How does risdiplam compare with other treatments for Types 1-3 spinal muscular atrophy: a systematic literature review and indirect treatment comparison.

Aim: To conduct indirect treatment comparisons between risdiplam and other approved treatments for spinal muscular atrophy (SMA). Patients & methods: Individual patient data from risdiplam trials were compared with aggregated data from published studies of nusinersen and onasemnogene abeparvovec, accounting for heterogeneity across studies. Results: In Type 1 SMA, studies of risdiplam and nusinersen included similar populations. Indirect comparison results found improved survival and motor function with risdiplam versus nusinersen. Comparison with onasemnogene abeparvovec in Type 1 SMA and with nusinersen in Types 2/3 SMA was challenging due to substantial differences in study populations; no concrete conclusions could be drawn from the indirect comparison analyses. Conclusion: Indirect comparisons support risdiplam as a superior alternative to nusinersen in Type 1 SMA.

Comparative Efficacy of Atezolizumab plus Bevacizumab and Other Treatment Options for Patients with Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis.

BACKGROUND: Most phase 3 clinical trials of systemic therapy for first-line unresectable hepatocellular carcinoma (HCC) have failed, with the exception of SHARP, REFLECT, and IMbrave150. We conducted indirect comparisons of therapies evaluated for first-line HCC treatment. SUMMARY: We conducted a systematic review and meta-analysis of treatments for adults with locally advanced or metastatic unresectable HCC and no prior systemic treatment, including atezolizu-mab plus bevacizumab, sorafenib, lenvatinib, nivolumab, selective internal radiotherapy (SIRT), transarterial chemoembolization, and placebo or best supportive care. Randomized controlled trials published from January 1, 2007, to March 12, 2020, were retrieved from MEDLINE and Embase. Qualitative assessment of heterogeneity evaluated study designs, populations, and outcomes. Indirect comparisons used generalized linear models with random effects within a Bayesian framework and informative priors. We calculated relative efficacy estimates with 95% credible intervals (CrIs) and Bayesian posterior probability estimates of atezolizumab-bevacizumab being superior to other treatments. Nine clinical studies with a total of 3,897 participants were identified from 8,783 records and used to build the all-trials evidence network. Indirect comparisons suggested an improved overall survival (OS) with atezolizumab-bevacizumab versus lenvatinib (odds ratio, 0.63 [95% CrI 0.39-1.04]; with 97% Bayesian posterior probability of being superior), nivolumab (0.68 [95% CrI 0.41-1.14]; 94%), sorafenib (0.59 [95% CrI 0.39-0.87]; 99%), SIRT (0.51 [95% CrI 0.32-0.82]; 100%), or placebo/best supportive care (0.40 [95% CrI 0.25-0.64]; 100%). KEY MESSAGES: Within the context of indirect comparisons, analyses of OS favored atezolizumab-bevacizumab versus other treatment options for patients with locally advanced or metastatic unresectable HCC.

Prognostic Factors and Treatment-Effect Modifiers in Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with type 1 SMA do not achieve major motor milestones, and death from respiratory failure typically occurs before 2 years of age. Individuals with types 2 and 3 SMA exhibit milder phenotypes and have better functional and survival outcomes. Herein, a systematic literature review was conducted to identify factors that influence the prognosis of types 1, 2, and 3 SMA. In untreated infants with type 1 SMA, absence of symptoms at birth, a later symptom onset, and a higher survival of motor neuron 2 (SMN2) copy number are all associated with increased survival. Disease duration, age at treatment initiation, and, to a lesser extent, baseline function were identified as potential treatment-modifying factors for survival, emphasizing that early treatment with disease-modifying therapies (DMT) is essential in type 1 SMA. In patients with types 2 and 3 SMA, factors considered prognostic of changes in motor function were SMN2 copy number, age, and ambulatory status. Individuals aged 6-15 years were particularly vulnerable to developing complications (scoliosis and progressive joint contractures) which negatively influence functional outcomes and may also affect the therapeutic response in patients. Age at the time of treatment initiation emerged as a treatment-effect modifier on the outcome of DMTs. Factors identified in this review should be considered prior to designing or analyzing studies in an SMA population, conducting population matching, or summarizing results from different studies on the treatments for SMA.

Matching-adjusted indirect comparison: entrectinib versus crizotinib in ROS1 fusion-positive non-small cell lung cancer.

Aim: To perform indirect treatment comparisons of entrectinib versus alternative ROS1 fusion-positive non-small cell lung cancer treatments. Methods: Relevant studies with crizotinib and chemotherapy as comparators of interest identified by systematic literature review were selected for matching-adjusted indirect comparison by feasibility assessment. Matching was based on known prognostic/predictive factors and scenario analyses were used for unreported confounders in comparator trials. Results: Entrectinib yielded significantly better responses versus crizotinib in all scenarios (odds ratio [OR]: 2.43-2.74). Overall survival (hazard ratio: 0.47-0.61) and adverse event-related discontinuation (OR: 0.79-0.90) favored entrectinib. Progression-free survival was similar across treatments, except in one scenario. Conclusion: These results suggested improved outcomes with entrectinib versus crizotinib/chemotherapy and may help to make better informed treatment decisions.

Systematic Review and Network Meta-analysis of Idiopathic Pulmonary Fibrosis Treatments.

BACKGROUND: The antifibrotics pirfenidone and nintedanib are both approved for the treatment of idiopathic pulmonary fibrosis (IPF) by regulatory agencies and are recommended by health technology assessment bodies. Other treatments such as N-acetylcysteine are used in clinical practice but have not received regulatory approval. No head-to-head trials have been conducted to directly compare the efficacy of these therapies in IPF. OBJECTIVE: To compare the efficacy of treatments for IPF. METHODS: A systematic review was conducted up to April 2015. Phase II/III randomized controlled trials in adults with IPF were eligible. A Bayesian network meta-analysis (NMA) was used to compare pirfenidone, nintedanib, and N-acetylcysteine with respect to forced vital capacity (FVC) and mortality. RESULTS: Nine studies were included in the NMA. For change from baseline in FVC, the NMA indicated that pirfenidone and nintedanib were more effective than placebo after 1 year (pirfenidone vs. placebo: difference = 0.12 liter (L), 95% credible interval [CrI] = 0.03-0.21 L; nintedanib vs. placebo: difference = 0.11 L, 95% CrI = 0.00-0.22 L). There was no evidence that N-acetylcysteine had an effect on FVC compared with placebo (N-acetylcysteine vs. placebo: difference = 0.01 L, 95% CrI = -0.15-0.17 L). Patients treated with pirfenidone also had a lower risk of experiencing a decline in percent predicted FVC of ≥ 10% over 1 year (odds ratio [OR]: 0.58, 95% CrI = 0.40-0.88), whereas there was no conclusive evidence of a difference between nintedanib and placebo (OR: 0.65, 95% CrI = 0.42-1.02). The NMA indicated that pirfenidone reduced all-cause mortality relative to placebo over 1 year (hazard ratio [HR]: 0.52, 95% CrI = 0.28-0.92). There was no evidence of a difference in all-cause mortality between nintedanib and placebo (HR: 0.70, 95% CrI = 0.32-1.55), or N-acetylcysteine and placebo (HR: 2.00, 95% CrI=0.46-8.62). CONCLUSIONS: Our primary analysis of the available evidence indicates that over 1 year, pirfenidone and nintedanib are effective at reducing lung-function decline, and pirfenidone may reduce the odds of experiencing a decline in percent predicted FVC of ≥10% compared with placebo in the first year of treatment. The results of our analysis also suggest that pirfenidone improves survival. DISCLOSURES: Fleetwood is an employee of Quantics Consulting. McCool and Glanville are employees of York Health Economics Consortium (YHEC). Quantics and YHEC received funding from F. Hoffmann-La Roche for conducting the systematic review and network meta-analysis reported in this paper. Edwards, Gsteiger, and Daigl are employees of F. Hoffmann-La Roche. Fisher was employed by InterMune UK, a wholly owned Roche subsidiary, until July 2015. He is currently employed by FIECON, which has received funding from F. Hoffmann-La Roche for consulting services. The systematic review and network meta-analysis reported in this paper were conducted by Fleetwood (Quantics Consulting) and McCool and Glanville (YHEC), funded by F. Hoffmann-La Roche. The original network analysis was funded by InterMune. Study concept and design were contributed by Edwards, Gsteiger, and Daigl, along with Fleetwood, McCool, and Glanville. Fleetwood, McCool, and Glanville collected the data, with assistance from Edwards, Gsteiger, and Daigl. Data interpretation was performed by Fleetwood and Fisher, with assistance from the other authors. The manuscript was written by Fleetwood, McCool, and Glanville, with assistance from Edwards, Daigl, and Fisher, and revised by all the authors.

Outcomes after orthopedic trauma.

BACKGROUND: Clinical orthopedic research needs better ability to assess patient expectations with regard to orthopedic trauma surgery outcomes. The aim of this study was to investigate to which extent patient expectations prior to surgery could be met after surgery. METHODS: Patients (≥18 years) with surgical ankle fractures were prospectively recruited at 5 orthopedic trauma clinics in the United States (USA), Canada, and Brazil and followed up for 12 months. Patients were asked to complete a previously validated trauma expectation factor (TEF) questionnaire prior to surgery and a trauma outcome measure (TOM) 1 year after surgery. RESULTS: At 1 year, 155 patients had provided complete records. Almost half (49%; 76/155) had a 1-year TOM score equaling or exceeding their preoperative TEF score (95% CI: 41-57%). The remaining scores failed to meet patient expectations. TOM scores matched or exceeded patient expectations for 33% of patients in the USA and 47% in Canada, but for 69% in Brazil ( p = 0.001 (USA); p = 0.024 (Canada)). This geographical effect was attributable to higher patient expectations in North America as compared to Brazil (average TEF scores: 36 (North America) versus 31 (Brazil); p < 0.001). Patients with lower household income or smokers were more likely to be satisfied with their treatment ( p = 0.02 and p = 0.05, respectively). Furthermore, patients with severe type C fractures had better rates of satisfaction (62%) than patients with simpler B (50%) or type A fractures (33%) ( p = 0.01 [C type versus A type]). CONCLUSIONS: Orthopedic surgeons have difficulty in meeting or exceeding presurgical patient expectations of long-term outcomes for ankle fracture surgery. This study provides evidence that culture, geography, and surgeon-patient communication have considerable influence on patient expectations.

Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis.

BACKGROUND: In clinical trials of idiopathic pulmonary fibrosis, rates of all-cause mortality are low. Thus prospective mortality trials are logistically very challenging, justifying the use of pooled analyses or meta-analyses. We did pooled analyses and meta-analyses of clinical trials of pirfenidone versus placebo to determine the effect of pirfenidone on mortality outcomes over 120 weeks. METHODS: We did a pooled analysis of the combined patient populations of the three global randomised phase 3 trials of pirfenidone versus placebo-Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY 004 and 006; trial durations 72-120 weeks) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND 016; 52 weeks)-for all-cause mortality, treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality at weeks 52, 72, and 120. We also did meta-analyses of these data and data from two Japanese trials of pirfenidone versus placebo-Shionogi Phase 2 (SP2) and Shionogi Phase 3 (SP3; trial durations 36-52 weeks). FINDINGS: At week 52, the relative risk of death for all four mortality outcomes was significantly lower in the pirfenidone group than in the placebo group in the pooled population (all-cause mortality hazard ratio [HR] 0·52 [95% CI 0·31-0·87; p=0·0107]; treatment-emergent all-cause mortality 0·45 [0·24-0·83; 0·0094]; idiopathic-pulmonary-fibrosis-related mortality 0·35 [0·17-0·72; 0·0029]; treatment-emergent idiopathic-pulmonary-fibrosis-related mortality 0·32 [0·14-0·76; 0·0061]). Consistent with the pooled analysis, meta-analyses for all-cause mortality at week 52 also showed a clinically relevant and significant risk reduction in the pirfenidone group compared with the placebo group. Over 120 weeks, we noted significant differences in the pooled analysis favouring pirfenidone therapy compared with placebo for treatment-emergent all-cause mortality (p=0·0420), idiopathic-pulmonary-fibrosis-related mortality (0·0237), and treatment-emergent idiopathic-pulmonary-fibrosis-related (0·0132) mortality; similar results were shown by meta-analyses. INTERPRETATION: Several analytic approaches demonstrated that pirfenidone therapy is associated with a reduction in the relative risk of mortality compared with placebo over 120 weeks. FUNDING: F Hoffmann-La Roche/Genentech.

Decrease of morbidity in road traffic accidents in a high income country - an analysis of 24,405 accidents in a 21 year period.

BACKGROUND: The WHO initiated the "Decade of Action for Road Safety" because the fatality on road traffic accidents could become the fifth leading cause of death in 2030. On the contrary, fatalities continue to decrease in high income countries. The aim of the study was to find evidence for changes in injury severity of passenger car occupants after road traffic accidents in Germany over time, and to find contributing factors. METHODS: Data from the German In Depth Accident Study (GIDAS), representative for Germany, was used. A total of 24.405 accidents, reported from 1991 until 2011. 44.503 adult passenger car occupants were examined. A multivariable logistic regression model was developed to find reasons for observed trends over time. RESULTS: The relative decrease in mortality was 68.8% from 1991 until 2011. Between 2006 and 2011, the percentage of severely injured traffic victims was less than half, both in terms of the whole body and individual body regions. For injuries with an Abbreviated Injury Scale (AIS) ≥ 2, the percentage of persons with lower leg injuries declined by 72.5%, followed by the percentage of persons with pelvic injuries (61.5%), upper extremity injuries (57.7%), head injuries (54.3%), thorax injuries (50.0%), and abdomen injuries (40.0%). The multivariable regression model found 13 independent variables associated with injury prevention (e.g. seat belt use: OR 0.41, CI 95% 0.32-0.49; airbag: OR 0.86, CI 95% 0.75-0.99). The implementation of protective factors increased over time while accident constellations with a high probability for severe injury decreased over time. CONCLUSION: The decrease of severe injuries after road traffic accidents can be only attributed to a comprehensive approach including the enforcement of road safety policies and innovations in car engineering and emergency medicine. Traffic related measures and alcohol level control, and seat belt usage enforcement next to other technical advances are considered especially important.

How to document and report orthopedic complications in clinical studies? A proposal for standardization.

INTRODUCTION: The documentation of complications is critical for the evaluation of therapeutic interventions in orthopedics. However, there is a lack of accepted methodological standardization and definitions. We propose a concept to support the consensus development of a standardized management and classification of complications in clinical research. METHODS: Complication events are examined regarding their clinical presentation, their timing of occurrence as well as their potential causal interrelationship for any given patient. Their clinical presentation is distinguished by their likely triggers, their therapeutic management, and their outcome. Complications are events (including relevant deviations from their expected healing process) that are harmful to patients and can be described as local to the treated injury/disease or systemic (when they affect the rest of the body). The treatment of a complication, e.g. by way of an unplanned surgical intervention, and its outcome should be carefully documented. Complication review boards with independent clinicians should be established to validate complication records. APPLICATION AND RELEVANCE: In this proposal, a number of complication examples are presented to illustrate the concept and demonstrate its practical use. This management and classification system has already proven valuable in the documentation and analysis of complication data from a number of published clinical studies. Because of this new standardized assessment process, it facilitates the communication of complications between clinicians and researchers, and helps to develop clear definitions for specific orthopedic complications.

TEFTOM: A Promising General Trauma Expectation/Outcome Measure-Results of a Validation Study on Pan-American Ankle and Distal Tibia Trauma Patients.

Background. In orthopedics, there is no instrument specifically designed to assess patients' expectations of their final surgery outcome in general trauma populations. We developed the Trauma Expectation Factor Trauma Outcome Measure (TEFTOM) to investigate the fulfilment of patients' expectations one year after surgery as a measure of general trauma surgical outcomes. The aim of this paper was to assess the psychometric characteristics of this new general trauma outcome measure. Methods. The questionnaire was tested in 201 ankle and distal tibia fracture patients scheduled for surgery. Patients were followed up for twelve months. The TEFTOM questionnaire was evaluated for its criterion validity, internal consistency, reproducibility, and responsiveness. Results. TOM showed good criterion validity against the American Academy of Orthopaedic Surgeons Foot and Ankle Scale (Pearson's correlation coefficient = 0.69-0.77). Internal consistency was acceptable for TEF (Cronbach's alpha = 0.65-0.76) and excellent for TOM (Cronbach's alpha = 0.76-0.85). Reproducibility was moderate to very good (intraclass coefficient correlation (ICC) ≥0.67) for TEF and very good (ICC ≥0.92) for TOM. TOM also proved to be responsive to changes in patients' condition over time (Wald test; P < 0.001). Conclusions. TEFTOM is a promising tool for measuring general trauma outcomes in terms of patients' expectation fulfilment that proved to be valid, internally consistent, reproducible, and responsive to change.