Reporting of noninferiority and equivalence randomized trials for major prostaglandins: A systematic survey of the ophthalmology literature

<p>Abstract</p> <p>Background</p> <p>Standards for reporting clinical trials have improved the transparency of patient-important research. The Consolidated Standards of Reporting Trials (CONSORT) published an extension to address noninferiority and equivalence trials. We aimed to determine the reporting quality of prostaglandin noninferiority and equivalence trials in the treatment of glaucoma.</p> <p>Methods</p> <p>We searched, independently and in duplicate, 6 electronic databases for eligible trials evaluating prostaglandins. We abstracted data on reporting of methodological criteria, including reporting of per-protocol [PP] and intention-to-treat [ITT] analysis, sample size estimation with margins, type of statistical analysis conducted, efficacy summaries, and use of hyperemia measures.</p> <p>Results</p> <p>Trials involving the four major prostaglandin groups (latanoprost, travoprost, bimatoprost, unoprostone) were analyzed. We included 36 noninferiority and 11 equivalence trials. Seventeen out of the included 47 trials (36%, 95% Confidence Intervals [CI]: 24–51) were crossover designs. Only 3 studies (6%, 95% CI: 2–17) reported a presented results of both ITT and PP populations. Twelve studies (26%, 95% CI: 15–39) presented only ITT results but mentioned that PP population had similar results. Thirteen trials (28%, 95% CI: 17–42) presented only PP results with no mention of ITT population results while 17 studies (36%, 95% CI: 24–51) presented only ITT results with no mention of PP population results. Thirty-four (72%, 95% CI: 58–83) of studies adequately described their margin of noninferiority/equivalence. Sequence generation was reported in 22/47 trials (47%, 95% CI: 33–61). Allocation concealment was reported in only 10/47 (21%, 95% CI: 12–35) of the trials. Thirty-five studies (74%, 95% CI: 60–85) employed masking of at least two groups, 4/47 (9%, 95% CI: 3–20) masked only patients and 8/47 (17%, 95% CI: 9–30) were open label studies. Eight (17%, 95% CI: 9–30) of the 47 trials employed a combined test of noninferiority and superiority. We also found 6 differing methods of evaluating hyperemia.</p> <p>Conclusion</p> <p>The quality of reporting noninferiority/equivalency trials in the field of glaucoma is markedly heterogeneous. The adoption of the extended CONSORT statement by journals will potentially improve the transparency of this field.</p

Metastatic Renal Cell Cancer Treatments: An Indirect Comparison Meta-Analysis

Background: Treatment for metastatic renal cell cancer (mRCC) has advanced dramatically withunderstanding of the pathogenesis of the disease. New treatment options may provide improvedprogression-free survival (PFS). We aimed to determine the relative effectiveness of new therapiesin this field. Methods: We conducted comprehensive searches of 11 electronic databases from inception toApril 2008. We included randomized trials (RCTs) that evaluated bevacizumab, sorafenib, andsunitinib. Two reviewers independently extracted data, in duplicate. Our primary outcome wasinvestigator-assessed PFS. We performed random-effects meta-analysis with a mixed treatmentcomparison analysis. Results: We included 3 bevacizumab (2 of bevacizumab plus interferon-a [IFN-a]), 2 sorafenib, 1sunitinib, and 1 temsirolimus trials (total n = 3,957). All interventions offer advantages for PFS.Using indirect comparisons with interferon-α as the common comparator, we found that sunitinibwas superior to both sorafenib (HR 0.58, 95% CI, 0.38–0.86, P = &lt; 0.001) and bevacizumab + IFNa(HR 0.75, 95% CI, 0.60–0.93, P = 0.001). Sorafenib was not statistically different from bevacizumab+IFN-a in this same indirect comparison analysis (HR 0.77, 95% CI, 0.52–1.13, P = 0.23). Usingplacebo as the similar comparator, we were unable to display a significant difference betweensorafenib and bevacizumab alone (HR 0.81, 95% CI, 0.58–1.12, P = 0.23). Temsirolimus providedsignificant PFS in patients with poor prognosis (HR 0.69, 95% CI, 0.57–0.85). Conclusion: New interventions for mRCC offer a favourable PFS for mRCC compared tointerferon-α and placebo

Facility-Level Factors Influencing Retention of Patients in HIV Care in East Africa

Losses to follow-up (LTFU) remain an important programmatic challenge. While numerous patient-level factors have been associated with LTFU, less is known about facility-level factors. Data from the East African International epidemiologic Databases to Evaluate AIDS (EA-IeDEA) Consortium was used to identify facility-level factors associated with LTFU in Kenya, Tanzania and Uganda. Patients were defined as LTFU if they had no visit within 12 months of the study endpoint for pre-ART patients or 6 months for patients on ART. Adjusting for patient factors, shared frailty proportional hazard models were used to identify the facility-level factors associated with LTFU for the pre- and post-ART periods. Data from 77,362 patients and 29 facilities were analyzed. Median age at enrolment was 36.0 years (Interquartile Range: 30.1, 43.1), 63.9% were women and 58.3% initiated ART. Rates (95% Confidence Interval) of LTFU were 25.1 (24.7-25.6) and 16.7 (16.3-17.2) per 100 person-years in the pre-ART and post-ART periods, respectively. Facility-level factors associated with increased LTFU included secondary-level care, HIV RNA PCR turnaround time >14 days, and no onsite availability of CD4 testing. Increased LTFU was also observed when no nutritional supplements were provided (pre-ART only), when TB patients were treated within the HIV program (pre-ART only), and when the facility was open ≤4 mornings per week (ART only). Our findings suggest that facility-based strategies such as point of care laboratory testing and separate clinic spaces for TB patients may improve retention

The safety of over-the-counter niacin. A randomized placebo-controlled trial [ISRCTN18054903]

BACKGROUND: Niacin is widely available over the counter (OTC). We sought to determine the safety of 500 mg immediate release niacin, when healthy individuals use them as directed. METHODS: 51 female and 17 male healthy volunteers (mean age 27 years SD 4.4) participated in a randomized placebo-controlled blinded trial of a single dose of an OTC, immediate-release niacin 500 mg (n = 33), or a single dose of placebo (n = 35) on an empty stomach. The outcomes measured were self-reported incidence of flushing and other adverse effects. RESULTS: 33 volunteers on niacin (100%) and 1 volunteer on placebo (3%) flushed (relative risk 35, 95% confidence interval (CI) 6.8–194.7). Mean time to flushing on niacin was 18.2 min (95% CI: 12.7–23.6); mean duration of flushing was 75.4 min (95% CI: 62.5–88.2). Other adverse effects occurred commonly in the niacin group: chills (51.5% vs. 0%, P < .0001), generalized pruritus (75% vs. 0%, P = <.001), gastrointestinal upset (30% vs. 3%, P = .005), and cutaneous tingling (30% vs. 0%, P = <.001). Six participants did not tolerate the adverse effects of niacin and 3 required medical attention. CONCLUSION: Clinicians counseling patients about niacin should alert patients not only about flushing but also about gastrointestinal symptoms, the most severe in this study. They should not trust that patients would receive information about these side effects or their prevention (with aspirin) from the OTC packet insert

Metastatic renal cell cancer treatments: An indirect comparison meta-analysis

Abstract Background Treatment for metastatic renal cell cancer (mRCC) has advanced dramatically with understanding of the pathogenesis of the disease. New treatment options may provide improved progression-free survival (PFS). We aimed to determine the relative effectiveness of new therapies in this field. Methods We conducted comprehensive searches of 11 electronic databases from inception to April 2008. We included randomized trials (RCTs) that evaluated bevacizumab, sorafenib, and sunitinib. Two reviewers independently extracted data, in duplicate. Our primary outcome was investigator-assessed PFS. We performed random-effects meta-analysis with a mixed treatment comparison analysis. Results We included 3 bevacizumab (2 of bevacizumab plus interferon-a [IFN-a]), 2 sorafenib, 1 sunitinib, and 1 temsirolimus trials (total n = 3,957). All interventions offer advantages for PFS. Using indirect comparisons with interferon-α as the common comparator, we found that sunitinib was superior to both sorafenib (HR 0.58, 95% CI, 0.38–0.86, P = < 0.001) and bevacizumab + IFN-a (HR 0.75, 95% CI, 0.60–0.93, P = 0.001). Sorafenib was not statistically different from bevacizumab +IFN-a in this same indirect comparison analysis (HR 0.77, 95% CI, 0.52–1.13, P = 0.23). Using placebo as the similar comparator, we were unable to display a significant difference between sorafenib and bevacizumab alone (HR 0.81, 95% CI, 0.58–1.12, P = 0.23). Temsirolimus provided significant PFS in patients with poor prognosis (HR 0.69, 95% CI, 0.57–0.85). Conclusion New interventions for mRCC offer a favourable PFS for mRCC compared to interferon-α and placebo

A taxonomy for community-based care programs focused on HIV/AIDS prevention, treatment, and care in resource-poor settings

Community-based care (CBC) can increase access to key services for people affected by HIV/AIDS through the mobilization of community interests and resources and their integration with formal health structures. Yet, the lack of a systematic framework for analysis of CBC focused on HIV/AIDS impedes our ability to understand and study CBC programs. We sought to develop taxonomy of CBC programs focused on HIV/AIDS in resource-limited settings in an effort to understand their key characteristics, uncover any gaps in programming, and highlight the potential roles they play. Our review aimed to systematically identify key CBC programs focused on HIV/AIDS in resource-limited settings. We used both bibliographic database searches (Medline, CINAHL, and EMBASE) for peer-reviewed literature and internet-based searches for gray literature. Our search terms were &#x2018;HIV&#x2019; or &#x2018;AIDS&#x2019; and &#x2018;community-based care&#x2019; or &#x2018;CBC&#x2019;. Two co-authors developed a descriptive taxonomy through an iterative, inductive process using the retrieved program information. We identified 21 CBC programs useful for developing taxonomy. Extensive variation was observed within each of the nine categories identified: region, vision, characteristics of target populations, program scope, program operations, funding models, human resources, sustainability, and monitoring and evaluation strategies. While additional research may still be needed to identify the conditions that lead to overall program success, our findings can help to inform our understanding of the various aspects of CBC programs and inform potential logic models for CBC programming in the context of HIV/AIDS in resource-limited settings. Importantly, the findings of the present study can be used to develop sustainable HIV/AIDS-service delivery programs in regions with health resource shortages

Media reporting of tenofovir trials in Cambodia and Cameroon

BACKGROUND: Two planned trials of pre-exposure prophylaxis tenofovir in Cambodia and Cameroon to prevent HIV infection in high-risk populations were closed due to activist pressure on host country governments. The international news media contributed substantially as the primary source of knowledge transfer regarding the trials. We aimed to characterize the nature of reporting, specifically focusing on the issues identified by media reports regarding each trial. METHODS: With the aid of an information specialist, we searched 3 electronic media databases, 5 electronic medical databases and extensively searched the Internet. In addition we contacted stakeholder groups. We included media reports addressing the trial closures, the reasons for the trial closures, and who was interviewed. We extracted data using content analysis independently, in duplicate. RESULTS: We included 24 reports on the Cambodian trial closure and 13 reports on the Cameroon trial closure. One academic news account incorrectly reported that it was an HIV vaccine trial that closed early. The primary reasons cited for the Cambodian trial closure were: a lack of medical insurance for trial related injuries (71%); human rights considerations (71%); study protocol concerns (46%); general suspicions regarding trial location (37%) and inadequate prevention counseling (29%). The primary reasons cited for the Cameroon trial closure were: inadequate access to care for seroconverters (69%); participants not sufficiently informed of risks (69%); inadequate number of staff (46%); participants being exploited (46%) and an unethical study design (38%). Only 3/23 (13%) reports acknowledged interviewing research personnel regarding the Cambodian trial, while 4/13 (30.8%) reports interviewed researchers involved in the Cameroon trial. CONCLUSION: Our review indicates that the issues addressed and validity of the media reports of these trials is highly variable. Given the potential impact of the media in formulation of health policy related to HIV, efforts are needed to effectively engage the media during periods of controversy in the HIV/AIDS epidemic

Adherence to HAART: A Systematic Review of Developed and Developing Nation Patient-Reported Barriers and Facilitators

BACKGROUND: Adherence to highly active antiretroviral therapy (HAART) medication is the greatest patient-enabled predictor of treatment success and mortality for those who have access to drugs. We systematically reviewed the literature to determine patient-reported barriers and facilitators to adhering to antiretroviral therapy. METHODS AND FINDINGS: We examined both developed and developing nations. We searched the following databases: AMED (inception to June 2005), Campbell Collaboration (inception to June 2005), CinAhl (inception to June 2005), Cochrane Library (inception to June 2005), Embase (inception to June 2005), ERIC (inception to June 2005), MedLine (inception to June 2005), and NHS EED (inception to June 2005). We retrieved studies conducted in both developed and developing nation settings that examined barriers and facilitators addressing adherence. Both qualitative and quantitative studies were included. We independently, in duplicate, extracted data reported in qualitative studies addressing adherence. We then examined all quantitative studies addressing barriers and facilitators noted from the qualitative studies. In order to place the findings of the qualitative studies in a generalizable context, we meta-analyzed the surveys to determine a best estimate of the overall prevalence of issues. We included 37 qualitative studies and 47 studies using a quantitative methodology (surveys). Seventy-two studies (35 qualitative) were conducted in developed nations, while the remaining 12 (two qualitative) were conducted in developing nations. Important barriers reported in both economic settings included fear of disclosure, concomitant substance abuse, forgetfulness, suspicions of treatment, regimens that are too complicated, number of pills required, decreased quality of life, work and family responsibilities, falling asleep, and access to medication. Important facilitators reported by patients in developed nation settings included having a sense of self-worth, seeing positive effects of antiretrovirals, accepting their seropositivity, understanding the need for strict adherence, making use of reminder tools, and having a simple regimen. Among 37 separate meta-analyses examining the generalizability of these findings, we found large heterogeneity. CONCLUSIONS: We found that important barriers to adherence are consistent across multiple settings and countries. Research is urgently needed to determine patient-important factors for adherence in developing world settings. Clinicians should use this information to engage in open discussion with patients to promote adherence and identify barriers and facilitators within their own populations