Fingolimod Versus Dimethyl-fumarate in Multiple Sclerosis

NCT03345940 | Terminated Phase 4 DMC

• 1 other identifier: 2017-000559-26
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

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).

Conditions

Relapsing Remitting Multiple Sclerosis

Keywords

Multiple Sclerosis

Outcome Measures

Primary Outcomes (1)

• effectiveness of fingolimod 0.5 mg once daily versus dimethyl-fumarate 240 mg twice daily

  losing the NEDA status

  24 Months

Secondary Outcomes (13)

• Annual relapse rate

  over 12 and 24 months

• Number of Gd+ MRI lesions

  at 12 and 24 months

• Brain volume loss

  at 12 and 24 months

• Prevention of sustained disability progression (EDSS worsening)

  over 24 months

• Prevention of Objective sustained disability progression

  over 12 and 24 months

Study Arms (2)

Fingolimod 0.5 mg/day

ACTIVE COMPARATOR

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

Drug: Fingolimod

Dimethyl Fumarate 240 mg twice daily

ACTIVE COMPARATOR

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

Drug: Dimethyl Fumarate

Interventions

Fingolimod DRUG

Fingolimod is a currently approved oral DMT for the treatment of relapsing remitting MS. It modulates sphingosine-1 phosphate receptors.

Fingolimod 0.5 mg/day

Dimethyl Fumarate DRUG

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.

Dimethyl Fumarate 240 mg twice daily

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta: lead
• Patient-Centered Outcomes Research Institute: collaborator
• Universita degli Studi di Genova: collaborator

Study Sites (1)

Fondazione IRCCS Istituto Neurologico C. Besta, Neuroimmunology Unit

Milan, 20133, Italy

Location

Related Publications (9)

• Patsopoulos NA. A pragmatic view on pragmatic trials. Dialogues Clin Neurosci. 2011;13(2):217-24. doi: 10.31887/DCNS.2011.13.2/npatsopoulos.

  PMID: 21842619 BACKGROUND

• Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, Li B, Cappiello L, von Rosenstiel P, Lublin FD. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Jun;13(6):545-56. doi: 10.1016/S1474-4422(14)70049-3. Epub 2014 Mar 28.

  PMID: 24685276 BACKGROUND

• Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):387-401. doi: 10.1056/NEJMoa0909494. Epub 2010 Jan 20.

  PMID: 20089952 BACKGROUND

• Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT; CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1087-97. doi: 10.1056/NEJMoa1206328.

  PMID: 22992072 BACKGROUND

• Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1098-107. doi: 10.1056/NEJMoa1114287.

  PMID: 22992073 BACKGROUND

• Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):402-15. doi: 10.1056/NEJMoa0907839. Epub 2010 Jan 20.

  PMID: 20089954 BACKGROUND

• Hutchinson M, Fox RJ, Havrdova E, Kurukulasuriya NC, Sarda SP, Agarwal S, Siddiqui MK, Taneja A, Deniz B. Efficacy and safety of BG-12 (dimethyl fumarate) and other disease-modifying therapies for the treatment of relapsing-remitting multiple sclerosis: a systematic review and mixed treatment comparison. Curr Med Res Opin. 2014 Apr;30(4):613-27. doi: 10.1185/03007995.2013.863755. Epub 2013 Nov 26.

  PMID: 24195574 BACKGROUND

• Giovannoni G, Cook S, Rammohan K, Rieckmann P, Sorensen PS, Vermersch P, Hamlett A, Viglietta V, Greenberg S; CLARITY study group. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol. 2011 Apr;10(4):329-37. doi: 10.1016/S1474-4422(11)70023-0.

  PMID: 21397565 BACKGROUND

• Nixon R, Bergvall N, Tomic D, Sfikas N, Cutter G, Giovannoni G. No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis. Adv Ther. 2014 Nov;31(11):1134-54. doi: 10.1007/s12325-014-0167-z. Epub 2014 Nov 21.

  PMID: 25414048 BACKGROUND

Related Links

• 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.

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis

Interventions

Fingolimod Hydrochloride; Dimethyl Fumarate

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Sphingosine; Amino Alcohols; Alcohols; Organic Chemicals; Propylene Glycols; Glycols; Amines; Fumarates; Dicarboxylic Acids; Acids, Acyclic; Carboxylic Acids

Study Officials

• Renato Mantegazza, MD

  Fondazione IRCCS Istituto Neurologico Carlo Besta

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2017
• First Posted: November 17, 2017
• Study Start: April 30, 2017
• Primary Completion: October 30, 2019
• Study Completion: October 30, 2019
• Last Updated: October 31, 2019

Record last verified: 2019-10

Locations

IT (1)