An Open Label Extension Trial of Eculizumab in Relapsing NMO Patients

A Phase III, Open-label, Extension Trial of ECU-NMO-301 to Evaluate the Safety and Efficacy of Eculizumab in Patients With Relapsing Neuromyelitis Optica (NMO)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02003144

Enrollment

119

Registered

2013-12-06

Start date

2015-01-12

Completion date

2021-07-12

Last updated

2022-08-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorder

Keywords

Long-term safety study, Extension trial, Eculizumab, Neuromyelitis Optica Spectrum Disorder, Devic's disease, Transverse Myelitis, Optic Neuritis, Relapse, NMO-IgG, CNS Autoimmune Disorders, Demyelinating Disorders

Brief summary

The purpose of this study is to determine whether eculizumab long-term use is safe and effective in patients with relapsing NMO.

Detailed description

This study is an open label extension study to confirm the long term safety and efficacy of eculizumab in subjects with relapsing NMO who have completed the initial double-blind, randomized, placebo-controlled trial ECU-NMO-301.

Interventions

BIOLOGICALeculizumab

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: 1. Patient completed the ECU-NMO-301 trial 2. Patient has given written informed consent Key

Exclusion criteria

1. Patients who have withdrawn from the ECU-NMO-301 trial as a result of an AE related to trial drug 2. Female patients who are pregnant, breastfeeding, or intend to conceive during the course of the trial

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	Baseline up to end of study (up to 6.5 years)	An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment-emergent adverse events (TEAEs) were defined as an AE with onset on or after the first study drug dose in Study ECU-NMO-302. A serious adverse event (SAE) was defined as an untoward medical occurrence that at any dose either results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Number of Participants With At Least 1 Post Baseline Columbia-Suicide Severity Rating Scale (C-SSRS) Assessment (Suicide-Related Thoughts or Behaviours) Abnormality	Baseline up to end of study (up to 6.5 years)	The C-SSRS is a validated questionnaire to capture occurrence, severity, and frequency of suicide-related thoughts and behaviours, and has a binary response (yes/no). Suicidal Ideation: a yes answer to any one of 5 suicidal ideation questions: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Planned) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; and Active Suicidal Ideation with Specific Plan and Intent. Suicidal Behaviour: a yes answer to any of 5 suicidal behaviour questions: Preparatory Acts or Behaviour, Aborted Attempt, Interrupted Attempt, Actual Attempt (non-fatal), and Completed Suicide. Suicidal Ideation or Behaviour: a yes answer to the following question: Self-injurious behaviour without suicidal intent.
Number of Participants With An On-trial Relapse as Determined by The Treating Physician	Baseline up to end of study (up to 6.5 years)	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.
On-Trial Annualized Relapse Rate (ARR) as Determined by The Treating Physician	Baseline up to end of study (up to 6.5 years)	The On-trial ARR was computed as the total number of relapses divided by the total number of participant years in the study period.

Secondary

Measure	Time frame	Description
Change From Baseline in Expanded Disability Status Scale (EDSS) Score	Baseline, Weeks 52, 104 and 156	Disease-related disability was measured by the EDSS. The EDSS quantifies disability in 8 Functional Systems (FS) and allows neurologists to assign a Functional System Score (FSS) in each of these. The Functional Systems are pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and other. 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. Baseline was defined as the last available assessment prior to the first study drug infusion in Study ECU-NMO-302.
Change From Baseline in Kurtzke Visual Functional System Scores (FSS) in Participants With Abnormal Baseline Visual Function	Baseline, Weeks 52, 104 and 156	The EDSS assesses multiple Kurtzke functional systems in the context of a standard neurological exam, including visual function. The visual score ranges from 0 to 6. A score of 0 implies the participant has normal visual function. Higher scores represent worse disability. Baseline is defined as the last available assessment prior to the first study drug infusion in Study EC-NMO-302.
Change From Baseline in Modified Rankin Scale (mRS) Score	Baseline, Weeks 52, 104 and 156	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 symptoms at all) to 6 (death) in whole-point increments. A decrease in score indicates improvement. Baseline was defined as the last available assessment prior to the first study drug infusion in Study ECU-NMO-302.
Change From Baseline in Hauser Ambulation Index (HAI) in Participants With Abnormal Baseline Ambulatory Function	Baseline, Weeks 52, 104 and 156	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 active) and 9 being the worst (restricted to wheelchair; unable to transfer self independently). A decrease in score indicates improvement. Baseline is defined as the last available assessment prior to the first study drug infusion in Study ECU-NMO-302.
Change From Baseline in European Quality of Life (EuroQoL) 5-Dimension Visual Analog Scale (EQ-5D VAS) Health Status Score	Baseline, Weeks 52, 104 and 156	The EQ-5D is a generic, standardized participant self-administered health status instrument. EQ-5D general health status can also be measured by a visual analog scale (EQ-5D VAS). EQ-5D-VAS recorded the participant's self-rated health on a vertical visual analog scale (VAS) that allowed the participants to indicate their health state that ranged from 0 (worst imaginable) to 100 (best imaginable). Baseline is defined as the last available assessment prior to the first study drug infusion in Study ECU-NMO-302.

Countries

Argentina, Australia, Canada, Colombia, 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

Participants who completed Study ECU-NMO-301 (NCT01892345) were eligible to participate in Study ECU-NMO-302. This is an open-label study in which all participants were administered intravenous eculizumab. However, to maintain the blind of Study ECU-NMO-301, all participants underwent a 4-week Blind Induction Phase before entering the Open-label Maintenance Phase.

Participants by arm

Arm	Count
Placebo/Eculizumab Blind Induction Phase: Participants who had received blinded treatment with placebo in Study ECU-NMO-301 were administered eculizumab (900 mg) plus matching placebo via IV infusion on Day 1 and Weeks 1 through 3. Open-Label Maintenance Phase: Participants received open-label eculizumab (1200 mg) via IV infusion every 2 weeks starting at Week 4 and continued for up to 6.5 years.	41
Eculizumab/Eculizumab Blind Induction Phase: Participants who had received blinded treatment with eculizumab in Study ECU-NMO-301 were administered eculizumab (1200 mg) via IV infusion on Day 1 and Week 2 and placebo at Weeks 1 and 3. Open-Label Maintenance Phase: Participants received open-label eculizumab (1200 mg) via IV infusion every 2 weeks starting at Week 4 and continued for up to 6.5 years.	78
Total	119

Withdrawals & dropouts

Period	Reason	FG000	FG001
Open Label Maintenance Phase	Adverse Event	2	1
Open Label Maintenance Phase	Lost to Follow-up	0	1
Open Label Maintenance Phase	Other than specified	2	4
Open Label Maintenance Phase	Physician Decision	1	1
Open Label Maintenance Phase	Pregnancy	0	2
Open Label Maintenance Phase	Withdrawal by Subject	4	5

Baseline characteristics

Characteristic	Eculizumab/Eculizumab	Total	Placebo/Eculizumab
Age, Continuous	46.6 years STANDARD_DEVIATION 13.77	46.4 years STANDARD_DEVIATION 13.73	46.0 years STANDARD_DEVIATION 13.82
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants	13 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	63 Participants	100 Participants	37 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants	6 Participants	2 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized Asian	32 Participants	45 Participants	13 Participants
Race/Ethnicity, Customized Black or African American	3 Participants	10 Participants	7 Participants
Race/Ethnicity, Customized Other	1 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized Unknown or Not Reported	1 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized White	40 Participants	61 Participants	21 Participants
Sex: Female, Male Female	74 Participants	110 Participants	36 Participants
Sex: Female, Male Male	4 Participants	9 Participants	5 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 41	0 / 78	0 / 119
other Total, other adverse events	40 / 41	70 / 78	110 / 119
serious Total, serious adverse events	14 / 41	26 / 78	40 / 119

Outcome results

Primary

Number of Participants With An On-trial Relapse as Determined by The Treating Physician

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.

Time frame: Baseline up to end of study (up to 6.5 years)

Population: The Extension Full Analysis Set consisted of all participants who had received at least 1 dose of eculizumab in Study ECU-NMO-302 and had a post-IP-infusion efficacy assessment.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Placebo/Eculizumab	Number of Participants With An On-trial Relapse as Determined by The Treating Physician	5 Participants
Eculizumab/Eculizumab	Number of Participants With An On-trial Relapse as Determined by The Treating Physician	8 Participants

Primary

Number of Participants With At Least 1 Post Baseline Columbia-Suicide Severity Rating Scale (C-SSRS) Assessment (Suicide-Related Thoughts or Behaviours) Abnormality

The C-SSRS is a validated questionnaire to capture occurrence, severity, and frequency of suicide-related thoughts and behaviours, and has a binary response (yes/no). Suicidal Ideation: a yes answer to any one of 5 suicidal ideation questions: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Planned) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; and Active Suicidal Ideation with Specific Plan and Intent. Suicidal Behaviour: a yes answer to any of 5 suicidal behaviour questions: Preparatory Acts or Behaviour, Aborted Attempt, Interrupted Attempt, Actual Attempt (non-fatal), and Completed Suicide. Suicidal Ideation or Behaviour: a yes answer to the following question: Self-injurious behaviour without suicidal intent.

Time frame: Baseline up to end of study (up to 6.5 years)

Population: The Extension Safety Set consisted of all participants who had received at least 1 dose of eculizumab in Study ECU-NMO-302.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Placebo/Eculizumab	Number of Participants With At Least 1 Post Baseline Columbia-Suicide Severity Rating Scale (C-SSRS) Assessment (Suicide-Related Thoughts or Behaviours) Abnormality	Suicidal Ideation	4 Participants
Placebo/Eculizumab	Number of Participants With At Least 1 Post Baseline Columbia-Suicide Severity Rating Scale (C-SSRS) Assessment (Suicide-Related Thoughts or Behaviours) Abnormality	Suicidal Behavior	0 Participants
Placebo/Eculizumab	Number of Participants With At Least 1 Post Baseline Columbia-Suicide Severity Rating Scale (C-SSRS) Assessment (Suicide-Related Thoughts or Behaviours) Abnormality	Suicidal Ideation or Behavior	4 Participants
Eculizumab/Eculizumab	Number of Participants With At Least 1 Post Baseline Columbia-Suicide Severity Rating Scale (C-SSRS) Assessment (Suicide-Related Thoughts or Behaviours) Abnormality	Suicidal Ideation	5 Participants
Eculizumab/Eculizumab	Number of Participants With At Least 1 Post Baseline Columbia-Suicide Severity Rating Scale (C-SSRS) Assessment (Suicide-Related Thoughts or Behaviours) Abnormality	Suicidal Behavior	1 Participants
Eculizumab/Eculizumab	Number of Participants With At Least 1 Post Baseline Columbia-Suicide Severity Rating Scale (C-SSRS) Assessment (Suicide-Related Thoughts or Behaviours) Abnormality	Suicidal Ideation or Behavior	5 Participants

Primary

Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events

An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment-emergent adverse events (TEAEs) were defined as an AE with onset on or after the first study drug dose in Study ECU-NMO-302. A serious adverse event (SAE) was defined as an untoward medical occurrence that at any dose either results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.

Time frame: Baseline up to end of study (up to 6.5 years)

Population: The Extension Safety Set consisted of all participants who had received at least 1 dose of eculizumab in Study ECU-NMO-302.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Placebo/Eculizumab	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	TEAEs	41 Participants
Placebo/Eculizumab	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	SAEs	14 Participants
Eculizumab/Eculizumab	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	TEAEs	70 Participants
Eculizumab/Eculizumab	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events	SAEs	26 Participants

Primary

On-Trial Annualized Relapse Rate (ARR) as Determined by The Treating Physician

The On-trial ARR was computed as the total number of relapses divided by the total number of participant years in the study period.

Time frame: Baseline up to end of study (up to 6.5 years)

Population: The Extension Full Analysis Set consisted of all participants who had received at least 1 dose of eculizumab in Study ECU-NMO-302 and had a post-IP-infusion efficacy assessment.

Arm	Measure	Value (MEAN)	Dispersion
Placebo/Eculizumab	On-Trial Annualized Relapse Rate (ARR) as Determined by The Treating Physician	0.128 relapses/years on study	Standard Deviation 0.4576
Eculizumab/Eculizumab	On-Trial Annualized Relapse Rate (ARR) as Determined by The Treating Physician	0.061 relapses/years on study	Standard Deviation 0.2186

Secondary

Change From Baseline in European Quality of Life (EuroQoL) 5-Dimension Visual Analog Scale (EQ-5D VAS) Health Status Score

The EQ-5D is a generic, standardized participant self-administered health status instrument. EQ-5D general health status can also be measured by a visual analog scale (EQ-5D VAS). EQ-5D-VAS recorded the participant's self-rated health on a vertical visual analog scale (VAS) that allowed the participants to indicate their health state that ranged from 0 (worst imaginable) to 100 (best imaginable). Baseline is defined as the last available assessment prior to the first study drug infusion in Study ECU-NMO-302.