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- Registro de ensayos clínicos de EE. UU.
- Ensayo clínico NCT00939549
High Dose Cyclophosphamide Followed by Glatiramer Acetate in the Treatment of Relapsing Remitting Multiple Sclerosis (HiCy)
Phase II Study of High Dose Cyclophosphamide Followed by Glatiramer Acetate in the Treatment of Relapsing Remitting Multiple Sclerosis
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
Multiple sclerosis (MS) is an autoimmune disease characterized by progressive immune-mediated destruction of myelin and axons within the CNS. Despite the development, approval and clinical utilization of several medicines for patients with MS, most patients continue to accrue progressive disability. High-dose cyclophosphamide is chemotherapy treatment option for severe, refractory, immune-mediated illnesses such as MS. There is growing evidence that high dose cyclophosphamide is well tolerated and effective in MS. Our experience with 9 patients who underwent treatment at the Johns Hopkins Hospital yielded impressive results with a significant 40% reduction in baseline disability and an 81% reduction in MRI gadolinium enhancing lesions. Five out of 9 patients had recurrence of new brain MRI lesions during 24 months of follow-up, recurring in 4 patients during the first year of follow-up. Our findings suggest that high-dose cyclophosphamide holds promise in inducing remission and reducing disability in relapsing remitting MS however the recurrence of MS disease activity (evidenced by worsening disability, clinical exacerbations or ongoing MRI evidence of new lesions) suggests that high-dose cyclophosphamide given as a treatment on its own, is not sufficient to induce long-term remission.
Glatiramer acetate has been shown to be a more general suppressor of autoimmune disease, inhibiting the onset of experimental animal models of uveoretinitis, rheumatoid arthritis, immune rejection of grafts against host and host against graft disease, and inflammatory bowel disease. Glatiramer acetate was originally developed based on the observation that it inhibited the onset of clinical disease in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Glatiramer acetate suppression of EAE was found to be a general phenomenon not restricted to a particular species, disease type or encephalitogen used for the induction of EAE. A unique feature of glatiramer acetate is its promiscuous binding with high affinity to various class II MHC molecules and it potent induction of Th2 regulatory T cells. Moreover glatiramer acetate has subsequently been shown to be a more general suppressor of autoimmune disease, inhibiting the onset of experimental uveoretinitis, immune rejection of grafts against host and host against graft disease, and experimental inflammatory bowel disease.
We plan to investigate the properties of glatiramer acetate against the recurrence of MS disease activity following high dose cyclophosphamide induced cessation detectable autoimmunity. This study is a prospective, open-label two-year follow-up study in 12 patients with relapsing-remitting MS who are unable to tolerate or have failed to optimally respond to conventional therapy and are at high risk of disease progression and loss of function. Patients who elect to enter the study will be given a single course of high-dose, cyclophosphamide regimen without transplantation. Patients will then receive 20 mg of glatiramer acetate subcutaneously 4 to 6 weeks after the last dose of high-dose cyclophosphamide, to allow the immune system to have time to begin to reconstitute without glatiramer acetate but still provide sufficient time for glatiramer acetate to vaccinate against recurrence of MS disease activity.
The primary outcome of this pilot study will be to determine if high followed by a maintenance dose of glatiramer acetate is safe in this patient population. We hypothesize that institution of glatiramer acetate treatment following high-dose cyclophosphamide treatment will extend the period of disease free activity and further reduce the disability in patients with relapsing remitting MS.
Tipo de estudio
Fase
- Fase 2
Contactos y Ubicaciones
Ubicaciones de estudio
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Maryland
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Baltimore, Maryland, Estados Unidos, 21287
- Johns Hopkins Hospital Multiple Sclerosis Center
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion criteria
- Males and females between the ages of 18 and 70 years, inclusive.
- Diagnosis of clinically definite MS according to the McDonald Criteria.
- Must have been on conventional immunomodulatory treatment (interferon beta-1a, glatiramer acetate, or natalizumab) for at least 3 months OR have not tolerated conventional treatment OR have refused to start conventional treatment.
- 2 or more total gadolinium enhancing lesions on each of two pretreatment MRI scans at screening and enrollment.
- Subject must have EDSS ranging from 1.5 to 6.5.
- Subject must have had at least one clinical exacerbation in the last year and this must have occurred after having been on Avonex, Betaseron, Copaxone, Rebif or Natalizumab therapy for at least 3 months. This does not apply if subject has refused to start conventional therapy.
- Subject must have had a sustained (≥ 3 months) increase of > 1.0 on the EDSS (historical estimate allowed) between 3.0 and 5.5 or > 0.5 between 5.5 and 6.5 (while on therapy).
- Written informed consent prior to any testing under this protocol, including screening tests and evaluations that are not considered part of the subject's routine care.
- Women of childbearing potential should have a negative pregnancy test prior to entry into the study.
Exclusion criteria
- Any risk of pregnancy--ALL female patients must have an effective means of birth control or be infertile due to hysterectomy, fallopian tube surgery, or premature menopause.
- Cardiac ejection fraction of < 45%.
- Serum creatinine > 2.0.
- Patients who are pre-terminal or moribund.
- Bilirubin > 2.0, transaminases > 2x normal.
- Patients with EDSS < 3.0 or > 6.5.
- Patients with pacemakers and implants who cannot get serial MRIs.
- Patients with active infections until infection is resolved.
- Patients with WBC count < 3000 cells/µl, platelets < 100,000 cells/µl and untransfused hemoglobin < 10 g/dl.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: N / A
- Modelo Intervencionista: Asignación de un solo grupo
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: High-dose cyclohosphamide
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Cyclophosphamide 50 mg/kg IV each day for four consecutive days.
Glatiramer acetate 20 mg SC daily for 1 year.
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Periodo de tiempo |
---|---|
Safety - Serious adverse events
Periodo de tiempo: 2 years
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2 years
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Medidas de resultado secundarias
Medida de resultado |
Periodo de tiempo |
---|---|
Radiologic - reduction in the number of gadolinium enhancing lesions, T2 plaque burden, and change in brain parenchymal fraction.
Periodo de tiempo: 2 years
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2 years
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Clinical/Neurological - Change in disability
Periodo de tiempo: 2 years
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2 years
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Immunological - change in immune profile
Periodo de tiempo: 2 years
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2 years
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: Justin McArthur, MBBS, MPH, Johns Hopkins University
- Investigador principal: Robert Brodsky, M.D, Johns Hopkins University
- Director de estudio: Daniel Harrison, MD, Johns Hopkins University
Publicaciones y enlaces útiles
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Actual)
Finalización del estudio (Actual)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimar)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Procesos Patológicos
- Enfermedades del Sistema Nervioso
- Enfermedades del sistema inmunológico
- Enfermedades Autoinmunes Desmielinizantes, SNC
- Enfermedades Autoinmunes del Sistema Nervioso
- Enfermedades desmielinizantes
- Enfermedades autoinmunes
- Esclerosis múltiple
- Esclerosis
- Esclerosis Múltiple Recurrente-Remitente
- Efectos fisiológicos de las drogas
- Mecanismos moleculares de acción farmacológica
- Agentes antirreumáticos
- Agentes antineoplásicos
- Agentes inmunosupresores
- Factores inmunológicos
- Agentes antineoplásicos, alquilantes
- Agentes alquilantes
- Agonistas mieloablativos
- Adyuvantes, Inmunológicos
- Ciclofosfamida
- Acetato de Glatirámero
- (T,G)-A-L
Otros números de identificación del estudio
- NA_00016884
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