Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.

IMPORTANCE: Muscle-related statin intolerance is reported by 5% to 20% of patients. OBJECTIVE: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. DESIGN, SETTING, AND PARTICIPANTS: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. INTERVENTIONS: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). MAIN OUTCOME AND MEASURES: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. RESULTS: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8 mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). CONCLUSIONS AND RELEVANCE: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01984424.

Retrospective comparison of traditional and artificial intelligence-based heart failure phenotyping in a US health system to enable real-world evidence.

OBJECTIVE: Quantitatively evaluate the quality of data underlying real-world evidence (RWE) in heart failure (HF). DESIGN: Retrospective comparison of accuracy in identifying patients with HF and phenotypic information was made using traditional (ie, structured query language applied to structured electronic health record (EHR) data) and advanced (ie, artificial intelligence (AI) applied to unstructured EHR data) RWE approaches. The performance of each approach was measured by the harmonic mean of precision and recall (F1 score) using manual annotation of medical records as a reference standard. SETTING: EHR data from a large academic healthcare system in North America between 2015 and 2019, with an expected catchment of approximately 5 00 000 patients. POPULATION: 4288 encounters for 1155 patients aged 18-85 years, with 472 patients identified as having HF. OUTCOME MEASURES: HF and associated concepts, such as comorbidities, left ventricular ejection fraction, and selected medications. RESULTS: The average F1 scores across 19 HF-specific concepts were 49.0% and 94.1% for the traditional and advanced approaches, respectively (p<0.001 for all concepts with available data). The absolute difference in F1 score between approaches was 45.1% (98.1% relative increase in F1 score using the advanced approach). The advanced approach achieved superior F1 scores for HF presence, phenotype and associated comorbidities. Some phenotypes, such as HF with preserved ejection fraction, revealed dramatic differences in extraction accuracy based on technology applied, with a 4.9% F1 score when using natural language processing (NLP) alone and a 91.0% F1 score when using NLP plus AI-based inference. CONCLUSIONS: A traditional RWE generation approach resulted in low data quality in patients with HF. While an advanced approach demonstrated high accuracy, the results varied dramatically based on extraction techniques. For future studies, advanced approaches and accuracy measurement may be required to ensure data are fit-for-purpose.

A Phase 4, Open-Label, Single-Arm Study Assessing the Efficacy and Safety of Ivabradine in African American Patients with Heart Failure and Reduced Ejection Fraction.

INTRODUCTION: There are limited data on ivabradine therapy in black patients and none in African Americans. We performed an open-label, prospective study at two centers in the United States. African American patients with heart failure (HF) (N = 30), left ventricular ejection fraction ≤ 35%, and in sinus rhythm with resting heart rate (HR) ≥ 70 bpm received ivabradine 2.5-7.5 mg twice daily for 57 days. METHODS: The primary endpoint was change in HR from baseline to day 57, compared with the -5 bpm change observed in the absence of ivabradine in the placebo group of the SHIFT study. The safety endpoint was treatment-emergent adverse events (TEAEs). Exploratory endpoints were change from baseline to day 57 in 6-minute walk test (6MWT) distance, HR difference during a 6MWT (i.e. HR at minute 6 - resting HR), and physical activity counts. RESULTS: At day 57, the estimated least squares mean change from baseline in HR was -9.5 bpm (95% CI -13.0, -6.0). The estimated mean treatment difference with ivabradine versus a presumed -5 bpm change from baseline HR, as seen in the placebo group of the SHIFT study, was -4.5 bpm (95% CI -8.0, -1.0; p = 0.013). The mean (SE) changes in 6MWT distance and HR difference during the 6MWT were 16.3 (10.8) meters and 2.3 (3.7) bpm, respectively. Ivabradine therapy did not result in greater physical activity. TEAEs were reported in 11 (36.7%) patients. CONCLUSION: These data support ivabradine use in African American patients with HF with reduced ejection fraction who meet typical treatment criteria. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03456856.

Romosozumab in Skeletally Mature Adults with a Fresh Unilateral Tibial Diaphyseal Fracture: A Randomized Phase-2 Study.

BACKGROUND: Romosozumab is an antibody that binds and inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. A double-blinded, randomized, phase-2, dose-finding trial was performed to evaluate the effect of romosozumab on the radiographic and clinical outcomes of surgical fixation of tibial diaphyseal fractures. METHODS: Patients (18 to 82 years old) were randomized 3:1:1:1:1:1:1:1:1:1 to a placebo or 1 of 9 romosozumab treatment groups. Patients received subcutaneous injections of romosozumab or the placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary outcome was the time to radiographic evidence of healing ("radiographic healing") analyzed after the week-24 assessments had been completed for all patients. RESULTS: A total of 402 patients were randomized: 299 to the romosozumab group and 103 to the placebo group. The median time to radiographic healing (the primary outcome) ranged from 14.4 to 18.6 weeks in the romosozumab groups and was 16.4 weeks (95% confidence interval [CI]: 14.6 to 18.0 weeks) in the placebo group, which was not a significant difference. There was also no significant difference in the median time to clinical healing, no relationship between romosozumab dose/frequency and unplanned revision surgery, and no apparent treatment benefit in terms of physical function. The safety and tolerability profile of romosozumab was comparable with that of the placebo. CONCLUSIONS: Romosozumab did not accelerate tibial fracture-healing in this patient population. Additional studies of patients at higher risk for delayed healing are needed to explore the potential of romosozumab to accelerate tibial fracture-healing. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

A Randomized, Placebo-Controlled Study of Romosozumab for the Treatment of Hip Fractures.

BACKGROUND: Romosozumab is a bone-forming antibody that increases bone formation and decreases bone resorption. We conducted a double-blinded, randomized, phase-2, dose-finding trial to evaluate the effect of romosozumab on the clinical outcomes of open reduction and internal fixation of intertrochanteric or femoral neck hip fractures. METHODS: Patients (55 to 94 years old) were randomized 2:3:3:3 to receive 3 subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary end point was the difference in the mean timed "Up & Go" (TUG) score over weeks 6 to 20 for romosozumab versus placebo. Additional end points included the time to radiographic evidence of healing and the score on the Radiographic Union Scale for Hip (RUSH). RESULTS: A total of 332 patients were randomized: 243 to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; and 210 mg, n = 90) and 89 to receive a placebo. Although TUG scores improved during the study, they did not differ significantly between the romosozumab and placebo groups over weeks 6 to 20 (p = 0.198). The median time to radiographic evidence of healing was 16.4 to 16.9 weeks across treatment groups. The RUSH scores improved over time across treatment groups but did not differ significantly between the romosozumab and placebo groups. The overall safety and tolerability profile of romosozumab was comparable with that of the placebo. CONCLUSIONS: Romosozumab did not improve the fracture-healing-related clinical and radiographic outcomes in the study population. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin-Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) Trial.

Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). However, 5% to 10% of statin-treated patients report intolerance, mostly due to muscle-related adverse effects. Challenges exist to objective identification of statin-intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL-C reduction. We report the design of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3), a phase 3, multicenter, randomized, double-blind, ezetimibe-controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin-controlled, double-blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL-C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co-primary endpoints: mean percent change from baseline in LDL-C at weeks 22 and 24 and percent change from baseline in LDL-C at week 24. Key secondary efficacy endpoints include change from baseline in LDL-C, percent of patients attaining LDL-C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014.

The tactics of modern-day regulatory trials.

Fractures are an important public health problem affecting patients of all ages. Although most fractures heal quickly, some heal poorly and some do not heal at all. To achieve an optimal healing outcome, the standard of care for most fractures consists of reduction followed by immobilization, with a myriad of options regarding the approach to fracture-healing. Currently, biopharmaceutical companies are sponsoring research with regard to products that aim to enhance or accelerate fracture-healing; however, as there are no approved and marketed systemic therapies for fracture-healing, the development and commercialization process for such products will require close collaboration between industry, academia, and regulators to determine how to bring these products to market in the most efficient manner. The following manuscript provides a brief overview of the regulatory process in the United States for systemic therapies in fracture-healing and discusses key issues that may arise in connection with the regulatory approval of these novel investigational treatments.