Research Focus Overview

Research Focus Overview

The Mellen Center in Cleveland and the Lou Ruvo Center for Brain Health in Las Vegas have very active clinical trials and experimental therapeutics programs. Dr. Ontaneda directs the overall program, but all Mellen Center professional staff and fellows participate in clinical trials in various roles. Clinical trials have investigated disease modifying therapies, overall treatment approaches, neuroprotective strategies, and repair-promoting strategies (including cell-based therapies) in relapsing and progressive multiple sclerosis, pediatric multiple sclerosis, neuromyelitis optica spectrum disorders, myelin oligodendrocyte antibody associated disease, and autoimmune encephalitis. These trials have included Phase 1 safety studies, Phase 2 proof-of-concept trials, pivotal Phase 3 trials, long-term extension studies, and phase 4 post-marketing studies.

The Mellen Center Academic Coordinating Center provides academic administration for multicenter trials, including trial design, core laboratories, data management, and statistical analysis. Mellen Center staff have been involved in varying capacities in the development of nearly every medication approved to treat multiple sclerosis and have served as the Coordinating Principal Investigator of multinational industry-sponsored pivotal Phase 3 trials, including IMPACT (interferon beta-1a), SENTINEL (natalizumab), TRANSFORMS (fingolimod), FORTE (glatiramer acetate), CONFIRM (dimethyl fumarate), GATE (generic glatiramer acetate), and RADIANCE (ozanimod). In addition, Mellen staff have served on numerous study steering committees, data safety monitoring boards, eligibility or endpoint adjudication committees, advisory committees, and grant peer-review committees.

The Mellen Center is involved not only in industry-sponsored studies but staff also have directed several large, grant-funded trials, including a Phase 1/2 trial of mesenchymal stem cell transplantation supported by Department of Defense (DOD) and National Institutes of Health (NIH), a multicenter Phase 2 trial of ibudilast funded by NIH and conducted through the NeuroNext network, an international pragmatic trial of escalation versus early highly efficacious therapeutic strategies supported by Patient-Centered Outcomes Research Institute (PCORI), and a randomized trial of immunoablation followed by autologous hematopoietic stem cell transplantation (NIH), a randomized clinical trial examining clinical and economic outcomes of teleneurology versus standard care funded by the National Institute of Nursing Research (NIH).

Research participants for trials conducted at the Mellen Center leverage the large clinical practice at the center (approximately 10,000 patients). We utilize state of the art technology to conduct automated searches for clinical trial participants and quantitation of all pre-screening, screening, and enrollment activities. A large clinical research administrative program supports conduct of clinical trial led at Mellen Center, as well as studies where Mellen Center serves as a site. 

Contact Information

Daniel Ontaneda, MD PhD


Contracts for industry-sponsored clinical trials from Acorda, Adamas, Anokion, Athena, Atlas5D, Avanir, Biogen, Brystol Myers Squibb, Elan, Brainstorm Cell Therapeutics, EMD Serono/Merck, Genentech,Hoffman-La Roche, Horizon Therapeutics,  Immunex, Mallinckrodt, MedDay, Medimmune, Novartis, Pharmacia, Receptos/Celgene, Sanofi/Genzyme, Synthon, Teva, TG Therapeutics, and UCB Therapeutics

PCORI R-1610-37047, Determining the effectiveness of early Intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis (DELIVER-MS), Ontaneda (PI) 02/2018 – 01/2023

NMSS R-1902-33619 DELIVER-MS: NMSS Biobank Funding, Ontaneda (PI) 04/2021 – 03/2023

Multiple Sclerosis National Centre UK 17NS023 DELIVER-MS: UK MS Society Funding, Ontaneda (PI) 04/2019 – 03/2024

NIH U01NS116776-01 Central vein sign: a diagnostic biomarker in Multiple Sclerosis, Ontaneda (PI) 07/2020-06/2024

NIH 5UM1AI109565Best Available Therapy Versus Autologous Hematopoetic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) (BEAT-MS), Cohen (SC Chair)

NIH 1R01NR020323-01A1 Clinical and Economic Impact of Teleneurology vs Standard in Clinic Care for Multiple Sclerosis: A Randomized Trial, McGinley (PI), 09/2022-08/2027



Benefit of intramuscular interferon beta-1a on MSFC progression in secondary progressive MS. Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Kooijmans MF, Rudick RA, Sandrok AW, Simon JH, Simonian NA, Tsao EC, Whitaker JN, for the IMPACT Investigators. Neurology 2002;59:679-687. PMID: 12221157

Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Cohen JA, Imrey PB, Calabresi PA, Edwards KR, Eickenhorst T, Felton WL, Fisher E, Fox RJ, Goodman AD, Hara-Cleaver C, Hutton GJ, Mandell BF, Scott TF, Zhang H Apperson-Hansen C, Beck GJ, Houghtaling PL, Karafa MT, Stadtler M for the ACT Investigators.Neurology 2009;72:535-541. PMID: 19204263

Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study. RA, Weinstock-Guttman B, Bourdette D, Foulds P, You X, Rudick RA. Mult Scler. 2010;16(5):588-96. PMID: 20167591

Oral fingolimod or intramuscular interferon in relapsing multiple sclerosis. Cohen JA, Barkhof F, Comi G, Hartung H-P, 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, for the TRANSFORMS Study Group. N Engl J Med 2010;362:402-415. PMID: 20089954

Alemtuzumab versus interferon beta as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara M, Compston DAS, for the CARE-MS I investigators. Lancet 2012;380:1819-1828. PMID: 23122652

Disability outcomes in multiple sclerosis clinical trials: current status and future prospects. Cohen JA, Reingold SC, Polman CH, Wolinsky JS, on behalf of the International Advisory Committee on Clinical Trials in Multiple Sclerosis. Lancet Neurol 2012;11:467-476. PMID: 22516081.

Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. 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.N Engl J Med. 2012;367(12):1087-97. PMID: 22992072

Equivalence of generic glatiramer acetate in multiple sclerosis. Cohen JA, Belova A, Selmaj K, Wolf C, Oberyé J, van den Tweel E, PhD, Mulder R, Koper N, Voortman G, Barkhof F, for the GATE Study Group. JAMA Neurol 2015;72:1433-1441. PMID: 26458034

MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. Fox RJ, Cree BA, De Sèze J, Gold R, Hartung HP, Jeffery D, Kappos L, Kaufman M, Montalbán X, Weinstock-Guttman B, Anderson B, Natarajan A, Ticho B, Duda P.Neurology. 2014;82(17):1491-8. PMID: 24682966

Clinical trials in progressive multiple sclerosis: Lessons learned and future perspectives. D, Fox RJ, Chataway J.Lancet Neurol. 2015;14(2):208-223. PMID: 25772899.

Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomized, placebo-controlled, phase 2 trial. Cohen JA, Arnold DL, Comi G, Bar-Or A, Gujrathi S, Hartung JP, Cravets M, Olson A, Frohna PA, and Selmaj KW, for the RADIANCE Study Group. Lancet Neurol 2016;15:373-381. PMID: 26879276.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Fox RJ, Coffey CS, Cudkowicz ME, Gleason T, Goodman A, Klawiter EC, Matsuda K, McGovern M, Conwit R, Naismith R, Ashokkumar A, Bermel R, Ecklund D, Koepp M, Long J, Natarajan S, Ramachandran S, Skaramagas T, Thornell B, Yankey J, Agius M, Bashir K, Cohen B, Coyle P, Delgado S, Dewitt D, Flores A, Giesser B, Goldman M, Jubelt B, Lava N, Lynch S, Miravalle A, Moses H, Ontaneda D, Perumal J, Racke M, Repovic P, Riley C, Severson C, Shinnar S, Suski V, Weinstock-Gutman B, Yadav V, Zabeti A. Clin Trials. 2016;50:166-77. PMID: 27521810.

Clinical outcome measures for progressive MS trials. Ontaneda D, Cohen JA, Amato MP. Mult Scler J 2017;23(12):1627-1635. PMID: 29041863.

Progressive multiple sclerosis: Prospects for disease therapy, repair, and restoration of function. Ontaneda D, Thompson AJ, Fox RJ, Cohen JA. Lancet. 2017;389(10076):1357-1366. PMID: 27889191.

Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Cohen JA, Imrey PB, Planchon SM, Bermel RA, Fisher E, Fox RJ, Bar-Or A, Sharp SL, Skaramagas TT, Jagodnik P, Karafa M, Morrison S, Reese Koc J, Gerson SL, Lazarus HM. Mult Scler J published online 06 April 2017. PMID: 28381130

Safety and efficacy of ADS-5102 (amantadine) extended release capsules to improve walking in multiple sclerosis: a randomized, placebo-controlled, phase 2 trial. Cohen JA, Hunter SF, Brown TR, Gudesblatt M, Thrower BW, Llorens L, Souza-Prien CJ, Ruby AE, Chernoff DN, Patni R. Mult Scler J Epub ahead of print 25 January 2018. PMID: 29368539.

Fox RJ, Coffey CS, Conwit R, Cudkowicz ME, Gleason T, Goodman A, Klawiter EC, Matsuda K, McGovern M, Naismith RT, Ashokkumar A, Barnes J, Ecklund D, Klingner E, Koepp M, Long JD, Natarajan S, Thornell B, Yankey J, Bermel RA, Debbins JP,Huang X, Jagodnik P, Lowe MJ, Nakamura K, Narayanan S, Sakaie KE, Thoomukuntla B, Zhou X, Krieger S, Alvarez E, Apperson M, Bashir K, Cohen BA, Coyle PK, Delgado S, Dewitt LD, Flores A, Giesser BS, Goldman MD, Jubelt B, Lava N, Lynch SG, Moses H, Ontaneda D, Perumal JS, Racke M, Repovic P, Riley CS, Severson C, Shinnar S, Suski V, Weinstock-Guttman B, Yadav V, Zabeti A; NN102/SPRINT-MS Trial Investigators. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018 Aug 30;379(9):846-855. doi: 10.1056/NEJMoa1803583. PMID: 30157388; PMCID: PMC6172944.

Comi G, Kappos L, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala Havrdová E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Ding N, Cohen JA; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019 Nov;18(11):1009-1020. doi: 10.1016/S1474-4422(19)30239-X. Epub 2019 Sep 3. PMID: 31492651.

Ontaneda D, Tallantyre EC, Raza PC, Planchon SM, Nakamura K, Miller D, Hersh C, Craner M, Bale C, Chaudhry B, Gunzler DD, Love TE, Gerry S, Coles A, Cohen JA, Evangelou N. Determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis: The DELIVER-MS study protocol. Contemp Clin Trials. 2020 Aug;95:106009. doi: 10.1016/j.cct.2020.106009. Epub 2020 Apr 19. PMID: 32320842.

Garjani A, Liu BJ, Allen CM, Gunzler DD, Gerry SW, Planchon SM, das Nair R,Chataway J, Tallantyre EC, Ontaneda D, Evangelou N. Decentralised clinical trials in multiple sclerosis research. Mult Scler. 2022 Jun 23:13524585221100401. doi: 10.1177/13524585221100401. Epub ahead of print. PMID: 35735014.

Fox RJ, Wiendl H, Wolf C, De Stefano N, Sellner J, Gryb V, Rejdak K, Bozhinov PS, Tomakh N, Skrypchenko I, Muehler AR. A double-blind, randomized, placebo-controlled phase 2 trial evaluating the selective dihydroorotate dehydrogenase inhibitor vidofludimus calcium in relapsing-remitting multiple sclerosis. Ann Clin Transl Neurol. 2022 Jul;9(7):977-987. doi: 10.1002/acn3.51574. Epub 2022 Jun 14. PMID: 35698927; PMCID: PMC9268865.

Members & Collaborations

Members & Collaborations