Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

BACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles. On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer (NSCLC), we aimed to assess efficacy and safety of this combination in a phase 3 trial. METHODS: In our double-blind, placebo-controlled, randomised phase 3 trial (BeTa), we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment. Patients were randomly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab (bevacizumab group) or erlotinib plus placebo (control group) according to a computer-generated randomisation sequence by use of an interactive voice response system. The primary endpoint was overall survival in all enrolled patients. Patients, study staff, and investigators were masked to treatment assignment. We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses. This trial is registered with ClinicalTrials.gov, number NCT00130728. FINDINGS: Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group (hazard ratio [HR] 0·97, 95% CI 0·80-1·18, p=0·7583). Median overall survival was 9·3 months (IQR 4·1-21·6) for patients in the bevacizumab group compared with 9·2 months (3·8-20·2) for controls. Progression-free survival seemed to be longer in the bevacizumab group (3·4 months [1·4-8·4]) than in the control group (1·7 months [1·3-4·1]; HR 0·62, 95% CI 0·52-0·75) and objective response rate suggested some clinical activity of bevacizumab and erlotinib. However, these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done, to control type I error rate. In the bevacizumab group, 130 (42%) of 313 patients with safety data had a serious adverse event, compared with 114 (36%) controls. There were 20 (6%) grade 5 adverse events, including two arterial thromboembolic events, in the bevacizumab group, and 14 (4%) in the control group. INTERPRETATION: Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC. FUNDING: Genentech.

Reducing bias in parameter estimates from stepwise regression in proportional hazards regression with right-censored data.

When variable selection with stepwise regression and model fitting are conducted on the same data set, competition for inclusion in the model induces a selection bias in coefficient estimators away from zero. In proportional hazards regression with right-censored data, selection bias inflates the absolute value of parameter estimate of selected parameters, while the omission of other variables may shrink coefficients toward zero. This paper explores the extent of the bias in parameter estimates from stepwise proportional hazards regression and proposes a bootstrap method, similar to those proposed by Miller (Subset Selection in Regression, 2nd edn. Chapman & Hall/CRC, 2002) for linear regression, to correct for selection bias. We also use bootstrap methods to estimate the standard error of the adjusted estimators. Simulation results show that substantial biases could be present in uncorrected stepwise estimators and, for binary covariates, could exceed 250% of the true parameter value. The simulations also show that the conditional mean of the proposed bootstrap bias-corrected parameter estimator, given that a variable is selected, is moved closer to the unconditional mean of the standard partial likelihood estimator in the chosen model, and to the population value of the parameter. We also explore the effect of the adjustment on estimates of log relative risk, given the values of the covariates in a selected model. The proposed method is illustrated with data sets in primary biliary cirrhosis and in multiple myeloma from the Eastern Cooperative Oncology Group.

Long-term effects of protease-inhibitor-based combination therapy on CD4 T-cell recovery in HIV-1-infected children and adolescents.

BACKGROUND: There is limited evidence about longer-term effects of combination antiretroviral therapy that includes protease inhibitors (PIs) on the immunological status of HIV-1-infected children. Better understanding might help to resolve questions on when to initiate treatment. METHODS: The change in percentage of CD4-positive T lymphocytes (CD4%) was investigated in 1012 previously treated HIV-1-infected children (aged 0-17 years) who were enrolled in research clinics in the USA before 1996 and followed up to 2000. 702 started PI-based combination therapy. Data analyses ignored subsequent treatment changes. FINDINGS: Among the 1012 children, the median CD4% increased from 22% to 28% between 1996, when PIs were first prescribed, and 2000. For the 702 who started PI-based therapy, the mean CD4% increase after 3 years was largest among participants with the greatest immunosuppression (15.7%, 10.6%, 5.1%, and 2.0% for participants with CD4% before therapy of <5%, 5-14%, 15-24%, and >25%; p<0.0001). After adjustment for pre-PI CD4%, the mean increase was largest among the youngest participants (9.2%, 8.0%, and 4.3% for ages <5 years, 5-9 years, and >10 years; p=0.001). However, only a minority of significantly immunocompromised participants (33%, 26%, and 49% of those with pre-PI CD4% of <5%, 5-14%, or 15-24%) achieved CD4% values above 25%, whereas 84% of those with pre-PI values above 25% maintained such values. INTERPRETATION: Although PI-based therapy was associated with substantial improvements in CD4%, initiation before severe immunosuppression and at younger ages may be more effective for recovery or maintenance of normal CD4%. Randomised investigation of when to start combination therapy in children, particularly infants, is needed.

Quality of life in an urban Asian population: the impact of ethnicity and socio-economic status.

The relationships between ethnicity, socio-economic status (SES) and health-related quality of life (HRQoL) have not been well characterised in most Asian populations. We therefore studied the influence of ethnicity and SES on HRQoL in a multi-ethnic urban Asian population, adjusting for the influence of other known determinants of HRQoL. In a disproportionately stratified, cross-sectional, population-based survey, Chinese, Malay and Indian subjects in Singapore completed the Short Form 36 Health Survey (SF-36) HRQoL measure and were assessed to determine demographic, socio-economic, psychosocial and other characteristics. Multiple linear regression models were used to study the influence of ethnicity and SES on SF-36 scores while adjusting for the influence of other determinants of HRQoL. The survey participation rate was 92.8%. Ethnic differences in HRQoL were present for all 8 SF-36 scales (p<0.001 for all scales except General Health) among the 4122 Chinese, Malays and Indians surveyed. These ethnic groups also differed in several known determinants of HRQoL (e.g., Chinese had more years of education and Indians had more chronic medical conditions). After adjusting for the influence of these factors, ethnicity and SES independently influenced HRQoL, with mean differences in SF-36 scores due to ethnicity ranging from 1.4 to 13.1 points. Educational level and housing type (markers of SES) were also associated with SF-36 scores (0.5-0.6 point increase per year of education and 3.5-4.0 point increase with better housing type, respectively). Better HRQoL was also associated with better family support, and poorer HRQoL with acute and chronic medical conditions and sick days. The study concludes that ethnicity and SES are associated with clinically important differences in HRQoL in a multi-ethnic, urban Asian population.

Validation of the Medical Outcomes Study HIV Health Survey as a measure of quality of life in HIV-infected patients in Singapore.

Measurement of quality of life is crucial to assess the full impact of antiretroviral therapy on patient morbidity. No quality of life instruments have been validated in an Asian HIV-infected patient population, but it is important to do so given the increasing involvement of the region in clinical trials. We set out to validate the Medical Outcomes Study HIV Health Survey (MOS-HIV) in HIV infected patients in Singapore. Clinically stable outpatients were asked to complete the 30-item MOS-HIV (English or Chinese translation). Patients were also asked about the frequency of selected disease symptoms, and clinical and demographic data were recorded from the case sheet. 163 patients (90% Chinese, 96% male, mean age 38 years, mean CD4 count 159 cells/mm(3)) participated in the study and completed the questionnaire to a satisfactory standard. The questionnaire showed good internal consistency (Cronbach's alpha >0.7 in all cases). There were significant differences in quality of life scores between Centers for Disease Control disease stages, and significant correlations with CD4 count and symptom score, confirming the discriminant validity of the MOS-HIV. Factor analysis revealed two components corresponding to physical and mental health which were similar to those of studies in Western countries except that pain was more closely related to mental than physical health. Linear regression analysis identified symptom burden as the major predictor of physical and mental health. We concluded that the MOS-HIV is a valid measure of quality of life in this HIV patient population in Singapore, and is therefore likely to be useful in future clinical trials in the region. In the era of chronic HIV disease, close attention to symptoms (disease or drug-related) is warranted due to their major adverse influence on mental and physical aspects of quality of life.

Does being bilingual in English and Chinese influence responses to Quality-of-Life scales?

BACKGROUND: It is not known if the inclusion of bilinguals affects the results of research using Quality-of-Life (QoL) scales. OBJECTIVE: To determine the influence of bilingualism on responses to a QoL scale. RESEARCH DESIGN: In this cross sectional study, a population-based, disproportionately stratified random sample of monolingual and bilingual ethnic Chinese completed the Short-Form 36 Health Survey (SF-36) in English or Chinese (representing an alphabet and pictogram based language respectively). Cumulative logit regression models were used to assess the influence of bilingualism on SF-36 scores, while adjusting for the influence of questionnaire language and known determinants of QoL. RESULTS: English or Chinese SF-36 versions were completed by 1331 and 1380 subjects respectively (49% female, aged 21-65 years, 1366 bilingual, 501 English monolingual, 844 Chinese monolingual), with response rates exceeding 85%. Fifty percent of subjects were bilingual. Bilinguals differed from monolinguals in known determinants of QoL, being younger, better educated, and having fewer chronic medical conditions, and had SF-36 scores up to 8 points higher than monolinguals. After adjusting for these differences, bilingualism did not influence scores for any of eight SF-36 scales, whereas questionnaire language influenced scores for four scales. Use of the English SF-36 was associated with higher scores for General Health, Vitality, Role Emotional and Mental Health Scales (odds ratios 1.35-1.41), though the magnitude of these odds ratios suggests this association may not be clinically important. CONCLUSION: Bilingualism did not influence responses to a QoL scale in this large, population-based study of subjects fluent in an alphabet and/or pictogram based language.