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Rituximab for the Treatment of Refractory Inflammatory Myopathies and Refractory Myasthenia Gravis (FORCE)

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ClinicalTrials.gov Identifier: NCT00774462
Recruitment Status : Completed
First Posted : October 17, 2008
Last Update Posted : December 11, 2012
Sponsor:
Collaborators:
Institut National de la Santé Et de la Recherche Médicale, France
Roche Pharma AG
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE October 16, 2008
First Posted Date  ICMJE October 17, 2008
Last Update Posted Date December 11, 2012
Study Start Date  ICMJE January 2008
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 16, 2008)
Score of muscular strength (Kendall's muscular testing for myositis or MG muscular score for myasthenia) [ Time Frame: at month 12 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2008)
  • - Score of muscular strength (Kendall's muscular testing for myositis or MG muscular score for myasthenia) [ Time Frame: at day 21 and month 12 ]
  • - Improvement of functional scale score (SF36) [ Time Frame: at day 21 and month 12 ]
  • - Decrease of CK levels [ Time Frame: at day 21 and month 12 ]
  • - Evolution of auto-antibody titers [ Time Frame: at day 21 and month 12 ]
  • - Improvement of extra-muscular activity of the disease such as the level of lung involvement by pulmonary function tests [ Time Frame: at day 21 and month 12 ]
  • - Improvement in the treatment burden defined as the possibility to decrease the dose or stop some of the drugs used at entry [ Time Frame: at day 21 and month 12 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rituximab for the Treatment of Refractory Inflammatory Myopathies and Refractory Myasthenia Gravis
Official Title  ICMJE FORCE: Rituximab (CD 20+-B Cell-depleting Monoclonal Antibody) for the Treatment of Refractory Inflammatory Myopathies With Specific Antibodies and Refractory Myasthenia Gravis
Brief Summary The traditional treatment of inflammatory myopathies (IM) and generalized myasthenia gravis (MG) is immunosuppressive therapy, usually beginning with corticosteroids. However, up to 70% of treated patients show an incomplete response, including 10 - 30% who are unresponsive. Corticosteroids and other immunosuppressive therapies presented also many side effects. We propose to evaluate in a pilot, open, prospective, multicentric, phase II study, the interest of rituximab in the treatment of patients with primary IM associated with specific AAb (anti-synthetase and anti-SRP AAbs), or MG (with anti-AchR AAbs), refractory to conventional therapies. Twenty fourth patients with primary IM (12 with anti-synthetase, 12 with anti-SRP AAbs), and 12 with MG will be included in the study.
Detailed Description

Rituximab, a chimeric monoclonal antibody specific for human CD20, which targets B lymphocytes, has been first developed as biotherapy for the treatment of B lymphoma. In this context, hundred thousands patients received this drug, with a very good tolerance. Recently, interest has grown in the pivotal role of B cells for auto-immune humorally mediated diseases. Rituximab could then be a potential new biological treatment for such diseases, especially for patients refractory to conventional therapies. As a Muscular Diseases Centre, we have a large recruitment of patients with inflammatory myopathies (IM) and myasthenia gravis (MG). Although the physiopathogenesis of these two conditions differ, both can be associated with specific auto-antibodies (AAbs) and their therapeutic management is almost similar. The traditional treatment approach to IM and generalized MG is immunosuppressive therapy, usually beginning with corticosteroids. However, up to 70% of treated patients show an incomplete response, including 10 - 30% who are unresponsive. We propose to evaluate in a pilot, open, prospective, multicentric, phase II study, the interest of rituximab in the treatment of patients with primary IM associated with specific AAb (anti-synthetase and anti-SRP AAbs), or MG (with anti-AchR AAbs), refractory to conventional therapies.

Inclusions criteria are IM (as defined by the 119th European Neuromuscular Centre workshop) or generalised MG (as defined by the Texas Clinical Classification System) associated with specific AAbs (anti-synthetases (JO1, PL7 or PL12), or anti-SRP for primary IM, and anti-AchR for MG) and refractory to conventional treatments defined as an inadequate response to, or intolerable side effects with conventional treatments, such as corticosteroids, azathioprine, methotrexate, cyclophosphamide, cyclosporine, IgIV and/or plasma exchange.

The therapeutical schema is rituximab 1000 mg, 2 times (at day 0 and 15), followed by one single injection (1000 mg) 6 months latter and end of follow up at 1 year.

The efficacy is evaluated by an improvement of Kendall's muscular testing or MG muscular score at month 12. Secondary criteria include Kendall's muscular testing or MG muscular score at day 21 and month 7, quality of life auto-questionnaire (SF 36), evolution of CK levels and AAb titers.

Twenty fourth patients with primary IM (12 with anti-synthetase, 12 with anti-SRP AAbs), and 12 with MG will be included in the study. If a success is observed in at least 6 patients, it will be possible to conclude that the response rate is above 25% (lower 90% confidence interval for observed response rate 50%).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myositis
  • Myasthenia Gravis
Intervention  ICMJE Drug: Rituximab
Rituximab 1000 mg intravenous, 2 times, 2 weeks apart and 1000 mg 6 months after the last injection
Study Arms  ICMJE Experimental: 1
Intervention: Drug: Rituximab
Publications * Allenbach Y, Guiguet M, Rigolet A, Marie I, Hachulla E, Drouot L, Jouen F, Jacquot S, Mariampillai K, Musset L, Grenier P, Devilliers H, Hij A, Boyer O, Herson S, Benveniste O. Efficacy of Rituximab in Refractory Inflammatory Myopathies Associated with Anti- Synthetase Auto-Antibodies: An Open-Label, Phase II Trial. PLoS One. 2015 Nov 5;10(11):e0133702. doi: 10.1371/journal.pone.0133702. eCollection 2015.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 10, 2012)
30
Original Estimated Enrollment  ICMJE
 (submitted: October 16, 2008)
36
Actual Study Completion Date  ICMJE December 2011
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • For myositis III. Idiopathic myositis

    1. Myositis as defined by the 119th ENMC:

      1. Proximal myopathy with weakness
      2. Subacute or insidious onset over 18 years
      3. Myogenic syndrome on EMG (optional)
      4. Muscle fibre necrosis and regeneration and/or inflammatory cell infiltrate on muscular biopsy
    2. Specific AAbs : anti-synthetases (anti-JO1, anti-PL7, or anti-PL12), or anti-SRP.

      IV. Refractory to the conventional treatments Resistance to conventional treatments is defined as an inadequate response to, or intolerable side effects with conventional treatments, such as corticosteroids, azathioprine, methotrexate, cyclophosphamide, cyclosporine, IgIV and/or plasma exchange. At least one or more of these drugs or therapeutical approaches (used alone or as a combination) must have been unsuccessfully tested before inclusion. Inadequate response is defined as the lack of improvement and/or the degradation of evaluation parameters (defined bellow) despite these conventional therapies, that led to a modification or a reintroduction of treatment.

  • For myasthenia III. Generalised MG

Generalised seropositive MG as defined by the Texas Clinical Classification System:

  1. Extraocular muscle weakness quantified with MG muscle score (MMS), whose inter and inter observer reproducibility has been demonstrated [44].
  2. Specific AAbs : anti-AchR IV. Refractory to the conventional treatments Resistance to conventional treatments is defined as an inadequate response to, or intolerable side effects with conventional treatments, such as corticosteroids, azathioprine, methotrexate, cyclophosphamide, cyclosporine, IgIV and/or plasma exchange. At least one or more of these drugs or therapeutical approaches (used alone or as a combination) must have been unsuccessfully tested before inclusion. Inadequate response is defined as the lack of improvement and/or the degradation of evaluation parameters (defined bellow) despite these conventional therapies, that led to a modification or a reintroduction of treatment

Exclusion Criteria:

  • Other muscular diseases, such as:

    1. Inclusion body myositis
    2. Macrophagic myofasciitis
    3. Inherited myopathies
  • Secondary IM to one other connective tissue disorders

    1. Systemic scleroderma (ARA and/or "LEROY AND MEDSGER" criteria)
    2. Sjögren's syndrome (European criteria)
    3. Systemic lupus erythematosus (ACR criteria)
    4. Rheumatoid arthritis (ACR criteria)
    5. Mixed connective tissue disease (ACR criteria)
  • Other myasthenic syndrome, such as:

    1. Non generalised, ocular MG
    2. Lambert Eaton syndrome
    3. MG associated with malignant thymoma
    4. Inherited myasthenic syndrome
  • Cancer (or cancer-associated myositis)
  • Age < 18 years
  • Pregnancy
  • HIV seropositivity
  • Evolutive infection (B, C hepatitis, tuberculosis)
  • Lack of approved consent
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00774462
Other Study ID Numbers  ICMJE P051204
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE
  • Institut National de la Santé Et de la Recherche Médicale, France
  • Roche Pharma AG
Investigators  ICMJE
Principal Investigator: Olivier BENVENISTE, PUPH Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date December 2007

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP