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Fingolimod Versus Dimethyl-fumarate in Multiple Sclerosis (PRAG-MS)

Primary Purpose

Relapsing Remitting Multiple Sclerosis

Status
Terminated
Phase
Phase 4
Locations
Italy
Study Type
Interventional
Intervention
Fingolimod
Dimethyl Fumarate
Sponsored by
Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsing Remitting Multiple Sclerosis focused on measuring Multiple Sclerosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult patients with RRMS eligible to be treated with both FTY and DMF. Patients eligible for enrolment are patients for whom both drugs can be prescribed, upon clinical judgement and local label indication.
  • Patients must be able to sign and date a written informed consent prior to entering the study. Where the subject is unable to write, consent may be given and recorded through appropriate alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and date the informed consent document.
  • Women of child-bearing potential must have a negative serum pregnancy test before enrollment and must practice an effective method of birth control, in line with normal clinical practice recommendations.

Exclusion Criteria:

  • any FTY/DMF contraindication, as for authorized indications or clinical judgment;
  • present immunodeficiency syndrome (primary or secondary immune deficiency);
  • abnormal lymphocyte count;
  • severe chronic active infections or acute infections not resolved at the time of the enrolment;
  • evidence of active tuberculosis (TB);
  • history of either untreated or inadequately treated latent TB infection;
  • progressive Multifocal Leukoencephalopathy, even if only suspected;
  • active malignancies;
  • severe liver impairment (Child-Pugh class C);
  • macular edema;
  • sieronegative for antibodies IgG anti-VZV;
  • hypersensitivity to the active substances or to any of the excipients;
  • cardiac contraindications to FTY (patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure (HF) requiring hospitalization or Class III/IV HF; history or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker);
  • pregnancy or breastfeeding;
  • concomitant treatment with any other approved or investigational DMTs or other prohibited treatments.

Sites / Locations

  • Fondazione IRCCS Istituto Neurologico C. Besta, Neuroimmunology Unit

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Fingolimod 0.5 mg/day

Dimethyl Fumarate 240 mg twice daily

Arm Description

The study drugs, FTY and DMT, are approved and available on the market and safety and tolerability profile of both the drugs is well known. In our study, patients will be treated according to the clinical practice. Dose: FTY 0.5 mg/day or DMF 240 mg twice daily

The study drugs, FTY and DMT, are approved and available on the market and safety and tolerability profile of both the drugs is well known. In our study, patients will be treated according to the clinical practice. Dose: FTY 0.5 mg/day or DMF 240 mg twice daily

Outcomes

Primary Outcome Measures

effectiveness of fingolimod 0.5 mg once daily versus dimethyl-fumarate 240 mg twice daily
losing the NEDA status

Secondary Outcome Measures

Annual relapse rate
compare the effectiveness of the two oral DMTs in terms of prevention of clinical relapses
Number of Gd+ MRI lesions
compare the effectiveness of the two oral DMTs in terms of prevention of MRI activity
Brain volume loss
compare the effectiveness of the two oral DMTs in terms of prevention of brain atrophy
Prevention of sustained disability progression (EDSS worsening)
percentage of patients with confirmed increase of 1 point on the EDSS scale
Prevention of Objective sustained disability progression
percentage of patients with change in gait performance (limb range of motion) assessed by inertial sensors
Patient-NEDA
Percentage of patients maintaining patient-NEDA status
Prevention of Cognitive decline
Change in cognitive impairment index (CII) assessed by Brief Repeatable Battery of Neuropsychological tests (BRB-N)
Evaluation of social cognition
Change in social cognition assessed by Story based Empathy task (SET)
Evaluation of quality of decision making
Change in quality of decision making assessed by Game of Dice Task (GDT)
Preservation of Quality of life
Multiple Sclerosis Quality of Life-54 (MSQOL-54) is a multidimensional health-related quality of life measure that combines both generic and MS-specific items into a single instrument. This 54-item instrument generates 12 subscales along with 2 summary scores, and 2 additional single-item measures. The MSQOL-54 is a structured, self-report questionnaire that the patient can generally complete with little or no assistance. MSQOL-54 scale scores are expressed on a 0-100 scale: higher scores indicating better functioning. There is no single overall score. Two summary scores, physical health and mental health, can be derived from a weighted combination of scale scores. In addition there are 12 subscales: physical function, role limitations-physical, role limitations-emotional, pain, emotional well-being, energy, health perceptions, social function, cognitive function, health distress, overall quality of life, sexual function and satisfaction with sexual function and change in health.
Convenience perception
Convenience perception as measured by the convenience scale within Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). The scores in each domain of the TSQM-9 will be calculated as recommended by the instrument's authors (Atkinson MJ, et all. Health Qual Life Outcomes. 2004 Feb 26; 2:12)
Psychiatric symptoms
Symptomatic changes as determinated by Hospital Anxiety & Depression Scale (HADS). HADS anxiety (HADS-A) and depression (HADS-D) scores range from 0 (no symptoms) to 21 (most severe Study Protocol, VS1 Page 26 of 48 symptoms).
Fatigue
Symptomatic changes as determinated by Modified Fatigue Impact Scale (MFIS). The MFIS is a valid and reliable 21-question scale (score range, 0-84), with lower total scores indicating lower impact of fatigue on patient function.

Full Information

First Posted
May 16, 2017
Last Updated
October 29, 2019
Sponsor
Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Collaborators
Patient-Centered Outcomes Research Institute, Universita degli Studi di Genova
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1. Study Identification

Unique Protocol Identification Number
NCT03345940
Brief Title
Fingolimod Versus Dimethyl-fumarate in Multiple Sclerosis
Acronym
PRAG-MS
Official Title
A Multicentric Randomized PRAGmatic Trial to Compare the Effectiveness of Fingolimod Versus Dimethyl-Fumarate on Patient Overall Disease Experience in Relapsing Remitting Multiple Sclerosis: Novel Data to Inform Decision-makers
Study Type
Interventional

2. Study Status

Record Verification Date
October 2019
Overall Recruitment Status
Terminated
Why Stopped
termination of the study due to the slowness of the recruitment activity, according to the contract signed with the Sponsor
Study Start Date
April 30, 2017 (Actual)
Primary Completion Date
October 30, 2019 (Actual)
Study Completion Date
October 30, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Collaborators
Patient-Centered Outcomes Research Institute, Universita degli Studi di Genova

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This will be a 1:1 randomized open label trial. European and outside Europe centres will be involved. Aim of the project is to conduct a head-to-head comparison of effectiveness of two approved disease modifying treatments (DMTs) in patients with relapsing remitting multiple sclerosis (RRMS). The term effectiveness refers to efficacy in a real life setting: this is intended to be in fact the first pragmatic multi-centre randomised controlled trial to directly assess the effectiveness of the new oral agents approved for MS (fingolimod/FTY versus dimethyl-fumarate/DMF) on disease activity, disability progression, quality of life, functioning and symptoms. It will be a randomized trial taking place in clinical care setting and comparing existing therapies, any of which may constitute standard care for naive patients or sub optimal responders to first-line drugs. Post hoc analysis will also identify the better treatment strategy on the different patient subgroups. Patient overall disease experience will be considered for the first time as the most important outcome. In fact, in addition to classical "no evidence of disease activity" (NEDA), a new composite NEDA taking account also of patient point of view and quality of life, will be proposed. Finally,the specific effectiveness profile of the two DMTs will be addressed, by exploring comparative benefits on different outcomes (disease activity, disability progression, brain atrophy, quality of life, fatigue, psychiatric and cognitive symptoms, medication satisfaction).
Detailed Description
Background and significance 1. The expansion of the treatment landscape in MS has increased the complexity of treatment decisions. Recommendations and algorithms can help to maximize the benefit of each available therapy; however, there is currently no consensus algorithm available, with most of the recently published recommendations being regional and most guidelines currently used in clinical practice, being driven by the labels of the therapies. The lack of head-to-head clinical trials for approved drugs is crucial since head-to-head trials constitute the gold standard for efficacy comparisons. This kind of information is mandatory for informed and objective health decisions. The present proposal aims at filling this critical gap in evidence. Randomized head-to-head trials are the best method for evaluating the efficacy of different treatments and to help the clinicians and the patients in health decision making. Randomized controlled trials, designed as experiments with high internal validity, have the ability to determine cause effect relationships. These experiments employ comprehensive designs to control for most, if not all, sources of bias by means of randomization, blinding, allocation concealment, etc. Usually, extended inclusion and exclusion criteria are used to identify a clearly defined population group of participants who would benefit from the intervention under investigation. Although the above experimental design, if correctly applied, leads to well-controlled trials with statistically credible results, the applicability of these results to real life practice may be questionable. Here the investigators aim at conducting a comparative open label trial preserving the internal validity due to randomization and generalizability due to a pragmatic design. The term pragmatic is used for trials designed to test the effectiveness of the intervention in a broad routine clinical practice. The explanatory trial is designed in order to control for all known biases and confounders, so that the intervention's effect is maximized. The pragmatic trial, on the other hand, is designed to test interventions in the full spectrum of everyday clinical settings in order to maximize applicability and generalizability.1 This is intended to be the first pragmatic multi-centre randomised controlled trial to directly assess the effectiveness of the new oral agents approved for MS (FTY/gilenya versus DMF/tecfidera). FTY (0.5 mg/day) and DMF (240 mg twice daily) are both efficacious in the treatment of MS and both offer the convenience of an oral administration. As such they are similarly valuable alternative treatments for MS patients, and are indeed frequently proposed as possible alternative treatment options to MS patients. Indication for FTY is restricted in Europe to second line in first-line therapy non responders or in active naïve patients. DMF is highly prescribed also in active naive patients and as switching strategy in patients who do not adequately respond to self-injectable DMTs, such as FTY. The need for randomized trials with approved drugs exists when treatment decision in clinical practice is challenged by the lack of evidence of superiority of one drug for a specific group of patients. The efficacy profile of the two oral drug have been characterized in large clinical development programs. Oral therapies have been shown to offer benefits with regard to these clinical and MRI outcomes when compared with placebo in phase 3 trials.2-5 The clinical efficacy of these therapies over traditional injectable DMTs has been demonstrated for FTY in the trial assessing injectable interferon versus FTY720 oral in RRMS (TRANSFORMS).6 Findings of these phase 3 trials indicate that oral therapies may represent an advance in the treatment of MS because they offer effective treatment options that are often better tolerated and more convenient than the traditional injectable DMTs. There are no head-to-head controlled trials comparing the efficacy of the different oral DMTs. This is an area of much interest to neurologists and healthcare decision makers; therefore, indirect treatment comparisons have recently been performed. Of these, a recent study has compared FTY with DMF using a network meta-analysis approach and found no significant differences in relapse rate or in the proportion of patients with disability progression.7 Standard network meta-analysis methods may be susceptible to bias because of differences in trial populations and methodologies. Subgroup and post hoc analyses of the phase 3 trials of DMTs have demonstrated that differences in patient baseline characteristics influence the observed effect of DMTs on relapse rate and disability progression,6,8 and that the application of different definitions of disability progression has a large impact on disability outcomes.9 Therefore, it is important to adjust for these potentially confounding factors when assessing the comparative efficacy of these oral DMTs. It has been reported that FTY therapy results in a higher probability of no evidence of disease activity (NEDA) than DMF therapy when phase 3 trial data are indirectly compared and differences between trials are adjusted for.10 These findings must, however, be interpreted with caution, owing to the assumptions inherent in any modeling approach. The need for high-quality, widely applicable evidence is gaining momentum, especially amidst health care policy makers. The increased costs of interventions and health care in a resource-limited environment have fueled the demand for clinically effective and applicable evidence. Here the investigators aim at conducting a comparative open label trial preserving the internal validity due to randomization and generalizability due to a pragmatic design. It will be the first randomized pragmatic trials in MS. Policy makers have an active interest in pragmatic trials, since these are designed to answer the question most relevant to a decision maker's agenda: comparative effectiveness of interventions in the routine practice. The availability of comparative data from routine practice will help policy makers to efficiently allocate resources and manpower and will drive patients and clinicians in shared and informed health decisions. The evolving MS landscape, in which a number of new treatments are appearing-each with their own benefits and risks-will require a change in the nature of interactions between patients and their physicians, with a shared approach to clinical decision making that emphasizes patient-related goals. Together, these innovations in MS management offer exciting new opportunities to optimize treatment outcomes. This will necessitate attention both to traditional clinical endpoints such as relapses and disability, to objective radiological surrogates of disease activity, and to newer outcome measures such as brain atrophy , cognition and patient-reported outcomes. In line with this, the present proposal aims at comparing the effectiveness of two oral MS agents on patient overall disease experience. If, traditionally, both clinical trials and routine medical care have relied on outcomes assessed by healthcare professionals, here the investigators want to focus also on the importance of self-evaluation of health, thus growing participation of individuals in their own care. The investigators can foresee a continuum where patient empowerment contributes to improve his/her healthcare and, at the same time, makes valuable medical data accessible to the medical community for future therapeutic developments. The whole idea of applicable and generalizable research is very appealing and of benefit to the health sciences community.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsing Remitting Multiple Sclerosis
Keywords
Multiple Sclerosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
55 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Fingolimod 0.5 mg/day
Arm Type
Active Comparator
Arm Description
The study drugs, FTY and DMT, are approved and available on the market and safety and tolerability profile of both the drugs is well known. In our study, patients will be treated according to the clinical practice. Dose: FTY 0.5 mg/day or DMF 240 mg twice daily
Arm Title
Dimethyl Fumarate 240 mg twice daily
Arm Type
Active Comparator
Arm Description
The study drugs, FTY and DMT, are approved and available on the market and safety and tolerability profile of both the drugs is well known. In our study, patients will be treated according to the clinical practice. Dose: FTY 0.5 mg/day or DMF 240 mg twice daily
Intervention Type
Drug
Intervention Name(s)
Fingolimod
Intervention Description
Fingolimod is a currently approved oral DMT for the treatment of relapsing remitting MS. It modulates sphingosine-1 phosphate receptors.
Intervention Type
Drug
Intervention Name(s)
Dimethyl Fumarate
Intervention Description
Dimethyl Fumarate is a currently approved oral DMT for the treatment of relapsing remitting MS. The mode of action comprises immunomodulatory effects and an activation of nuclear (erythroid-derived 2) related factor mediated antioxidative response pathways leading to additional cytoprotective effects.
Primary Outcome Measure Information:
Title
effectiveness of fingolimod 0.5 mg once daily versus dimethyl-fumarate 240 mg twice daily
Description
losing the NEDA status
Time Frame
24 Months
Secondary Outcome Measure Information:
Title
Annual relapse rate
Description
compare the effectiveness of the two oral DMTs in terms of prevention of clinical relapses
Time Frame
over 12 and 24 months
Title
Number of Gd+ MRI lesions
Description
compare the effectiveness of the two oral DMTs in terms of prevention of MRI activity
Time Frame
at 12 and 24 months
Title
Brain volume loss
Description
compare the effectiveness of the two oral DMTs in terms of prevention of brain atrophy
Time Frame
at 12 and 24 months
Title
Prevention of sustained disability progression (EDSS worsening)
Description
percentage of patients with confirmed increase of 1 point on the EDSS scale
Time Frame
over 24 months
Title
Prevention of Objective sustained disability progression
Description
percentage of patients with change in gait performance (limb range of motion) assessed by inertial sensors
Time Frame
over 12 and 24 months
Title
Patient-NEDA
Description
Percentage of patients maintaining patient-NEDA status
Time Frame
over 24 months
Title
Prevention of Cognitive decline
Description
Change in cognitive impairment index (CII) assessed by Brief Repeatable Battery of Neuropsychological tests (BRB-N)
Time Frame
over 12 and 24 months
Title
Evaluation of social cognition
Description
Change in social cognition assessed by Story based Empathy task (SET)
Time Frame
over 12 and 24 months
Title
Evaluation of quality of decision making
Description
Change in quality of decision making assessed by Game of Dice Task (GDT)
Time Frame
over 12 and 24 months
Title
Preservation of Quality of life
Description
Multiple Sclerosis Quality of Life-54 (MSQOL-54) is a multidimensional health-related quality of life measure that combines both generic and MS-specific items into a single instrument. This 54-item instrument generates 12 subscales along with 2 summary scores, and 2 additional single-item measures. The MSQOL-54 is a structured, self-report questionnaire that the patient can generally complete with little or no assistance. MSQOL-54 scale scores are expressed on a 0-100 scale: higher scores indicating better functioning. There is no single overall score. Two summary scores, physical health and mental health, can be derived from a weighted combination of scale scores. In addition there are 12 subscales: physical function, role limitations-physical, role limitations-emotional, pain, emotional well-being, energy, health perceptions, social function, cognitive function, health distress, overall quality of life, sexual function and satisfaction with sexual function and change in health.
Time Frame
over 12 and 24 months
Title
Convenience perception
Description
Convenience perception as measured by the convenience scale within Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). The scores in each domain of the TSQM-9 will be calculated as recommended by the instrument's authors (Atkinson MJ, et all. Health Qual Life Outcomes. 2004 Feb 26; 2:12)
Time Frame
over 12 and 24 months
Title
Psychiatric symptoms
Description
Symptomatic changes as determinated by Hospital Anxiety & Depression Scale (HADS). HADS anxiety (HADS-A) and depression (HADS-D) scores range from 0 (no symptoms) to 21 (most severe Study Protocol, VS1 Page 26 of 48 symptoms).
Time Frame
over 12 and 24 months
Title
Fatigue
Description
Symptomatic changes as determinated by Modified Fatigue Impact Scale (MFIS). The MFIS is a valid and reliable 21-question scale (score range, 0-84), with lower total scores indicating lower impact of fatigue on patient function.
Time Frame
over 12 and 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult patients with RRMS eligible to be treated with both FTY and DMF. Patients eligible for enrolment are patients for whom both drugs can be prescribed, upon clinical judgement and local label indication. Patients must be able to sign and date a written informed consent prior to entering the study. Where the subject is unable to write, consent may be given and recorded through appropriate alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and date the informed consent document. Women of child-bearing potential must have a negative serum pregnancy test before enrollment and must practice an effective method of birth control, in line with normal clinical practice recommendations. Exclusion Criteria: any FTY/DMF contraindication, as for authorized indications or clinical judgment; present immunodeficiency syndrome (primary or secondary immune deficiency); abnormal lymphocyte count; severe chronic active infections or acute infections not resolved at the time of the enrolment; evidence of active tuberculosis (TB); history of either untreated or inadequately treated latent TB infection; progressive Multifocal Leukoencephalopathy, even if only suspected; active malignancies; severe liver impairment (Child-Pugh class C); macular edema; sieronegative for antibodies IgG anti-VZV; hypersensitivity to the active substances or to any of the excipients; cardiac contraindications to FTY (patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure (HF) requiring hospitalization or Class III/IV HF; history or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker); pregnancy or breastfeeding; concomitant treatment with any other approved or investigational DMTs or other prohibited treatments.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Renato Mantegazza, MD
Organizational Affiliation
Fondazione IRCCS Istituto Neurologico Carlo Besta
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fondazione IRCCS Istituto Neurologico C. Besta, Neuroimmunology Unit
City
Milan
ZIP/Postal Code
20133
Country
Italy

12. IPD Sharing Statement

Plan to Share IPD
Undecided
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http://novartis.medicalcongressposters.com/Default.aspx?doc=9ce32
Description
9. Bergvall N, Sfikas N, Alsop J, Chin P, von Rosensteil P, Kappos L. Consequences of different definitions of confirmed disability progression across randomised trials of MS therapies.

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Fingolimod Versus Dimethyl-fumarate in Multiple Sclerosis

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