Devic's Disease, Neuromyelitis Optica
Conditions
Keywords
NMO, Devic's disease, Neuromyelitis optica, NMO-IgG, Aquaporin-4 antibody, Eculizumab, Complement
Brief summary
The purpose of this study is to determine if the drug eculizumab reduces the attack rate and improves outcome in patients with neuromyelitis optica.
Detailed description
It has been shown in some scientific studies that the the antibody marker specific for neuromyelitis optica (NMO), known as NMO-Immunoglobulin G (IgG), causes inflammation in brain tissues by activating a substance called complement. Complement can greatly increase the immune attack in the optic nerves (causing optic neuritis (ON)), spinal cords (causing transverse myelitis (TM)) and brains of patients with NMO. Eculizumab has already been shown to be effective in a rare blood disorder known as paroxysmal nocturnal hemoglobinuria (PNH). Attacks of PNH are also mediated through complement. Therefore, the investigators of this study are investigating whether by 'turning off' complement in NMO, further attacks of NMO can be prevented. The primary (most important) objectives of this study are to determine: Whether Eculizumab reduces relapse frequency in patients with relapsing NMO. The number of attacks during the one year treatment period will be compared to the number of attacks that occurred prior to initiation of eculizumab treatment. For patients with more than 2 year disease duration, the average number of attacks in the preceding 2 years will be calculated. For patients with less than 2 years disease duration the number of attacks in the preceding year will be used. The safety profile of eculizumab in patients with NMO. The secondary objectives are to determine: Whether eculizumab maintains or improves walking, visual function and quality of life as measured by a variety of established disability scales. We will also assess the severity of an individual attack and the degree of recovery. How the drug behaves in the patient's blood (called pharmacodynamics and pharmacokinetics). Depending on our preliminary investigations we may evaluate patient cerebrospinal fluid in the laboratory to see how effective eculizumab is at getting into the cerebrospinal fluid from the blood stream, and to see if the drug reverses the biological effects of the NMO-IgG antibody.
Interventions
DRUGEculizumab
The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. The first infusion will be given at Mayo Clinic site; subsequent infusions will be administered in the subject's home by a company which will send a nurse to administer the infusion. Subjects will receive therapy for a total of 12 months.
Sponsors
Alexion Pharmaceuticals, Inc.
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of NMO, as defined by 2006 criteria OR NMO seropositive spectrum disorder (Recurrent ON or longitudinally extensive transverse myelitis (LETM)). All patients must be NMO-IgG seropositive. 2. Clinical evidence of at least 2 relapses in last 6 months or 3 relapses in the last 12 months (with at least 1 relapse occurring in the preceding 6 months). 3. Age ≥18 years 4. Corrected visual acuity 20/100 or better in at least one eye. If fails item # 4 then entry allowed but only if last attack was myelitis and only attacks of myelitis are considered as outcome measurement. 5. Ambulatory (with or without walker). If fails item # 5 then entry allowed but only if last attack was ON and only attacks of ON are considered as outcome measurement. 6. Provision of written informed consent (see attached) to participate in the study. 7. N. meningitidis vaccination at least 14 days prior to receiving the first eculizumab infusion. If patient in midst of an acute relapse, then relapse will be treated with standard therapy and vaccination given only after a minimum of 4 weeks post attack onset.
Exclusion criteria
Candidates will be excluded from study entry if any of the following criteria are met at the time of randomization: 1. Progressive neurological deterioration unrelated to relapses of ON or myelitis. 2. Pregnant, breastfeeding, or intending to conceive during the course of the study 3. Patients will not participate in any other clinical therapeutic study or will not have participated in any other experimental treatment study within 30 days of screening 4. Patients with a history of splenectomy, because of a potential increased risk of developing meningococcal infection.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Median Number of Neuromyelitis Optica (NMO) Attacks Per Year | baseline, after 12 months of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Expanded Disability Status Scale (EDDS) Score | baseline, 12 months | The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death) in half-point increments. |
| Number of Subjects With Change in Visual Acuity in at Least One Eye by at Least One Point | 12 months | Visual acuity was measured using the the Visual Acuity subscale of the Opticospinal Impairment Score (OSIS) for Exacerbations. This subscale ranges from 0 (normal) to 8 (no light perception). |
| Number of Subjects With Change in Ambulation by at Least 1 Point | 12 months | Ambulation was measured by the Hauser Ambulation Index, which ranges from 0 (asymptomatic; fully active) to 9 (restricted to wheelchair; unable to transfer self independently.) |
| Number Subjects Experiencing an NMO Attack in 12 Months of Eculizumab Treatment | 12 months | — |
| Percentage Hemolysis | baseline, 6 weeks, 3 months, 6 months, 9 months, 12 months | Percentage of hemolysis is a measure of complement activity. Less than 20% lysis is deemed to be complete complement inhibition. |
| Mean Eculizumab Concentration in Cerebrospinal Fluid (CSF) | 3 months | — |
| Mean Complement Protein 5 (C5) Concentration in CSF | baseline, 3 months | — |
| Mean Serum Concentration of Eculizumab | 6 weeks, 3 months, 6 months, 9 months, 12 months | — |
Countries
United States
Participant flow
Recruitment details
Between October 2009 and November 2010, subjects were directly recruited at the Mayo Clinics in Rochester, Minnesota and Scottsdale, Arizona, or identified through the Mayo Clinic study-specific repository or clinicoserological database.
Participants by arm
| Arm | Count |
|---|---|
| Eculizumab The patient will receive eculizumab at a dose of 600mg intravenously (an infusion given into the vein) each week for 4 weeks, then 900mg intravenously at the fifth week, then 900mg every 2 weeks for 48 weeks. Subjects will receive therapy for a total of 12 months. | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Eculizumab |
|---|---|
| Age Continuous | 41.1 years |
| Coexisting autoimmune diseases Idiopathic thrombocytopenic purpura | 2 participants |
| Coexisting autoimmune diseases Mixed connective tissue disease | 2 participants |
| Coexisting autoimmune diseases Myasthenia gravis | 2 participants |
| Coexisting autoimmune diseases No coexisting autoimmune disease | 10 participants |
| Diagnosis Neuromyelitis optica | 8 participants |
| Diagnosis Relapsing optic neuritis | 2 participants |
| Diagnosis Relapsing transverse myelitis | 4 participants |
| Ethnic origin African American | 2 participants |
| Ethnic origin Hispanic | 3 participants |
| Ethnic origin White | 9 participants |
| Expanded Disability Status Scale (EDSS) Score | 4.8 units on a scale |
| Number of previous attacks per subject | 5.5 attacks per subject |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 0 Participants |
| Type of previous attacks at enrollment Brainstem | 1 attacks |
| Type of previous attacks at enrollment Multifocal optic neuritis and transverse myelitis | 3 attacks |
| Type of previous attacks at enrollment Optic neuritis | 28 attacks |
| Type of previous attacks at enrollment Other multifocal | 2 attacks |
| Type of previous attacks at enrollment Transverse myelitis | 52 attacks |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 9 / 14 |
| serious Total, serious adverse events | 1 / 14 |
Outcome results
Primary
Median Number of Neuromyelitis Optica (NMO) Attacks Per Year
Time frame: baseline, after 12 months of treatment
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eculizumab | Median Number of Neuromyelitis Optica (NMO) Attacks Per Year | Baseline | 3 attacks per year |
| Eculizumab | Median Number of Neuromyelitis Optica (NMO) Attacks Per Year | After 12 months of treatment | 0 attacks per year |
Comparison: Comparison between before treatment and one year after treatment.p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Change in Expanded Disability Status Scale (EDDS) Score
The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death) in half-point increments.
Time frame: baseline, 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Eculizumab | Change in Expanded Disability Status Scale (EDDS) Score | -0.7 units on a scale |
Comparison: Comparison was made between baseline and after 12 months of treatment.p-value: 0.0078Wilcoxon (Mann-Whitney)
Secondary
Mean Complement Protein 5 (C5) Concentration in CSF
Time frame: baseline, 3 months
Population: At 3 months, C5 was undetectable in 6 subjects; patient 13 was excluded because she had temporarily discontinued treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eculizumab | Mean Complement Protein 5 (C5) Concentration in CSF | Baseline | 144 ng/mL | Standard Deviation 75.5 |
| Eculizumab | Mean Complement Protein 5 (C5) Concentration in CSF | 3 months | 60.8 ng/mL | Standard Deviation 23.3 |
Comparison: Comparison was between 3 months and baseline.p-value: 0.0019Wilcoxon (Mann-Whitney)
Secondary
Mean Eculizumab Concentration in Cerebrospinal Fluid (CSF)
Time frame: 3 months
Population: 12 subjects including subject 13 agreed to have CSF draw at the 3 month visit, but subject 13 was excluded because she had temporarily discontinued treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eculizumab | Mean Eculizumab Concentration in Cerebrospinal Fluid (CSF) | 34.7 ng/mL | Standard Deviation 18.7 |
Secondary
Mean Serum Concentration of Eculizumab
Time frame: 6 weeks, 3 months, 6 months, 9 months, 12 months
Population: Patient 13 was excluded from the 3 months measurement because she had temporarily discontinued treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eculizumab | Mean Serum Concentration of Eculizumab | 12 months | 246 micrograms/mL | Standard Deviation 102 |
| Eculizumab | Mean Serum Concentration of Eculizumab | 6 weeks | 206 micrograms/mL | Standard Deviation 77 |
| Eculizumab | Mean Serum Concentration of Eculizumab | 3 months | 187 micrograms/mL | Standard Deviation 91.2 |
| Eculizumab | Mean Serum Concentration of Eculizumab | 9 months | 230 micrograms/mL | Standard Deviation 85.3 |
Secondary
Number of Subjects With Change in Ambulation by at Least 1 Point
Ambulation was measured by the Hauser Ambulation Index, which ranges from 0 (asymptomatic; fully active) to 9 (restricted to wheelchair; unable to transfer self independently.)
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Number of Subjects With Change in Ambulation by at Least 1 Point | 3 participants |
Secondary
Number of Subjects With Change in Visual Acuity in at Least One Eye by at Least One Point
Visual acuity was measured using the the Visual Acuity subscale of the Opticospinal Impairment Score (OSIS) for Exacerbations. This subscale ranges from 0 (normal) to 8 (no light perception).
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Number of Subjects With Change in Visual Acuity in at Least One Eye by at Least One Point | 5 participants |
Secondary
Number Subjects Experiencing an NMO Attack in 12 Months of Eculizumab Treatment
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eculizumab | Number Subjects Experiencing an NMO Attack in 12 Months of Eculizumab Treatment | 2 participants |
Secondary
Percentage Hemolysis
Percentage of hemolysis is a measure of complement activity. Less than 20% lysis is deemed to be complete complement inhibition.
Time frame: baseline, 6 weeks, 3 months, 6 months, 9 months, 12 months
Population: Subject 13 was excluded at 3 months visit because she had temporarily discontinued treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eculizumab | Percentage Hemolysis | Baseline | 88.5 percentage of hemolysis | Standard Deviation 13.2 |
| Eculizumab | Percentage Hemolysis | 6 weeks | 0.4 percentage of hemolysis | Standard Deviation 0.8 |
| Eculizumab | Percentage Hemolysis | 3 months | 0 percentage of hemolysis | Standard Deviation 0 |
| Eculizumab | Percentage Hemolysis | 6 months | 0.2 percentage of hemolysis | Standard Deviation 0.6 |
| Eculizumab | Percentage Hemolysis | 9 months | 0.4 percentage of hemolysis | Standard Deviation 0.9 |
| Eculizumab | Percentage Hemolysis | 12 months | 0.9 percentage of hemolysis | Standard Deviation 1.5 |
Comparison: Comparison is between 6 weeks and baseline.p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: Comparison is between 3 months and baseline.p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: Comparison is between 6 months and baselinep-value: 0.0001Wilcoxon (Mann-Whitney)
Comparison: Comparison is between 9 months and baseline.p-value: 0.0001Wilcoxon (Mann-Whitney)
Comparison: Comparison is between 12 months and baseline.p-value: <0.0001Wilcoxon (Mann-Whitney)