Linda Yau

BACKGROUND: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear. METHODS: We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28. RESULTS: A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).

BACKGROUND: We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC). METHODS: We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided. RESULTS: Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location. CONCLUSIONS: These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.

We consider intent-to-treat (IT) analysis of clinical trials involving longitudinal data subject to drop-out. Common methods, such as Last Observation Carried Forward imputation or incomplete-data methods based on models that assume random dropout, have serious drawbacks in the IT setting. We propose a method that involves multiple imputation of the missing values following drop-out based on an "as treated" model, using actual dose after drop-out if this is known, or imputed doses that incorporate a variety of plausible alternative assumptions if unknown. The multiply-imputed data sets are then analyzed using IT methods, were subjects are classified by randomization group rather than by the dose actually received. Results from the multiply-imputed data sets are combined using the methods of Rubin (1987, Multiple Imputation for Nonresponse in Surveys). A novel feature of the proposed method is that the models for imputation differ from the model used for the analysis of the filled-in data. The method is applied to data on a clinical trial for Tacrine in the treatment of Alzheimer's disease.

BACKGROUND: Abacavir sulfate/lamivudine (ABC/3TC) and tenofovir DF/emtricitabine (TDF/FTC) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment. This is the first completed, randomized clinical trial to directly compare the efficacy, safety, and tolerability of these agents, each in combination with lopinavir/ritonavir in antiretroviral-naive patients. METHODS: Six hundred and eighty-eight antiretroviral-naive, HIV-1-infected patients were randomized in this double-blind, placebo-matched, multicenter, noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg, both with lopinavir/ritonavir 800 mg/200 mg. Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing = failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks. RESULTS: At week 48, 68% in the ABC/3TC group vs. 67% in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml (intent-to-treat exposed missing = failure, 95% confidence interval on the difference -6.63 to 7.40, P = 0.913), demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48. Noninferiority of the two regimens was sustained at week 96 (60% vs. 58%, respectively, 95% confidence interval -5.41 to 9.32, P = 0.603). In addition, efficacy of both regimens was similar in patients with baseline HIV-1 RNA >or= 100 000 copies/ml or CD4 cell counts below 50 cells/microl. Median CD4 recovery (ABC/3TC vs. TDF/FTC, cells/microl) was +250 vs. +247 by week 96. Premature study discontinuation due to adverse events occurred in 6% of patients in both groups. Protocol-defined virologic failure occurred in 14% of patients in both groups. CONCLUSION: Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients.