Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorder
Conditions
Keywords
Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorder, Devic's Disease, Transverse Myelitis, Optic Neuritis, Relapse, Eculizumab, Soliris, CNS Autoimmune Disorders, Demyelinating Disorders, NMO, NMOSD
Brief summary
The objective of this study is to evaluate the safety and efficacy of eculizumab in pediatric participants (aged 2 to \< 18 years) with relapsing neuromyelitis optica spectrum disorder (NMOSD).
Interventions
DRUGEculizumab
Following a weight-based weekly dose of eculizumab during an induction phase, participants will receive weight-based doses of eculizumab every 2 weeks during the Primary Treatment Period and Extension Treatment Period.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Male or female participants aged 2 years to \< 18 years with body weight ≥ 10 kilograms (kg). 2. Vaccinated against Neisseria meningitidis within 3 years prior to, or at the time of initiating eculizumab. Participants who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic antibiotics until 2 weeks after the vaccination. 3. Documented vaccination against haemophilus influenzae type b and streptococcus pneumoniae infections at least 2 weeks prior to dosing as per local and country-specific immunization guidelines for the appropriate age group. 4. Anti-aquaporin-4 antibody-positive and diagnosis of NMOSD as defined by the 2015 International Panel for Neuromyelitis Optica Diagnosis criteria. 5. Historical Relapse Rate of at least 2 relapses in the last 2 years, and with at least 1 relapse in the year prior to Screening. 6. EDSS score ≤ 7. 7. Participants who enter the study receiving supportive immunosuppressive therapies (ISTs) for the prevention of relapse, either in combination or monotherapy, must be on a stable dosing regimen of adequate duration. 8. Female participants of childbearing potential must have a negative pregnancy test (serum human chorionic gonadotropin) at Screening and follow protocol-specified contraception guidance for avoiding pregnancy while on treatment and for 5 months after the last dose of eculizumab. 9. Male participants with a female spouse/partner of childbearing potential or a pregnant or breastfeeding spouse or partner must agree to use double barrier contraception (male condom plus appropriate barrier method for the female partner) while on treatment and for at least 5 months after the last dose of eculizumab.
Exclusion criteria
1. Parent or legal guardian is an Alexion employee. 2. Pregnant, breastfeeding, or intending to conceive during the course of the study. 3. Participants known to be human immunodeficiency virus positive or with congenital immunodeficiency. 4. Unresolved meningococcal or other serious infection. 5. Any unresolved acute or chronic systemic bacterial or other infection that is clinically significant in the opinion of the Investigator and has not been treated with appropriate antibiotics. 6. Use of rituximab or other biologicals such as tocilizumab within 6 months prior to Screening. 7. Use of mitoxantrone within 3 months prior to Screening. 8. Use of intravenous immunoglobulin or plasma exchange within 3 weeks prior to Screening. 9. Use of immunomodulatory therapies for multiple sclerosis within 3 months prior to Screening. 10. Has previously received treatment with eculizumab or other complement inhibitors.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change Between the Baseline Annualized Relapse Rate (ARR) and the On-Trial ARR at Week 52/53 | Baseline, Week 52/53 | ARR was calculated as the number of relapses for each participant divided by the number of years of treatment for that participant. Baseline ARR was based on 24 months prior to screening. |
| Time to First On-trial Relapse | Baseline up to Week 52/53 | Time to First Relapse was defined as beginning at the time the participant's first dose of eculizumab was administered until the participant's first on-trial relapse was reported by the Investigator. Participants who did not experience an on-trial relapse were censored at the end of the study period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Hauser Ambulation Index (HAI) Score at Week 52/53 | Baseline, Weeks 52/53 | 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 ranged 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. |
| Number of Participants With Shift From Baseline in Visual Acuity (VA) | Baseline, Week 52/53 | The Snellen chart was used to assess VA. The Snellen chart quantifies ability to read letters of varying sizes at a fixed distance in relation to the distance at which a participant with normal vision could read the same letters. The test was performed at a standard distance, typically 6 meters or 20 feet. The Snellen chart is typically recorded as acuity ratio distance (6 meters or 20 feet), so for normal VA it would be recorded as 20/20 or 6/6. Visual acuity was summarized according to the eye with greater worsening at the end of primary treatment period (Week 52/53). Data are presented for number of participants with a shift from baseline in VA presented per the different levels of acuity ratio distance. Baseline was defined as the last available assessment prior to the first IP study drug infusion for all participants regardless of treatment group. Visual Acuity data are only reported for the categories with available data at Baseline and Week 52/53. |
| Number of Participants With Shift From Baseline in Confrontational Visual Fields (VF) | Baseline, Weeks 52/53 | Confrontational visual fields were summarized according to the number of quadrants with deficits across both eyes. Baseline was defined as the last available assessment prior to the first IP study drug infusion for all participants regardless of treatment group. |
| Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Score at Week 52/53 | Baseline, Weeks 52/53 | PedsQL included a child self-report for participants 5 to 18 years with a 23-item PedsQL Generic Core Scales report. The PedsQL Generic Core Scales report included 4 scales, physical functioning, emotional functioning, social functioning, and school functioning. Each item used a 5-point rating scale (from 0=never to 4=almost always). Items are reverse scored and linearly transformed to a 0 (almost always) -100 (never) scale. All summary/total scores were mean of specific items where higher score indicated better HRQoL. |
| Serum Eculizumab Concentration at Week 52 | Week 52 | — |
| Change From Baseline in Serum Free Complement Protein 5 (C5) Concentrations at Week 52 | Baseline, Week 52 | — |
| Number of Participants With Shift From Baseline in Color Vision | Baseline, Weeks 52/53 | Color vision was evaluated as the shift from baseline and described for participants with normal color vision at baseline in at least one eye. Participants with 13 or less correctly identified Ishihara plates were considered as having abnormal color vision, participants with 14 or more correctly identified plates were considered as having normal color vision. Baseline was defined as the last available assessment prior to the first IP study drug infusion for all participants regardless of treatment group. |
| Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Week 52/53 | Baseline, Week 52/53 | 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. |
Countries
Canada, Germany, Italy, Japan, South Korea, Spain, United States
Participant flow
Pre-assignment details
All 5 participants were in the \>=40 kilograms (kg) weight cohort at enrollment. Therefore, all 5 participants received the same dose of study drug for the Induction Period and the Maintenance Period as described in the study arm.
Participants by arm
| Arm | Count |
|---|---|
| Eculizumab Induction Period: Participants received eculizumab (900 mg) via IV infusion once a week for 4 weeks. Maintenance Period: Participants received eculizumab (1200 mg) via IV infusion every 2 weeks from fifth dose (Week 4) onwards and then every 2 weeks. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Other than specified | 3 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Eculizumab |
|---|---|
| Age, Continuous | 12.0 years STANDARD_DEVIATION 4.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 2 / 5 |
Outcome results
Primary
Change Between the Baseline Annualized Relapse Rate (ARR) and the On-Trial ARR at Week 52/53
ARR was calculated as the number of relapses for each participant divided by the number of years of treatment for that participant. Baseline ARR was based on 24 months prior to screening.
Time frame: Baseline, Week 52/53
Population: Full Analysis Set included all participants who received at least 1 dose of eculizumab. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | Change Between the Baseline Annualized Relapse Rate (ARR) and the On-Trial ARR at Week 52/53 | -3.01 relapses per participant per year | Standard Deviation 2.504 |
Primary
Time to First On-trial Relapse
Time to First Relapse was defined as beginning at the time the participant's first dose of eculizumab was administered until the participant's first on-trial relapse was reported by the Investigator. Participants who did not experience an on-trial relapse were censored at the end of the study period.
Time frame: Baseline up to Week 52/53
Population: Full Analysis Set included all participants who received at least 1 dose of eculizumab. Note that since no participants experienced a On-trial Relapse, data was not collected for this Outcome Measure.
Secondary
Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Week 52/53
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, Week 52/53
Population: Full Analysis Set included all participants who received at least 1 dose of eculizumab. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Week 52/53 | -0.75 score on a scale | Standard Deviation 1.708 |
Secondary
Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Score at Week 52/53
PedsQL included a child self-report for participants 5 to 18 years with a 23-item PedsQL Generic Core Scales report. The PedsQL Generic Core Scales report included 4 scales, physical functioning, emotional functioning, social functioning, and school functioning. Each item used a 5-point rating scale (from 0=never to 4=almost always). Items are reverse scored and linearly transformed to a 0 (almost always) -100 (never) scale. All summary/total scores were mean of specific items where higher score indicated better HRQoL.
Time frame: Baseline, Weeks 52/53
Population: Full Analysis Set included all participants who received at least 1 dose of eculizumab. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Score at Week 52/53 | -5.01 score on a scale | Standard Deviation 10.401 |
Secondary
Change From Baseline in Serum Free Complement Protein 5 (C5) Concentrations at Week 52
Time frame: Baseline, Week 52
Population: PK/PD analysis set included participants who received at least 1 dose of eculizumab and who had evaluable PK/PD data. for the endpoint. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure .
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eculizumab | Change From Baseline in Serum Free Complement Protein 5 (C5) Concentrations at Week 52 | Baseline | 166.67 micrograms/milliliters | Standard Deviation 50.203 |
| Eculizumab | Change From Baseline in Serum Free Complement Protein 5 (C5) Concentrations at Week 52 | Change from Baseline at Week 52 | -166.64 micrograms/milliliters | Standard Deviation 50.194 |
Secondary
Change From Baseline in the Hauser Ambulation Index (HAI) Score at Week 52/53
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 ranged 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, Weeks 52/53
Population: Full Analysis Set included all participants who received at least 1 dose of eculizumab. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | Change From Baseline in the Hauser Ambulation Index (HAI) Score at Week 52/53 | 0.0 score on a scale | Standard Deviation 0 |
Secondary
Number of Participants With Shift From Baseline in Color Vision
Color vision was evaluated as the shift from baseline and described for participants with normal color vision at baseline in at least one eye. Participants with 13 or less correctly identified Ishihara plates were considered as having abnormal color vision, participants with 14 or more correctly identified plates were considered as having normal color vision. Baseline was defined as the last available assessment prior to the first IP study drug infusion for all participants regardless of treatment group.
Time frame: Baseline, Weeks 52/53
Population: Full Analysis Set included all participants who received at least 1 dose of eculizumab. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eculizumab | Number of Participants With Shift From Baseline in Color Vision | No Change from Normal | 4 Participants |
| Eculizumab | Number of Participants With Shift From Baseline in Color Vision | Worsened from Baseline | 0 Participants |
Secondary
Number of Participants With Shift From Baseline in Confrontational Visual Fields (VF)
Confrontational visual fields were summarized according to the number of quadrants with deficits across both eyes. Baseline was defined as the last available assessment prior to the first IP study drug infusion for all participants regardless of treatment group.
Time frame: Baseline, Weeks 52/53
Population: Full Analysis Set included all participants who received at least 1 dose of eculizumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eculizumab | Number of Participants With Shift From Baseline in Confrontational Visual Fields (VF) | 2 to 0 | 1 Participants |
| Eculizumab | Number of Participants With Shift From Baseline in Confrontational Visual Fields (VF) | 0 to 0 | 2 Participants |
Secondary
Number of Participants With Shift From Baseline in Visual Acuity (VA)
The Snellen chart was used to assess VA. The Snellen chart quantifies ability to read letters of varying sizes at a fixed distance in relation to the distance at which a participant with normal vision could read the same letters. The test was performed at a standard distance, typically 6 meters or 20 feet. The Snellen chart is typically recorded as acuity ratio distance (6 meters or 20 feet), so for normal VA it would be recorded as 20/20 or 6/6. Visual acuity was summarized according to the eye with greater worsening at the end of primary treatment period (Week 52/53). Data are presented for number of participants with a shift from baseline in VA presented per the different levels of acuity ratio distance. Baseline was defined as the last available assessment prior to the first IP study drug infusion for all participants regardless of treatment group. Visual Acuity data are only reported for the categories with available data at Baseline and Week 52/53.
Time frame: Baseline, Week 52/53
Population: Full Analysis Set included all participants who received at least 1 dose of eculizumab. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eculizumab | Number of Participants With Shift From Baseline in Visual Acuity (VA) | Shift from VA 20/20-20/29 to VA 20/20-20/29 | 3 Participants |
| Eculizumab | Number of Participants With Shift From Baseline in Visual Acuity (VA) | Shift from VA 20/30-20/59 to VA 20/20-20/29 | 1 Participants |
Secondary
Serum Eculizumab Concentration at Week 52
Time frame: Week 52
Population: Pharmacokinetic/Pharmacodynamic (PK/PD) analysis set included participants who received at least 1 dose of eculizumab and who had evaluable PK/PD data for the endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eculizumab | Serum Eculizumab Concentration at Week 52 | Pre-dose: 5-90 Minutes | 460.7 micrograms/milliliters | Standard Deviation 65.04 |
| Eculizumab | Serum Eculizumab Concentration at Week 52 | Post-dose: 60 minutes | 971.3 micrograms/milliliters | Standard Deviation 198.04 |