 (MPDN+PDN+CSA), Group 3 (MPDN+PDN+MTX)
	Comments	We used the Kaplan-Meier method to produce survival curves (groups 1 versus groups 2 and 3) and compared them with the Log-Rank test. We judged a p value less than 0·05 significant. We reported in the table the incidence rates with 95% confidence intervals of the 3 groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Relative risk
	Estimated Value	1.65
	Confidence Interval	(2-Sided) 95%; 1.24 to 2.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	RR related to prednisone alone (group 1) versus prednisone plus ciclosporin (group 2) and prednisone plus methotrexate arm (group 3).

Adverse Events

Time Frame	5 years
Arm/Group Title	MPDN+PDN		MPDN+PDN+CSA		MPDN+PDN+MTX
Arm/Group Description	MPDN+PDN MPDN= methylprednisolone PDN= prednisone or equivalent 3 MPDN pulse + PDN: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years.		MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A 3 MPDN pulse + PDN + CSA: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Cyclosporine 5 mg/Kg/day in 2 oral doses		MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate 3 MPDN pulse + PDN + MTX: 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Methotrexate 15-20 mg/m2 once per week. Patients treated with MTX will receive concomitant folic or folinic acid according to the attending physician decision.
All Cause Mortality
	MPDN+PDN		MPDN+PDN+CSA		MPDN+PDN+MTX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MPDN+PDN		MPDN+PDN+CSA		MPDN+PDN+MTX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/47 (2.1%)		5/46 (10.9%)		2/46 (4.3%)
Gastrointestinal disorders
Appendicitis	0/47 (0%)	0	1/46 (2.2%)	1	0/46 (0%)	0
Infections and infestations
Sepsis	0/47 (0%)	0	1/46 (2.2%)	1	0/46 (0%)	0
Nervous system disorders
Posterior reversible encephalopathy	0/47 (0%)	0	1/46 (2.2%)	1	0/46 (0%)	0
Convulsion	0/47 (0%)	0	1/46 (2.2%)	1	0/46 (0%)	0
Skin and subcutaneous tissue disorders
Subcutaneous abscess	1/47 (2.1%)	1	0/46 (0%)	0	0/46 (0%)	0
Paronychia	0/47 (0%)	0	0/46 (0%)	0	1/46 (2.2%)	1
Dermo-hypodermitis	0/47 (0%)	0	0/46 (0%)	0	1/46 (2.2%)	1
Vascular disorders
Deep vein thrombosis	0/47 (0%)	0	1/46 (2.2%)	1	0/46 (0%)	0
Other (Not Including Serious) Adverse Events
	MPDN+PDN		MPDN+PDN+CSA		MPDN+PDN+MTX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/47 (61.7%)		35/46 (76.1%)		29/46 (63%)
Cardiac disorders
Tachycardia	0/47 (0%)		3/46 (6.5%)		0/46 (0%)
Endocrine disorders
Cushing syndrome	9/47 (19.1%)		6/46 (13%)		9/46 (19.6%)
Eye disorders
Eye disorders	0/47 (0%)		3/46 (6.5%)		3/46 (6.5%)
Gastrointestinal disorders
Nausea	3/47 (6.4%)		4/46 (8.7%)		4/46 (8.7%)
Abdominal pain	2/47 (4.3%)		7/46 (15.2%)		0/46 (0%)
Infections and infestations
Infection and infestations	5/47 (10.6%)		14/46 (30.4%)		14/46 (30.4%)
Injury, poisoning and procedural complications
General disorders and administration site conditions	1/47 (2.1%)		9/46 (19.6%)		2/46 (4.3%)
Investigations
Increases in serum creatinine	0/47 (0%)		3/46 (6.5%)		3/46 (6.5%)
Metabolism and nutrition disorders
Weight gain	3/47 (6.4%)		1/46 (2.2%)		3/46 (6.5%)
Metabolic disorders	3/47 (6.4%)		4/46 (8.7%)		4/46 (8.7%)
Musculoskeletal and connective tissue disorders
Musculoskeletal disorders	1/47 (2.1%)		5/46 (10.9%)		4/46 (8.7%)
Nervous system disorders
Headache	1/47 (2.1%)		5/46 (10.9%)		1/46 (2.2%)
Psychiatric disorders
Psychiatric disorders	2/47 (4.3%)		5/46 (10.9%)		4/46 (8.7%)
Skin and subcutaneous tissue disorders
Hypertrichosis	5/47 (10.6%)		8/46 (17.4%)		1/46 (2.2%)
Hirsutism	1/47 (2.1%)		11/46 (23.9%)		1/46 (2.2%)
Alopecia	1/47 (2.1%)		4/46 (8.7%)		2/46 (4.3%)
Vascular disorders
Vascular disorders	2/47 (4.3%)		7/46 (15.2%)		1/46 (2.2%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.