A Randomized Controlled Trial of Eculizumab in AQP4 Antibody-positive Participants With NMO (PREVENT Study)

NCT01892345 | Terminated Phase 3 Results DMC

• 1 other identifier: ECU-NMO-301
• Study Type: interventional
• Target: 143
• Locations: 18 countries
• Sites: 70

Brief Summary

The objectives of this time-to-event study were to assess the efficacy and safety of eculizumab as compared with placebo in participants with neuromyelitis optica spectrum disorder (NMOSD) who were anti-aquaporin-4 (AQP4) antibody-positive.

Conditions

Neuromyelitis Optica; Neuromyelitis Optica Spectrum Disorder

Keywords

Neuromyelitis Optica; Neuromyelitis Optica Spectrum Disorder; Devic's disease, Transverse Myelitis; Optic Neuritis; relapse; eculizumab; soliris; NMO-IgG; CNS Autoimmune Disorders; Demyelinating Disorders; NMO; NMOSD

Outcome Measures

Primary Outcomes (1)

• Participants With An Adjudicated On-trial Relapse

  An On-trial Relapse was defined as a new onset of neurologic symptoms or worsening of existing neurologic symptoms with an objective change (clinical sign) on neurologic examination that persisted for more than 24 hours as confirmed by the treating physician. An adjudicated On-trial Relapse was defined by the protocol and positively adjudicated by the relapse adjudication committee.

  Baseline, Up To 211 Weeks (End of Study)

Secondary Outcomes (6)

• Adjudicated On-trial Annualized Relapse Rate (ARR)

  Baseline, Up To 211 Weeks (End of Study)

• Change From Baseline In EDSS At End Of Study

  Baseline, Up To 211 Weeks (End of Study)

• Change From Baseline In Modified Rankin Scale (mRS) Score At End Of Study

  Baseline, Up To 211 Weeks (End of Study)

• Change From Baseline In Hauser Ambulation Index (HAI) Score At End of Study

  Baseline, Up To 211 Weeks (End of Study)

• Change From Baseline In European Quality Of Life (EuroQoL) Health 5-Dimension Questionnaire (EQ-5D) Visual Analogue Scale At End Of Study

  Baseline, Up To 211 Weeks (End of Study)

Study Arms (2)

Eculizumab

EXPERIMENTAL

Biological/Vaccine: Eculizumab; Induction Period: Participants received eculizumab (900 milligrams \[mg\]) via intravenous (IV) infusion once a week (every 7 ± 2 days) for 4 weeks followed by eculizumab 1200 mg for the fifth dose (Week 4). This was followed by the Maintenance Period: Participants received eculizumab (1200 mg) via IV infusion every 2 weeks (every 14 ± 2 days) from the sixth dose (Week 6) onwards.

Drug: Eculizumab

Placebo

PLACEBO COMPARATOR

Placebo contains the same buffer components without the active ingredient. Induction Period: Participants received matching placebo (900 mg) via IV infusion once a week (every 7 ± 2 days) for 4 weeks, followed by matching placebo (1200 mg) for the fifth dose (Week 4). This was followed by the Maintenance Period: Participants received matching placebo (1200 mg) via IV infusion every 2 weeks (every 14 ± 2 days) from the sixth dose (Week 6) onwards.

Drug: Placebo

Interventions

Eculizumab DRUG

Induction Phase: 900 mg IV weekly for 4 weeks, followed by 1200 mg for the fifth dose; Maintenance Phase: 1200 mg IV every 2 weeks

Also known as: Soliris

Eculizumab

Placebo DRUG

Induction Phase: matching placebo (900 mg) IV weekly for 4 weeks, followed by matching placebo (1200 mg) for the fifth dose; Maintenance Phase: matching placebo (1200 mg) IV every 2 weeks

Placebo

Eligibility Criteria

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

You may qualify if:

• Male or female participants ≥ 18 years old.
• Diagnosis of NMO or NMOSD.
• AQP4 antibody seropositive.
• Historical relapse of at least 2 relapses in the last 12 months or 3 relapses in the last 24 months with at least 1 relapse in the 12 months prior to the screening.
• Expanded Disability Status Scale score ≤ 7.
• If a participant entered the study receiving immunosuppressive therapy (IST) for relapse prevention, the participant must have been on a stable maintenance dose of IST(s), as defined by the treating physician, prior to Screening and must have remained on that dose for the duration of the study, unless the participant experienced a relapse.
• Female participants of childbearing potential were to have a negative pregnancy test (serum human chorionic gonadotropin). Participants were required to practice an effective, reliable, and medically approved contraceptive regimen during the study and for up to 5 months following discontinuation of treatment.

You may not qualify if:

• Use of rituximab within 3 months prior to Screening.
• Use of mitoxantrone within 3 months prior to Screening.
• Use of intravenous immunoglobulin within 3 weeks prior to Screening.

Sponsors & Collaborators

• Alexion Pharmaceuticals, Inc.: lead

Study Sites (70)

Mayo Clinic Arizona

Scottsdale, Arizona, 85259, United States

Location

The Research Center of Southern California

Carlsbad, California, 92011, United States

Location

Georgetown University Hospital

Washington D.C., District of Columbia, 20007, United States

Location

University of Miami McKnight Brain Institute

Miami, Florida, 33136, United States

Location

Neurological Services of Orlando

Orlando, Florida, 32806, United States

Location

Fort Wayne Neurological Center

Fort Wayne, Indiana, 46804, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

Baptist Health Lexington

Lexington, Kentucky, 40503, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

John Hopkins University School of Medicine

Baltimore, Maryland, 21287, United States

Location

Mayo Clinic - Rochester

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Multiple Sclerosis Comprehensive Care Center, NYU Langone Medical Center

New York, New York, 10016, United States

Location

The Ohio State University, Wexner Medical Center, CarePoint at Gahanna

Gahanna, Ohio, 43230, United States

Location

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Multiple Sclerosis Treatment Center of Dallas

Dallas, Texas, 75246, United States

Location

University of Utah Health Care

Salt Lake City, Utah, 84132, United States

Location

Swedish Neuroscience Institute

Seattle, Washington, 98122, United States

Location

Hospital General de Agudos Juan Antonio Fernandez

Ciudad Autonoma, Buenos Aires, Buenos Aires, 1425, Argentina

Location

Hospital J. M. Ramos Mejia

Ciudad Autonoma, Buenos Aires, Buenos Aires, C1221, Argentina

Location

Hospital Universitario Austral

Pilar, Buenos Aires, B1629ODT, Argentina

Location

Fundacion Rosarina de Neuro Rehabilitacion

Rosario, Santa Fe Province, S2000BZL, Argentina

Location

University of Sydney, Brain and Mind Center

Camperdown, New South Wales, 2050, Australia

Location

St. Vincent's Hospital Melbourne

Fitzroy, Victoria, 3065, Australia

Location

Clinical Hospital Centre Zagreb

Zagreb, 10000, Croatia

Location

Vseobecna fakultni nemocnice Neurologicka klinika

Prague, 128 21, Czechia

Location

Århus Universitetshospital

Aarhus, 8000, Denmark

Location

Universitaetsklinikum Heidelberg, Abteilung Neuroonkologie

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

Klinikum rechts der Isar der TU Muenchen, Neurologische Klinik und Poliklinik

Munich, Bavaria, 81675, Germany

Location

Universitaetsmedizin Rostock, Klinik für Neurologie

Rostock, 18147, Germany

Location

Prince of Wales Hospital

Shatin, Hong Kong

Location

Universitaria Policlinico di Catania

Catania, 95123, Italy

Location

Azienda Ospedaliera Universitaria Federico II

Napoli, 80131, Italy

Location

Azienda Ospedaliera San Camillo Forlanini

Rome, 00151, Italy

Location

Neurological Centre of Latium Dipartimento di Neuroscienze

Rome, 00178, Italy

Location

Chiba University Hospital

Chiba, Chiba, 260-8677, Japan

Location

Hyogo College of Medicine Hospital

Nishinomiya-shi, Hyōgo, 663-8501, Japan

Location

Kyoto Min-iren Chuo Hospital

Kyoto, Kyoto, 604-8453, Japan

Location

Tohoku University Hospital

Sendai, Miyagi, 980-8574, Japan

Location

Tokyo Medical and Dental University

Bunkyo-ku, Tokyo, 113-8519, Japan

Location

Yamaguchi University Hospital

Ube-shi, Yamaguchi, 755-8505, Japan

Location

Kyushu University Hospital

Fukuoka, 812-8582, Japan

Location

National Center Hospital, NCNP

Tokyo, 187-8551, Japan

Location

Hospital Kuala Lumpur

Kuala Lumpur, 50586, Malaysia

Location

Republican Clinical Hospital for Rehabilitation of Healthcare Ministry of Republic of Tatarstan

Kazan', 420021, Russia

Location

FSBHI 'Siberian Clinical Center of FMBA'

Krasnoyarsk, 630037, Russia

Location

Federal State Budget Institution of Healthcare - Siberian District Medical Center of FMBA of Russia

Novosibirsk, 630067, Russia

Location

SBEIHPE "Rostov SMU of MoH of RF"

Rostov-on-Don, 344022, Russia

Location

First Pavlov State Medical University of St.Petersburg

Saint Petersburg, 197022, Russia

Location

National Cancer Center

Goyang-si, Gyeonggi-do, 10408, South Korea

Location

Korea University Anam Hospital

Seoul, 02841, South Korea

Location

Seoul University National Hospital

Seoul, 03080, South Korea

Location

Severance Hospital, Yonsei University

Seoul, 03722, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Hospital de Cruces

Barakaldo, Bizkaia, 48903, Spain

Location

Hospital Universitario Reina Sofia

Córdoba, 14011, Spain

Location

Hospital Universitario Clinico San Carlos

Madrid, 28040, Spain

Location

Cheng Hsin General Hospital

Taipei, 112, Taiwan

Location

Navamindradhiraj University, Vajira Hospital

Dusit, 10300, Thailand

Location

Thammasat University Hospital

Pathum Thani, 12120, Thailand

Location

Sunprasitthiprasong Hospital

Ubon Ratchathani, 34000, Thailand

Location

Hacettepe University Medical Faculty

Ankara, 06100, Turkey (Türkiye)

Location

Istanbul University Cerrahpasa Medical Faculty

Istanbul, 34098, Turkey (Türkiye)

Location

Istanbul Bilim Universty Medical Fac.

Istanbul, 34381, Turkey (Türkiye)

Location

Dokuz Eylul University Medicine Faculty

Izmir, 35340, Turkey (Türkiye)

Location

Kocaeli University Medical Faculty

Kocaeli, 41380, Turkey (Türkiye)

Location

Ondokuz Mayis Univ. Med. Fac.

Samsun, 55139, Turkey (Türkiye)

Location

The Walton Centre

Liverpool, L9 7LJ, United Kingdom

Location

John Radcliffe Hospital

Oxford, OX3 9DU, United Kingdom

Location

Related Publications (6)

• Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, Lucchinetti CF, O'Toole O, Wingerchuk DM. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 2013 Jun;12(6):554-62. doi: 10.1016/S1474-4422(13)70076-0. Epub 2013 Apr 26.

  PMID: 23623397 BACKGROUND

• Pittock SJ, Berthele A, Fujihara K, Kim HJ, Levy M, Palace J, Nakashima I, Terzi M, Totolyan N, Viswanathan S, Wang KC, Pace A, Fujita KP, Armstrong R, Wingerchuk DM. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019 Aug 15;381(7):614-625. doi: 10.1056/NEJMoa1900866. Epub 2019 May 3.

  PMID: 31050279 RESULT

• Singh P, Gao X, Kleijn HJ, Bellanti F, Pelto R. Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Neuromyelitis Optica Spectrum Disorder. Front Neurol. 2021 Nov 3;12:696387. doi: 10.3389/fneur.2021.696387. eCollection 2021.

  PMID: 34803867 DERIVED

• Pittock SJ, Fujihara K, Palace J, Berthele A, Kim HJ, Oreja-Guevara C, Nakashima I, Levy M, Shang S, Yountz M, Miller L, Armstrong R, Wingerchuk DM; PREVENT Study Group. Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension. Mult Scler. 2022 Mar;28(3):480-486. doi: 10.1177/13524585211038291. Epub 2021 Sep 9.

  PMID: 34498507 DERIVED

• Kim HJ, Nakashima I, Viswanathan S, Wang KC, Shang S, Miller L, Yountz M, Wingerchuk DM, Pittock SJ, Levy M, Berthele A, Totolyan N, Palace J, Barnett MH, Fujihara K; PREVENT Study Group. Eculizumab in Asian patients with anti-aquaporin-IgG-positive neuromyelitis optica spectrum disorder: A subgroup analysis from the randomized phase 3 PREVENT trial and its open-label extension. Mult Scler Relat Disord. 2021 May;50:102849. doi: 10.1016/j.msard.2021.102849. Epub 2021 Feb 20.

  PMID: 33676197 DERIVED

• Palace J, Wingerchuk DM, Fujihara K, Berthele A, Oreja-Guevara C, Kim HJ, Nakashima I, Levy M, Terzi M, Totolyan N, Viswanathan S, Wang KC, Pace A, Yountz M, Miller L, Armstrong R, Pittock S; PREVENT Study Group. Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial. Mult Scler Relat Disord. 2021 Jan;47:102641. doi: 10.1016/j.msard.2020.102641. Epub 2020 Nov 26.

  PMID: 33310418 DERIVED

Related Links

• Alexion Clinical Trials Website

MeSH Terms

Conditions

Neuromyelitis Optica; Myelitis, Transverse; Optic Neuritis; Recurrence; Demyelinating Diseases

Interventions

eculizumab

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Optic Nerve Diseases; Cranial Nerve Diseases; Eye Diseases; Autoimmune Diseases; Immune System Diseases; Myelitis; Central Nervous System Infections; Infections; Paraneoplastic Syndromes, Nervous System; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Paraneoplastic Syndromes; Central Nervous System Diseases; Spinal Cord Diseases; Neurodegenerative Diseases; Neuroinflammatory Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

After rigorous review of blinded study data, the Sponsor terminated the study at 23 adjudicated events, not the protocol-specified 24. This was not driven by safety or efficacy concerns, but rather by uncertainty in estimating final event occurrence.

Results Point of Contact

• Title: Alexion Pharmaceuticals, Inc.
• Organization: Alexion Pharmaceuticals, Inc.

clinicaltrials@alexion.com

855-752-2356

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 20, 2013
• First Posted: July 4, 2013
• Study Start: April 11, 2014
• Primary Completion: July 17, 2018
• Study Completion: July 17, 2018
• Last Updated: June 26, 2019
• Results First Posted: June 26, 2019

Record last verified: 2019-06

Locations

DK (1); DE (3); AU (2); KR (5); MY (1); TH (3); ES (3); IT (4); CR (1); TW (1); AR (4); HK (1); RU (5); TU (6); JP (8); US (19); CZ (1); GB (2)