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

Condition(s) targeted: Multiple Sclerosis, Chronic Progressive

Intervention: Cyclophosphamide (drug) (Drug); Methylprednisolone (drug) (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: University Hospital, Bordeaux

Official(s) and/or principal investigator(s):
Bruno Brochet, Professor, Principal Investigator, Affiliation: University Hospital, Bordeaux, France
Paul Perez, Dr, Study Chair, Affiliation: University Hospital, Bordeaux, France

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.

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 design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

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)

Secondary outcome:

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

Disability self-assessment questionnaires

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.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

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.

CH de la Cote Basque, Bayonne 64109, France

CHU Besançon, Besançon 25030, France

Hôpital Pellegrin, Département de neurologie, Bordeaux 33076, France

CHU Caen, Caen 14033, France

Hôpital Gabriel Montpied, Clermont Ferrand 63003, France

AP HP Henri Mondor, Créteil 94010, France

CHU Dijon, Dijon 21033, France

CHU Lille Hôpital Salengro, Lille 59037, France

CHU Limoges, Limoges 87042, France

GHICL Hôpital St. Philibert, Lomme 59462, France

(CHU Lyon) Hôpital neurologique, Lyon 69394, France

Hôpital La Timone, Marseille 13385, France

(CHR Metz-Thionville) Hôpital Notre Dame de Bon Secours, Metz 57038, France

(CHU Montpellier), Hôpital de Gui de Chauliac, Montpellier 34295, France

CHU Nancy Hôpital central, Nancy 54035, France

Hôpital Guillaume et René Laënnec, Nantes 44093, France

CHU Nice Hôpital Pasteur, Nice 06002, France

(CHU Nîmes) Hôpital Caremeau, Nîmes 30029, France

(AP HP) Hôpital Tenon, Paris 75970, France

Fondation Rothschild, Paris 75019, France

Centre Hospitalier de Pau, Pau 64046, France

CHU de POISSY, Poissy 78300, France

(CHU Reims) Hôpital Robert Debré, Reims 51092, France

CHU Ponchaillou, Rennes 35033, France

CH d'Angoulême Girac, Saint Michel 16470, France

(CHRU Starsbourg) Hôpital civil, Strasbourg 67091, France

Starting date: December 2005
Last updated: March 14, 2012