RESUMO
Importance: Additional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression. Objective: To evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS. Design, Setting, and Participants: This double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of -0.3 points per month. Interventions: Study treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment. Main Outcomes and Measures: The primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS). Results: A total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n = 255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n = 127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was -14.67 points (SE, 0.89 points; 95% CI, -16.42 to -12.91 points) for ravulizumab and -13.33 points (SE, 1.22 points; 95% CI, -15.72 to -10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, -1.34 [1.46] points; 95% CI, -4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, -15.7 to 26.6 points; P = .61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%]). Conclusions and Relevance: This trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS. Trial Registration: ClinicalTrials.gov Identifier: NCT04248465.
RESUMO
BACKGROUND: Although many apheresis centers offer extracorporeal photopheresis (ECP), little is known about current treatment practices. METHODS: An electronic survey was distributed to assess ECP practice internationally. RESULTS: Of 251 responses, 137 met criteria for analysis. Most respondents were from North America (80%). Nurses perform ECP at most centers (84%) and the majority of centers treat adults only (52%). Most centers treat fewer than 50 patients/year (83%) and perform fewer than 300 procedures/year (70%). Closed system devices (XTS and/or Cellex) are used to perform ECP at most centers (96%). The most common indications for ECP are acute/chronic skin graft versus host disease (89%) and cutaneous T-cell lymphoma (63%). The typical wait time for ECP treatment is less than 2 weeks (91%). Most centers do not routinely perform quality control assessment of the collected product (66%). There are device-specific differences in treatment parameters. For example, XTS users more frequently have a minimum weight limit (P = 0.003) and use laboratory parameters to determine eligibility for treatment (P = 0.03). Regardless of device used, the majority of centers assess the clinical status of the patient before each procedure. Greater than 50% of respondents would defer treatment for hemodynamic instability due to active sepsis or heart failure, positive blood culture in the past 24 h or current fever. CONCLUSION: This survey based study describes current ECP practices. Further research to provide evidence for optimal standardization of patient qualifications, procedure parameters and product quality assessment is recommended.
