; and the Zilucoplan MG Study Group IMPORTANCE Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. Therefore, there is a significant need for targeted, well-tolerated therapies with the potential to improve disease control and enhance quality of life. OBJECTIVE To evaluate the clinical effects of zilucoplan, a subcutaneously (SC) self-administered macrocyclic peptide inhibitor of complement component 5, in a broad population of patients with moderate to severe gMG. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled phase 2 clinical trial at 25 study sites across North America recruited participants between December 2017 and August 2018. Fifty-seven patients were screened, of whom 12 did not meet inclusion criteria and 1 was lost to follow-up after randomization but before receiving study drug, resulting in a total of 44 acetylcholine receptor autoantibody (AChR-Ab)-positive patients with gMG with baseline Quantitative Myasthenia Gravis (QMG) scores of at least 12, regardless of treatment history. INTERVENTIONS Patients were randomized 1:1:1 to a daily SC self-injection of placebo, 0.1-mg/kg zilucoplan, or 0.3-mg/kg zilucoplan for 12 weeks. MAIN OUTCOMES AND MEASURES The primary and key secondary end points were the change from baseline to week 12 in QMG and MG Activities of Daily Living scores, respectively. Significance testing was prespecified at a 1-sided α of .10. Safety and tolerability were also assessed. RESULTS The study of 44 patients was well balanced across the 3 treatment arms with respect to key demographic and disease-specific variables. The mean age of patients across all 3 treatment groups ranged from 45.5 to 54.6 years and most patients were white (average proportions across 3 treatment groups: 78.6%-86.7%). Clinically meaningful and statistically significant improvements in primary and key secondary efficacy end points were observed. Zilucoplan at a dose of 0.3 mg/kg SC daily resulted in a mean reduction from baseline of 6.0 points in the QMG score (placebo-corrected change,-2.8; P = .05) and 3.4 points in the MG Activities of Daily Living score (placebo-corrected change,-2.3; P = .04). Clinically meaningful and statistically significant improvements were also observed in other secondary end points, the MG Composite and MG Quality-of-Life scores. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but slower in onset and less pronounced than with the 0.3-mg/kg dose. Rescue therapy (intravenous immunoglobulin or plasma exchange) was required in 3 of 15, 1 of 15, and 0 of 14 participants in the placebo, 0.1-mg/kg zilucoplan, and 0.3-mg/kg zilucoplan arms, respectively. Zilucoplan was observed to have a favorable safety and tolerability profile. CONCLUSIONS AND RELEVANCE Zilucoplan yielded rapid, meaningful, and sustained improvements over 12 weeks in a broad population of patients with moderate to severe AChR-Ab...
A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.
Objective We aimed to determine if treatment of male sexual partners of women with recurrent BV with oral metronidazole twice daily for 7 days (i.e. multi-dose metronidazole) significantly decreased BV recurrence rates in the female. Methods This was a multi-center, two-arm, double-blinded, placebo-controlled study. Women with recurrent BV and a current diagnosis of BV by Amsel and Nugent were enrolled. Multi-dose metronidazole for 7 days was dispensed to women. Male partners were randomized to placebo versus multi-dose metronidazole for 7 days and asked to refrain from unprotected sex for 14 days. Female follow-up visits were conducted at day 21 and 8 and 16 weeks. Male follow-up visits occurred at days 14-21. BV cure was defined as 0-2 Amsel criteria and Nugent score 0-6 in the female partner with the primary endpoint at 16 weeks. Results Two-hundred fourteen couples were enrolled. In the intent-to-treat population, there was no significant difference between treatment arms for the primary outcome. BV treatment failure occurred in 81% and 80% of women in the metronidazole and placebo arms through the third follow-up visit, respectively (p>0.999). However, women whose male partners were adherent to study medication were less likely to fail treatment (adjusted relative risk (ARR)=0.85; 95% CI 0.73-0.99; p=0.035). This finding persisted in post-hoc comparisons in the metronidazole arm. Conclusion Overall, this study did not find that male partner treatment with multi-dose metronidazole significantly reduces BV recurrence in female partners although women whose partners were adherent to multi-dose metronidazole were less likely to fail treatment.
Results 110 samples,~10 from each CST, were selected. 5.5% (n=6) had Amsel-BV, 32.7% (n=36) Nugent-BV, and 36.4% (n=40) had low-Lactobacillus CSTs (IV, VI, VII); 8.2% had symptoms. Among Amsel-BV samples, 83.3% had Nugent-BV, 16.7% had intermediate Nugent score and all were CST IV. 86.1% of women with Nugent-BV and 85% of women with low-Lactobacillus CSTs did not have Amsel-BV. 22.2% of those with Nugent-BV did not have low-Lactobacillus CSTs; of these 50% were CST III (L. iners-dominated). 46.7% of CST-III had a vaginal pH !4.5, and 13.3% had a Nugent BV score. 22 samples had a vaginal pH!4.5 and a normal Nugent score: 45.5% were in CST III, 9.1% in low-Lactobacillus CSTs. 30.6% women with Nugent-BV had a vaginal pH <4.5; of these 45.5% were in CST IV. Conclusion Nugent score and low-Lactobacillus CST were concordant. L. iners-dominated CSTs often had normal Nugent scores and high pH. Among mostly asymptomatic women, a large proportion with low-Lactobacillus CSTs did not have Amsel-BV. Future studies assessing long term clinical outcomes will be needed to determine whether molecular methods provide added actionable or prognostic information. Disclosure No significant relationships.
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