Neuromyelitis Optica Spectrum Disorder
Conditions
Keywords
neuromyelitis optica spectrum disorder, azathioprine, rituximab, clinical trial, annual relapse rate, expanded disability status scale
Brief summary
The purpose of this study is to compare annual relapse rate, expanded disability status scale, and side effects of azathioprine and rituximab in patients with neuromyelitis optica spectrum disorder during a one year follow up through a randomized clinical trial.
Detailed description
Neuromyelitis Optica Spectrum Disorder (NMO-SD) is a recurrent inflammatory demyelinating disease affecting the central nervous system. The disease is clinically recognized by optic neuritis and transverse myelitis and is associated with high risk of mortality. Each attack worsens patients' disability. This means that after 5 years of the disease onset, half of patients need to use wheelchair and approximately 50% of them become blind. Considering that the disease can be disabling for patients, the maintenance treatment should be applied in addition to treatment of acute attacks, in order to prevent future recurrences. Acute attacks are usually treated with high doses of intravenous corticosteroids. Plasmapheresis is also used when patients fail to response to corticosteroids. B lymphocyte inhibitors are used as the maintenance therapy in these patients. First line therapeutic medications include azathioprine and rituximab which are being recommended for long term therapy and second line medications include methotrexate and mycophenolate mofetil. Azathioprine is an immune-modulatory agent which is available in the oral form and don't require hospitalization to be administered, however, because of side effects such as bone marrow suppression and hepatotoxicity, periodic check of blood cells and liver enzymes are needed. Rituximab is a cluster of differentiation antigen 20 inhibitor which leads to decreased B lymphocytes and antibody in patients. This medication is only available in the injectable form and needs hospitalization to be administered. Close monitory is needed during the administration considering severe side effects such as allergic reactions and respiratory distress. However, laboratory tests are not needed in patients taking rituximab although it is more expensive than azathioprine. No clinical trial has been performed previously to compare clinical efficacy of these two drugs in NMO-SD patients. Therefore, we aimed to compare their efficacy through a randomized clinical trial.
Interventions
DRUGAzathioprine
Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.
DRUGRituximab
Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.
Sponsors
Isfahan University of Medical Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of neuromyelitis optica spectrum disorder based on the recent guidelines in 2015 * Expanded disability status scale between 0 and 7 * Age between 18 and 50 years old
Exclusion criteria
* Pregnancy or lactation during the study * Deciding to leave the study by patient * Lack of consent to enter the study * Lack of cooperation for follow up * Severe side effect of the medication * Treatment with other immunosuppressant medications (including but not limited to cyclophosphamide, mycophenolate mofetil, methotrexate, others) within two months before intervention * Taking any other immunosuppressant or other type of medication (including herbal drugs) without permission of the physician during the study. * Presence of other autoimmune disease (including but not limited to Behcet disease, systemic lupus erythematosus, rheumatoid arthritis, and others) * Presence of liver disorders * Presence of hematologic disorders * Presence of heart failure * Receipt of a live vaccine within 4 weeks prior to intervention * Previous treatment with Azathioporine or Rituximab * History of HIV, hepatitis B, or hepatitis C * Ongoing daily steroid use * History of severe allergic or anaphylactic reaction to monoclonal antibodies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annual Relapse Rate | one year | annual relapse rate will be measured in the baseline (according to patients' history in the last year) and after 12 months of intervention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Expanded Disability Status Scale | one year | expanded disability status scale will be measured in the baseline and after 12 months of intervention. Expanded disability status scale (EDSS) is a measure of disability for patients. The score ranges from 0-10, with 0 showing normal neurological exam and 10 showing death due to the disabling disease. Thus, higher scores represent more profound levels of disability. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Drug Reactions | one year | adverse drug reactions will be observed closely and reported during the intervention. We will compare the number of adverse drug reactions in two groups. Also, adverse drug reactions will be described by details in each group. |
Countries
Iran
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azathioprine Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500.
Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose. | 46 |
| Rituximab Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months.
Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months. | 40 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Immigration to another region | 0 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 4 |
Baseline characteristics
| Characteristic | Rituximab | Total | Azathioprine |
|---|---|---|---|
| Age, Continuous | 34.33 years STANDARD_DEVIATION 5.86 | 33.14 years STANDARD_DEVIATION 7.32 | 32.11 years STANDARD_DEVIATION 9.36 |
| Annualized relapse rate | 1.30 numbers of relapses STANDARD_DEVIATION 0.65 | 1.15 numbers of relapses STANDARD_DEVIATION 0.51 | 1.02 numbers of relapses STANDARD_DEVIATION 0.39 |
| Expanded disability status scale | 3.55 units on a scale STANDARD_DEVIATION 1.95 | 2.96 units on a scale STANDARD_DEVIATION 1.52 | 2.40 units on a scale STANDARD_DEVIATION 1.24 |
| Positive AQP4-IgG | 17 Participants | 42 Participants | 25 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Iran | 40 participants | 86 participants | 46 participants |
| Sex: Female, Male Female | 34 Participants | 72 Participants | 38 Participants |
| Sex: Female, Male Male | 6 Participants | 14 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 40 |
| other Total, other adverse events | 2 / 46 | 3 / 40 |
| serious Total, serious adverse events | 1 / 46 | 1 / 40 |
Outcome results
Primary
Annual Relapse Rate
annual relapse rate will be measured in the baseline (according to patients' history in the last year) and after 12 months of intervention.
Time frame: one year
Population: Per protocol analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azathioprine | Annual Relapse Rate | Baseline | 1 Number of relapses | Standard Deviation 0.38 |
| Azathioprine | Annual Relapse Rate | Outcome | 0.51 Number of relapses | Standard Deviation 0.55 |
| Rituximab | Annual Relapse Rate | Outcome | 0.21 Number of relapses | Standard Deviation 0.42 |
| Rituximab | Annual Relapse Rate | Baseline | 1.30 Number of relapses | Standard Deviation 0.68 |
Secondary
Expanded Disability Status Scale
expanded disability status scale will be measured in the baseline and after 12 months of intervention. Expanded disability status scale (EDSS) is a measure of disability for patients. The score ranges from 0-10, with 0 showing normal neurological exam and 10 showing death due to the disabling disease. Thus, higher scores represent more profound levels of disability.
Time frame: one year
Population: Per protocol analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azathioprine | Expanded Disability Status Scale | Baseline | 2.40 score on a scale | Standard Deviation 1.24 |
| Azathioprine | Expanded Disability Status Scale | Outcome | 1.95 score on a scale | Standard Deviation 1.13 |
| Rituximab | Expanded Disability Status Scale | Baseline | 3.55 score on a scale | Standard Deviation 1.95 |
| Rituximab | Expanded Disability Status Scale | Outcome | 2.56 score on a scale | Standard Deviation 1.99 |
Other Pre-specified
Number of Participants With Adverse Drug Reactions
adverse drug reactions will be observed closely and reported during the intervention. We will compare the number of adverse drug reactions in two groups. Also, adverse drug reactions will be described by details in each group.
Time frame: one year
Population: intention to treat analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azathioprine | Number of Participants With Adverse Drug Reactions | 3 Participants |
| Rituximab | Number of Participants With Adverse Drug Reactions | 4 Participants |