Tolerance and Efficacy of Rituximab in Sjogren's Disease - Full Text View

Purpose

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


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Tolerance and Efficacy of Rituximab in Sjogren's Disease

Resource links provided by NLM:

Genetics Home Reference related topics: Sjögren syndrome

MedlinePlus related topics: Tears

Drug Information available for: Rituximab

U.S. FDA Resources

Further study details as provided by University Hospital, Brest:

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. [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Variations from baseline to week 24 of clinical, biological and histological data [ Time Frame: 24, 36 and 48 weeks ] [ Designated as safety issue: Yes ]


Enrollment:	122
Study Start Date:	March 2008
Study Completion Date:	January 2013
Primary Completion Date:	January 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

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,

Eligibility


Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00740948

Locations


France
CHU de Brest
Brest, France, 29200
CHU Clermont-Ferrand
Clermont-ferrand, France, 63003
GH Le Havre
Le Havre, France, 76 083
AP-HP Bicêtre
Le KREMLIN-BICETRE, France, 94275
Ch Le Mans
Le Mans, France, 72 037
CHRU de LILLE
Lille, France, 59 037
CHU de Marseille
Marseille, France
Hopital LAPEYRONIE
Montpellier, France, 34 295
CHU de Nantes
Nantes, France, 44 093
Hôpital Cochin APHP
Paris, France, 75 679
CHU Bichat
Paris, France, 75018
Hôpital SUD CHU Rennes
Rennes, France, 35 203
CHU Rouen
Rouen, France, 76 031
CHU de Strasbourg
Strasbourg, France, 67 200

Sponsors and Collaborators

University Hospital, Brest

Ministry of Health, France

Investigators


Principal Investigator:	Alain SARAUX, Pr	University Hospital, Brest

More Information

Publications:

Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, Roudaut A, Jamin C, Renaudineau Y, Roué IQ, Cochener B, Youinou P, Saraux A. Improvement of Sjögren's syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum. 2007 Mar 15;57(2):310-7.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Costa S, Schutz S, Cornec D, Uguen A, Quintin-Roué I, Lesourd A, Berthelot JM, Hachulla E, Hatron PY, Goeb V, Vittecoq O, Pers JO, Marcorelles P, Saraux A, Devauchelle-Pensec V. B-cell and T-cell quantification in minor salivary glands in primary Sjögren's syndrome: development and validation of a pixel-based digital procedure. Arthritis Res Ther. 2016 Jan 20;18:21. doi: 10.1186/s13075-016-0924-2.

Jousse-Joulin S, Devauchelle-Pensec V, Cornec D, Marhadour T, Bressollette L, Gestin S, Pers JO, Nowak E, Saraux A. Brief Report: Ultrasonographic Assessment of Salivary Gland Response to Rituximab in Primary Sjögren's Syndrome. Arthritis Rheumatol. 2015 Jun;67(6):1623-8. doi: 10.1002/art.39088.

Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, Puéchal X, Le Guern V, Sibilia J, Gottenberg JE, Chiche L, Hachulla E, Hatron PY, Goeb V, Hayem G, Morel J, Zarnitsky C, Dubost JJ, Pers JO, Nowak E, Saraux A. Treatment of primary Sjögren syndrome with rituximab: a randomized trial. Ann Intern Med. 2014 Feb 18;160(4):233-42.


Responsible Party:	University Hospital, Brest
ClinicalTrials.gov Identifier:	NCT00740948 History of Changes
Other Study ID Numbers:	TEARS
Study First Received:	August 22, 2008
Last Updated:	March 4, 2015
Health Authority:	France: Agence Nationale de Sécurité du Médicament et des produits de santé

Keywords provided by University Hospital, Brest:


Sjogren's disease Rituximab Treatment anti CD20

Additional relevant MeSH terms:


Sjogren's Syndrome Arthritis, Rheumatoid Arthritis Joint Diseases Musculoskeletal Diseases Rheumatic Diseases Xerostomia Salivary Gland Diseases Mouth Diseases Stomatognathic Diseases Dry Eye Syndromes	Lacrimal Apparatus Diseases Eye Diseases Connective Tissue Diseases Autoimmune Diseases Immune System Diseases Rituximab Antineoplastic Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents

ClinicalTrials.gov processed this record on September 29, 2016

Tolerance and Efficacy of Rituximab in Sjogren's Disease (TEARS)