Clinical Trials Register

Summary
EudraCT Number:	2006-005357-29
Sponsor's Protocol Code Number:	WA20500
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-04-17
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

Bulgarian Drug Agency

A.2

EudraCT number

2006-005357-29

A.3

Full title of the trial

A Randomised, Double-Blind, Placebo Controlled, Parallel-Group, Multicenter Study To Evaluate The Efficacy and Safety of Two Doses of Ocrelizumab in Subjects With WHO or ISN Class III or IV Nephritis Due To Systemic Lupus Erythematosus

A.3.1

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

Clinical trial to study a drug in people with kidney disease related to lupus

A.3.2

Name or abbreviated title of the trial where available

BELONG

A.4.1

Sponsor's protocol code number

WA20500

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	F. Hoffmann-La Roche Ltd
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	F.Hoffmann-La Roche Ltd.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F.Hoffmann-La Roche Ltd.
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.com

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	No
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	ocrelizumab
D.3.2	Product code	RO 496-4913
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	ocrelizumab
D.3.9.2	Current sponsor code	RO 496-4913
D.3.9.3	Other descriptive name	RhuMAb 2H7
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	30
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	Yes
D.3.11.9	Recombinant medicinal product	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	humanized monoclonal antibody

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	Concentrate for 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

Patients with ISN/RPS or WHO class III or IV Active Lupus Nephritis

E.1.1.1

Medical condition in easily understood language

Lupus Nephritis

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.1
E.1.2	Level	PT
E.1.2	Classification code	10025140
E.1.2	Term	Lupus nephritis
E.1.2	System Organ Class	10038359 - Renal and urinary disorders

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 investigate the ability of the ocrelizumab regimen in
combination with standard of care treatment (SOC) to induce a
complete or partial renal response, as assessed by renal function,
urinary sediment and proteinuria in patients with ISN/RPS or
WHO class III or IV lupus nephritis.

E.2.2

Secondary objectives of the trial

• To assess the safety and tolerability of ocrelizumab.
• To evaluate the PK, immunogenicity and PD parameters of ocrelizumab in this patient population.
• To evaluate corticosteroid sparing in patients receiving ocrelizumab.
• To evaluate the effect of ocrelizumab on extra-renal disease manifestations
• To evaluate the impact of ocrelizumab on symptoms and patient functioning using the SF-36, Facit Fatigue and modified Brief Pain Inventory (mBPI-SF).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must meet the following criteria to be eligible for study entry. Documentation of each specific criterion must be present in the patient’s chart notes:

1. Age 16 years or above at the time of the screening unless the inclusion of minors is prohibited by the local regulations.

2. Ability and willingness to provide written informed consent (or to obtain consent from a parent guardian where applicable) and to comply with the schedule of protocol requirements.

3. Diagnosis of SLE according to ACR criteria. At least 4 criteria must have been present for the diagnosis of SLE. The 4 criteria do not have to be present at the time of screening.

4. Active lupus nephritis defined as follows: Biopsy proven (within 6 months prior to randomization) WHO or ISN Class III or IV LN (excluding III (C), IV-S (C) and IV-G (C),
Patients are permitted to have co-existing Class V. Whenever possible, biopsies should be graded and reported following ISN/RPS classification scheme. In cases where this is not possible, it is acceptable to include patients with WHO class III or IV GN, provided
that no more than 50% of glomeruli show sclerosis or fibrosis (see Exclusion
Criterion # 2).
AND
The presence of: Urinary protein to Urinary creatinine ratio ≥ 1. The proteinuria
must not have improved by ≥ 50% in the preceding 6 months.
The urine sample used to define this ratio is the 24 hour screening sample which
is measured by the central laboratory. If collection and analysis of a 24 hour
urine sample is not possible prior to randomization then a timed urine collection
(at least 12 hours) should be obtained.
Determination of eligibility based on a first-void morning ‘spot’ urine sample is
acceptable if collection and analysis of a timed urine sample is not possible prior
to randomization.

5. For patients of reproductive potential (males and females), a reliable means of contraception must be used for the duration of the study (e.g. hormonal contraceptive, intrauterine device, physical barrier) according to local guidelines and the treating physician’s recommendations. The relevant section of the product label for CYC, MMF or AZA (as appropriate) should be followed.

6. Female patients of childbearing potential must have a negative serum pregnancy test from the screening visit prior to enrollment at Day 1.

E.4

Principal exclusion criteria

Exclusions Related to SLE
1. Currently active retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia or dementia.
2. Severe renal impairment as defined by calculated (by Cockcroft-Gault) GFR < 25 mL/min, or the presence of oliguria (defined as a documented urine volume
< 400 mL/24hr) or renal biopsy results indicating chronic irreversible renal scarring (either > 50% of glomeruli with sclerosis or > 50% interstitial fibrosis on renal biopsy).
Exclusions Related to General Health
3. Lack of peripheral venous access.
4. Pregnancy or breast feeding mothers.
5. History of severe allergic or anaphylactic reactions to humanized, chimeric or murine monoclonal antibodies or i.v. immunoglobulin.
6. Known severe chronic pulmonary disease (FEV1 < 50% predicted or functional dyspnea ≥ Grade 3 on the MRC Dyspnea Scale).
7. Evidence of significant uncontrolled concomitant diseases in any organ system not related to SLE (e.g. renal thrombosis, atherosclerotic cardiovascular disease, diabetes mellitus, accelerated hypertension, poorly controlled COPD or asthma
etc), which, in the investigator’s opinion, would preclude patient participation.
8. Concomitant condition (e.g. asthma, Crohn’s disease, etc) which has required treatment with systemic corticosteroid (excluding topical or inhaled steroids) at any time in the 52 weeks prior to screening.
9. Known HIV or chronic active Hepatitis B or chronic active Hepatitis C infection.
10. Known active clinically significant infection of any kind (with the exception of
fungal infection of nail beds or oral thrush) or any major episode of infection
requiring hospitalization or treatment with intravenous anti-infectives in the
14 days prior to Day 1. Patients may be enrolled in the presence of recent minor
infections not requiring treatment with anti-infectives (e.g. viral upper
respiratory tract infection, viral gastroenteritis), if in the investigator’s opinion,
the infection has resolved prior to Day 1 and is unlikely to present additional
risk to the subject.
11. History of serious recurrent or chronic infection. A chest radiograph will be performed during screening, if not performed in the 12 weeks prior to screening, to assess infection. If there is any evidence of pulmonary infection a chest radiograph should be performed.
12. History of cancer, including solid tumors, hematological malignancies and carcinoma in situ (except basal cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured).
13. History of alcohol or drug abuse in the 52 weeks prior to screening.
14. Major surgery in the 4 weeks prior to screening, excluding diagnostic surgery.
Exclusions Related to Medications
15. Previous treatment with CAMPATH-1H.
16. Previous treatment with a BAFF directed treatment (e.g. anti-BLyS) in the 12 months prior to screening.
17. Previous treatment with a B-cell targeted therapy (e.g. anti-CD20, anti-CD22 other than one directed at BAFF ).
18. Treatment with any investigational agent in the 28 days prior to screening or within five half-lives of the investigational drug (whichever is longer).
19. Receipt of any live vaccines in the 6 weeks prior to Day 1 (it is recommended that a patient’s vaccination record and the need for immunization prior to receiving ocrelizumab should be carefully investigated).
20. Intolerance or contraindication to oral or i.v. corticosteroids.
21. Treatment with more than 1 g CYC (cumulative dose) in the 6 months prior to screening period.
22. Receipt of more than 3 g i.v. pulse methylprednisolone (cumulative dose) within the 12 weeks prior to Screening.
23. Receipt of prednisone doses > 20 mg/day (or equivalent, including parenteral
corticosteroids, except for pulse steroids as defined in exclusion criterion #22) for
longer than 14 days within a 12 weeks period prior to screening. During the 14 days
prior to screening patients may have been treated with high-dose oral prednisone (up to 1 mg/kg/day).
24. Treatment with a systemic calcineurin inhibitor (e.g. cyclosporin, tacrolimus) within
the 12 weeks prior to screening.
Exclusions Related to Laboratory Findings
25. Aspartate aminotransferase or alanine aminotransferase or amylase > 2.5 times the upper limit of normal, unless caused by SLE. Patients with elevated serum amylase may be eligible if serum lipase is within normal limits and clinical signs of pancreatitis are not present.
26. Neutrophils < 1.5 x 10^9/L
If the absolute neutrophil count is 1.5 x 10^9/L but the investigator has assessed the neutropenia is due to SLE, the patient may be eligible for the study. This determination will be made after discussion with the Medical Monitor.
27. Hemoglobin < 7 g/dL.
28. Platelet count < 50 x 10^9/L
28. 29. 30. Refer to the protocol (section 4.3)

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint of this study is the proportion of patients with a clinical response in the following three mutually exclusive categories at Week 48:
1. Patients who achieve a Complete Renal Response (CRR)
2. Patients who achieve a Partial Renal Response (PRR)

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Week 48
2. Week 48

E.5.2

Secondary end point(s)

1. Proportion of patients who achieve a renal response, major clinical response, or partial clinical response
2. Proportion of patients who achieve a reduction from baseline in SLEDAI 2K score, no worsening in physician's global assessment, no new BILAG A organ domain score, and no more than 1 new BILAG B organ domain score
3. Change in SF-36 subscale FACTIT-Fatigue assessment, change from baseline in pain quality, and impact of pain on daily function
4. Proportion of patients who achieve a CRR or PRR and who have received a daily dose of corticosteroids from Week 24 and average corticosteroid burden

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Weeks 48, 72, and 96
2. Week 48
3. Week 48
4. Week 48

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

Yes

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

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

quality of life

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.8.3

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

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

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

Please refer to setion 3.1.6 "End of Study" of the Protocol

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	Yes
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
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	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	4
F.4.2	For a multinational trial
F.4.2.1	In the EEA	174
F.4.2.2	In the whole clinical trial	369

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

2008-05-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-06-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-10-23

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