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

NCT ID: NCT00241254

Last Updated: 2012-03-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 138 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-12-31
• Study Completion Date: 2012-03-31

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.

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.

Conditions

Multiple Sclerosis, Chronic Progressive

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

1

Cyclophosphamide

Group Type: EXPERIMENTAL

Cyclophosphamide (drug)

Intervention Type: DRUG

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

2

Methylprednisolone

Group Type: ACTIVE_COMPARATOR

Methylprednisolone (drug)

Intervention Type: DRUG

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

Interventions

Cyclophosphamide (drug)

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

Intervention Type: DRUG

Methylprednisolone (drug)

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

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ministry of Health, France

OTHER_GOV

Sponsor Role: collaborator

University Hospital, Bordeaux

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bruno Brochet, Professor

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Bordeaux, France

Paul Perez, Dr

Role: STUDY_CHAIR

University Hospital, Bordeaux, France

Locations

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

Fondation Rothschild

Paris, , France

(AP HP) Hôpital Tenon

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, , France

Countries

France

References

Brochet B, Deloire MS, Perez P, Loock T, Baschet L, Debouverie M, Pittion S, Ouallet JC, Clavelou P, de Seze J, Collongues N, Vermersch P, Zephir H, Castelnovo G, Labauge P, Lebrun C, Cohen M, Ruet A; PROMESS study investigators. Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis. PLoS One. 2017 Jan 3;12(1):e0168834. doi: 10.1371/journal.pone.0168834. eCollection 2017.

Reference Type: DERIVED

PMID: 28045953 (View on PubMed)

Other Identifiers

2004-005

Identifier Type: -

Identifier Source: secondary_id

9408-04

Identifier Type: -

Identifier Source: org_study_id