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

Sponsor

University Hospital, Bordeaux (Other)

Overall Status

Completed

CT.gov ID

NCT00241254

Collaborator

Ministry of Health, France (Other)

138

Enrollment

Locations

Arms

Duration (Months)

5.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

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

Study Type:

Interventional

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 :

Dec 1, 2005

Actual Primary Completion Date :

Mar 1, 2010

Actual Study Completion Date :

Mar 1, 2012

Arms and Interventions

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.

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

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	Country	Postal Code
1	CH de la Cote Basque	Bayonne	France	64109
2	CHU Besançon	Besançon	France	25030
3	Hôpital Pellegrin, Département de neurologie	Bordeaux	France	33076
4	CHU Caen	Caen	France	14033
5	Hôpital Gabriel Montpied	Clermont Ferrand	France	63003
6	AP HP Henri Mondor	Créteil	France	94010
7	CHU Dijon	Dijon	France	21033
8	CHU Lille Hôpital Salengro	Lille	France	59037
9	CHU Limoges	Limoges	France	87042
10	GHICL Hôpital St. Philibert	Lomme	France	59462
11	(CHU Lyon) Hôpital neurologique	Lyon	France	69394
12	Hôpital La Timone	Marseille	France	13385
13	(CHR Metz-Thionville) Hôpital Notre Dame de Bon Secours	Metz	France	57038
14	(CHU Montpellier), Hôpital de Gui de Chauliac	Montpellier	France	34295
15	CHU Nancy Hôpital central	Nancy	France	54035
16	Hôpital Guillaume et René Laënnec	Nantes	France	44093
17	CHU Nice Hôpital Pasteur	Nice	France	06002
18	(CHU Nîmes) Hôpital Caremeau	Nîmes	France	30029
19	Fondation Rothschild	Paris	France	75019
20	(AP HP) Hôpital Tenon	Paris	France	75970
21	Centre Hospitalier de Pau	Pau	France	64046
22	CHU de POISSY	Poissy	France	78300
23	(CHU Reims) Hôpital Robert Debré	Reims	France	51092
24	CHU Ponchaillou	Rennes	France	35033
25	CH d'Angoulême Girac	Saint Michel	France	16470
26	(CHRU Starsbourg) Hôpital civil	Strasbourg	France	67091

Sponsors and Collaborators

University Hospital, Bordeaux
Ministry of Health, France

Investigators

Principal Investigator: Bruno Brochet, Professor, University Hospital, Bordeaux, France
Study Chair: Paul Perez, Dr, University Hospital, Bordeaux, France