High Dose Cyclophosphamide Followed by Glatiramer Acetate in the Treatment of Relapsing Remitting Multiple Sclerosis (HiCy)

This study has suspended participant recruitment.
(Suspended for revisions to the protocol.)
Sponsor:
Information provided by:
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00939549
First received: July 14, 2009
Last updated: November 8, 2010
Last verified: November 2010
  Purpose

The purpose of this study is to determine if high-dose cyclophosphamide followed by a maintenance dose of glatiramer acetate is safe in patients with relapsing remitting multiple sclerosis (MS). The investigators 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 multiple sclerosis. The investigators plan to investigate the properties of glatiramer acetate against the recurrence of MS disease activity following high dose cyclophosphamide induced cessation detectable autoimmunity. The investigators hypothesize that glatiramer acetate, given in the phase of immune reconstitution after high-dose cyclophosphamide, may bias the immune system to a more tolerated state, thus leading to more stable and potentially permanent remissions.


Condition Intervention Phase
Relapsing Remitting Multiple Sclerosis
Drug: Cyclophosphamide/Glatiramer acetate
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of High Dose Cyclophosphamide Followed by Glatiramer Acetate in the Treatment of Relapsing Remitting Multiple Sclerosis

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • Safety - Serious adverse events [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Radiologic - reduction in the number of gadolinium enhancing lesions, T2 plaque burden, and change in brain parenchymal fraction. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Clinical/Neurological - Change in disability [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Immunological - change in immune profile [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 12
Study Start Date: March 2011
Estimated Study Completion Date: March 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: High-dose cyclohosphamide Drug: Cyclophosphamide/Glatiramer acetate
Cyclophosphamide 50 mg/kg IV each day for four consecutive days. Glatiramer acetate 20 mg SC daily for 1 year.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  1. Males and females between the ages of 18 and 70 years, inclusive.
  2. Diagnosis of clinically definite MS according to the McDonald Criteria.
  3. 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.
  4. 2 or more total gadolinium enhancing lesions on each of two pretreatment MRI scans at screening and enrollment.
  5. Subject must have EDSS ranging from 1.5 to 6.5.
  6. 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.
  7. 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).
  8. 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.
  9. Women of childbearing potential should have a negative pregnancy test prior to entry into the study.

Exclusion criteria

  1. 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.
  2. Cardiac ejection fraction of < 45%.
  3. Serum creatinine > 2.0.
  4. Patients who are pre-terminal or moribund.
  5. Bilirubin > 2.0, transaminases > 2x normal.
  6. Patients with EDSS < 3.0 or > 6.5.
  7. Patients with pacemakers and implants who cannot get serial MRIs.
  8. Patients with active infections until infection is resolved.
  9. Patients with WBC count < 3000 cells/µl, platelets < 100,000 cells/µl and untransfused hemoglobin < 10 g/dl.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00939549

Locations
United States, Maryland
Johns Hopkins Hospital Multiple Sclerosis Center
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Investigators
Principal Investigator: Justin McArthur, MBBS, MPH Johns Hopkins University
Principal Investigator: Robert Brodsky, M.D Johns Hopkins University
Study Director: Daniel Harrison, MD Johns Hopkins University
  More Information

Publications:
Responsible Party: Justin McArthur, MBBS MPH, Johns Hopkins University School of Medicine
ClinicalTrials.gov Identifier: NCT00939549     History of Changes
Other Study ID Numbers: J0840, NA_00016884
Study First Received: July 14, 2009
Last Updated: November 8, 2010
Health Authority: United States: Institutional Review Board

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
High dose cyclophosphamide

Additional relevant MeSH terms:
Multiple Sclerosis
Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes
Cyclophosphamide
Copolymer 1
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Adjuvants, Immunologic

ClinicalTrials.gov processed this record on April 16, 2014