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

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

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.

Pittock SJ, Nakahara J, Parks B, Allen K, Fam S.

2026-03-10

10.1002/acn3.70353

Immediate and sustained terminal complement inhibition with ravulizumab in patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder

Stephan Ortiz, Sean J. Pittock, Achim Berthele, Michael Levy, Ichiro Nakashima et al. (10 authors)

Frontiers in Neurology2024-01-315 citations

10.3389/fneur.2024.1332890

Efficacy and safety of ravulizumab in adults with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: outcomes from the phase 3 CHAMPION-NMOSD trial (S5.002)

Sean J. Pittock, Michael Barnett, Jeffrey L. Bennett, Achim Berthele, J. de Sèze et al. (15 authors)

Neurology2023-04-252 citations

10.1212/wnl.0000000000202922

Efficacy subgroup analyses from the phase 3 CHAMPION-NMOSD trial in adults with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (S5.003)

Michaël Levy, Sean J. Pittock, Michael Barnett, Jeffrey L. Bennett, Achim Berthele et al. (15 authors)

Neurology2023-04-25

10.1212/wnl.0000000000203035

Long-term safety and effectiveness of eculizumab in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: a 2-year interim analysis of post-marketing surveillance in Japan

Ichiro Nakashima, Jin Nakahara, Hiroaki Yokote, Yasuhiro Manabe, Kazumi Okamura et al. (7 authors)

Therapeutic Advances in Neurological Disorders2023-01-0121 citations

10.1177/17562864231181177

Long-Term Eculizumab in AQP4+ NMOSD: Relapse-Risk Reduction and Safety in PREVENT and its Completed Open-Label Extension

Achim Berthele, Dean M. Wingerchuk, Kazuo Fujihara, Jacqueline Palace, Michael Levy et al. (12 authors)

Neurology2022-12-05

10.1212/01.wnl.0000903068.75712.b8

Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Neuromyelitis Optica Spectrum Disorder

Pratap Singh, Xiang Gao, Huub Jan Kleijn, Francesco Bellanti, Ryan Pelto

Frontiers in Neurology2021-11-0322 citations

10.3389/fneur.2021.696387

Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension

Sean J. Pittock, Kazuo Fujihara, Jacqueline Palace, Achim Berthele, Ho Jin Kim et al. (14 authors)

Multiple Sclerosis Journal2021-09-0975 citations

10.1177/13524585211038291

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.

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.

2021-02-205 citations

10.1016/j.msard.2021.102849

Long‐Term Safety and Efficacy of Eculizumab in Aquaporin‐4 <scp>IgG‐Positive NMOSD</scp>

Dean M. Wingerchuk, Kazuo Fujihara, Jacqueline Palace, Achim Berthele, Michael Levy et al. (15 authors)

Annals of Neurology2021-02-1791 citations

10.1002/ana.26049

Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial.

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.

2020-11-2628 citations

10.1016/j.msard.2020.102641

Efficacy and Safety of Eculizumab in Patients with Neuromyelitis Optica Spectrum Disorder Previously Treated with Rituximab: Findings from the Phase 3 PREVENT Study (1788)

Michael Levy, Achim Berthele, Ho Jin Kim, Kazuo Fujihara, Ichiro Nakashima et al. (17 authors)

Neurology2020-04-143 citations

10.1212/wnl.94.15_supplement.1788

Impact of Eculizumab on Hospitalization Rates and Relapse Treatment in Patients with Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder: the Phase 3 PREVENT Study (1780)

Ho Jin Kim, Sean J. Pittock, Achim Berthele, Kazuo Fujihara, Michael Levy et al. (16 authors)

Neurology2020-04-142 citations

10.1212/wnl.94.15_supplement.1780

Long-term Safety and Efficacy of Eculizumab in Neuromyelitis Optica Spectrum Disorder (1494)

Dean M. Wingerchuk, Sean J. Pittock, Achim Berthele, Kazuo Fujihara, Ho Jin Kim et al. (16 authors)

Neurology2020-04-142 citations

10.1212/wnl.94.15_supplement.1494

Infection Risk in Patients with Complement-Mediated Neurological Disorders Receiving Eculizumab: Findings from Two Phase 3 Studies and Their Extensions in Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder (AQP4+ NMOSD) and Acetylcholine-Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis (AChR+ gMG) (1829)

Todd Levine, Renato Mantegazza, Celia Oreja‐Guevara, Cynthia Carrillo-Infante, Roger Kaprielian et al. (8 authors)

Neurology2020-04-141 citations

10.1212/wnl.94.15_supplement.1829

Impact of Eculizumab on Health Outcomes in Patients with Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder: Findings from the PREVENT Study (1765)

Achim Berthele, Sean J. Pittock, Kazuo Fujihara, Ho Jin Kim, Michael Levy et al. (15 authors)

Neurology2020-04-141 citations

10.1212/wnl.94.15_supplement.1765

Eculizumab in Aquaporin-4–Positive Neuromyelitis Optica Spectrum Disorder

Sean J. Pittock, Achim Berthele, Kazuo Fujihara, Ho Jin Kim, Michael Levy et al. (15 authors)

New England Journal of Medicine2019-05-03795 citations

10.1056/nejmoa1900866

Interventions

DRUGEculizumab

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

DRUGPlacebo

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

Key Inclusion Criteria: 1. Male or female participants ≥ 18 years old. 2. Diagnosis of NMO or NMOSD. 3. AQP4 antibody seropositive. 4. 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. 5. Expanded Disability Status Scale score ≤ 7. 6. 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. 7. 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. Key

Exclusion criteria

1. Use of rituximab within 3 months prior to Screening. 2. Use of mitoxantrone within 3 months prior to Screening. 3. Use of intravenous immunoglobulin within 3 weeks prior to Screening.

Design outcomes

Primary

Measure	Time frame	Description
Participants With An Adjudicated On-trial Relapse	Baseline, Up To 211 Weeks (End of Study)	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.

Secondary

Measure	Time frame	Description
Change From Baseline In EDSS At End Of Study	Baseline, Up To 211 Weeks (End of Study)	Disease-related disability was measured by the EDSS. The EDSS is an ordinal clinical rating scale that ranges from 0 (normal neurologic examination) to 10 (death) in half-point increments. A decrease in score indicates improvement.
Change From Baseline In Modified Rankin Scale (mRS) Score At End Of Study	Baseline, Up To 211 Weeks (End of Study)	Disease-related disability was measured by the mRS score. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered from a neurological disability. The scale ranges from 0 (no disability) to 6 (death) in whole-point increments. A decrease in score indicates improvement.
Adjudicated On-trial Annualized Relapse Rate (ARR)	Baseline, Up To 211 Weeks (End of Study)	The adjudicated On-trial ARR was computed as the total number of relapses divided by the total number of patient years in the study period. A central independent committee was used to adjudicate all On-trial Relapses as determined by the treating physician. Results reported as adjusted adjudicated On-trial ARR based on a Poisson regression adjusted for randomization strata and historical ARR in 24 months prior to Screening.
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)	The EuroQoL EQ-5D is a generic, standardized, self-administered instrument that provides a simple, descriptive profile and a single index value for health status. Assessments were made using the EQ-5D Visual Analogue Scale, which captures the self-rating of current health status using a visual thermometer with the endpoints of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom. An increase in score indicates improvement.
Change From Baseline In EuroQoL EQ-5D Index Score At End Of Study	Baseline, Up To 211 Weeks (End of Study)	The EuroQoL EQ-5D is a generic, standardized, self-administered instrument that provides a simple, descriptive profile and a single index value for health status. Index scores range from less than 0 to 1, with higher scores representing a better health status.
Change From Baseline In Hauser Ambulation Index (HAI) Score At End of Study	Baseline, Up To 211 Weeks (End of Study)	The HAI evaluates gait and was used to assess the time and effort used by the participant to walk 25 feet (8 meters). The scale ranges from 0 to 9, with 0 being the best score (asymptomatic; fully ambulatory with no assistance) and 9 being the worst (restricted to wheel chair; unable to transfer self independently). A decrease in score indicates improvement.

Countries

Argentina, Australia, Croatia, Czechia, Denmark, Germany, Hong Kong, Italy, Japan, Malaysia, Russia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States

Participant flow

Pre-assignment details

Main inclusion criteria were: participants aged ≥ 18 years old with NMO/NMOSD, AQP4 antibody-positive, historical relapse of at least 2 in last 12 months or 3 in last 24 months with at least 1 in 12 months prior to screening, Expanded Disability Status Scale score ≤ 7. If receiving immunosuppressive therapies, must be on a stable maintenance dose.

Participants by arm

Arm	Count
Eculizumab Induction Period: Participants received eculizumab (900 mg) via IV infusion once a week (every 7 ± 2 days) for 4 weeks followed by eculizumab 1200 mg for the fifth dose (Week 4). Maintenance Period: Participants received eculizumab (1200 mg) via IV infusion every 2 weeks (every 14 ± 2 days) from the sixth dose (Week 6) onwards.	96
Placebo 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). 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.	47
Total	143

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	2
Overall Study	Death	1	0
Overall Study	Lost to Follow-up	3	0
Overall Study	Withdrawal by Subject	12	1

Baseline characteristics

Characteristic	Eculizumab	Placebo	Total
Age, Continuous	43.9 years STANDARD_DEVIATION 13.32	45.0 years STANDARD_DEVIATION 13.29	44.3 years STANDARD_DEVIATION 13.27
Ethnicity (NIH/OMB) Hispanic or Latino	13 Participants	3 Participants	16 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	78 Participants	41 Participants	119 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants	3 Participants	8 Participants
Overall Stratification Groupings (4 strata) at Randomization High EDSS (≥ 2.5 to ≤ 7) and Treatment Naive	12 Participants	5 Participants	17 Participants
Overall Stratification Groupings (4 strata) at Randomization High EDSS (≥ 2.5 to ≤ 7): Change in IST	29 Participants	15 Participants	44 Participants
Overall Stratification Groupings (4 strata) at Randomization High EDSS (≥ 2.5 to ≤ 7): Same IST	44 Participants	22 Participants	66 Participants
Overall Stratification Groupings (4 strata) at Randomization Low EDSS (≤ 2.0)	11 Participants	5 Participants	16 Participants
Race/Ethnicity, Customized Asian	37 Participants	15 Participants	52 Participants
Race/Ethnicity, Customized Black or African American	9 Participants	8 Participants	17 Participants
Race/Ethnicity, Customized Other or Unknown	4 Participants	0 Participants	4 Participants
Race/Ethnicity, Customized White	46 Participants	24 Participants	70 Participants
Sex: Female, Male Female	88 Participants	42 Participants	130 Participants
Sex: Female, Male Male	8 Participants	5 Participants	13 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 96	0 / 47
other Total, other adverse events	86 / 96	43 / 47
serious Total, serious adverse events	30 / 96	26 / 47

Outcome results

Primary

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.

Time frame: Baseline, Up To 211 Weeks (End of Study)

Population: Full Analysis Set (FAS): all participants who were randomized to treatment, received at least 1 dose of study drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Eculizumab	Participants With An Adjudicated On-trial Relapse	3 Participants
Placebo	Participants With An Adjudicated On-trial Relapse	20 Participants

p-value: <0.000195% CI: [0.017, 0.197]Stratified Log-Rank Test

Secondary

Adjudicated On-trial Annualized Relapse Rate (ARR)

The adjudicated On-trial ARR was computed as the total number of relapses divided by the total number of patient years in the study period. A central independent committee was used to adjudicate all On-trial Relapses as determined by the treating physician. Results reported as adjusted adjudicated On-trial ARR based on a Poisson regression adjusted for randomization strata and historical ARR in 24 months prior to Screening.

Time frame: Baseline, Up To 211 Weeks (End of Study)

Population: Full Analysis Set (FAS): all participants who were randomized to treatment and who received at least 1 dose of study drug.

Arm	Measure	Value (NUMBER)
Eculizumab	Adjudicated On-trial Annualized Relapse Rate (ARR)	0.016 relapses/years on study
Placebo	Adjudicated On-trial Annualized Relapse Rate (ARR)	0.350 relapses/years on study

Secondary

Change From Baseline In EDSS At End Of Study

Disease-related disability was measured by the EDSS. The EDSS is an ordinal clinical rating scale that ranges from 0 (normal neurologic examination) to 10 (death) in half-point increments. A decrease in score indicates improvement.

Time frame: Baseline, Up To 211 Weeks (End of Study)

Population: Full Analysis Set (FAS): all participants who were randomized to treatment and who received at least 1 dose of study drug.

Arm	Measure	Value (MEAN)	Dispersion
Eculizumab	Change From Baseline In EDSS At End Of Study	-0.18 units on a scale	Standard Deviation 0.814
Placebo	Change From Baseline In EDSS At End Of Study	0.12 units on a scale	Standard Deviation 0.945

Secondary

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

The EuroQoL EQ-5D is a generic, standardized, self-administered instrument that provides a simple, descriptive profile and a single index value for health status. Assessments were made using the EQ-5D Visual Analogue Scale, which captures the self-rating of current health status using a visual thermometer with the endpoints of 100 (best imaginable health state) at the top and zero (worst imaginable health state) at the bottom. An increase in score indicates improvement.

Time frame: Baseline, Up To 211 Weeks (End of Study)

Population: Full Analysis Set (FAS): all participants who were randomized to treatment and who received at least 1 dose of study drug.

Arm	Measure	Value (MEAN)	Dispersion
Eculizumab	Change From Baseline In European Quality Of Life (EuroQoL) Health 5-Dimension Questionnaire (EQ-5D) Visual Analogue Scale At End Of Study	5.4 units on a scale	Standard Deviation 18.53
Placebo	Change From Baseline In European Quality Of Life (EuroQoL) Health 5-Dimension Questionnaire (EQ-5D) Visual Analogue Scale At End Of Study	0.6 units on a scale	Standard Deviation 16.39

Secondary

Change From Baseline In EuroQoL EQ-5D Index Score At End Of Study

The EuroQoL EQ-5D is a generic, standardized, self-administered instrument that provides a simple, descriptive profile and a single index value for health status. Index scores range from less than 0 to 1, with higher scores representing a better health status.

Time frame: Baseline, Up To 211 Weeks (End of Study)

Population: Full Analysis Set (FAS): all participants who were randomized to treatment and who received at least 1 dose of study drug.

Arm	Measure	Value (MEAN)	Dispersion
Eculizumab	Change From Baseline In EuroQoL EQ-5D Index Score At End Of Study	0.05 units on a scale	Standard Deviation 0.179
Placebo	Change From Baseline In EuroQoL EQ-5D Index Score At End Of Study	-0.04 units on a scale	Standard Deviation 0.212

Secondary

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

The HAI evaluates gait and was used to assess the time and effort used by the participant to walk 25 feet (8 meters). The scale ranges from 0 to 9, with 0 being the best score (asymptomatic; fully ambulatory with no assistance) and 9 being the worst (restricted to wheel chair; unable to transfer self independently). A decrease in score indicates improvement.

Time frame: Baseline, Up To 211 Weeks (End of Study)

Population: Full Analysis Set (FAS): all participants who were randomized to treatment and who received at least 1 dose of study drug.

Arm	Measure	Value (MEAN)	Dispersion
Eculizumab	Change From Baseline In Hauser Ambulation Index (HAI) Score At End of Study	-0.4 units on a scale	Standard Deviation 1.08
Placebo	Change From Baseline In Hauser Ambulation Index (HAI) Score At End of Study	0.5 units on a scale	Standard Deviation 1.61

Secondary

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

Disease-related disability was measured by the mRS score. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered from a neurological disability. The scale ranges from 0 (no disability) to 6 (death) in whole-point increments. A decrease in score indicates improvement.

Time frame: Baseline, Up To 211 Weeks (End of Study)

Population: Full Analysis Set (FAS): all participants who were randomized to treatment and who received at least 1 dose of study drug.

Arm	Measure	Value (MEAN)	Dispersion
Eculizumab	Change From Baseline In Modified Rankin Scale (mRS) Score At End Of Study	-0.2 units on a scale	Standard Deviation 0.72
Placebo	Change From Baseline In Modified Rankin Scale (mRS) Score At End Of Study	0.1 units on a scale	Standard Deviation 0.75

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

Conditions

Keywords

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Participants With An Adjudicated On-trial Relapse

Adjudicated On-trial Annualized Relapse Rate (ARR)

Change From Baseline In EDSS At 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

Change From Baseline In EuroQoL EQ-5D Index Score At End Of Study

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

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