Considerations for master protocols using external controls.

There has been an increasing use of master protocols in oncology clinical trials because of its efficiency to accelerate cancer drug development and flexibility to accommodate multiple substudies. Depending on the study objective and design, a master protocol trial can be a basket trial, an umbrella trial, a platform trial, or any other form of trials in which multiple investigational products and/or subpopulations are studied under a single protocol. Master protocols can use external data and evidence (e.g. external controls) for treatment effect estimation, which can further improve efficiency of master protocol trials. This paper provides an overview of different types of external controls and their unique features when used in master protocols. Some key considerations in master protocols with external controls are discussed including construction of estimands, assessment of fit-for-use real-world data, and considerations for different types of master protocols. Similarities and differences between regular randomized controlled trials and master protocols when using external controls are discussed. A targeted learning-based causal roadmap is presented which constitutes three key steps: (1) define a target statistical estimand that aligns with the causal estimand for the study objective, (2) use an efficient estimator to estimate the target statistical estimand and its uncertainty, and (3) evaluate the impact of causal assumptions on the study conclusion by performing sensitivity analyses. Two illustrative examples for master protocols using external controls are discussed for their merits and possible improvement in causal effect estimation.

Tumor-Agnostic Approvals: Insights and Practical Considerations.

Since the first approval of a tumor-agnostic indication in 2017, a total of seven tumor-agnostic indications involving six drugs have received approval from the FDA. In this paper, the master protocol subteam of the Statistical Methods in Oncology Scientific Working Group, Biopharmaceutical Session, American Statistical Association, provides a comprehensive summary of these seven tumor-agnostic approvals, describing their mechanisms of action; biomarker prevalence; study design; companion diagnostics; regulatory aspects, including comparisons of global regulatory requirements; and health technology assessment approval. Also discussed are practical considerations relating to the regulatory approval of tumor-agnostic indications, specifically (i) recommendations for the design stage to mitigate the risk that exceptions may occur if a treatment is initially hypothesized to be effective for all tumor types and (ii) because drug development continues after approval of a tumor-agnostic indication, recommendations for further development of tumor-specific indications in first-line patients in the setting of a randomized confirmatory basket trial, acknowledging the challenges in this area. These recommendations and practical considerations may provide insights for the future development of drugs for tumor-agnostic indications.

Statistical Considerations on the Use of RWD/RWE for Oncology Drug Approvals: Overview and Lessons Learned.

Despite increasing utilization of real-world data (RWD)/real-world evidence (RWE) in regulatory submissions, their application to oncology drug approvals has seen limited success. Real-world data is most commonly summarized as a benchmark control for a single arm study or used to augment the concurrent control in a randomized clinical trial (RCT). While there has been substantial research on usage of RWD/RWE, our goal is to provide a comprehensive overview of their use in oncology drug approval submissions to inform future RWD/RWE study design. We will review examples of applications and summarize the strengths and weaknesses of each example identified by regulatory agencies. A few noteworthy case studies will be reviewed in detail. Operational aspects of RWD/RWE study design/analysis will be also discussed.

Borrowing Concurrent Information from Non-Concurrent Control to Enhance Statistical Efficiency in Platform Trials.

A platform trial is a trial involving an innovative adaptive design with a single master protocol to efficiently evaluate multiple interventions. It offers flexible features such as dropping interventions for futility and adding new interventions to be evaluated during the course of a trial. Although there is a consensus that platform trials can identify beneficial interventions with fewer patients, less time, and a higher probability of success than traditional trials, there remains debate on certain issues, one of which is whether (and how) the non-concurrent control (NCC) (i.e., patients in the control group recruited prior to the new interventions) can be combined with the current control (CC) in the analysis, especially if there is a change of standard of care during the trial. METHODS: In this paper, considering time-to-event endpoints under the proportional hazard model assumption, we introduce a new concept of NCC concurrent observation time (NCC COT), and propose to borrow NCC COT through left truncation. This assumes that the NCC COT and CC are comparable. If the protocol does not prohibit NCC patients to change the standard of care while on study, NCC COT and CC likely will share the same standard of care. A simulated example is provided to demonstrate the approach. RESULTS: Using exponential distributions, the simulated example assumes that NCC COT and CC have the same hazard, and the treatment group has a lower hazard. The estimated HR comparing treatment to the pooled control group is 0.744 (95% CI 0.575, 0.962), whereas the comparison to the CC group alone is 0.755 (95% CI 0.566, 1.008), with corresponding p-values of 0.024 versus 0.057, respectively. This suggests that borrowing NCC COT can improve statistical efficiency when the exchangeability assumption holds. CONCLUSION: This article proposes an innovative approach of borrowing NCC COT to enhance statistical inference in platform trials under appropriate scenarios.

FORT-1: Phase II/III Study of Rogaratinib Versus Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on FGFR1/3 mRNA Expression.

PURPOSE: Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, showed promising phase I efficacy and safety in patients with advanced urothelial carcinoma (UC) with FGFR1-3 mRNA overexpression. We assessed rogaratinib efficacy and safety versus chemotherapy in patients with FGFR mRNA-positive advanced/metastatic UC previously treated with platinum chemotherapy. METHODS: FORT-1 (ClinicalTrials.gov identifier: NCT03410693) was a phase II/III, randomized, open-label trial. Patients with FGFR1/3 mRNA-positive locally advanced or metastatic UC with ≥ 1 prior platinum-containing regimen were randomly assigned (1:1) to rogaratinib (800 mg orally twice daily, 3-week cycles; n = 87) or chemotherapy (docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2 intravenously once every 3 weeks; n = 88). The primary end point was overall survival, with objective response rate (ORR) analysis planned following phase II accrual. Because of comparable efficacy between treatments, enrollment was stopped before progression to phase III; a full interim analysis of phase II was completed. RESULTS: ORRs were 20.7% (rogaratinib, 18/87; 95% CI, 12.7 to 30.7) and 19.3% (chemotherapy, 17/88; 95% CI, 11.7 to 29.1). Median overall survival was 8.3 months (95% CI, 6.5 to not estimable) and 9.8 months (95% CI, 6.8 to not estimable; hazard ratio, 1.11; 95% CI, 0.71 to 1.72; P = .67). Grade 3/4 events occurred in 37 (43.0%)/4 (4.7%) patients and 32 (39.0%)/15 (18.3%), respectively. No rogaratinib-related deaths occurred. Exploratory analysis of patients with FGFR3 DNA alterations showed ORRs of 52.4% (11/21; 95% CI, 29.8 to 74.3) for rogaratinib and 26.7% (4/15; 95% CI, 7.8 to 55.1) for chemotherapy. CONCLUSION: To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with FGFR-altered UC, showing comparable efficacy and manageable safety. Exploratory testing suggested FGFR3 DNA alterations in association with FGFR1/3 mRNA overexpression may be better predictors of rogaratinib response.

Current usage and challenges of master protocols-based on survey results by ASA BIOP oncology methodology working group master protocol sub-team.

Background: Master protocol trials, such as basket trials, umbrella trials or platform trials, have the potential of increasing efficiency in modern drug development. Meanwhile, though the concept of master protocol is getting more and more accepted, many challenges exist from design to implementation of these trials. To understand current usage and challenges of master protocol trials in action, American Statistical Association (ASA) Biopharmaceutical Section (BIOP) Oncology Methods Scientific Working Group Master Protocol Sub-team conducted a survey with the goal of providing valuable information for the community to understand the current usage of master protocol, with the goal to identify the challenges. Methods: A total of 19 questions were included in an online survey that was distributed between April and May 2021. To avoid over-reporting within an organization, a pre-determined list of contacts from 37 organizations were reached out with the shared online link of the survey. Literature research and experience from the working group on challenges of master protocols are also summarized and discussed extensively. Results: A total of 39 responses were received from 37 organizations. Thirty-one (79%) respondents indicated that they had trials with master protocol(s) in planning or implementation in their organization with most applications (54%) in oncology. Self-reported challenges on trial design, regulatory engagement and trial implementations were further summarized in the report. Conclusions: The survey results were consistent with previous literatures and expectations of members from the Scientific Working Group Sub-team. Multiple stakeholders are called to work collaboratively to remove roadblocks for future usage of master protocol trials.

Statistical and Operational Considerations for 2-Stage Adaptive Designs with Simultaneous Evaluation of Overall and Marker-Selected Populations in Oncology Confirmatory Trials.

In biomarker enrichment study designs that start with an all-comer population, simultaneous evaluation of the entire and the marker-selected populations can be more desirable than pre-specifying the testing order, when the degree of marker predictiveness is uncertain. While there has been substantial research on this approach, our goal is to provide a complete overview and guidance in all aspects of this approach, including the interim analysis potentially using different endpoints, combination tests with associated multiplicity control, and the final treatment effect estimation. Regulatory/operational aspects and actual cases demonstrating the potential advantage of this approach are also described.

Accuracy and Safety of Novel Designs for Phase I Drug-Combination Oncology Trials.

Despite numerous innovative designs having been published for phase I drug-combination dose finding trials, their use in real applications is rather limited. As a working group under the American Statistical Association Biopharmaceutical Section, our goal is to identify the unique challenges associated with drug combination, share industry's experiences with combination trials, and investigate the pros and cons of the existing designs. Toward this goal, we review seven existing designs and distinguish them based on the criterion of whether their primary objectives are to find a single maximum tolerated dose (MTD) or the MTD contour (i.e., multiple MTDs). Numerical studies, based on either industry-specified fixed scenarios or randomly generated scenarios, are performed to assess their relative accuracy, safety, and ease of implementation. We show that the algorithm-based 3+3 design has poor performance and often fails to find the MTD. The performance of model-based combination trial designs is mixed: some demonstrate high accuracy of finding the MTD but poor safety, while others are safe but with compromised identification accuracy. In comparison, the model-assisted designs, such as BOIN and waterfall designs, have competitive and balanced performance in the accuracy of MTD identification and patient safety, and are also simple to implement, thus offering an attractive approach to designing phase I drug-combination trials. By taking into consideration the design's operating characteristics, ease of implementation and regulation, the need for advanced infrastructures, as well as the risk of regulatory acceptance, our paper offers practical guidance on the selection of a suitable dose-finding approach for designing future combination trials.

S-Decorated Porous Ti3 C2 MXene Combined with In Situ Forming Cu2 Se as Effective Shuttling Interrupter in Na-Se Batteries.

Given natural abundance of Na and superior kinetics of Se, Na-Se batteries have attracted much attention but still face the problem of shuttling effect of soluble intermediates. The first-principle calculations reveal the S-decorated Ti3 C2 exhibits increased binding energy to sodium polyselenides, suggesting a better capture and restriction on intermediates. The obtained Se@S-decorated porous Ti3 C2 (Se@S-P-Ti3 C2 ) exhibits a high reversible capacity of 765 mAh g-1 at 0.1 A g-1 (calculated based on Se), ≈1.2, 1.3, and 1.7 times of Se@porous Ti3 C2 (Se@P-Ti3 C2 ), Se@Ti3 C2 , and Se, respectively. It gives considerable capacity of 664 mAh g-1 at 20 A g-1 and impressive cycling stability over 2300 cycles with an ultralow capacity decay of 0.003% per cycle. The excellent electrochemical performance can be ascribed to the S-modified porous Ti3 C2 , which provides effective immobilization toward polyselenides, makes full use of nanosized Se, and alleviates volume expansion during sodiation/desodiation. Additionally, in situ forming Cu2 Se can generate Cu nanoparticles through discharge process and then transform polyselenides into solid-phase Cu2 Se, further suppressing the shuttling effect. This work provides a practical strategy to immobilize and transform sodium polyselenides for high-capacity and long-life Na-Se batteries.

Practical Considerations and Recommendations for Master Protocol Framework: Basket, Umbrella and Platform Trials.

Master protocol, categorized as basket trial, umbrella trial or platform trial, is an innovative clinical trial framework that aims to expedite clinical drug development, enhance trial efficiency, and eventually bring medicines to patients faster. Despite a clear uptake on the advantages in the concepts and designs, master protocols are still yet to be widely used. Part of that may be due to the fact that the master protocol framework comes with the need for new statistical designs and considerations for analyses and operational challenges. In this article, we provide an overview of the master protocol framework, unify the definitions with some examples, review the statistical methods for the designs and analyses, and focus our discussions on some practical considerations and recommendations of master protocols to help practitioners better design and implement such studies.

Large-scale two-dimensional titanium carbide MXene as SERS-active substrate for reliable and sensitive detection of organic pollutants.

As a new class of two-dimensional material, MXene not only has the unique planar structure, electronic and optical properties, but also has a large surface area and hydrophilicity, which make them to build as potential SERS substrates with good sensitivity and stability. In this work, we reported a modified method by adjusting the ratio of HCl to LiF and reducing sonicate time to form large-sized monolayer Ti3C2Tx nanosheets. SERS performance of Ti3C2Tx was demonstrated by detecting dye molecules such as CV, R6G and MG. A remarkable enhanced effect was obtained, and Raman signals up to 10-8 M could be detected. Furthermore, the relationship between SERS effects and illumination laser wavelengths of different probe molecules has been studied, the results showed the selectivity between dye molecules and the excitation wavelengths. Besides, the uniformity and stability of the substrates have been proved by mapping experiments in a large area (80 × 80 µm2). The results demonstrated that Ti3C2Tx nanosheets can be built as lager-sized, uniform and stable sensor for ultra-sensitive detection of organic dye pollutant molecules.

Effect of Baseline Subretinal Fluid on Treatment Outcomes in VIVID-DME and VISTA-DME Studies.

PURPOSE: To evaluate the effect of baseline subretinal fluid (SRF) on treatment outcomes with intravitreal aflibercept injection (IAI) versus laser treatment in patients with diabetic macular edema (DME) in the VIVID and VISTA studies. DESIGN: Post hoc analysis of 2 randomized controlled trials. PARTICIPANTS: Eight hundred seventy-two patients with DME. METHODS: We randomized patients to receive IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser. MAIN OUTCOME MEASURES: Effect of presence or absence of baseline SRF on visual outcomes in the integrated dataset at weeks 52 and 100. RESULTS: Mean best-corrected visual acuity (BCVA) gains in the 2q4, 2q8, and laser arms at week 52 were +14.5, +11.0, and -2.3 letters, respectively, (those with baseline SRF) and +10.3, +10.6, and +2.5 letters, respectively, (those without). At week 100, mean gains were +13.5, +10.9, and -2.3 letters (those with baseline SRF) and +10.6, +10.0, and +2.7 letters (those without). The treatment effect for IAI versus laser from baseline to week 52 of 100 was greater for patients with baseline SRF versus those without (nominal P < 0.001, for interaction). The proportions of patients who gained 15 letters or more in the 2q4, 2q8, and laser arms at week 52 were 52.3%, 40.2%, and 8.9%, respectively, (those with baseline SRF) and 30.9%, 29.1%, and 8.2%, respectively, (those without) and at week 100 were 50.0%, 35.4%, and 12.9%, respectively, (those with baseline SRF) and 33.3%, 30.5%, and 12.5%, respectively, (those without). Time to first sustained SRF clearance seemed to be shorter in the IAI arms versus laser. The overall safety profile was similar in the IAI arms. CONCLUSIONS: This post hoc analysis demonstrated the visual outcome benefits of IAI over laser, regardless of baseline SRF status. A greater treatment effect of IAI was observed in patients with baseline SRF versus those without; however, no meaningful impact of baseline SRF status on treatment outcomes with IAI was demonstrated, indicating that the differential effects of laser might have been the driving force behind the different treatment outcomes in both groups.

Impact of Baseline Central Retinal Thickness on Outcomes in the VIVID-DME and VISTA-DME Studies.

PURPOSE: To report the impact of baseline central retinal thickness (CRT) on outcomes in patients with diabetic macular edema (DME) in VIVID-DME and VISTA-DME. METHODS: Post hoc analyses of two randomized controlled trials in which 862 DME patients were randomized 1 : 1 : 1 to treatment with intravitreal aflibercept 2.0 mg every 4 weeks (2q4), intravitreal aflibercept 2.0 mg every 8 weeks after five initial monthly doses (2q8), or macular laser photocoagulation at baseline and as needed. We compared visual and anatomical outcomes in subgroups of patients with baseline CRT < 400 µm and ≥400 µm. RESULTS: At weeks 52 and 100, outcomes with intravitreal aflibercept 2q4 and 2q8 were superior to those in laser control-treated patients regardless of baseline CRT. When looked at in a binary fashion, the treatment effect of intravitreal aflibercept versus laser was not significantly better in the ≥400 µm than the <400 µm group; when looked at as a continuous variable, baseline CRT seemed to have an impact on the treatment effect of intravitreal aflibercept versus laser. CONCLUSIONS: Post hoc analyses of VIVID-DME and VISTA-DME demonstrated the benefits of intravitreal aflibercept treatment in DME patients with baseline CRT < 400 µm and ≥400 µm. This trial is registered with NCT01331681 and NCT01363440.

Impact of baseline Diabetic Retinopathy Severity Scale scores on visual outcomes in the VIVID-DME and VISTA-DME studies.

BACKGROUND/AIMS: To evaluate intravitreal aflibercept versus laser in subgroups of patients with baseline Diabetic Retinopathy Severity Scale (DRSS) scores ≤43, 47, and ≥53 in VIVID-DME and VISTA-DME. METHODS: Patients with diabetic macular oedema were randomised to receive intravitreal aflibercept 2 mg every 4 weeks (2q4), intravitreal aflibercept 2 mg every 8 weeks after five initial monthly doses (2q8), or macular laser photocoagulation at baseline with sham injections at every visit. These post hoc analyses evaluate outcomes based on baseline DRSS scores in patients in the integrated dataset. The 2q4 and 2q8 treatment groups were also pooled. RESULTS: 748 patients had a baseline DRSS score based on fundus photographs (≤43, n=301; 47, n=153; ≥53, n=294). At week 100, the least squares mean difference between treatment groups (effect of intravitreal aflibercept above that of laser, adjusting for baseline best-corrected visual acuity) was 8.9 (95% CI 5.99 to 11.81), 9.7 (95% CI 5.54 to 13.91), and 11.0 (95% CI 7.96 to 14.1) letters in those with baseline DRSS scores ≤43, 47, and ≥53, respectively. The proportions of patients with ≥2 step DRSS score improvement were greater in the intravitreal aflibercept group versus laser, respectively, for those with baseline DRSS scores of ≤43 (13% vs 5.9%), 47 (25.8% vs 4.5%), and ≥53 (64.5% vs 28.4%). CONCLUSIONS: Regardless of baseline DRSS score, functional outcomes were superior in intravitreal aflibercept-treated patients, demonstrating consistent treatment benefit across various baseline levels of retinopathy. TRIAL REGISTRATION NUMBERS: NCT01331681 and NCT01363440, Post-results.

Evaluating the Impact of Intravitreal Aflibercept on Diabetic Retinopathy Progression in the VIVID-DME and VISTA-DME Studies.

PURPOSE: To evaluate the impact of intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Tarrytown, NY) versus laser on progression of diabetic retinopathy (DR) severity in Intravitreal Aflibercept Injection in Vision Impairment due to DME (VIVID-DME) and Study of Intravitreal Aflibercept Injection in Patients with Diabetic Macular Edema (VISTA-DME). DESIGN: Secondary and exploratory analyses of 2 phase 3, randomized, controlled studies. PARTICIPANTS: All patients with a baseline Diabetic Retinopathy Severity Scale (DRSS) score based on fundus photograph (full analysis), patients who progressed to proliferative DR (PDR) (safety analysis) in VIVID-DME (n = 403) and VISTA-DME (n = 459), or both. METHODS: We randomized patients with diabetic macular edema (DME) to intravitreal aflibercept 2 mg every 4 weeks (2q4), intravitreal aflibercept 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation at baseline and sham injections at every visit. MAIN OUTCOME MEASURES: Proportions of patients with 2-step or more and 3-step or more improvements from baseline in DRSS score, who progressed to PDR, and who underwent panretinal photocoagulation (PRP). RESULTS: Among patients with an assessable baseline DRSS score, most showed moderately severe or severe nonproliferative DR. The proportions of patients treated with 2q4, 2q8, and laser with a 2-step or more improvement in DRSS score at week 100 were 29.3%, 32.6%, and 8.2%, respectively, in VIVID-DME and 37.0%, 37.1%, and 15.6%, respectively, in VISTA-DME; the proportions with a 3-step or more improvement in DRSS score were 7.3%, 2.3%, and 0%, respectively, and 22.7%, 19.9%, and 5.2%, respectively. Fewer patients in the 2q4 and 2q8 groups versus the laser group progressed to PDR at week 100 in VISTA-DME (1.5% and 2.2% vs. 5.3%) and VIVID-DME (3.2% and 2.0% vs. 12.3%). The proportions of patients who underwent PRP were 2.9%, 0.7%, and 4.5%, respectively, in VIVID-DME and 1.9%, 0.7%, and 5.2%, respectively, in VISTA-DME. The most frequent serious ocular adverse event at week 100 was cataract (pooled intravitreal aflibercept, 1.7% of patients; laser, 3.5% of patients). CONCLUSIONS: These analyses demonstrate the benefit of intravitreal aflibercept over laser with respect to DR progression, suggesting a benefit on DME, and on underlying DR.

Morphology and Visual Acuity in Aflibercept and Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration in the VIEW Trials.

PURPOSE: To compare the efficacy of intravitreal aflibercept and ranibizumab on the exudative activity of neovascular age-related macular degeneration (nAMD) using optical coherence tomography (OCT) and to correlate morphologic findings with visual acuity (VA) outcomes. DESIGN: Post hoc analysis of the prospective VIEW trials. PARTICIPANTS: Data of 1815 patients randomized to 0.5 mg ranibizumab every 4 weeks (Q4wks), 2 mg aflibercept Q4wks, or 2 mg aflibercept every 8 weeks (Q8wks). METHODS: Standardized OCT evaluation was performed by masked reading centers for the presence of intraretinal cystoid fluid (IRC), subretinal fluid (SRF), and pigment epithelial detachment (PED). Rates of feature resolution were compared between drugs and regimen. Associations between morphologic features and VA were analyzed using multivariate modeling. MAIN OUTCOME MEASURES: Resolution rates of IRC, SRF, and PED, and associations between morphology and VA. RESULTS: At baseline, the proportions of eyes with IRC, SRF, and PED were balanced between the aflibercept and ranibizumab groups. At week 12, IRC resolved in 50% of eyes with both agents. Subretinal fluid resolved in 70% of pooled aflibercept-treated eyes and in 59% of ranibizumab-treated eyes, and PED resolved in 29% and 24% of pooled aflibercept-treated eyes and ranibizumab-treated eyes, respectively. At week 52, IRC resolved in 57% (aflibercept Q4wks), 50% (aflibercept Q8wks), and 52% (ranibizumab) of patients; SRF resolved in 75% (both aflibercept Q4wks/Q8wks) and 66% (ranibizumab) of patients; and PED resolved in 40% (aflibercept Q4wks), 34% (aflibercept Q8wks), and 28% (ranibizumab) of patients. During fixed dosing (weeks 12-52) all exudative features showed synchronized fluctuations after treatment-free visits in the Q8wks aflibercept regimen. During pro re nata dosing (weeks 52-96), greater proportions of patients showed recurrent fluid in all treatment arms. Presence of IRC was generally associated with lower VA at baseline, which translated into poorer final VA outcomes. CONCLUSIONS: Fluid resolution in all compartments was consistently greater for aflibercept Q4wks than for aflibercept Q8wks and ranibizumab. At week 52, Q8wks aflibercept-treated eyes were, on average, as dry as or drier than with ranibizumab despite the extended treatment interval. Independent of agent or regimen, preexisting morphologic features of the retina at baseline markedly influenced VA outcomes.

INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD.

The Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasone to Indacaterol (INSTEAD) study investigated the effect of switching patients at low risk of chronic obstructive pulmonary disease (COPD) exacerbations from salmeterol/fluticasone (SFC; inhaled corticosteroid (ICS) regimen) to indacaterol monotherapy (non-ICS regimen). This 26-week, double-blind, double-dummy, parallel-group, phase IV study, randomised 581 patients with moderate COPD to indacaterol 150 µg once daily or SFC 50/500 µg twice daily. Patients had been receiving SFC 50/500 µg for ≥3 months, with no COPD exacerbations for more than a year before the study (patients for whom ICS is not recommended). The primary objective was to demonstrate non-inferiority of indacaterol to SFC, measured by trough forced expiratory volume in 1 second (FEV1) after 12 weeks (non-inferiority margin of 0.06 L). The primary objective was met, with a mean treatment difference of 9 mL (95% CI -45-26 mL). There were no significant differences between treatments in terms of breathlessness (transition dyspnoea index) or health status (Saint George's Respiratory Questionnaire) at weeks 12 or 26, or rescue medication use or COPD exacerbation rates over 26 weeks. Safety profiles of both treatments were as expected. This study demonstrated that patients with moderate COPD and no exacerbations in the previous year can be switched from SFC to indacaterol 150 µg with no efficacy loss.

Safety, tolerability, and efficacy of raltegravir in a diverse cohort of HIV-infected patients: 48-week results from the REALMRK Study.

The racial diversity and gender distribution of HIV-infected patients make it essential to confirm the safety and efficacy of raltegravir in these populations. A multicenter, open-label, single-arm observational study was conducted in a diverse cohort of HIV-infected patients (goals: ≥25% women; ≥50% blacks in the United States), enrolling treatment-experienced patients failing or intolerant to current antiretroviral therapy (ART) and treatment-naive patients (limited to ≤20%). All patients received raltegravir 400 mg b.i.d. in a combination antiretroviral regimen for up to 48 weeks. A total of 206 patients received study treatment at 34 sites in the United States, Brazil, Dominican Republic, Jamaica, and South Africa: 97 (47%) were female and 153 (74%) were black [116 (56%) in the United States]. Of these, 185 patients were treatment experienced: 97 (47%) were failing and 88 (43%) were intolerant to current therapy; 21 patients (10%) were treatment naive. Among treatment-intolerant patients, 55 (63%) had HIV-1 RNA<50 copies/ml at baseline. Overall, 15% of patients discontinued: 13% of men, 18% of women, 14% of blacks, and 17% of nonblacks. At week 48, HIV RNA was <50 copies/ml in 60/94 (64%) patients failing prior therapy, 61/80 (76%) patients intolerant to prior therapy, and 16/21 (76%) treatment-naive patients. Response rates were similar for men vs. women and black vs. nonblack patients. Drug-related clinical adverse events were reported by 8% of men, 18% of women, 14% of blacks, and 9% of nonblacks. After 48 weeks of treatment in a diverse cohort of HIV-infected patients, raltegravir was generally safe and well tolerated with potent efficacy regardless of gender or race.

Sustained efficacy and safety of raltegravir after 5 years of combination antiretroviral therapy as initial treatment of HIV-1 infection: final results of a randomized, controlled, phase II study (Protocol 004).

Raltegravir as initial HIV therapy was examined in a double-blind study; 160 patients were randomized to raltegravir (400 mg bid after dose-ranging), 38 to efavirenz, both with tenofovir/lamivudine. At week 240, HIV-RNA remained <50 copies per milliliter in 68.8% (raltegravir) versus 63.2% (efavirenz), and CD4 increases were 302 versus 276 cells per microliter, respectively. Early HIV-RNA decline predicted later CD4 increases in both groups. Raltegravir resistance was observed in 3 of 10 raltegravir recipients with virologic failure. Few drug-related adverse events were reported after week 48. Raltegravir had minimal effect on laboratory values, including lipids. Raltegravir with tenofovir/lamivudine showed durable efficacy and good tolerability over 5 years.

Improved survival among children with spina bifida in the United States.

OBJECTIVE: To evaluate trends in survival among children with spina bifida by race/ethnicity and possible prognostic factors in 10 regions of the United States. STUDY DESIGN: A retrospective cohort study was conducted of 5165 infants with spina bifida born during 1979-2003, identified by 10 birth defects registries in the United States. Survival probabilities and adjusted hazard ratios were estimated for race/ethnicity and other characteristics using the Cox proportional hazard model. RESULTS: During the study period, the 1-year survival probability among infants with spina bifida showed improvements for whites (from 88% to 96%), blacks (from 79% to 88%), and Hispanics (from 88% to 93%). The impact of race/ethnicity on survival varied by birth weight, which was the strongest predictor of survival through age 8. There was little racial/ethnic variation in survival among children born of very low birth weight. Among children born of low birth weight, the increased risk of mortality to Hispanics was approximately 4-6 times that of whites. The black-white disparity was greatest among children born of normal birth weight. Congenital heart defects did not affect the risk of mortality among very low birth weight children but increased the risk of mortality 4-fold among children born of normal birth weight. CONCLUSIONS: The survival of infants born with spina bifida has improved; however, improvements in survival varied by race/ethnicity, and blacks and Hispanics continued to have poorer survival than whites in the most recent birth cohort from 1998-2002. Further studies are warranted to elucidate possible reasons for the observed differences in survival.