Efficacy of Cyclophosphamide Versus Methylprednisolone in Patients With Secondary Progressive Multiple Sclerosis (PROMESS)
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Purpose
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 | Intervention | Phase |
|---|---|---|
|
Multiple Sclerosis, Chronic Progressive |
Drug: Cyclophosphamide (drug) Drug: Methylprednisolone (drug) |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, 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 |
- 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 ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
- 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) ] [ Designated as safety issue: No ]
- Number of MS relapses [ Time Frame: all along the follow up period ] [ Designated as safety issue: No ]
- Proportion of patients with adverse events and delay of occurrence of adverse events [ Time Frame: all along the follow up period ] [ Designated as safety issue: Yes ]
- Quality of life questionnaires [ Time Frame: visit 2, 13(at one year) and 19 (at two years) ] [ Designated as safety issue: No ]
- Disability self-assessment questionnaires [ Time Frame: visite 2, 13 et 19 ] [ Designated as safety issue: No ]
| Enrollment: | 138 |
| Study Start Date: | December 2005 |
| Study Completion Date: | March 2012 |
| Primary Completion Date: | March 2010 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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.
|
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.
Eligibility| Ages Eligible for Study: | 18 Years to 65 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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| France | |
| CH de la Cote Basque | |
| Bayonne, France, 64109 | |
| CHU Besançon | |
| Besançon, France, 25030 | |
| Hôpital Pellegrin, Département de neurologie | |
| Bordeaux, France, 33076 | |
| CHU Caen | |
| Caen, France, 14033 | |
| Hôpital Gabriel Montpied | |
| Clermont Ferrand, France, 63003 | |
| AP HP Henri Mondor | |
| Créteil, France, 94010 | |
| CHU Dijon | |
| Dijon, France, 21033 | |
| CHU Lille Hôpital Salengro | |
| Lille, France, 59037 | |
| CHU Limoges | |
| Limoges, France, 87042 | |
| GHICL Hôpital St. Philibert | |
| Lomme, France, 59462 | |
| (CHU Lyon) Hôpital neurologique | |
| Lyon, France, 69394 | |
| Hôpital La Timone | |
| Marseille, France, 13385 | |
| (CHR Metz-Thionville) Hôpital Notre Dame de Bon Secours | |
| Metz, France, 57038 | |
| (CHU Montpellier), Hôpital de Gui de Chauliac | |
| Montpellier, France, 34295 | |
| CHU Nancy Hôpital central | |
| Nancy, France, 54035 | |
| Hôpital Guillaume et René Laënnec | |
| Nantes, France, 44093 | |
| CHU Nice Hôpital Pasteur | |
| Nice, France, 06002 | |
| (CHU Nîmes) Hôpital Caremeau | |
| Nîmes, France, 30029 | |
| (AP HP) Hôpital Tenon | |
| Paris, France, 75970 | |
| Fondation Rothschild | |
| Paris, France, 75019 | |
| Centre Hospitalier de Pau | |
| Pau, France, 64046 | |
| CHU de POISSY | |
| Poissy, France, 78300 | |
| (CHU Reims) Hôpital Robert Debré | |
| Reims, France, 51092 | |
| CHU Ponchaillou | |
| Rennes, France, 35033 | |
| CH d'Angoulême Girac | |
| Saint Michel, France, 16470 | |
| (CHRU Starsbourg) Hôpital civil | |
| Strasbourg, France, 67091 | |
| Principal Investigator: | Bruno Brochet, Professor | University Hospital, Bordeaux, France |
| Study Chair: | Paul Perez, Dr | University Hospital, Bordeaux, France |
More Information
No publications provided
| Responsible Party: | University Hospital, Bordeaux |
| ClinicalTrials.gov Identifier: | NCT00241254 History of Changes |
| Other Study ID Numbers: | 9408-04, 2004-005 |
| Study First Received: | October 17, 2005 |
| Last Updated: | March 14, 2012 |
| Health Authority: | France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) |
Keywords provided by University Hospital, Bordeaux:
|
Multiple Sclerosis, Chronic Progressive Cyclophosphamide Methylprednisolone Randomized Controlled Trials Double-Blind Study |
Additional relevant MeSH terms:
|
Multiple Sclerosis Sclerosis Multiple Sclerosis, Chronic Progressive Demyelinating Autoimmune Diseases, CNS Autoimmune Diseases of the Nervous System Nervous System Diseases Demyelinating Diseases Autoimmune Diseases Immune System Diseases Pathologic Processes Cyclophosphamide Methylprednisolone Hemisuccinate Prednisolone Methylprednisolone acetate Prednisolone acetate |
Methylprednisolone Prednisolone hemisuccinate Prednisolone phosphate 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 Anti-Inflammatory Agents |
ClinicalTrials.gov processed this record on May 16, 2013