Clinical trial NCT00740948: Tolerance and Efficacy of Rituximab in Sjogren's Disease
Official title: Tolerance and Efficacy of Rituximab in Sjogren's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Sjogren's Disease
Keywords: Sjogren's disease
Rituximab
Treatment
anti CD20
Lead sponsor: University Hospital, Brest
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2008-08-25
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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 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,

Primary outcomes:
measure: 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.
timeFrame: 24 weeks
Secondary outcomes:
measure: Variations from baseline to week 24 of clinical, biological and histological data
timeFrame: 24, 36 and 48 weeks
Other outcomes:
Locations:
city: Brest
country: France
facility: CHU de Brest
city: Clermont-ferrand
country: France
facility: CHU Clermont-Ferrand
city: Le Havre
country: France
facility: GH Le Havre
city: Le KREMLIN-BICETRE
country: France
facility: AP-HP Bicêtre
city: Le Mans
country: France
facility: Ch Le Mans
city: Lille
country: France
facility: CHRU de LILLE
city: Marseille
country: France
facility: CHU de Marseille
city: Montpellier
country: France
facility: Hopital LAPEYRONIE
city: Nantes
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: Hôpital Cochin APHP
city: Paris
country: France
facility: CHU Bichat
city: Rennes
country: France
facility: Hôpital SUD CHU Rennes
city: Rouen
country: France
facility: CHU Rouen
city: Strasbourg
country: France
facility: CHU de Strasbourg
Study officials:
affiliation: University Hospital, Brest
name: Alain SARAUX, Pr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, Roudaut A, Jamin C, Renaudineau Y, Roue IQ, Cochener B, Youinou P, Saraux A. Improvement of Sjogren's syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum. 2007 Mar 15;57(2):310-7. doi: 10.1002/art.22536.
citation: Cornec D, Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, Puechal 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 Sjogren'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.
citation: Costa S, Schutz S, Cornec D, Uguen A, Quintin-Roue 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 Sjogren'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.
citation: 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 Sjogren's Syndrome. Arthritis Rheumatol. 2015 Jun;67(6):1623-8. doi: 10.1002/art.39088.
citation: Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, Puechal 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 Sjogren syndrome with rituximab: a randomized trial. Ann Intern Med. 2014 Feb 18;160(4):233-42. doi: 10.7326/M13-1085.