Clinical Trials Register

Summary
EudraCT Number:	2006-002306-64
Sponsor's Protocol Code Number:	Ritux-AS-01
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-10-04
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

Germany - PEI

A.2

EudraCT number

2006-002306-64

A.3

Full title of the trial

Open label clinical trial with Rituximab (MabThera ®) in Ankylosing Spondylitis - Extension of open label trial: Re-Treatment of patients who have shown response to first course of Rituximab

A.3.2

Name or abbreviated title of the trial where available

Ritux-AS-01

A.4.1

Sponsor's protocol code number

Ritux-AS-01

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	Charité Universitaetsmedizin
B.1.3.4	Country	Germany
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	Rituximab/ 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	European Union
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.3.1	Product name	MabThera
D.3.2	Product code	Ro45-2294
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	rituximab
D.3.9.1	CAS number	174722-31
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	Information not present in EudraCT

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Moderate to severe ankylosing spondylitis who have had an inadequate response to or do not tolerate conventional therapy including NSAIDs, DMARDs and TNF alpha inhibitors

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy and safety of rituximab when added to NSAIDs and/ or methotrexate both for TNFalpha inhibitor naïve or TNFalpha inhibitor failure patients with moderate to severe ankylosing spondylitis.

Primary endpoint: Efficacy Evaluation in week 24 and until study end: ASAS 20 in AS patients naïve to TNFalpha inhibitors as well as in AS patients with previous therapy with TNFalpha inhibitors.

Patients who have shown good response to initial treatment with Rituximab (good response defined as reaching ASAS20 criteria on two consecutive visitis between week 12 and week 24) are eligible for a second course of Rituximab if they show a flare of their disease (flare defined as a 1.5-point-worsening of the BASDAI score between week 24 and 48 compared to the best BASDAI score between week 12 and 24).

Primary endpoint for patients who are re-treated: ASAS20 response at week R-24.

E.2.2

Secondary objectives of the trial

Secondary endpoints:

Safety Evaluations: Adverse events, vital signs, physical examination results, and clinical laboratory values until week (R-) 48.

Efficacy Evaluations: ASAS 40 response, ASAS criteria for partial remission, 20%, 50% and 70% improvement of disease activity (BASDAI), improvement of BASMI, BASFI, SF-36, number of swollen joints, number of enthesitic regions (Maastricht Index), regression of inflammation (CRP, ESR), patients– and physicians global assessment, general and nocturnal pain, EQ-5D, socioeconomic questionnaire, MRI for acute and chronic lesions at 24 weeks and at 48 weeks compared to screening for patients receiving course 1 and MRI for acute and chronic lesions at week R-24 and R-48 for patients receiving course 2 (re-treatment), B cell and T cell analysis at weeks (R-) 4, (R-) 12, (R-) 24 and (R-) 48 for patients receiving course 1 (or(and) 2.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria:

- Patients 18 – 65 years of age who have moderate to severe ankylosing spondylitis.

- Active disease is defined as a BASDAI score of > = 4 plus a back pain score (BASDAI question 2) of >= 4 despite concurrent NSAID therapy, or intolerance to NSAIDs

- If on prednisone, £10 mg per day must be stable for 4 weeks prior to baseline.

- If on methotrexate, £ 25 mg per week must be stable for 4 weeks prior to baseline

- Women of child bearing potential must have a negative pregnancy urine test at study baseline and use an adequate, effective method of contraception (such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence, vasectomised partner) for a duration of 12 months after stop of rituximab therapy. Sexual active men must use an accepted method of contraception for a duration of 12 months after first administration of rituximab.

- Willingness and capability to give written informed consent, written consent for data protection (legal requirement in Germany: datenschutzrechtliche Einwilligung) and willingness to participate and to comply with the study

- Patients are eligible for a second course of rituximab if they: A) in response assessment period= week 12- week 24: have shown a response after the first administration of rituximab; response defined as reaching ASAS20 criteria (compared to screening) on at least two subsequent time points between week 12 and week 24, B) in flare assessment period (starting from week 24- 48): have a flare after they have shown response (as described above): flare defined as having a 1.5-point-worsening of the BASDAI score in comparison to the lowest BASDAI score between week 12 and week 24, and C) have completed week 24 (re-treatment 24 weeks after first administration of rituximab at the earliest)

E.4

Principal exclusion criteria

Exclusion criteria

Exclusion criteria related to general health conditions:
1. Patients with other chronic inflammatory articular disease or systemic autoimmune disease, e.g. Systemic lupus erythematosus, Sjögren’s syndrome, active rheumatoid vasculitis, a history of systemic diseases associated with arthritis, chronic fatigue syndrome
2. Any active infection, a history of recurrent clinically significant infection, a history of recurrent bacterial infections with encapsulated organisms
3. Primary or secondary immunodeficiency
4.History of cancer with curative treatment not longer than 5 years ago except basal-cell carcinoma of the skin that had been excised
5. A history of pulmonary or cardiac insufficiency, or serious and/or uncontrolled diseases that are likely to interfere with the evaluation of the patient's safety and of the study outcome
6.Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease ( e.g. heart failure class III/IV NYHA, cardiac infarct within last 6 month), nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders.
7.Neuropathy that can interfere with quality of life and/or pain assessment.
8.Patients with a history of a severe psychological illness or condition such as to interfere with the patient's ability to understand the requirements of the study.
9.History of current evidence of abuse of “hard” drugs (e.g. cocaine/ heroine) or alcoholism
10.Known hypersensitivity to any component of the product or to murine proteins (sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, HCl).
11.Women lactating, pregnant, nursing or of childbearing potential with a positive pregnancy test (urine test)
12.Males or females of reproductive potential not willing to use effective contraception (e.g. contraceptive pill, IUD, physical barrier) for up to 12.5 months after first infusion of rituximab
13.History of alcohol, drug or chemical abuse within 6 month prior to screening
14.Lack of peripheral venous accessExclusion criteria related to medications
15.If on leflunomide, leflunomide must have been terminated at least 8 weeks prior to the first rituximab infusion (or ≥ 28 days after 11 days of standard cholestyramine or activated charcoal washout).
16.If on TNFalpha blocking agent (infliximab, etancercept, adalimumab), the TNFa therapy must have been terminated at least 4 weeks prior to the first rituximab infusion if etanercept was used and at least 8 weeks if infliximab or adalimumab were used
17.Previous treatment with rituximab or intolerance to rituximab
18.Corticosteroids at doses exceeding 10 mg per day of prednisolone or the equivalent within the last 4 weeks prior to the first rituximab infusion
19.Intolerance or contraindication to drugs required for the treatment of the side effects of rituximab (e.g. paracetamol, acetaminophen, diphenhydramine, p.o. and i.v. corticosteroids, anti-emetics or H1 blockers)
20.Previous treatment with any investigational agent
21.Previous treatment with i.v. immunoglobulins
22.Receipt of a live vaccine within 4 weeks prior to treatment
23.Intra-articular or parenteral corticosteroids within 4 weeks prior to screening visitExclusion criteria related to lab findings
24.Haemoglobin < 8.5 g/dl
25.Neutrophil counts < 1.500 / µl
26.Platelet count < 75.000 / µl
27.Lower than 1 x 1000/µl lymphopenia for more than three months prior to inclusion.
28.Serum creatinine > 1.4 mg/dl for women or 1.6 mg/dl for men.
29.Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times upper limit of normal
30.Positive HIV, hepatitis B or C serology

Exclusion criteria related to formal aspects
31.Patients who participate currently in another clinical trial or patients who participated in another clinical trial during the last 30 days.
32.Patients who are underage or patients who are incapable to understand the aim, importance and consequences of the study and to give legal informed consent (according to § 40 Abs. 4 and § 41 Abs. 2 und Abs. 3 AMG).

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint: Efficacy Evaluation in week 24 and until study end: ASAS 20 in AS patients naïve to TNFalpha inhibitors as well as in AS patients with previous therapy with TNFalpha inhibitors. For patients going into the extension study: ASAS 20 at week R-24.

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

B and T cell analysis, MRI outcome acute and chronic inflammatory

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

one-armed open trial

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

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

Information not present in EudraCT

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

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.1.3

Elderly (>=65 years)

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)

Patients will receive the standard treatment with standard care as needed throughout and after the study. After week 48 an additional or changed treatment is left to the discretion of the investigator.
Any other specific treatment of the patient after study end is not planned. The investigator will inform the patients about all available standard-of-care treatments and the decision is left to the patient’s and investigator’s discretion.

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

2006-12-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-12-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2007-07-10

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