Clinical Trials Register

Summary
EudraCT Number:	2006-000078-65
Sponsor's Protocol Code Number:	Rituximab
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-10-18
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2006-000078-65

A.3

Full title of the trial

Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis (DM)and Adult Polmyositis (PM)

A.3.2

Name or abbreviated title of the trial where available

Rituximab in myositis (RIM)

A.4.1

Sponsor's protocol code number

Rituximab

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Karolinska University Hospital
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Mabthera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	Mabthera
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Adult polymyositis or adult dermatomyositis or juvenile dermatomyositis.

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10036102
E.1.2	Term	Polymyositis

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of intravenous rituximab in a randomized, double-blind, placebo-controlled, multicenter phase II/III trial of refractory myositis in adults and children.

E.2.2

Secondary objectives of the trial

To assess the determinants of treatment response and disease pathogenesis in patients receiving rituximab.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adults with definite or probable DM or PM and pediatric patients five years of age and over with definite or probable JDM by the criteria of Bohan and Peter. Patients without the rash of DM will require a muscle biopsy (not necessarily done at the enrollement) compatible with PM as determined by an experienced pathologist. In order to be enrolled with a diagnosis of refractory PM, patients' medical information will be reviewed and the diagnosis confirmed by a 3-member Adjudication Committee consisiting of 3 Steering Committee members/investigators. This adjudication process is necessary to exclude mimics of polyomyositis including but not limited to inclusion body myositis, toxic or metabolic myopathies and adult onset muscular dystrophies.
2. A diagnosis of JDM based on an age of onset (i.e. first symptom of myositis or the rash of dermatomyositis)< 18 years of age.
3. Disease duration > 6 months from diagnosis of myositis.
4. Refractory myositis as defined by the intolerance to or an inadequate response to corticosteroids plus an adequate regimen of at least one other IS agent such as azathioprine, methotrexate, IVIg, mycophenolate mofetil, cyclophosphamide, tacrolimus or cyclosporine A. The definition of intolerance is: side effects that require discontinuation of the medication or an underlying condition that precludes the further use of the medication. An adequate corticosteroid treatment trial is as follows:
- Adult IIM: prednisone (or an equivalent corticosteroid) at a dose of at least 60mg/day for one month
- JDM: 1.0mg/kg/day prednisone for at least one month
5. Baseline manual muscle testing which is based on a maximum MMT-8 score of 150. Subjects must have a score that is no greater than 125/150 in conjunction with 2 other abnormal core set measures include the following:
- Patient/Parent global VAS with a minimum value of 2.0 cm on a 10 cm scale
- MD Global VAS with a minimum value of 2.0 cm on a 10 cm scale
- CHAQ/HAQ disability index witha minimum value of 0.25
- Elevation of at least one of the muscle enzymes (which includes creatinine kinase (CK), aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (AST) at a minimum level of 1.3x ULN
If more than one muscle enzyme is identified as being elevated and meeting the above guidelines then the most abnormal will be selected and this enzyme will be the target enzyme followed to evaluate disease improvement or worsening.
- Global extramuscular disease activity score with a minimum value of 1.0cm on a 10cm VAS scale (this measure is the physician´s composite evaluation and is based on assessments of activity scores on the constitutional, cutaneous, sceletal, gastrointestinal, pulmonary and cardiac scales of the Myositis Disease Activity Assessment Tool (MDAAT)
6. If on Prednisone, the dose must be stable for 4 weeks prior to the screening visit (recommend < 1.0mg/kg(day)
7. Background therapy with at least 1 non-corticosteroid immunosupressive agent is required at a stable dose for at least 6 weeks prior to the screening visit.
- The IS agents include: methotrexate, azathioprine, cyclosporine, tacrolimus, cyclophosphamiode or mycophenolate mofetil
8. If an IS agennt was discontinued prior to the screening visit then there must be a:
-4week washout for methotrexate
-8 week washout for any other IS agent
9. If on plaquenil the dose should be stable for 8 weeks prior to Visit 1
10. If on statin agents the dose should be stable for 8 weeks prior to Visit 1
11. Ability of patient or parent to complete self-report questionnaires.
12.Pediatric patients must be at least 5 years of age (core set measures are reliable down to age 5 and the immune system has reached maturity at this age so the risk of immunosupression is lessened)
13. Absolute neutrophile count > 1000/mm3; plateletes > 100.000/mm3; hemoglobin > 10gm/dl
14. Men and women of reproductive potential must agree to use a reliable method of birth control during the 45 week duration of the trial described in the reproductive risks section of the protocol.
15. Age of legal consent will follow aplicable regulatory laws commensurate with the country in which clinical trial is being conducted. Children ages 12-17 or younger children who are developmentally able to sign his/her name must give assent.
16. Patients must agree to forgo immunization with a live vaccine during the course of study.
17. Patients must have not consumed any creatinine-containing products in the form of dietary supplemets 30 days prior to the screening visit and agree not to consume any creatinine products in the form of dietary supplemets throughout the study duration. (Natural sources of creatinine such as meats, salmon and tuna are acceptable)

E.4

Principal exclusion criteria

1. Drug induced myositis (myositis in patients taking medication known to induce myositis-like syndromes, including but not limited to statin agents, fibric acid derivates, colchicine, and hydroxychloroquine).
2. Use of colchicine during study participation is not allowed.
3. Juvenile polymyositis; inclusion body myositis; cancer-associated myositis, defined as the diagnosis of myositis within 2 years of the diagnosis of cancer except basal or squamous cell skin cancer or carcinoma in situ of the cervix if at least 5 years since excision.
4. Myositis in overlap with another connective tissue disease (CTD) that precludes the accurate assessment of a treatment response (the 3-member committee discussed inder Inclusion Criteria 1 above will also determine the eligibility of such patients with myositis and an associated CTD).
5. History of receiving live vaccination 4 weeks prior to initiation of study treatment.
6. Joint disease or other musculoskeletal condition, which precludes the ability to quantitative muscle strength
7. Known hypersensitivity to murine proteins
8. Concomitant illness that would prevent adequate patient assessment or pose an added risk for study paticipants:
-reccurent or chronic infections, including HIV, hepatitis B and C
-known liver disease (i.e. cirrhosis or other conditions compromising the synthetic function of the liver)
-disorders that would preclude accurate assessment of neuromuscular function
-cardiomyopathy/congestive heart failure/arrythmia (or NYHA Clasification III or IV disease)
-psychiatric illness that precludes compliance or neuromuscular assessment
-serum creatinine > 2.0mg/dl
-IgG or IgM levels at baseline that are below the normal range (for pediatrics age adjusted normal ranges will be followed)
9. Pregnant females or nursing mothers
10. Life threatening non-myositis illness that would interfere with patient´s ability to complete the study.
11. Known or suspected history of drug or alcohol abuse within the past 6 months as determined by the medical record or patient interview.
12. Anticipated poor compliance
13. Participation in another clinical (experimental) study within 30 days of screening visit.
14. Any history or evidence of severe illness or any other condition that would make the patient, in the opinion of the investigator unsuitable for the study.
15. Any history of receiving rituximab.
16. Evidence of prior infection of Hepatitis B and Hepatitis C
17. Initiation of an excercise program within 4 weeks of screening visit or initiation of an excercise program during the study

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this trial is to compare the time to achieve the definition of improvement (DOI) between the two groups of rituximab-treated patients.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2007-10-18.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Young childre, from five years of age

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

202

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

A re-treatment arm will allow for further documentation of safety and adverse events and documentation of long-term efficacy. Therefore patients, who meet the definition of improvement during the trial and then meet the criteria by week 36, will be offered retreatment with rituximab.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2007-11-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-10-10

P. End of Trial
P.	End of Trial Status	Completed

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