Clinical Trials Register

Summary
EudraCT Number:	2015-005749-30
Sponsor's Protocol Code Number:	2015-00887
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-04-28
Trial results	View 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

Sweden - MPA

A.2

EudraCT number

2015-005749-30

A.3

Full title of the trial

A randomized, doubleblind, placebo-controlled multicenter trial to evaluate the safety and efficacy of rituximab (Mabthera) in subjects with new onset myasthenia gravis; the RINOMAX study

EN RANDOMISERAD, DUBBELBLIND, PLACEBOKONTROLLERAD MULTICENTERSTUDIE SOM UTVÄRDERAR SÄKERHET OCH EFFEKT AV RITUXIMAB (Mabthera) HOS PATIENTER MED NYDEBUTERAD GENERALISERAD MYASTENIA GRAVIS (MG).

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical trial investigating the effect and safety of the drug rituximab in patients with new onset myasthenia gravis, an autoimmune condition affecting muscle strenght

En klinisk studie som utvärderar effekt och säkerhet av rituximab för personer med nydebuterad myastenia gravis, en autoimmun sjukdom som påverkar muskelstyrkan

A.3.2

Name or abbreviated title of the trial where available

Rinomax

A.4.1

Sponsor's protocol code number

2015-00887

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Karolinska Institutet
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	Swedish Research Council
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Karolinska Institutet
B.5.2	Functional name of contact point	Neuroimmunology Unit CMM L8;4
B.5.3	Address:
B.5.3.1	Street Address	Karolinska University Hospital
B.5.3.2	Town/ city	Stockholm
B.5.3.3	Post code	17176
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+46851779840
B.5.5	Fax number	+46851773757
B.5.6	E-mail	fredrik.piehl@ki.se

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 Limited
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.4	EV Substance Code	SUB12570MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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	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

New onset myasthenia gravis

Nydebuterad myastenia gravis

E.1.1.1

Medical condition in easily understood language

New onset myasthenia gravis

Nydebuterad myastenia gravis

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10029205
E.1.2	Term	Nervous system disorders
E.1.2	System Organ Class	10029205 - Nervous system disorders

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 evaluate if rituximab is more effective than placebo to achieve minimal clinical MG symptoms without need of high doses of oral corticosteroids at 16 weeks after treatment

Att utvärdera om rituximab är mer effektivt än placebo för att uppnå minimala kliniska MG symptom utan behov av högre doser orala kortikosteroider vid 16 veckor efter behandling.

E.2.2

Secondary objectives of the trial

Is Rituximab more effective than placebo in achieving improvement in standardized QMG at 24 weeks after treatment?

Is Rituximab more effective than placebo in achieving improvement in the ability to perform activities of daily live at 16 weeks after treatment?

Is Rituximab more effective than placebo in achieving improvement in experienced quality of life at 16 weeks after treatment?

Är rituximab mer effektivt än placebo för att uppnå förbättring i standardiserat muskulärt uttröttbarhetstest vid 24 veckor efter behandling?

Är rituximab mer effektivt än placebo för att uppnå förbättring i förmåga att utföra aktiviteter i dagliga livet vid 16 veckor efter behandling?

Är rituximab mer effektivt än placebo för att uppnå förbättring i upplevd livskvalitet vid 16 veckor efter behandling?

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients with oculo bulbar, bulbar or generalized MG ≥ 18 years of age and not more than 12 months ago estimated the onset of symptoms of generalized symptoms or neurophysiological detection of generalized disease.
2. The diagnosis of MG should be produced by the following tests:
Clinical neurological status with motor effects consistent with MG, and at least two of the following:
A positive serological test for anti-acetylcholine receptor antibodies (AChR),
and / or
b. For MG typical deviation during neurophysiological testing of the neuromuscular transmission with single fiber electromyography (SFEMG) and / or repetitive nerve stimulation (RNS)
and/or
c Positive choline esterase blocker response, e.g. edrophonium and/or oral cholinesterase inhibitors, as judged by the treating physician.
3. MGFA clinical classification Class II to IV at screening.
4. Quantitative MG score ≥ 6 at screening
5. Women of childbearing potential must have a negative pregnancy test.
6. Patients must have given written informed consent.
7. Patients must be able and willing to comply with all study procedures.

1. Patienter med okulobulbär, bulbär eller generaliserad MG ≥ 18 års ålder och högst 12 månader sedan uppskattad symptomdebut av generaliserade symptom eller neurofysiologisk detektion av generaliserad sjukdom.
2. Diagnosen MG ska ställas genom följande tester:
Kliniskt neurologiskt status med motorisk påverkan förenlig med MG och minst två av följande:
A. Positivt serologiskt test för anti-acetylkolinreceptor-antikroppar (AChR),
och/eller
B. För MG typisk avvikelse vid neurofysiologisk testning av neuromuskulär transmission med singel fiber elektromyografi (SFEMG) och/eller upprepad nervstimulering (RNS),
och/eller
C.Positivt antikolinesterastest, t.ex. edrofoniumkloridtest eller förbättring av MG-symptom med orala kolinesterashämmare enligt den behandlande läkarens bedömning.
3. MGFA klinisk klassificering klass II till IV vid screening.
4. Kvantitativt MG score ≥ 6 vid screening
5. Kvinnor i fertil ålder måste ha ett negativt graviditetstest.
6. Patienter måste ha lämnat skriftligt informerat samtycke.
7. Patienterna måste kunna och vara villiga att följa alla studieprocedurer.

E.4

Principal exclusion criteria

1. Weakness that only affect ocular or periocular muscles (MGFA class I).
2. MG crisis at screening (MGFA Class V)
3. Already implemented thymectomy. In order to avoid difficulties to evaluate the effect of the study drug, thymectomy, in cases where it is indicated, should be scheduled to the follow-up period, ie after the first 24 weeks.
4. Strong suspicion of thymoma, where a thymectomy is indicated within 24 weeks according to the treating physician.
5. Active tumor disease, if not adequately treated.
6. Pregnancy and lactation.
7. Ongoing acute or chronic viral or systemic bacterial infections including HIV, latent hepatitis B, which is clinically significant, according to the study doctor's opinion and not treated with appropriate antibiotics / antiviral drug.
8. Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease.
9. 9. Previously use of immunosuppressive drugs, including rituximab, azathioprine, cyclosporine and MMF. Prednisolone at a dose of ≤40mg / d within 3 months and IVIG and PLEX 12 months of the screening date is not an exclusion criterion. Also note that this does not apply to treatment with immunosuppressive drugs / corticosteroids (except rituximab) in another indication than MG, provided that it is > 12 months since the treatment ended.10. Hypersensitivity to the active substance or to murine proteins or to any of the excipients of the study drug
11. Participation in another trial to study drug or exposure to any other study drugs, study product or study procedures within 30 days prior to screening.
12. Any medical condition which, according to the study physician's opinion, may interfere with the patient's participation in the study, pose any additional risk to the patient, or that complicate the assessment of patients

1. Svaghet som endast påverkar okulära eller periokulära muskler (MGFA klass I).
2. MG-kris vid screening (MGFA klass V)
3. Redan genomförd tymektomi. För att undvika svårigheter med att utvärdera effekten av studieläkemedlet ska tymektomi, i de fall det är indicerat, planeras till uppföljningsperioden, dvs först efter de första 24 veckorna.
4. Stark misstanke om tymom och där tymektomi enligt behandlande läkare bör genomföras inom 24 veckor.
5. Aktiv tumörsjukdom, om denna inte är adekvat behandlad
6. Graviditet eller amning.
7. Någon pågående akut eller kronisk viral eller systemisk bakteriell infektion inklusive HIV, latent hepatit B, som är kliniskt signifikant enligt studieläkarens åsikt och som inte behandlats med lämpliga antibiotika/antiviralt läkemedel.
8. Svår hjärtsvikt (New York Heart Association klass IV) eller svår okontrollerad hjärtsjukdom .
9. Tidigare användning av immunosuppressiva läkemedel inkluderande rituximab, azatioprin, ciklosporin och MMF. Användning av Prednisolon i en dos om ≤40mg/d inom 3 månader och IVIG och PLEX 12 månader från screeningdatumet utgör ej ett exklusionskriterium. Observera också att detta ej gäller behandling med immunosuppressiva läkemedel/kortokosteroider (undantaget rituximab) på annan indikation än MG, förutsatt att det gått >12 månader sedan behandlingen avslutats.
10. Överkänslighet mot den aktiva substansen eller mot murina proteiner eller mot något annat hjälpämne i studieläkemedlet
11. Deltagande i någon annan prövning av studieläkemedel eller exponering för något annat studieläkemedel, studieprodukt eller studieprocedurer inom 30 dagar före screening.
12. Något medicinskt tillstånd som, enligt studieläkarens åsikt, kan interferera med patientens deltagande i studien, utgör någon ytterligare risk för patienten, eller som försvårar bedömningen av patienterna

E.5 End points

E.5.1

Primary end point(s)

Percentage of patients with a QMG score ≤4 and daily prednisone dose ≤10mg 16 weeks after treatment

Andel av patienter med QMG poäng ≤ 4 och en daglig Prednisolondos ≤ 10mg vid 16 veckor efter behandling

E.5.1.1

Timepoint(s) of evaluation of this end point

At 16 weeks after treatment

Vid 16 veckor efter behandling

E.5.2

Secondary end point(s)

QMG score at 24 weeks after treatment
MG-ADL score at 16 weeks after treatment
MG-QOL scores at 16 weeks after treatment

QMG poäng vid 24 veckor efter behandling
MG-ADL poäng vid 16 veckor efter behandling
MG-QOL poäng vid 16 veckor efter behandling

E.5.2.1

Timepoint(s) of evaluation of this end point

At 16 and 24 weeks after treatment

Vid 16 och 24 veckor efter behandling

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

Yes

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.6

Cross over

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.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

Last visit of the last subject undergoing the trial

Sista besök av den sista försökspersonen i studien

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

After completion of the study, the patient will be treated according to the clinical judgment of the treating physician

Patienten kommer efter studiens avslut att behandlas enligt klinisk bedömning av den behandlande läkaren.

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

2016-06-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-02-05

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