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

This study has been completed.
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
ClinicalTrials.gov Identifier:
NCT00774462
First received: October 16, 2008
Last updated: December 10, 2012
Last verified: December 2007
  Purpose

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.


Condition Intervention Phase
Myositis
Myasthenia Gravis
Drug: Rituximab
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: FORCE: Rituximab (CD 20+-B Cell-depleting Monoclonal Antibody) for the Treatment of Refractory Inflammatory Myopathies With Specific Antibodies and Refractory Myasthenia Gravis

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Score of muscular strength (Kendall's muscular testing for myositis or MG muscular score for myasthenia) [ Time Frame: at month 12 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • - Score of muscular strength (Kendall's muscular testing for myositis or MG muscular score for myasthenia) [ Time Frame: at day 21 and month 12 ] [ Designated as safety issue: No ]
  • - Improvement of functional scale score (SF36) [ Time Frame: at day 21 and month 12 ] [ Designated as safety issue: No ]
  • - Decrease of CK levels [ Time Frame: at day 21 and month 12 ] [ Designated as safety issue: No ]
  • - Evolution of auto-antibody titers [ Time Frame: at day 21 and month 12 ] [ Designated as safety issue: No ]
  • - 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 ] [ Designated as safety issue: No ]
  • - 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 ] [ Designated as safety issue: No ]

Enrollment: 30
Study Start Date: January 2008
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: Rituximab
Rituximab 1000 mg intravenous, 2 times, 2 weeks apart and 1000 mg 6 months after the last injection
Other Name: Rituximab

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%).

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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: NCT00774462

Locations
France
Service de Médecine Interne 1 / Groupe Hospitalier Pitié-Salpêtrière
Paris, France, 75651 Cedex 13
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Institut National de la Santé Et de la Recherche Médicale, France
Roche Pharma AG
Investigators
Principal Investigator: Olivier BENVENISTE, PUPH Assistance Publique - Hôpitaux de Paris
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT00774462     History of Changes
Other Study ID Numbers: P051204
Study First Received: October 16, 2008
Last Updated: December 10, 2012
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Myositis
Anti-synthetase
Anti-SRP
Myasthenia gravis
Rituximab

Additional relevant MeSH terms:
Myositis
Muscular Diseases
Myasthenia Gravis
Muscle Weakness
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Autoimmune Diseases of the Nervous System
Neuromuscular Junction Diseases
Autoimmune Diseases
Immune System Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Pathologic Processes
Signs and Symptoms
Antibodies, Monoclonal
Rituximab
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antirheumatic Agents

ClinicalTrials.gov processed this record on August 28, 2014