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Efficacy of Cyclophosphamide Versus Methylprednisolone in Patients With Secondary Progressive Multiple Sclerosis (PROMESS)

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ClinicalTrials.gov Identifier: NCT00241254
Recruitment Status : Completed
First Posted : October 18, 2005
Last Update Posted : March 15, 2012
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by (Responsible Party):
University Hospital, Bordeaux

Study Description
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Brief Summary:
Preliminary not-controlled clinical studies of the efficacy of monthly intravenous cyclophosphamide administration in secondary progressive multiple sclerosis reported encouraging results, but no randomized controlled trial has been conducted so far. The primary objective of this trial is to evaluate the efficacy of IV cyclophosphamide as compared to IV methylprednisolone administered every 4 weeks during 1 year and every 8 weeks during 1 year, on the delay to confirmed disability deterioration as assessed by the Expanded Disability Status Scale (EDSS) in patients with secondary progressive multiple sclerosis. The secondary objectives are to evaluate safety, tolerability and efficacy at 2 years on the Multiple Sclerosis Functional Composite (MSFC), the percentage of patients with disability deterioration (EDSS) and the number of relapses. An intention-to-treat statistical analysis will be carried out.

Condition or disease Intervention/treatment Phase
Multiple Sclerosis, Chronic Progressive Drug: Cyclophosphamide (drug) Drug: Methylprednisolone (drug) Phase 3

Detailed Description:

Background

Preliminary not-controlled clinical studies of the efficacy of monthly intravenous cyclophosphamide administration in secondary progressive multiple sclerosis reported encouraging results, but no randomized controlled trial has been conducted so far. A slight efficacy of Methylprednisolone has been reported in this indication.

Objectives

The primary objective is to evaluate the efficacy of IV cyclophosphamide on the prevention of disability deterioration in patients with secondary progressive multiple sclerosis.

The secondary objectives are to evaluate safety, tolerability and efficacy of IV cyclophosphamide on the Multiple Sclerosis Functional Composite (MSFC) and the number of relapses.

Study design

Randomized double-blind two-arm controlled trial.

Intervention

Experimental group : IV cyclophosphamide infusion administered every 4 weeks during 1 year and every 8 weeks during 1 year.

Control group : IV methylprednisolone infusion administered every 4 weeks during 1 year and every 8 weeks during 1 year.

Outcomes

Primary outcome : delay to disability deterioration as assessed by the Expanded Disability Status Scale (EDSS: 0.5 or 1 point increase, depending on baseline score) evaluated every 4 weeks for one year, then every 8 weeks for one year.

Secondary outcomes : proportion of patients with disability deterioration (EDSS: 0.5 or 1 point increase, depending on baseline score), Multiple Sclerosis Functional Composite (MSFC) and the Z scores of MSFC three components, number of MS relapses, proportion of patients with adverse events and delay of occurrence of adverse events, quality of life questionnaires.

  • Quality of life questionnaires
  • Disability self-assessment questionnaires Main time of assessment : 2 years.

Sample size

360 patients

Statistical analysis

Intention-to-treat analysis.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 138 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Double-blind, Two-arm, Multicenter, Randomized Trial to Evaluate Efficacy of Cyclophosphamide Versus Methylprednisolone in Patients With Recent Secondary Progressive Multiple Sclerosis: P.R.OM.E.S.S Study
Study Start Date : December 2005
Actual Primary Completion Date : March 2010
Actual Study Completion Date : March 2012

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: 1
Cyclophosphamide
 Drug: Cyclophosphamide (drug)
IV cyclophosphamide infusion administered every 4 weeks during 1 year and every 8 weeks during 1 year.
Active Comparator: 2
Methylprednisolone
 Drug: Methylprednisolone (drug)
Control group : IV methylprednisolone infusion administered every 4 weeks during 1 year and every 8 weeks during 1 year.


Outcome Measures
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Primary Outcome Measures :
  1. Delay to disability deterioration as assessed by the Expanded Disability Status Scale (EDSS: 0.5 or 1 point increase, depending on baseline score) [ Time Frame: every 4 weeks for one year, then every 8 weeks for one year ]

Secondary Outcome Measures :
  1. Proportion of patients with disability deterioration (EDSS: 0.5 or 1 point increase, depending on baseline score) [ Time Frame: every month during one year then every two months during the 2nd year ]
  2. Multiple Sclerosis Functional Composite (MSFC) and the Z scores of MSFC three components [ Time Frame: Visit number 1, 2, 13(at one year),19 (at two years) and 20 (last visit) ]
  3. Number of MS relapses [ Time Frame: all along the follow up period ]
  4. Proportion of patients with adverse events and delay of occurrence of adverse events [ Time Frame: all along the follow up period ]
  5. Quality of life questionnaires [ Time Frame: visit 2, 13(at one year) and 19 (at two years) ]
  6. Disability self-assessment questionnaires [ Time Frame: visite 2, 13 et 19 ]

Eligibility Criteria
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Layout table for eligibility information
Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Multiple sclerosis (MS) subjects (Mc Donald et al criteria),
  • Aged 18 to 65
  • Diagnosis of secondary progressive MS ( Lublin and Reingold criteria)
  • Progressive deterioration phase of at least 6 months and less than 4 years.
  • Reduction of walking capacity and increase EDSS not ascribed to consequence of relapses (at least 0.5 point) in the last 12 months
  • EDSS between 4.0 and 6.5 included
  • Female participating must use contraceptives while on study drug
  • Written informed consent
  • Patient protected by French social security system

Exclusion Criteria:

  • Others diseases interfering with MS or treatment
  • Recent history (within the previous 2 years) of drug or alcohol abuse.
  • Patients with psychiatric illnesses who are unable to provide written, informed consent prior to any testing under this protocol
  • Hemorrhagic cystitis
  • Pregnant or lactating women
  • Known allergy at cyclophosphamide, corticoids and in particular methylprednisolone
  • Persistent infectious diseases
  • Patients with bladder permanent catheterization
  • Known history of cardiac arrhythmia after methylprednisolone intravenous treatment
  • Abnormal screening/baseline blood tests exceeding any of the limits defined below : Hb < 9g/dl or Total white blood cell count less than 3 000/mm3 or lymphocytes count less than 900/ mm3 or Platelet count less than 125 000/mm3
  • Gastric or duodenal ulcer in evolution
  • Gut diverticulosis
  • Diabetes mellitus
  • Known history of active hepatitis (ASAT >3 X ULN)
  • Known history of renal failure (creatinine level > 180 µmol/L)
  • Psychosis
  • Current or past (< 3 months) participation in another drug trial
  • Prior use of cyclophosphamide, lymphoid irradiation, monoclonal antibodies anti CD4 or anti CD52 or anti-VLA-4 therapies, cladribine ou cyclosporine A
  • Other clinical types of MS : Secondary progressive phase evolving for more than 4 years ; Remittent type of MS without progression between relapses ; Primary progressive type of MS
  • Use of interferon beta, methotrexate or imurel in the month prior to study.
  • Treatment with intravenous monthly corticoids in the year prior to study.
  • Treatment with corticoids (3 to 5 days) in the 2 month prior to study.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00241254


Locations
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Sponsors and Collaborators
University Hospital, Bordeaux
Ministry of Health, France
Investigators
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Principal Investigator: Bruno Brochet, Professor University Hospital, Bordeaux, France
Study Chair: Paul Perez, Dr University Hospital, Bordeaux, France
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: University Hospital, Bordeaux
ClinicalTrials.gov Identifier: NCT00241254    
Other Study ID Numbers: 9408-04
2004-005
First Posted: October 18, 2005    Key Record Dates
Last Update Posted: March 15, 2012
Last Verified: March 2012
Keywords provided by University Hospital, Bordeaux:
Multiple Sclerosis, Chronic Progressive
Cyclophosphamide
Methylprednisolone
Randomized Controlled Trials
Double-Blind Study
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Chronic Progressive
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
 Cyclophosphamide
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents