SOLIRIS STUDY DESIGN FOR NMOSD
SOLIRIS® (eculizumab) was studied in PREVENT and PREVENT OLE for over 3 years in adult patients with anti-AQP4 antibody-positive NMOSD1-4
PREVENT and PREVENT OLE study design1-4
PREVENT was a randomized, double-blind, placebo-controlled, time-to-event trial in 143 adults with anti-AQP4 antibody-positive NMOSD in 70 sites across 18 countries1,2
To preserve the blinded nature, all patients underwent a 4-week blind induction phase prior to entering the PREVENT OLE. Supportive immunosuppressive therapy for relapse prevention was allowed during the study at the treating physician’s discretion.4
Duration
*All patients must have been vaccinated against Neisseria meningitidis if not already vaccinated. Patients must have been vaccinated at least 14 days prior to receiving the first dose of study drug or been vaccinated and received treatment with appropriate antibiotics until 14 days after vaccination.1-3
†The trial was designed to end after the 24th patient had a relapse event confirmed by a blinded, independent adjudication committee.2
PREVENT study endpoints1,2
Primary endpoint
- Time to first adjudicated on-trial relapse
Primary analysis
- Relative risk reduction
- Estimated number of patients relapse-free at 48 weeks
- Total number of adjudicated relapses by treatment group
- Kaplan-Meier curve for time to first adjudicated relapse by treatment group
Prespecified subgroup analysis
- Time to first adjudicated on-trial relapse in patients who were not receiving immunosuppressive therapy at baseline (24% of patients)
Secondary endpoints
- Adjudicated annualized relapse rate (ARR)
- Neurologic function
- Disease-related disability
Additional outcome measurements
- NMOSD interventions
- Safety and tolerability
Defining relapses2
On-trial relapse was defined as new onset of neurologic symptoms or worsening of existing neurologic symptoms that:
- Presented as objective change (clinical sign) on the neurologic examination
- Persisted for more than 24 hours
- Were identified by the treating physician
- Were attributable to NMOSD rather than other causes
- Were preceded by at least 30 days of clinical stability
Changes in imaging with no related clinical findings were not considered an on-trial relapse.
All relapses were retrospectively adjudicated by the Relapse Adjudication Committee (RAC), an independent panel of 3 experts (2 neurologists and 1 neuro-ophthalmologist) who were blinded to the treatment assignment.
PREVENT patient criteria1,2
Key inclusion criteria
- Age ≥18 years
- Confirmed diagnosis of NMO or NMOSD (defined by Wingerchuk et al 2006 or 2007 criteria, respectively)
- Historical relapses
- ≥2 in the last 12 months, or
- 3 in the last 24 months, with ≥1 in the 12 months prior to screening
- Expanded Disability Status Scale (EDSS) score ≤7
- On a stable dosage of immunosuppressive therapy and corticosteroids ≤20 mg/day*
Key exclusion criteria
- Use of rituximab or mitoxantrone within 3 months prior to screening
- Use of IVIg within 3 weeks prior to screening
- Use of prednisone >20 mg/day or equivalent
- Unresolved meningococcal disease
- Any systemic bacterial or other infection considered clinically significant or not treated with appropriate antibiotics
*Patients were not required to be on immunosuppressive therapy.1
PREVENT patient demographics and baseline characteristics2,3
| SOLIRIS (N=96) | Placebo (N=47) | |
|---|---|---|
| Female, n (%) | 88 (92) | 42 (89) |
| Age, mean years ± SD | 43.9 ± 13.32 | 45.0 ± 13.29 |
| Race, n (%) | ||
| Asian | 37 (38.5) | 15 (31.9) |
| Black or African American | 9 (9.4) | 8 (17.0) |
| White | 46 (47.9) | 24 (51.1) |
| Other or unknown | 4 (4.2) | 0 (0) |
| ARR during previous 24 months, mean ± SD | 1.94 ± 0.90 | 2.07 ± 1.04 |
| EDSS score, median (range) | 4.0 (1.0-7.0) | 4.0 (1.0-6.5) |
| Immunosuppressive therapy at baseline, n (%) | ||
| None | 21 (22) | 13 (28) |
| Glucocorticoids alone | 16 (17) | 11 (23) |
| Azathioprine with or without glucocorticoids | 37 (39) | 13 (28) |
| Mycophenolate mofetil with or without glucocorticoids | 17 (18) | 8 (17) |
| Other drug with or without glucocorticoidsa | 5 (5) | 2 (4) |
| Supportive immunosuppressive therapy used at any time before the trial, n (%) | 88 (92) | 45 (96) |
| Glucocorticoids | 68 (71) | 30 (64) |
| Azathioprine | 61 (64) | 26 (55) |
| Mycophenolate mofetil | 27 (28) | 15 (32) |
| Rituximab | 26 (27) | 20 (43) |
| Cyclophosphamide | 8 (8) | 5 (11) |
| Methotrexate | 4 (4) | 5 (11) |
| Cyclosporine and tacrolimus | 3 (3) | 3 (6) |
| Mitoxantrone and cladribine | 3 (3) | 3 (6) |
| Intravenous immune globulin | 2 (2) | 2 (4) |
| Tocilizumab | 2 (2) | 0 |
| Mizoribine | 1 (1) | 2 (4) |
aOther drugs include cyclosporine, cyclophosphamide, methotrexate, mizoribine, and tacrolimus.2
PREVENT OLE4
Primary objective
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
SOLIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1)]. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.
- Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of SOLIRIS, unless the risks of delaying SOLIRIS therapy outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria.
- Patients receiving SOLIRIS are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected.
Because of the risk of serious meningococcal infections, SOLIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2)].
CONTRAINDICATIONS
- SOLIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection.
WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections
SOLIRIS, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors.
Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with SOLIRIS. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information.
If urgent SOLIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including SOLIRIS. The benefits and risks of treatment with SOLIRIS, as well as those associated with antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis.
Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination.
Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of SOLIRIS in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated.
ULTOMIRIS and SOLIRIS REMS
Due to the risk of serious meningococcal infections, SOLIRIS is available only through a restricted program called ULTOMIRIS and SOLIRIS REMS.
Prescribers must enroll in the REMS, counsel patients about the risk of serious meningococcal infection, provide patients with REMS educational materials, assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of SOLIRIS. Antibacterial drug prophylaxis must be prescribed if treatment must be started urgently and the patient is not up to date with both meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of SOLIRIS. Patients must receive counseling about the need to receive meningococcal vaccines and to take antibiotics as directed, the signs and symptoms of meningococcal infection, and be instructed to carry the Patient Safety Card with them at all times during and for 3 months following SOLIRIS treatment.
Further information is available at www.UltSolREMS.com or 1-888-765-4747.
Other Infections
Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.
SOLIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Patients receiving SOLIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination.
Thrombosis Prevention and Management
The effect of withdrawal of anticoagulant therapy during SOLIRIS treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management.
Infusion-Related Reactions
Administration of SOLIRIS may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of SOLIRIS. Interrupt SOLIRIS infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.
ADVERSE REACTIONS
The most frequently reported adverse reactions in the NMOSD placebo-controlled trial (≥10%) were: upper respiratory infection, nasopharyngitis, diarrhea, back pain, dizziness, influenza, arthralgia, pharyngitis, and contusion.
To report SUSPECTED ADVERSE REACTIONS contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
INDICATION
SOLIRIS is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.
Please see full Prescribing Information for SOLIRIS, including Boxed WARNING regarding serious and life-threatening or fatal meningococcal infections.
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
SOLIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1)]. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.
- Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of SOLIRIS, unless the risks of delaying SOLIRIS therapy outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria.
- Patients receiving SOLIRIS are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected.
Because of the risk of serious meningococcal infections, SOLIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2)].
CONTRAINDICATIONS
- SOLIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection.
WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections
SOLIRIS, a complement inhibitor, increases a patient’s susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors.
Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with SOLIRIS. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information.
If urgent SOLIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including SOLIRIS. The benefits and risks of treatment with SOLIRIS, as well as those associated with antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis.
Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination.
Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of SOLIRIS in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated.
ULTOMIRIS and SOLIRIS REMS
Due to the risk of serious meningococcal infections, SOLIRIS is available only through a restricted program called ULTOMIRIS and SOLIRIS REMS.
Prescribers must enroll in the REMS, counsel patients about the risk of serious meningococcal infection, provide patients with REMS educational materials, assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of SOLIRIS. Antibacterial drug prophylaxis must be prescribed if treatment must be started urgently and the patient is not up to date with both meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of SOLIRIS. Patients must receive counseling about the need to receive meningococcal vaccines and to take antibiotics as directed, the signs and symptoms of meningococcal infection, and be instructed to carry the Patient Safety Card with them at all times during and for 3 months following SOLIRIS treatment.
Further information is available at www.UltSolREMS.com or 1-888-765-4747.
Other Infections
Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.
SOLIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Patients receiving SOLIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination.
Thrombosis Prevention and Management
The effect of withdrawal of anticoagulant therapy during SOLIRIS treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management.
Infusion-Related Reactions
Administration of SOLIRIS may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of SOLIRIS. Interrupt SOLIRIS infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.
ADVERSE REACTIONS
The most frequently reported adverse reactions in the NMOSD placebo-controlled trial (≥10%) were: upper respiratory infection, nasopharyngitis, diarrhea, back pain, dizziness, influenza, arthralgia, pharyngitis, and contusion.
To report SUSPECTED ADVERSE REACTIONS contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
INDICATION
SOLIRIS is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.
Please see full Prescribing Information for SOLIRIS, including Boxed WARNING regarding serious and life-threatening or fatal meningococcal infections.
References
1. SOLIRIS. Prescribing information. Alexion Pharmaceuticals, Inc. 2. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med. 2019;381(7):614-625. doi:10.1056/NEJMoa1900866 3. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med. 2019;381(7)(suppl 1-36):614-625. doi:10.1186/1742-2094-9-14 4. Data on file. Alexion Pharmaceuticals, Inc. 5. A randomized controlled trial of eculizumab in AQP4 antibody-positive participants with NMO (PREVENT study). ClinicalTrials.gov identifier: NCT01892345. Updated June 26, 2019. Accessed March 9, 2023. https://clinicaltrials.gov/ct2/show/NCT01892345