ABSTRACT
Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. Findings: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6-89] months; median weight: 7.86 [range, 3.2-20.2] kg; duration of follow-up: 3-22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8-21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28-548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3-223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2-209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services.
ABSTRACT
BACKGROUND: Measurement of pressure pain threshold (PPT) is a way to determine one of the many potential treatment effects of spinal manipulative therapy. OBJECTIVE: To determine how multiple spinal manipulations administered in a single-session affected PPTs at local and distal sites in asymptomatic individuals. METHODS: Participants were randomly assigned into one of three groups: Group one (n = 18) received a lumbar manipulation followed by a cervical manipulation. Group two (n = 17) received a cervical manipulation followed by a lumbar manipulation. The control group (n = 19) received two bouts of five minutes of rest. At baseline and after each intervention or rest period, each participant's PPTs were obtained using a handheld algometer. The PPTs were tested bilaterally over the lateral epicondyles of the humerus and over the mid-bellies of the upper trapezius, lumbar paraspinal, and the tibialis anterior muscles. This study was registered with ClinicalTrials.gov, and its Identifier is NCT02828501. RESULTS: Repeated-measures ANOVAs and Kruskal-Wallis tests showed no significant within- or between-group differences in PPT. Within-group effect sizes in the changes of PPT ranged from -.48 at the left paraspinal muscles to .24 at the left lateral humeral epicondyle. Statistical power to detect significant differences at α of 0.05 was calculated to be 0.94. CONCLUSIONS: This study suggests that in young adults who do not have current or recent symptoms of spinal pain, multiple within-session treatments of cervical and lumbar spinal manipulation fail to influence PPTs. Changes in PPT that are observed in symptomatic individuals are likely to be primarily influenced by pain-related neuromodulators rather than by an isolated, mechanical effect of spinal manipulation.
