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

Primary Purpose

Myositis, Myasthenia Gravis

Status

Completed

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

Rituximab

About this trial

This is an interventional treatment trial for Myositis focused on measuring Myositis, Anti-synthetase, Anti-SRP, Myasthenia gravis, Rituximab

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

Extraocular muscle weakness quantified with MG muscle score (MMS), whose inter and inter observer reproducibility has been demonstrated [44].
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

Sites / Locations

Service de Médecine Interne 1 / Groupe Hospitalier Pitié-Salpêtrière

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm Description

Outcomes

Primary Outcome Measures

Score of muscular strength (Kendall's muscular testing for myositis or MG muscular score for myasthenia)

Secondary Outcome Measures

- Score of muscular strength (Kendall's muscular testing for myositis or MG muscular score for myasthenia)

- Improvement of functional scale score (SF36)

- Decrease of CK levels

- Evolution of auto-antibody titers

- Improvement of extra-muscular activity of the disease such as the level of lung involvement by pulmonary function tests

- Improvement in the treatment burden defined as the possibility to decrease the dose or stop some of the drugs used at entry

Full Information

NCT ID

NCT00774462

First Posted

October 16, 2008

Last Updated

December 10, 2012

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

Institut National de la Santé Et de la Recherche Médicale, France, Roche Pharma AG

1. Study Identification

Unique Protocol Identification Number

NCT00774462

Brief Title

Rituximab for the Treatment of Refractory Inflammatory Myopathies and Refractory Myasthenia Gravis

Acronym

FORCE

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2007

Overall Recruitment Status

Completed

Study Start Date

January 2008 (undefined)

Primary Completion Date

December 2011 (Actual)

Study Completion Date

December 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

Institut National de la Santé Et de la Recherche Médicale, France, Roche Pharma AG

4. Oversight

Data Monitoring Committee

5. Study Description

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%).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myositis, Myasthenia Gravis

Keywords

Myositis, Anti-synthetase, Anti-SRP, Myasthenia gravis, Rituximab

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Rituximab

Intervention Description

Rituximab 1000 mg intravenous, 2 times, 2 weeks apart and 1000 mg 6 months after the last injection

Primary Outcome Measure Information:

Title

Score of muscular strength (Kendall's muscular testing for myositis or MG muscular score for myasthenia)

Time Frame

at month 12

Secondary Outcome Measure Information:

Title

- Score of muscular strength (Kendall's muscular testing for myositis or MG muscular score for myasthenia)

Time Frame

at day 21 and month 12

Title

- Improvement of functional scale score (SF36)

Time Frame

at day 21 and month 12

Title

- Decrease of CK levels

Time Frame

at day 21 and month 12

Title

- Evolution of auto-antibody titers

Time Frame

at day 21 and month 12

Title

- 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

Title

- 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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: For myositis III. Idiopathic myositis Myositis as defined by the 119th ENMC: Proximal myopathy with weakness Subacute or insidious onset over 18 years Myogenic syndrome on EMG (optional) Muscle fibre necrosis and regeneration and/or inflammatory cell infiltrate on muscular biopsy 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: Extraocular muscle weakness quantified with MG muscle score (MMS), whose inter and inter observer reproducibility has been demonstrated [44]. 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: Inclusion body myositis Macrophagic myofasciitis Inherited myopathies Secondary IM to one other connective tissue disorders Systemic scleroderma (ARA and/or "LEROY AND MEDSGER" criteria) Sjögren's syndrome (European criteria) Systemic lupus erythematosus (ACR criteria) Rheumatoid arthritis (ACR criteria) Mixed connective tissue disease (ACR criteria) Other myasthenic syndrome, such as: Non generalised, ocular MG Lambert Eaton syndrome MG associated with malignant thymoma Inherited myasthenic syndrome Cancer (or cancer-associated myositis) Age < 18 years Pregnancy HIV seropositivity Evolutive infection (B, C hepatitis, tuberculosis) Lack of approved consent

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Olivier BENVENISTE, PUPH

Organizational Affiliation

Assistance Publique - Hôpitaux de Paris

Official's Role

Principal Investigator

Facility Information:

Facility Name

Service de Médecine Interne 1 / Groupe Hospitalier Pitié-Salpêtrière

City

Paris

ZIP/Postal Code

75651 Cedex 13

Country

France

12. IPD Sharing Statement

Citations:

PubMed Identifier

26539981

Citation

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.

Results Reference

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Rituximab for the Treatment of Refractory Inflammatory Myopathies and Refractory Myasthenia Gravis

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