Search

ObjectiveADAPT+ assessed the long-term safety, tolerability, and efficacy of efgartigimod in adult participants with generalized myasthenia gravis (gMG).MethodsADAPT+ was an open-label, single-arm, multicenter, up to 3-year extension of the pivotal phase 3 ADAPT study. Efgartigimod was administered in treatment cycles of 4 intravenous infusions (one 10 mg/kg infusion per week). Initiation of subsequent treatment cycles was individualized based on clinical evaluation. Safety endpoints included incidence and severity of adverse events. Efficacy endpoints assessed disease severity using Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores.ResultsAs of January 2022, 151 participants had rolled over to ADAPT+ and 145 had received ≥1 dose of efgartigimod, of whom, 111 (76.6%) were AChR-Ab+ and 34 (23.4%) were AChR-Ab−. Mean study duration (treatment plus follow-up) was 548 days, and participants received up to 17 treatment cycles, corresponding to 217.6 participant-years of exposure. In the overall population, 123 (84.8%) participants reported ≥1 treatment-emergent adverse event; most frequent were headache (36 [24.8%]), COVID-19 (22 [15.2%]), and nasopharyngitis (20 [13.8%]). Clinically meaningful improvement (CMI) in mean MG-ADL and QMG scores was seen as early as 1 week following the first infusion across multiple cycles in AChR-Ab+ and AChR-Ab− participants. Maximal MG-ADL and QMG improvements aligned with onset and magnitude of total IgG and AChR-Ab reductions. For AChR-Ab+ participants at any time point in each of the first 10 treatment cycles, more than 90% had a maximum reduction of ≥2 points (CMI) in MG-ADL total score; across the 7 cycles in which QMG was measured, 69.4% to 91.3% of participants demonstrated a maximum reduction of ≥3 points (CMI) in QMG total score. Many participants demonstrated improvements well beyond CMI thresholds. In AChR-Ab+ participants with ≥1 year of combined follow-up between ADAPT and ADAPT+, mean number of annualized cycles was 4.7 per year (median [range] 5.0 [0.5–7.6]).ConclusionResults of ADAPT+ corroborate the substantial clinical improvements seen with efgartigimod in ADAPT and support its long-term safety, tolerability, and efficacy, as well as an individualized dosing regimen for treatment of gMG.Clinical trial registrationhttps://classic.clinicaltrials.gov/ct2/show/NCT03770403, NCT03770403.

Background: Response adaptive randomization is popular in adaptive trial designs, but the literature detailing its execution is lacking. These designs are desirable for patients/stakeholders, particularly in comparative effectiveness research, due to the potential benefits including improving participant buy-in by providing more participants with better treatment during the trial. Frequentist approaches have often been used, but adaptive designs naturally fit the Bayesian methodology; it was developed to deal with data as they come in by updating prior information. Methods: PAIN-CONTRoLS was a comparative-effectiveness trial utilizing Bayesian response adaptive randomization to four drugs, nortriptyline, duloxetine, pregabalin, or mexiline, for cryptogenic sensory polyneuropathy (CSPN) patients. The aim was to determine which treatment was most tolerable and effective in reducing pain. Quit and efficacy rates were combined into a utility function to develop a single outcome, which with treatment sample size, drove the adaptive randomization. Prespecified interim analyses allowed the study to stop for early success or update the randomization probabilities to the better-performing treatments. Results: Seven adaptations to the randomization occurred before the trial ended due to reaching the maximum sample size, with more participants receiving nortriptyline and duloxetine. At the end of the follow-up, nortriptyline and duloxetine had lower probabilities of participants that had stopped taking the study medication and higher probabilities were efficacious. Mexiletine had the highest quit rate, but had an efficacy rate higher than pregabalin. Conclusions: Response adaptive randomization has become a popular trial tool, especially for those utilizing Bayesian methods for analyses. By illustrating the execution of a Bayesian adaptive design, using the PAIN-CONTRoLS trial data, this paper continues the work to provide literature for conducting Bayesian response adaptive randomized trials.

Objectives To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families.Design Retrospective cohort study.Setting Clinics across North America.Participants The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis.Methods Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed.Results Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members.Discussion The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.