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

Multiple Sclerosis, Chronic Progressive Clinical Trial

— PROMESS  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00241254
• Other study ID #: 9408-04
• Secondary ID: 2004-005
• Status: Completed
• Phase: Phase 3
• First received: October 17, 2005
• Last updated: March 14, 2012
• Start date: December 2005
• Est. completion date: March 2012

Study information

• Verified date: March 2012
• Source: University Hospital, Bordeaux
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 138
• Est. completion date: March 2012
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Chronic Progressive
• Sclerosis

Intervention

Drug:
• Cyclophosphamide (drug)
IV cyclophosphamide infusion administered every 4 weeks during 1 year and every 8 weeks during 1 year.
• Methylprednisolone (drug)
Control group : IV methylprednisolone infusion administered every 4 weeks during 1 year and every 8 weeks during 1 year.

Locations

Country	Name	City	State
France	CH de la Cote Basque	Bayonne
France	CHU Besançon	Besançon
France	Hôpital Pellegrin, Département de neurologie	Bordeaux
France	CHU Caen	Caen
France	Hôpital Gabriel Montpied	Clermont Ferrand
France	AP HP Henri Mondor	Créteil
France	CHU Dijon	Dijon
France	CHU Lille Hôpital Salengro	Lille
France	CHU Limoges	Limoges
France	GHICL Hôpital St. Philibert	Lomme
France	(CHU Lyon) Hôpital neurologique	Lyon
France	Hôpital La Timone	Marseille
France	(CHR Metz-Thionville) Hôpital Notre Dame de Bon Secours	Metz
France	(CHU Montpellier), Hôpital de Gui de Chauliac	Montpellier
France	CHU Nancy Hôpital central	Nancy
France	Hôpital Guillaume et René Laënnec	Nantes
France	CHU Nice Hôpital Pasteur	Nice
France	(CHU Nîmes) Hôpital Caremeau	Nîmes
France	(AP HP) Hôpital Tenon	Paris
France	Fondation Rothschild	Paris
France	Centre Hospitalier de Pau	Pau
France	CHU de POISSY	Poissy
France	(CHU Reims) Hôpital Robert Debré	Reims
France	CHU Ponchaillou	Rennes
France	CH d'Angoulême Girac	Saint Michel
France	(CHRU Starsbourg) Hôpital civil	Strasbourg

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Bordeaux	Ministry of Health, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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)	No
Secondary	Number of MS relapses		all along the follow up period	No
Secondary	Proportion of patients with adverse events and delay of occurrence of adverse events		all along the follow up period	Yes
Secondary	Quality of life questionnaires		visit 2, 13(at one year) and 19 (at two years)	No
Secondary	Disability self-assessment questionnaires		visite 2, 13 et 19	No