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Purpose:MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC).Patients and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/β-actin mRNA expression level and region.Results:Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61–1.01; P = 0.06] and OS (HR = 0.76; 95% CI: 0.56–1.04; P = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56–1.26; P = 0.40; OS, HR = 0.80; 95% CI: 0.51–1.26; P = 0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93–1.53; P = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20–2.24; P < 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously.Conclusions:First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.

Supplementary Data from MAVERICC, a Randomized, Biomarker-stratified, Phase II Study of mFOLFOX6-Bevacizumab versus FOLFIRI-Bevacizumab as First-line Chemotherapy in Metastatic Colorectal Cancer

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.)

Manufacturing process changes may alter the characteristics of a protein therapeutic. In 2009, somatropin (version 1.0), a recombinant human growth hormone therapeutic, underwent a manufacturing update (version 1.1). The immunogenicity of somatropin version 1.1 as a daily subcutaneous injection was evaluated in 2014 in a prospective, open-label, single-arm clinical study of treatment-naive pediatric patients with idiopathic human growth hormone deficiency for 1 year. The primary end point was the proportion of patients who developed antidrug antibodies (ADAs) after treatment. Eighty-two patients were enrolled. The mean (SD) treatment duration was 347 (53) days. The incidence of ADAs was 3.7%. No neutralizing antibodies were observed in the three patients with ADA-positive samples. Two patients (2.6%) had growth attenuation, but they were not ADA positive. The manufacturing changes for somatropin version 1.1 resulted in a similar safety and efficacy profile compared with somatropin version 1.0 and a different immunogenicity profile with a lower incidence of ADAs.

BackgroundCoronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Safety and efficacy of the anti–interleukin-6 receptor antibody tocilizumab was evaluated in patients hospitalized with Covid-19 pneumonia.MethodsNonventilated patients hospitalized with Covid-19 pneumonia were randomized (2:1) to tocilizumab (8 mg/kg intravenous) or placebo plus standard care. Sites enrolling high-risk and minority populations were emphasized. The primary endpoint was cumulative proportion of patients requiring mechanical ventilation or who had died by Day 28.ResultsOf 389 randomized patients, 249 patients received tocilizumab and 128 received placebo in the modified intent-to-treat population (Hispanic/Latino, 56.0%; Black/African American, 14.9%; American Indian/Alaska Native, 12.7%; White, 12.7%; other/unknown, 3.7%). The cumulative proportion (95% confidence interval [CI]) of patients requiring mechanical ventilation or who had died by Day 28 was 12.0% (8.52% to 16.86%) and 19.3 % (13.34% to 27.36%) for the tocilizumab and placebo arms, respectively (log-rank P=0.0360; hazard ratio, 0.56 [95% CI, 0.33 to 0.97]). Median time to clinical failure up to Day 28 favored tocilizumab over placebo (hazard ratio 0.55 [95% CI, 0.33 to 0.93]). All-cause mortality by Day 28 was 10.4% with tocilizumab and 8.6% with placebo (weighted difference, 2.0% [95% CI, – 5.2% to 7.8%). In the safety population, serious adverse events occurred in 15.2% of tocilizumab patients (38/250 patients) and 19.7% of placebo patients (25/127).ConclusionsThis trial demonstrated the efficacy and safety of tocilizumab over placebo in reducing the likelihood of progression to requiring mechanical ventilation or death in nonventilated patients hospitalized with Covid-19 pneumonia.Trial registrationClinicalTrials.govNCT04372186

Purpose: MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC). Patients and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/β-actin mRNA expression level and region. Results: Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61–1.01; P = 0.06] and OS (HR = 0.76; 95% CI: 0.56–1.04; P = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56–1.26; P = 0.40; OS, HR = 0.80; 95% CI: 0.51–1.26; P = 0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93–1.53; P = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20–2.24; P < 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously. Conclusions: First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.

ObjectiveTo determine the time to first clinically meaningful improvement in best-corrected visual acuity (BCVA) in patients treated with ranibizumab for diabetic macular oedema (DME) and identify predictors of early visual improvement.Methods and analysisWe retrospectively analysed the phase III RIDE (NCT00473382) and RISE (NCT00473330) trials, in which 759 patients with DME were randomised to monthly intravitreal ranibizumab 0.3 mg (n=250), ranibizumab 0.5 mg (n=252) or sham treatment (n=257). After month 24, 191 sham-treated patients crossed over to monthly ranibizumab 0.5 mg through month 36, while ranibizumab-treated patients continued treatment. Kaplan-Meier analyses assessed time to achieve ≥15 or ≥10 Early Treatment Diabetic Retinopathy Study (ETDRS) letter gains from baseline or ≥20/40 Snellen equivalent BCVA in each treatment arm. Baseline predictors of ≥15 ETDRS letter gains at month 6 were identified by logistic regression.ResultsMedian time to first ≥15 ETDRS letter gain was significantly shorter in patients who received ranibizumab (0.3 mg, 11.1 months; 0.5 mg, 10.9 months) than sham-treated patients who crossed over to ranibizumab 0.5 mg at month 24 (35.7 months; both pConclusionPrompt ranibizumab therapy for DME was associated with rapid, clinically meaningful vision gains that were maintained over 36 months of treatment. Lower BCVA, younger age and presence of subretinal fluid were predictive of early vision improvement.

To evaluate the incidence of collateral vessel formation and to determine their impact on best-corrected visual acuity and central foveal thickness in patients with branch or central retinal vein occlusion (BRVO, CRVO) receiving 0.3 mg or 0.5 mg of ranibizumab, or sham.This retrospective analysis was performed in patients with macular edema secondary to retinal vein occlusion who received 6 monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg), or sham, followed by 6 months of as-needed treatment. Collateral vessel presence, change from baseline best-corrected visual acuity, and change from baseline central foveal thickness were assessed at baseline and months 3, 6, 9, and 12.At month 12, 19.6% of BRVO patients receiving sham/0.5 mg and 16.7% receiving ranibizumab (0.3 mg and 0.5 mg pooled) manifested collaterals at the disk, whereas 48.2% and 47.2% displayed collaterals within the retina, respectively. In CRVO patients, 57.9% and 59.2% of all groups manifested collaterals on the disk, respectively, whereas 12.1% and 15.1% displayed collaterals within the retina. Mean best-corrected visual acuity gain in ranibizumab-treated BRVO and CRVO patients was similar, irrespective of collaterals within the retina (P0.05; CRVO: P0.05).The location of collaterals differed between retinal vein occlusion subtypes and ranibizumab treatment did not affect collateral vessel incidence. The presence of collaterals did not seem to impact best-corrected visual acuity gains at month 12 in both BRVO and CRVO patients receiving ranibizumab, whereas generally greater central foveal thickness reductions were observed with presence of collaterals in BRVO patients.

Purpose To assess time to first achievement of clinically significant visual acuity (VA) gains from baseline in patients with retinal vein occlusion (RVO) receiving ranibizumab versus sham treatment. Design Post hoc analyses of 2 phase 3 clinical trials assessing efficacy and safety of ranibizumab in patients with branch RVO (Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety [BRAVO] study; NCT00061594) and central RVO (Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety [CRUISE]; NCT00056836) over 12 months. Participants Seven hundred eighty-nine patients (BRAVO, n = 397; CRUISE, n = 392). Intervention Randomization to monthly intraocular ranibizumab injections (0.3 mg/0.5 mg) or sham. After 6 monthly injections (treatment period), patients meeting prespecified criteria received as-needed (pro re nata [PRN]) ranibizumab at their assigned dose (sham patients, ranibizumab 0.5 mg) through month 12 (observation period). BRAVO patients meeting specific eligibility criteria could receive rescue laser treatment once during the treatment and once during the observation periods. Main Outcome Measures Time to first gain of 15 letters or more from baseline, analyzed using Kaplan-Meier methods. To evaluate the effect of delaying ranibizumab treatment, sham patients' VA data also were analyzed, with month 6 considered as baseline to assess vision gains during the 6 months of receiving ranibizumab PRN. Results Median time to first 15-letter or more gain from baseline was 12.0 (sham), 4.8 (ranibizumab 0.3 mg), and 4.0 months (ranibizumab 0.5 mg) in BRAVO and 12.2, 5.9, and 5.2 months, respectively, in CRUISE. The cumulative proportion of patients who had ever gained 15 letters or more from baseline by month 12 was 50% (sham), 68% (ranibizumab 0.3 mg), and 71% (ranibizumab 0.5 mg) in BRAVO and 42%, 61%, and 66%, respectively, in CRUISE. After 6 months of ranibizumab PRN treatment, a cumulative 10.8% (BRAVO) and 26.2% (CRUISE) of initially sham-treated patients ever gained 15 letters or more. Conclusions This retrospective analysis shows that more than 50% of patients treated with monthly ranibizumab achieved clinically significant vision gains during the initial 6 months of treatment, which largely were maintained using PRN treatment to 12 months. In comparison, less than 50% of patients initially randomized to sham (and later receiving ranibizumab 0.5 mg PRN treatment) ever achieved clinically significant vision gains. These results suggest that initiating treatment immediately after diagnosis may provide the greatest vision gains. The potential benefits of early treatment should be evaluated further in prospective clinical studies.

Purpose To assess long-term safety and efficacy of intraocular ranibizumab injections in patients with macular edema after retinal vein occlusion (RVO). Design Open-label extension trial of the 12-month Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) and Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety (CRUISE) trials. Participants We included 304 patients who completed BRAVO and 304 patients who completed CRUISE. Methods Patients were seen at least every 3 months and given an intraocular injection of 0.5 mg ranibizumab if they met prespecified retreatment criteria. Main Outcome Measures Primary outcomes were incidence and severity of ocular and nonocular adverse events (AEs). Key efficacy outcomes included mean change from baseline best-corrected visual acuity (BCVA) letter score by Early Treatment Diabetic Retinopathy Study protocol and central foveal thickness. Results In patients who completed month 12, the mean number of injections (excluding month 12 injection) in the sham/0.5-, 0.3/0.5-, and 0.5-mg groups was 2.0, 2.4, and 2.1 (branch RVO) and 2.9, 3.8, and 3.5 (central RVO), respectively. The incidence of study eye ocular serious AEs (SAEs) and SAEs potentially related to systemic vascular endothelial growth factor inhibition across treatment arms was 2% to 9% and 1% to 6%, respectively. The mean change from baseline BCVA letter score at month 12 in branch RVO patients was 0.9 (sham/0.5 mg), −2.3 (0.3/0.5 mg), and −0.7 (0.5 mg), respectively. The mean change from baseline BCVA at month 12 in central RVO patients was −4.2 (sham/0.5 mg), −5.2 (0.3/0.5 mg), and −4.1 (0.5 mg), respectively. Conclusions No new safety events were identified with long-term use of ranibizumab; rates of SAEs potentially related to treatment were consistent with prior ranibizumab trials. Reduced follow-up and fewer ranibizumab injections in the second year of treatment were associated with a decline in vision in central RVO patients, but vision in branch RVO patients remained stable. Results suggest that during the second year of ranibizumab treatment of RVO patients, follow-up and injections should be individualized and, on average, central RVO patients may require more frequent follow-up than every 3 months. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

ritonavir (RTV) effectively boosts most protease inhibitors but is associated with significant dose-dependent adverse events (AEs). In an effort to better manage toxicities through a reduced dose of RTV, this study compared fosamprenavir (FPV) boosted with RTV 100 mg (FPV/r100) or with RTV 200 mg (FPV/r200) daily.this 24-week, open-label study enrolled patients taking a FPV/r 200-containing regimen who had HIV RNA400 copies/mL and randomized them 1:2 to continue that regimen or simplify to FPV/r100 once daily. Other medications were not altered. The primary endpoint was the percentage of patients without suspected or confirmed virologic failure (HIV RNA ≥ 400 copies/mL) through week 24 by a missing/discontinuation equals failure (M/D=F) analysis. Noninferiority criteria were demonstrated if the lower bound of the 95% confidence interval (CI) for the difference in the primary endpoint rates between groups was greater than -12.the 2 regimens met prespecified noninferiority criteria (FPV/r100, 92%; FPV/r 200, 94%; 95% CI, -9.36 to 5.12). At week 24, the percentage of patients with HIV RNA50 copies/mL by M/ D=F was 83% in the FPV/r100 group and 85% in the FPV/r 200 group. Drug-related grade 2-4 AEs were uncommon (FPV/r100, 4%; FPV/r 200, 7%). Median changes in lipids were similar in both groups, with the exception of triglycerides (FPV/r100, -21 mg/dL; FPV/r 200, -2 mg/dL).this 24-week study demonstrated that among previously suppressed patients, once-daily FPV/r100 was similar to FPV/r 200 in virologic and immunologic effects but was associated with greater decreases from baseline in triglyceride levels.

(2010). Simplified Maintenance Therapy With Abacavir/Lamivudine and Atazanavir After Discontinuation of Ritonavir. HIV Clinical Trials: Vol. 11, No. 3, pp. 170-173.

726 Background: Primary tumor location is an important prognostic factor in mCRC. Efficacy differences with EGFR antibodies by tumor location show a predictive effect (Arnold et al. Ann Oncol 2017). Two first-line (1L) pivotal bev trials showed the prognostic value of sidedness (Loupakis et al. J Natl Cancer Inst 2015). In this exploratory study, further analysis of the predictive effect of bev is presented. Methods: Data from two randomized phase III studies (NO16966 [NCT00069095], AVF2107g [NCT00109070]) of bev+CT vs CT-alone as 1L treatment for mCRC were analyzed retrospectively. Patients (pts) with sidedness information available were included; pts from NO16966 (part 1) randomized to CT only were excluded. Sidedness was identified by case report forms. Results: Sidedness was determined in 1590 pts (27% Right and 73% Left) out of 2214 pts total (Table). In the pooled analysis, PFS improved with bev+CT compared to CT only in both right-sided (HR=0.75; 95% CI 0.61, 0.93) and left-sided (HR=0.76; 95% CI 0.67, 0.86) mCRC with similar magnitude of benefit in both sides. OS also improved with bev+CT in right-sided (HR=0.82; 95% CI 0.65, 1.03) and left-sided (HR=0.85; 95% CI 0.74, 0.98) pts. Conclusions: This exploratory subgroup analysis of two pivotal studies indicates that the effect of bev is independent of tumor location in mCRC patients. Survival outcomes. Clinical trial information: NCT00069095 and NCT00109070. [Table: see text]

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.

Tumors arising from the colorectal tract are a heterogeneous complex of diseases that result from the accumulation of distinctive genetic and epigenetic alterations (1,2). Despite increased understanding into the molecular pathways underlying colorectal cancer (CRC), relatively few biomarkers are prognostic for survival (1–3). Germline mutations in DNA mismatch repair genes, definitive of Lynch syndrome, in stage II/III disease and BRAF V600E mutations in stage IV disease are notable exceptions (4–6). Biological and clinical evidence supports that proximal (right-sided) and distal (left-sided) CRCs follow different molecular pathways of carcinogenesis. Right-sided tumors are more likely to be diploid and to be characterized by mucinous histology, high microsatellite instability, CpG island methylation, and BRAF mutations (6–10). In contrast, left-sided tumors are frequently infiltrating, constricting lesions, with a phenotype that involves chromosomal instability and aneuploidy (7–9). Microarray studies of sporadic CRC biopsies demonstrate unique gene expression profiles for right- and left-sided cancers, potentially related to distinct embryonic origins and postnatal regulation (11,12). Extensive sequencing analyses described a characteristic branching pattern of cancer evolution supporting that tumor biology is characterized simultaneously by intratumor heterogeneity and the preservation of ancestral aberrations within the primary tumor and corresponding metastatic sites (13,14). Previous attempts to evaluate the effect of primary tumor location on outcome in metastatic CRC (mCRC) have been complicated by sample size, a high degree of heterogeneity in received treatments, and limited information on molecular and pathologic features (15−17). The objectives of the present analysis were first to assess primarily the prognostic impact and secondly the predictive effect of primary tumor location for an antiangiogenic treatment by interrogating three large independent patient cohorts. Because of the prognostic significance of BRAF mutations and mucinous histology (5,6,18) and the association of these characteristics with right-sided mCRC, a multivariable model and a subgroup analysis in nonmucinous and BRAF wild-type cancers were used to separately assess outcomes in the PROVETTA study (chosen as an exploratory set based on availability of clinical and molecular features). The prognostic effect of primary tumor location was subsequently verified and validated using data from two large phase III trials.

Summary Background Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients. Methods This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943. Findings At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference −4·84 to 7·05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2–4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir. Interpretation Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

Background The significance of asymptomatic hyperlactataemia is unknown. Methods We measured serial lactate levels in a group of HIV-infected subjects. Objectives were to identify covariates associated with hyperlactataemia, and to explore the natural history of hyperlactataemia. Results Overall, 1487 lactate measurements were performed on 396 subjects; 299 subjects had serial lactate testing, with a median of four performed per patient (range: 2–16). At study entry, lactate was >2.4 mmol/l in 6% of subjects and >3.6 mmol/l in 1%. A multiple logistic regression analysis revealed that cholesterol and current stavudine were the only predictors of hyperlactataemia. Lactate levels were highly reproducible both for short-term (within 3 months) and long-term (>1 year) follow-up. During the study period, 16 subjects were identified with sustained hyperlactataemia; 12/16 remained asymptomatic after a median of 210 days (30–585), and four developed symptoms suggestive of lactic acidosis syndrome. In three of the four, asymptomatic hyperlactataemia had preceded the onset of symptoms by 18–122 days. A longitudinal model showed a rapid rise of lactate levels from 0 to 12 months on nucleoside reverse transcriptase inhibitor (NRTI) and then stabilization. Lactate levels did not correlate with baseline or on-study development of lipoatrophy. Conclusions Even when optimal methods of collection are used, asymptomatic hyperlactataemia does exist and could be sustained in a subset of NRTI-treated subjects for as long as 585 days. A subset of these subjects became symptomatic, after as long as 122 days of asymptomatic hyperlactataemia. Asymptomatic hyperlactataemia is not predictive of lipoatrophy. This work was partly presented at the 9th Conference on Retroviruses & Opportunistic Infections. Seattle, Wash., USA, February 2002.

Information about the nucleoside analogue abacavir has been based primarily on the results of clinical trials, rather than on experience in the clinical practice setting. The Ziagen Optimal Regimen and Resistance Observational (ZORRO) trial was a Phase IV, open-label, community-based. study conducted over 16 weeks at 265 U.S. clinical practice sites to assess the real-world safety/tolerability and efficacy of abacavir-containing combination regimens. Of 833 HIV-infected patients enrolled, 791 had documented evidence of having taken abacavir (298 antiretroviral-naive, 490 antiretroviral-experienced, and 3 with missing data). Mean age was 40.3 years, 84% were male, 48% were Caucasian, and 33% were African-American. At baseline, the median plasma HIV-1 RNA was 4.34 log 1 0 copies/ mL and CD4 cell count was 321 cells/mm 3 . Adverse events were primarily gastrointestinal and transient. A suspected abacavir-related hypersensitivity reaction was reported in 7% of patients. Week 16, data in the total antiretroviral-naive and antiretroviral-experienced groups showed that median HIV-1 RNA was reduced by 1.64, 2.40, and 1.05 logo copies/mL below baseline, viral load was < 400 copies/mL in 68%, 69%, and 67% of patients (intent-to-treat: observed analysis), and median CD4 cell count was increased by 78, 120, and 54 cells/mm 3 above baseline. Overall, the safety and efficacy profile of abacavir-containing combination regimens in clinical practice patients appeared similar to that previously reported in clinical trials.

To compare pro re nata (PRN) and monthly injections of 0.5 mg ranibizumab in retinal vein occlusion (RVO) patients stabilized by monthly injections.Randomized, open-label, vision-examiner masked, 15-month study.Subjects with macular edema secondary to branch or central RVO.Subjects received monthly injections of 0.5 mg ranibizumab for 7 months and those meeting stability criteria between months 7 and 14 were randomized (1:1) to PRN injections versus continued monthly injections. Non-randomized (NR) subjects (never met stability criteria) received monthly injections.The primary endpoint was the slope of change in best-corrected visual acuity (BCVA) between months 7 and 15.There was no significant difference in the slope of change in BCVA between months 7 and 15 in patients treated PRN versus those treated with monthly injections (P = 0.509). Mean (± standard deviation) change from baseline BCVA in Early Treatment Diabetic Retinopathy Study letter score at month 15 was 21.0 ± 14.1 in the PRN group (n = 82) versus 18.7 ± 14.1 in the monthly group (n = 80) and 14.5 ± 14.7 in NR subjects (n = 13). The percentage of subjects who achieved BCVA ≥ 20/40 at month 15 was 76.8% in the PRN group, 71.3% in the monthly group, and 46.2% in NR subjects. The mean (± standard deviation) change from baseline central subfield thickness was -247.8 ± 207.5 μm in the PRN group, -289.9 ± 177.2 μm in the monthly group, and -93.2 ± 225.2 μm in NR subjects. There were no significant differences in mean BCVA gains or central subfield thickness reductions at month 15 between the PRN and monthly injection groups (all0.05).After edema resolution from 7 or more monthly ranibizumab injections in RVO subjects, visual outcomes at month 15 were excellent and not significantly different in subjects treated PRN versus those who continued monthly injections.

To assess time to first achievement of clinically significant visual acuity (VA) gains from baseline in patients with retinal vein occlusion (RVO) receiving ranibizumab versus sham treatment.Post hoc analyses of 2 phase 3 clinical trials assessing efficacy and safety of ranibizumab in patients with branch RVO (Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety [BRAVO] study; NCT00061594) and central RVO (Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety [CRUISE]; NCT00056836) over 12 months.Seven hundred eighty-nine patients (BRAVO, n = 397; CRUISE, n = 392).Randomization to monthly intraocular ranibizumab injections (0.3 mg/0.5 mg) or sham. After 6 monthly injections (treatment period), patients meeting prespecified criteria received as-needed (pro re nata [PRN]) ranibizumab at their assigned dose (sham patients, ranibizumab 0.5 mg) through month 12 (observation period). BRAVO patients meeting specific eligibility criteria could receive rescue laser treatment once during the treatment and once during the observation periods.Time to first gain of 15 letters or more from baseline, analyzed using Kaplan-Meier methods. To evaluate the effect of delaying ranibizumab treatment, sham patients' VA data also were analyzed, with month 6 considered as baseline to assess vision gains during the 6 months of receiving ranibizumab PRN.Median time to first 15-letter or more gain from baseline was 12.0 (sham), 4.8 (ranibizumab 0.3 mg), and 4.0 months (ranibizumab 0.5 mg) in BRAVO and 12.2, 5.9, and 5.2 months, respectively, in CRUISE. The cumulative proportion of patients who had ever gained 15 letters or more from baseline by month 12 was 50% (sham), 68% (ranibizumab 0.3 mg), and 71% (ranibizumab 0.5 mg) in BRAVO and 42%, 61%, and 66%, respectively, in CRUISE. After 6 months of ranibizumab PRN treatment, a cumulative 10.8% (BRAVO) and 26.2% (CRUISE) of initially sham-treated patients ever gained 15 letters or more.This retrospective analysis shows that more than 50% of patients treated with monthly ranibizumab achieved clinically significant vision gains during the initial 6 months of treatment, which largely were maintained using PRN treatment to 12 months. In comparison, less than 50% of patients initially randomized to sham (and later receiving ranibizumab 0.5 mg PRN treatment) ever achieved clinically significant vision gains. These results suggest that initiating treatment immediately after diagnosis may provide the greatest vision gains. The potential benefits of early treatment should be evaluated further in prospective clinical studies.

3515Background: Standard 1L mCRC treatment (tx) includes a CT backbone (e.g. modified leucovorin [LV]/5-fluorouracil [5-FU]/oxaliplatin [mFOLFOX6] or LV/ 5-FU/ irinotecan [FOLFIRI]) and a biologic ...

493 Background: Standard 1L mCRC treatment (tx) includes a CT backbone (e.g., modified leucovorin [LV]/5-fluorouracil [5-FU]/oxaliplatin [mFOLFOX6] or LV/ 5-FU/ irinotecan [FOLFIRI]) and biologic therapy (e.g., BV). The preferred CT backbone for anti VEGF tx is unknown. MAVERICC (NCT01374425), a global, randomized, open-label, phase 2 trial, assessed tx efficacy and safety of mFOLFOX6-BV vs FOLFIRI-BV in pts with mCRC. Intratumoral ERCC1 and plasma VEGF-A were studied as biomarkers for oxaliplatin- and BV-containing tx, respectively. Methods: Pts with mCRC (≥1 measurable metastatic lesion, ECOG performance status ≤1) were randomized 1:1 to receive BV (5 mg/kg) + mFOLFOX6 or FOLFIRI every 2 weeks, stratified by ERCC1 level (low [£1.7] vs high [>1.7]) and region. VEGF-A levels were measured at baseline. Primary objectives were to evaluate: ERCC1 as a biomarker of progression-free survival (PFS) in 1L mCRC tx (mFOLFOX-BV vs FOLFIRI); and VEGF-A as a biomarker for BV and as a biomarker in combination with ERCC1 for PFS following CT + BV. Secondary objectives were to evaluate: the effect of ERCC1 and VEGF-A on overall survival (OS), objective response rate, hepatic metastases resection, and safety. PFS and OS were estimated by Kaplan–Meier methods, hazard ratios (HR) were estimated by Cox regression, and p-values were based on stratified log-rank tests. ERCC1 biomarker analyses are presented here. Results: A total of 376 pts were randomized: median age, 61 yr; white race, 83%; US region, 85%. Baseline characteristics: ERCC1 high, 35%; KRAS mutant, 34%. Efficacy results are shown (see Table). Conclusion: Consistent with previous findings, PFS and OS were comparable in pts treated with either 1L mFOLFOX6-BV or FOLFIRI-BV. Exploratory analyses within pts with high ERCC1 levels suggest consistent results. VEGF-A analyses are ongoing. Clinical trial information: NCT01374425. [Table: see text] [Table: see text]

To assess long-term safety and efficacy of intraocular ranibizumab injections in patients with macular edema after retinal vein occlusion (RVO).Open-label extension trial of the 12-month Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) and Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety (CRUISE) trials.We included 304 patients who completed BRAVO and 304 patients who completed CRUISE.Patients were seen at least every 3 months and given an intraocular injection of 0.5 mg ranibizumab if they met prespecified retreatment criteria.Primary outcomes were incidence and severity of ocular and nonocular adverse events (AEs). Key efficacy outcomes included mean change from baseline best-corrected visual acuity (BCVA) letter score by Early Treatment Diabetic Retinopathy Study protocol and central foveal thickness.In patients who completed month 12, the mean number of injections (excluding month 12 injection) in the sham/0.5-, 0.3/0.5-, and 0.5-mg groups was 2.0, 2.4, and 2.1 (branch RVO) and 2.9, 3.8, and 3.5 (central RVO), respectively. The incidence of study eye ocular serious AEs (SAEs) and SAEs potentially related to systemic vascular endothelial growth factor inhibition across treatment arms was 2% to 9% and 1% to 6%, respectively. The mean change from baseline BCVA letter score at month 12 in branch RVO patients was 0.9 (sham/0.5 mg), -2.3 (0.3/0.5 mg), and -0.7 (0.5 mg), respectively. The mean change from baseline BCVA at month 12 in central RVO patients was -4.2 (sham/0.5 mg), -5.2 (0.3/0.5 mg), and -4.1 (0.5 mg), respectively.No new safety events were identified with long-term use of ranibizumab; rates of SAEs potentially related to treatment were consistent with prior ranibizumab trials. Reduced follow-up and fewer ranibizumab injections in the second year of treatment were associated with a decline in vision in central RVO patients, but vision in branch RVO patients remained stable. Results suggest that during the second year of ranibizumab treatment of RVO patients, follow-up and injections should be individualized and, on average, central RVO patients may require more frequent follow-up than every 3 months.

to evaluate raltegravir plus abacavir/lamivudine in antiretroviral-naïve, HIV-1-infected patients.SHIELD is an ongoing 96-week pilot study of abacavir/lamivudine 600 mg/300 mg once daily with raltegravir 400 mg twice daily among HLA-B*5701-negative adults with screening viral load (VL)1,000 copies/mL. HBsAg+ patients were excluded, as were patients with key mutation(s) to any study drug. Virologic failure (VF) was defined as either VL400 copies/mL at week 24 or confirmed virologic rebound.thirty-five patients enrolled (mean age 38.7 years). Most were white males, but 26% self-identified as Hispanic/Latino. At baseline, 34% had VL ≥ 100,000 copies/mL (median, 4.8 log10 copies/mL) and 20% had CD4 cell counts200 cells/mm3 (median, 301). One patient discontinued due to adverse events (AEs); one patient experienced VF. At week 48, 91% (32/35) had VL50 and400 copies/mL by missing/discontinuation equals failure analysis. Median CD4 cell count change from baseline was +247 cells/mm3. Five patients (14%) had treatment-related grade 2-4 AEs; no treatment-related serious AEs were reported. Over 48 weeks, median fasting lipids increased for total (+17%), LDL (+9%), and HDL (+6%) cholesterol but remained stable for triglycerides (-1%) and total:HDL cholesterol ratio (0%).in this pilot study, abacavir/lamivudine plus raltegravir was effective and generally well-tolerated over 48 weeks with modest changes in fasting lipids.

COL40263 was a pilot 48-week, open-label, multicenter study evaluating the efficacy and safety of once-daily coformulated abacavir/lamivudine/zidovudine plus tenofovir in ART-naive, HIV-infected subjects. We examined the patterns of resistance that were selected on-therapy through 48 weeks in subjects with virologic nonresponse (VF). A total of 123 antiretroviral-naive HIV-1-infected subjects with plasma HIV-1 RNAor = 30,000copies/ml were enrolled. For subjects with confirmed VF (HIV-1 RNAor = 400 copies/ml at week 24 or later), HIV population genotypic and phenotypic analysis was performed. Of the 123 enrolled subjects, 14 (11%) had confirmed plasma HIV-1 RNAor = 400 copies/ml through week 48. Of these subjects, 3/14 had evidence of drug resistance at baseline: 2/14 had HIV with K103N, Y188F/H/L/Y, and/or T215A and 1/14 had reduced zidovudine susceptibility. At the last time point analyzed, 4/14 subjects had wild-type HIV, while 10/14 subjects had HIV with either thymidine analogue mutations (TAMS) alone (3/10), TAMS + M184V (4/10), M184V only (1/10), or K65R/K (2/10). Matched phenotype was obtained for 13/14 subjects and 8/13 (62%) subjects had reduced susceptibility to one or more study drugs: 2/13 tenofovir, 3/13 abacavir, 4/13 zidovudine, and 7/13 lamivudine. The resistance pattern in COL40263 subjects with VF differs significantly from that reported for tenofovir-containing triple-nucleoside regimens. TAMs were detected in the majority (7/10) of samples from subjects with VF who selected any resistance mutation. These data suggest that TAMs selection is a preferred resistance route of this combination, with zidovudine modulating the resistance pathway against selection for K65R.

The KLEAN study extension assessed the long-term efficacy and safety of fosamprenavir-ritonavir (FPV/r) and lopinavir-ritonavir (LPV/r), both administered with abacavir/lamivudine (ABC/3TC) fixed dose combination, over 144 weeks.KLEAN was an open-label, noninferiority study that randomised antiretroviral-naïve patients to FPV/r twice daily (bid) or LPV/r bid with ABC/3TC once daily (qd). Patients with a viral load of400 copies/mL at Week 48 were eligible to participate in the KLEAN study extension (up to 144 weeks) and continued with their previously randomised therapy.The KLEAN study extension (48 to 144 weeks) randomized 199 patients. The proportion of TLOVR responders (HIV-1 RNA50 copies/mL) at Week 144 was 73% and 60% in the FPV/r and LPV/r arms, respectively. The proportion of TLOVR responders (50 copies/mL) was the same irrespective of baseline HIV-1 RNA (100,000 or 100,000 copies/mL). The Week 144 median (interquartile range) change from baseline CD4+ cell count was 300 (236-433) cells/mm3 and 335 (225-444) cells/mm3 in the FPV/r and LPV/r arms, respectively. Diarrhea was the most frequently reported adverse event. A small proportion of patients (FPV/r, 13%; LPV/r, 9%) discontinued study medication due to adverse events. Three patients (FPV/r, 1; LPV/r, 2) experienced virological failure between Week 48 and Week 144.The findings of the KLEAN study extension (48 to 144 weeks) support durable viral suppression with both FPV/r and LPV/r treatment regimens when used in combination with ABC/3TC irrespective of viral load at baseline. Both regimens were well tolerated and had similar safety profiles.

To assess the safety and efficacy of a 4-drug, 3-tablet, once-daily (qd) regimen consisting of abacavir/lamivudine/zidovudine (ABC/3TC/ZDV; 2 tablets) and tenofovir (TDF) in antiretroviral-naïve patients with plasma HIV-1 RNA 30,000 copies/mL at 48 weeks.All participants received ABC/3TC/ZDV (300/150/300 mg) and TDF (300 mg) qd in this pilot, open-label, multicenter study. Intent-to-treat (ITT) analyses were conducted to evaluate virologic and immunologic efficacy.Of the 123 participants enrolled, 52 (42%) prematurely discontinued study for adverse events (14), were lost to follow-up (13), had virologic nonresponse (12), and withdrew for other reasons (13). At week 48, by ITT missing=failure analysis, 41% (51/123) and 51% (63/123) of participants had plasma HIV-1 RNA50 copies/mL and400 copies/mL, respectively; by ITT-observed analysis, 75% (51/68) and 93% (63/68) had plasma HIV-1 RNA50 copies/mL and400 copies/mL, respectively; 11% (14/123) met virologic nonresponse criteria. Median week 48 change in CD4+ cell count from baseline was +127 cells/mm3. Median week 48 changes from baseline for fasting lipids were as follows: cholesterol (-9 mg/dL), HDL (+1 mg/dL), LDL (-9 mg/dL), and triglycerides (-4 mg/dL).A high rate of premature discontinuations contributed to the overall suboptimal virologic response to ABC/3TC/ZDV+TDF qd; however, the regimen was not associated with high rates of virologic failure previously observed with TDF+ABC/3TC.

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.

The effects of neonatal injection of estrogen and progesterone on the subsequent in vitro hormone responsiveness of murine mammary glands were determined by a coordinated study of the morphological development and the biochemical response of explants. After daily in vivo pretreatment with estrogen and progesterone, explants were cultured for 5 days in a chemically defined medium containing insulin alone or insulin, cortisol, and PRL. After the culture period, the morphological development of alveoli and lobules was rated. In addition, casein mRNA was quantitated using a specific complementary DNA hybridization probe. Perinatal 17 beta-estradiol exposure was found to increase casein mRNA content as well as lobular development. Conversely, perinatal progesterone treatment inhibited both casein mRNA induction and the formation of lobules. The administration of both estradiol and progesterone to newborns resulted in an antagonistic response between these two steroids, and there was no effect on casein mRNA levels or lobular development in comparison with untreated controls. Mammary tissues of perinatally estrogen-treate mice displayed greater lobular development and contained higher levels of casein mRNA in response to an extension of the duration of in vivo pretreatment from 6 to 9 days. A comparison of the PRL dose response in vitro suggested that exposure to estrogen perinatally sensitized the mammary tissue to the subsequent addition of PRL in culture. These studies indicate that injection of newborns with estrogen may enhance the subsequent hormonally regulated differentiation of the mammary gland. Exposure to progesterone may inhibit later development, and both steroids in combination may exert antagonistic effects. These effects were not mediated solely by alterations in the normal endocrine status of the treated animals but were reflected by the subsequent hormonal response of mammary explants in a defined culture medium. This altered sensitive to hormones may be important in the increased incidence of mammary dysplasias observed in these animals.