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
Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris and may become rapidly life-threatening or fatal if not recognized and treated early.
- Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
- Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of Soliris, unless the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection. (See Serious Meningococcal Infections for additional guidance on the management of the risk of meningococcal infection).
- Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.
Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS, prescribers must enroll in the program. Enrollment in the Soliris REMS program and additional information are available by telephone: 1-888-SOLIRIS (1-888-765-4747) or at www.solirisrems.com.
Contraindications
- Patients with unresolved serious Neisseria meningitidis infection
- Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying Soliris treatment outweigh the risks of developing a meningococcal infection
Warnings and Precautions
Serious Meningococcal Infections
Risk and Prevention
The use of Soliris increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis).
Vaccinate or revaccinate for meningococcal disease according to the most current ACIP recommendations for patients with complement deficiencies. Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of Soliris. If Soliris must be initiated immediately in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide 2 weeks of antibacterial drug prophylaxis. Discontinue Soliris in patients who are undergoing treatment for serious meningococcal infections.
REMS
Prescribers must counsel patients about the risk of meningococcal infection, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccine(s).
Other Infections
Serious infections with Neisseria species (other than N. meningitidis), including disseminated gonococcal infections, have been reported.
Patients may have increased susceptibility to infections, especially with encapsulated bacteria. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Use caution when administering Soliris to patients with any systemic infection.
Infusion-Related Reactions
Administration of Soliris may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. 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%) are: upper respiratory infection, nasopharyngitis, diarrhea, back pain, dizziness, influenza, arthralgia, pharyngitis, and contusion.
INDICATION
Neuromyelitis Optica Spectrum Disorder (NMOSD)
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 meningococcal infections.
WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris and may become rapidly life-threatening or fatal if not recognized and treated early.
- Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
- Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of Soliris, unless the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection. (See Serious Meningococcal Infections for additional guidance on the management of the risk of meningococcal infection).
- Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.
Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS, prescribers must enroll in the program. Enrollment in the Soliris REMS program and additional information are available by telephone: 1-888-SOLIRIS (1-888-765-4747) or at www.solirisrems.com.
Contraindications
- Patients with unresolved serious Neisseria meningitidis infection
- Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying Soliris treatment outweigh the risks of developing a meningococcal infection
Warnings and Precautions
Serious Meningococcal Infections
Risk and Prevention
The use of Soliris increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis).
Vaccinate or revaccinate for meningococcal disease according to the most current ACIP recommendations for patients with complement deficiencies. Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of Soliris. If Soliris must be initiated immediately in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide 2 weeks of antibacterial drug prophylaxis. Discontinue Soliris in patients who are undergoing treatment for serious meningococcal infections.
REMS
Prescribers must counsel patients about the risk of meningococcal infection, provide the patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccine(s).
Other Infections
Serious infections with Neisseria species (other than N. meningitidis), including disseminated gonococcal infections, have been reported.
Patients may have increased susceptibility to infections, especially with encapsulated bacteria. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Use caution when administering Soliris to patients with any systemic infection.
Infusion-Related Reactions
Administration of Soliris may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. 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%) are: upper respiratory infection, nasopharyngitis, diarrhea, back pain, dizziness, influenza, arthralgia, pharyngitis, and contusion.
INDICATION
Neuromyelitis Optica Spectrum Disorder (NMOSD)
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 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