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

• ClinicalTrials.gov Identifier: NCT00740948
• Recruitment Status: Completed
• First Posted: August 25, 2008
• Last Update Posted: March 5, 2015
• Sponsor: University Hospital, Brest
• Collaborator: Ministry of Health, France
• Information provided by (Responsible Party): University Hospital, Brest

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 (Clinical Trial)
• 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: March 2008
• Actual Primary Completion Date: January 2012
• Actual Study Completion Date: January 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.

Outcome Measures

Primary Outcome Measures :

1. 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 ]

Secondary Outcome Measures :

1. Variations from baseline to week 24 of clinical, biological and histological data [ Time Frame: 24, 36 and 48 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

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):

Cornec D, 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, Yves Hatron P, Goeb V, Hayem G, Morel J, Zarnitsky C, Dubost JJ, Saliou P, Pers JO, Seror R, Saraux A. Severe Health-Related Quality of Life Impairment in Active Primary Sjögren's Syndrome and Patient-Reported Outcomes: Data From a Large Therapeutic Trial. Arthritis Care Res (Hoboken). 2017 Apr;69(4):528-535. doi: 10.1002/acr.22974.

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
• Other Study ID Numbers: TEARS
• First Posted: August 25, 2008
• Last Update Posted: March 5, 2015
• Last Verified: March 2015

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, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents