IntroductionThere are numerous new systemic treatments for atopic dermatitis in various stages of development and most are being compared with placebo rather than active comparators. In order to understand the relative efficacy and safety of existing and new treatments for atopic dermatitis, robust mixed comparisons (ie, direct and indirect) would be beneficial. To address this gap, this protocol describes methods for a systematic review and network meta-analysis of systemic treatments for atopic dermatitis.Methods and analysisWe will update the search of a previous systematic review, including searches of the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database and the Global Resource of EczemA Trials database in addition to clinical trial protocol registries. Title, abstract and full paper screening as well as data extraction will be conducted in duplicate by independent researchers. Primary outcomes include efficacy with regards to clinician-reported signs and patient-reported symptoms and safety with regards to withdrawal from treatment due to adverse events and the occurrence of serious adverse events. Secondary outcomes will include change in quality of life and itch severity. Where possible and appropriate, network meta-analysis will be performed for each outcome using a random-effects model within a Bayesian framework. If appropriate, the review will be transitioned to a living review with continuous updating of the analysis.Ethics and disseminationDissemination in a peer-reviewed scientific journal is planned.PROSPERO registration numberCRD42018088112; Pre-results.

IMPORTANCE Most clinical trials assessing systemic immunomodulatory treatments for patients with atopic dermatitis are placebo-controlled. OBJECTIVE To compare the effectiveness and safety of systemic immunomodulatory treatments for patients with atopic dermatitis in a systematic review and network meta-analysis. DATA SOURCES The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of Eczema Trials database, and clinical trial registries were searched from inception to October 28, 2019. STUDY SELECTION English-language randomized clinical trials of 8 weeks or more of treatment with systemic immunomodulatory medications for moderate to severe atopic dermatitis were included. Titles, abstracts, and articles were screened in duplicate. Of 10 324 citations, 39 trials were included. DATA EXTRACTION AND SYNTHESIS Data were extracted in duplicate, and the review adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-Analyses guidelines. Random-effects bayesian network meta-analyses were performed and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. MAIN OUTCOMES AND MEASURES Prespecified outcomes were change in signs of disease, symptoms, quality of life, itch, withdrawals, and serious adverse events. RESULTS A total of 39 trials with 6360 patients examining 20 medications and placebo were included. Most trials were conducted for adults receiving up to 16 weeks of therapy. Dupilumab, 300 mg every 2 weeks, was associated with improvement in the Eczema Area and Severity Index score vs placebo (mean difference, 11.3-point reduction; 95% credible interval [CrI], 9.7-13.1 [high certainty]). Cyclosporine (standardized mean difference, −1.1; 95% CrI, −1.7 to −0.5 [low certainty]) and dupilumab (standardized mean difference, −0.9; 95% CrI, −1.0 to −0.8 [high certainty]) were similarly effective vs placebo in clearing clinical signs of atopic dermatitis and may be superior to methotrexate (standardized mean difference, −0.6; 95% CrI, −1.1 to 0.0 [low certainty]) and azathioprine (standardized mean difference, −0.4; 95% CrI, −0.8 to −0.1 [low certainty]). Several investigational medications for atopic dermatitis are promising, but data to date are limited to small early-phase trials. Safety analyses were limited by low event rates. CONCLUSIONS AND RELEVANCE Dupilumab and cyclosporine may be more effective for up to 16 weeks of treatment than methotrexate and azathioprine for treating adult patients with atopic dermatitis. More studies directly comparing established and novel treatments beyond 16 weeks are needed and will be incorporated into future updates of this review.

IMPORTANCE Systemic treatments for atopic dermatitis are being evaluated primarily in placebo-controlled trials; network meta-analysis can provide relative efficacy and safety estimates for treatments that have not been compared head to head. OBJECTIVE To compare reported measures of efficacy and assessments of safety in clinical trials of systemic treatments for atopic dermatitis in a living systematic review and network meta-analysis. DATA SOURCES The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of EczemA Trials database, and trial registries were searched through June 15, 2021. STUDY SELECTION Randomized clinical trials examining 8 or more weeks of treatment with systemic immunomodulatory medications for moderate-to-severe atopic dermatitis were included after screening titles, abstracts, and papers in duplicate. DATA EXTRACTION AND SYNTHESIS Data were abstracted in duplicate. Bayesian network meta-analyses and assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed. The updated analysis was completed from June to December 2021.MAIN OUTCOMES AND MEASURES Outcomes include change in Eczema Area and Severity Index (EASI), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Peak Pruritus Numeric Rating Scales (PP-NRS).RESULTS Since October 2019, 21 new studies were added, for a total of 60 trials with 16 579 patients. Up to 16 weeks of treatment in adults, abrocitinib, 200 mg daily (mean difference [MD], 2.2; 95% credible interval [CrI], 0.2-4.0; high certainty) and upadacitinib, 30 mg daily (MD, 2.7; 95% CrI, 0.6-4.7; high certainty) were associated with reduced EASI slightly more than dupilumab, 600 mg then 300 mg every 2 weeks. Abrocitinib, 100 mg daily (MD, −2.1; 95% CrI, −4.1 to −0.3; high certainty), baricitinib, 4 mg daily (MD, −3.2; 95% CrI, −5.7 to −0.8; high certainty), baricitinib, 2 mg daily (MD, −5.2; 95% CrI, −7.5 to −2.9; high certainty) and tralokinumab, 600 mg then 300 mg every 2 weeks (MD, −3.5; 95% CrI, −5.8 to −1.3; high certainty) were associated with reduced EASI slightly less than dupilumab. There was little or no difference between upadacitinib, 15 mg daily, and dupilumab (MD, 0.2; 95% CrI, −1.9 to 2.2; high certainty). The pattern of results was similar for POEM, DLQI, and PP-NRS. CONCLUSIONS AND RELEVANCEIn this systematic review and meta-analysis, abrocitinib, 200 mg; and upadacitinib, 30 mg daily, were associated with slightly better scores than dupilumab, and upadacitinib, 15 mg daily, was associated with similar scores to dupilumab. Abrocitinib, 100 mg daily, baricitinib, 4 mg and 2 mg daily, and tralokinumab, 300 mg, every 2 weeks were associated with slightly worse scores.

BackgroundClinicians are faced with an increasingly difficult choice regarding the optimal bronchodilator for patients with chronic obstructive pulmonary disease (COPD) given the number of new treatments. The objective of this study is to evaluate the comparative efficacy of indacaterol 75/150/300 μg once daily (OD), glycopyrronium bromide 50 μg OD, tiotropium bromide 18 μg/5 μg OD, salmeterol 50 μg twice daily (BID), formoterol 12 μg BID, and placebo for moderate to severe COPD.MethodsForty randomized controlled trials were combined in a Bayesian network meta-analysis. Outcomes of interest were trough and post-dose forced expiratory volume in 1 second (FEV1), St. George’s Respiratory Questionnaire (SGRQ) score and responders (≥4 points), and Transition Dyspnea Index (TDI) score and responders (≥1 point) at 6 months.ResultsIndacaterol was associated with a higher trough FEV1 than other active treatments (difference for indacaterol 150 μg and 300 μg versus placebo: 152 mL (95% credible interval (CrI): 126, 179); 160 mL (95% CrI: 133, 187)) and the greatest improvement in SGRQ score (difference for indacaterol 150 μg and 300 μg versus placebo: -3.9 (95% CrI -5.2, -2.6); -3.6 (95% CrI -4.8, -2.3)). Glycopyrronium and tiotropium 18 μg resulted in the next best estimates for both outcomes with minor differences (difference for glycopyrronium versus tiotropium for trough FEV1 and SGRQ: 18 mL (95% CrI: -16, 51); -0.55 (95% CrI: -2.04, 0.92).ConclusionIn terms of trough FEV1 and SGRQ score indacaterol, glycopyrronium, and tiotropium are expected to be the most effective bronchodilators.

Summary Background There are numerous trials and several meta-analyses comparing venous thromboembolism (VTE) prophylaxis options after total hip and knee replacement (THR and TKR). None prior included simultaneous comparison of new with older options. Objective To measure simultaneously the relative risk of VTE and hemorrhage for 12 prophylaxis options. Methods We abstracted VTE and hemorrhage information from randomized controlled trials published between January 1990 and June 2016 comparing 12 prophylaxis options. We then constructed networks to compute relative risk for each option relative to low molecular weight heparin at once daily dosing (LMWH Low). Results Main Relative to LMWH Low, direct oral Xa inhibitors had the lowest risk of total DVT - asymptomatic and symptomatic (OR 0.45 95% CI 0.35-0.57) translating to 53 to 139 fewer DVTs per 1000 patients. VKAs titrated to INR 2-3 predicted 56% more DVT events (OR 1.56 95% CI 1.14-2.14). Aspirin performed similarly (OR 0.80 95% CI 0.34-1.86) although small numbers prohibit firm conclusions. direct oral Xa inhibitors did not lead to significantly more bleeding (OR 1.21 95% CI 0.79-1.90). Secondary Relative to LMWH Low, direct oral Xa inhibitors prevented fourfold more symptomatic DVTs (OR 0.25 95% CI 0.13-0.47). Conclusions Relative to LMWH Low, direct oral Xa inhibitors had a more favorable profile of VTE and hemorrhage risk whereas VKAs had a less favorable profile. The profile of other agents was not more or less favorable. Clinicians should consider these profiles when selecting prophylaxis options.

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Background Patients with infantile-onset spinal muscular atrophy (SMA), a rare, genetic neuromuscular disease, do not achieve key motor function milestones (e.g., sitting) and have short life expectancy in the absence of treatment. Nusinersen is a disease-modifying therapy for patients with SMA. Objective The aim of this study was to estimate the cost-effectiveness of nusinersen compared to best supportive care (BSC) in patients diagnosed with infantile-onset SMA in the US. Methods A de novo economic model was developed with the following health states: “permanent ventilation”, “not sitting”, “sitting”, “walking”, and “death”. Short-term data were sourced from the pivotal clinical trials and studies of nusinersen (ENDEAR and SHINE). Motor function milestones achieved at the end of follow-up in the clinical trials were assumed to be sustained until death. Mortality risks were based on survival modelling of relevant published Kaplan–Meier data. Costs, life years (LYs), and quality-adjusted life years (QALYs) were discounted at 3% per annum, and the analyses were performed from a US health care sector perspective. Scenario analyses and sensitivity analyses were conducted to assess the robustness of the results to key parameters. Results In our base-case analysis, nusinersen treatment achieves greater QALYs and more LYs (3.24 and 7.64, respectively) compared with BSC (0.46 QALYs and 2.40 LYs, respectively), resulting in an incremental cost per QALY gained of approximately $1,112,000 and an incremental cost per LY gained of $590,000 for nusinersen compared to BSC. The incremental cost effectiveness ratios did not fall below $990,000 per QALY gained in scenario and sensitivity analyses. Results were most sensitive to the length of survival, background health care costs, and utility in the “not sitting” and “sitting” health states. Conclusions The estimated incremental cost-effectiveness of nusinersen from a US health care sector perspective exceeded traditional cost-effectiveness thresholds. Cost-effectiveness was dependent on assumptions made regarding survival, costs, utilities, and whether the motor function milestones were sustained over lifetime. Given the relatively short-term effectiveness data available for the treatment, a registry to collect long-term data of infantile-onset SMA patients is recommended.

To assess the 5-year budget impact of single-dose gene-replacement therapy AVXS-101 (onasemnogene abeparvovec) versus current standard-of-care (nusinersen) in US patients with Spinal Muscular Atrophy Type 1 (SMA1). Methods: We developed a multi-state survival Markov model with health-state transitions based on milestone attainment (sitting, walking) from published clinical trials. Survival benefit was estimated using long-term survival data from sitting and walking SMA patients and natural history data. We used published sources to estimate the size of eligible population and expected market share of each therapy before and after AVXS-101 approval. Costs related to drug acquisition and administration, expected hospital markups, adverse events and SMA care were sourced from published claims analysis data, literature, and expert opinion.