TEARS: Tolerance and Efficacy of Rituximab in Sjogren's Disease

Sponsor

University Hospital, Brest (Other)

Overall Status

Completed

CT.gov ID

NCT00740948

Collaborator

Ministry of Health, France (Other)

122

Enrollment

Locations

Arms

58.1

Duration (Months)

8.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

CLINICAL PHASE II INDICATION Sjogren's syndrome RATIONALE Sjögren's syndrome (SS) is an autoimmune disorder affecting 0.2% to 3% of the general population. Pharmacological treatment can improve the sicca symptoms, often transiently, but they are unable to modify the course of the disease.Open label studies suggested that low-dose rituximab produced acute and complete CD20 depletion in blood and tissue; was well tolerated without corticosteroid use; and significantly improved glandular and extra-glandular manifestations of pSS. Larger controlled studies are now warranted. Our hypothesis is that two infusions of 1000 mg of Rituximab may be better than placebo to treat patients suffering from pSS. To test this hypothesis, we propose to compare patients with recent and/or severe pSS treated with either Rituximab or placebo.

OBJECTIVES Primary objective : Evaluation of the efficacy defined as a 30% improvement between Day 1 and Week 24 in the values on 2 of the 4 VAS measuring global scores of the disease (activity of the disease including extra glandular manifestations), joint pain, fatigue, and the most disturbing dryness.Secondary objectives : Variations from baseline to week 24 of:

The 0-100-mm VAS scores for dry mouth, dry eyes, dry trachea, dry vagina, and dry skin; fatigue; pain; Tender and swollen joint counts; Tender points; Other systemic manifestation; Unstimulated salivary flow rate; Schirmer and van Bijsterveld scores (2-3); C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR); rheumatoid factor (RF); ANA; serum IgG, IgA, and IgM; complement; cryoglobulinemia; and counts of B and T cells; Evaluation of the safety of Rituximab during the study Evaluation of the improvement evaluated on VAS by the physician Evaluation of the disease activity scores as suggested by Bowman and Vitali Evaluation of Chisholm score, B cells characteristics and DNA microarray on labial accessory salivary gland (SG) biopsy samples, and salivary gland echography at inclusion and at week 24.

TRIAL DESIGN Multicenter, randomized, double-blind, placebo-controlled trial NUMBER OF SUBJECTS : 120

Condition or Disease	Intervention/Treatment	Phase
Sjogren's Disease	Drug: Rituximab (mabthera) Injection Drug: Placebo: NaCl 0.9% or Glucose 5%	Phase 2/Phase 3

Detailed Description

TARGET POPULATION Inclusion criteria : Patients will be eligible if :

they fulfill the new American-European Consensus Group criteria for pSS and have :

a recent (less than 10 years) and active disease as assessed by :
values > 50 mm on 2 of 4 visual analogue scales (VAS) (0-100mm) that evaluated global scores of the disease (activity of the disease including extra glandular manifestations), pain, sicca syndrome and fatigue over the last week.
Rheumatoid factor or SSA>1.5N or cryoglobulinemia or hypergammaglobulinemia or high level of beta2 microglobulinemia or hypocomplémentemia.
and/or at least one of the following severe signs: parotidomegaly, arthritis, purpura, pulmonary involvement, tubulopathy, neurological involvement, thrombocytopenia.

Additional inclusion criteria will be as follows:

informed consent
age 18-80 years,
stable non-steroidal anti-inflammatory drugs
and no prescription of immunosuppressive agents for at least 4 weeks prior to inclusion
Use of a reliable mean of contraception (for patients of reproductive potential)

Exclusion criteria :

Patients should be excluded if they have a secondary SS, if they received cytotoxic drugs during the previous 4 months, if they have severe renal or haematological failure, a history of cancer, hepatitis B or C, HIV, tuberculosis, severe diabetes or any other chronic disease or evidence of infection, if they have had severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or if they are unable to understand the protocol. Other : neutrophil count < 1.5 x 103/L, live/attenuated vaccine within 28 days prior to baseline, pregnancy, breast feeding,

Study Design

Study Type:

Interventional

Actual Enrollment :

122 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Tolerance and Efficacy of Rituximab in Sjogren's Disease

Study Start Date :

Mar 1, 2008

Actual Primary Completion Date :

Jan 1, 2012

Actual Study Completion Date :

Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Rituximab	Drug: Rituximab (mabthera) Injection 2 * 1g of Rituximab at the 1st day and at the 14th day.
Placebo Comparator: 2 Placebo	Drug: Placebo: NaCl 0.9% or Glucose 5% 2* 250ml of NaCl 0.9% or Glucose 5% at the 1st day and at the 14th day.

Arm

Intervention/Treatment

Experimental: 1

Rituximab

Drug: Rituximab (mabthera) Injection

2 * 1g of Rituximab at the 1st day and at the 14th day.

Placebo Comparator: 2

Placebo

Drug: Placebo: NaCl 0.9% or Glucose 5%

2* 250ml of NaCl 0.9% or Glucose 5% at the 1st day and at the 14th day.

Outcome Measures

Primary Outcome Measures

30% improvement between in the values on 2 of the 4 VAS measuring global scores of the disease (activity of the disease), joint pain, fatigue, and dryness. [24 weeks]

Secondary Outcome Measures

Variations from baseline to week 24 of clinical, biological and histological data [24, 36 and 48 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

they fulfill the new American-European Consensus Group criteria for pSS and have :
a recent (less than 10 years) and active disease as assessed by :
values > 50 mm on 2 of 4 visual analogue scales (VAS) (0-100mm) that evaluated global scores of the disease (activity of the disease including extra glandular manifestations), pain, sicca syndrome and fatigue over the last week.
Rheumatoid factor or anti SSA>1.5N or cryoglobulinemia or
hypergammaglobulinemia or high level of beta2 microglobulinemia or
hypocomplémentemia.
and/or at least one of the following severe signs:
parotidomegaly,
arthritis,
purpura,
pulmonary involvement,
tubulopathy,
neurological involvement,

informed consent age 18-80 years, stable non-steroidal anti-inflammatory drugs and no prescription of immunosuppressive agents for at least 4 weeks prior to inclusion Use of a reliable mean of contraception (for patients of reproductive potential)

Exclusion Criteria:

Patients should be excluded if they have a secondary SS,
if they received cytotoxic drugs during the previous 4 months,
if they have severe renal or haematological failure, a history of cancer, hepatitis B or C, HIV, tuberculosis, severe diabetes or any other chronic disease or evidence of infection,
if they have had severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
or if they are unable to understand the protocol.
Other : neutrophil count < 1.5 x 103/L, live/attenuated vaccine within 28 days prior to baseline, pregnancy, breast feeding,

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHU de Brest	Brest	France	29200
2	CHU Clermont-Ferrand	Clermont-ferrand	France	63003
3	GH Le Havre	Le Havre	France	76 083
4	AP-HP Bicêtre	Le KREMLIN-BICETRE	France	94275
5	Ch Le Mans	Le Mans	France	72 037
6	CHRU de LILLE	Lille	France	59 037
7	CHU de Marseille	Marseille	France
8	Hopital LAPEYRONIE	Montpellier	France	34 295
9	CHU de Nantes	Nantes	France	44 093
10	Hôpital Cochin APHP	Paris	France	75 679
11	CHU Bichat	Paris	France	75018
12	Hôpital SUD CHU Rennes	Rennes	France	35 203
13	CHU Rouen	Rouen	France	76 031
14	CHU de Strasbourg	Strasbourg	France	67 200