Investigator-reported Events Research Articles

Centrally adjudicated vs. investigator-reported outcomes in randomized heart failure trials

Abstract Background and Aims Heart failure endpoints in cardiovascular outcome trials are commonly identified through centralized adjudication of investigator-reported events. It remains unclear whether central adjudication improves the accuracy of treatment effect estimates in terms of log[hazard ratios (HR)]. Methods Data from seven cardiovascular outcome trials with >1000 patients that included centrally adjudicated heart failure outcomes were utilized to assess (i) the concordance between investigator-reported and centrally adjudicated heart failure and cardiovascular death events; (ii) rates of subsequent all-cause mortality following positively vs. negatively adjudicated heart failure events; and (iii) the correlation of log(HR) based on centrally adjudicated vs. investigator-reported events. Results Positive adjudication rates for investigator-reported events varied widely across trials, but were generally higher for cardiovascular death (range: 87.9%–99.2%) than for heart failure hospitalization (range: 61.6%–88.0%). The risk for subsequent all-cause death was similar for positively and negatively adjudicated heart failure hospitalizations. Log(HR) correlated well for cardiovascular death [R2 = .80, 95% credible interval (CrI): 0.53–0.93] and the composite of cardiovascular death or heart failure hospitalization (R2 = .79, 95% CrI: 0.46–0.93), but less for heart failure hospitalization (R2 = .57, 95% CrI: 0.10–0.83). Conclusions Positive adjudication rates were lower for heart failure events than cardiovascular death, but even negatively adjudicated heart failure events are prognostically important. Central adjudication of events did not alter the results (precision or estimated log(HR)), though some variation was observed, depending on the indication. The results suggest that the decision to pursue centralized adjudication of heart failure events in a specific trial may need to be individualized.

Comparison of Investigator-Reported vs Centrally Adjudicated Major Adverse Cardiac Events

In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, there was a significant reduction in the adjudicated primary outcome among patients with stable atherosclerotic vascular disease randomized to dual pathway inhibition (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily) vs aspirin monotherapy, but not with rivaroxaban 5 mg twice daily vs aspirin monotherapy. Whether the results are similar without adjudication is unknown. To examine the impact of dual pathway inhibition (with rivaroxaban plus aspirin) or rivaroxaban monotherapy compared with aspirin monotherapy on investigator-reported CV events and to understand the extent of concordance between investigator-reported and centrally adjudicated clinical events. This is a secondary analysis of the COMPASS trial, an international, double-blind, double-dummy, randomized clinical trial with a 3-by-2 partial factorial design that evaluated participants with stable atherosclerotic vascular disease receiving rivaroxaban plus aspirin, rivaroxaban monotherapy, or aspirin monotherapy. End points were collected by blinded site investigators and adjudicated by a blinded clinical end point committee. Data were analyzed from March 2013 through February 2017. Participants received dual inhibition pathway (2.5 mg rivaroxaban twice daily plus 100 mg aspirin once daily), rivaroxaban monotherapy (5 mg twice daily), or aspirin monotherapy (100 mg once daily). The primary efficacy outcome was a composite of cardiovascular (CV) death, stroke, or myocardial infarction (MI). Adjudicated and investigator-reported end points were compared. A total of 27 395 patients (mean [SD] age, 68.2 [7.9] years; 78.0% men) were assessed, including 9152 patients randomized to dual pathway inhibition, 9117 patients randomized to rivaroxaban monotherapy, and 9126 patients randomized to aspirin monotherapy. Adjudication reduced the number of events by 10% to 15% for most end points. Among investigator-reported end points, dual pathway inhibition significantly reduced the rate of the primary efficacy outcome compared with aspirin alone (411 patients [4.5%] vs 542 patients [5.9%]; hazard ratio [HR], 0.75 [95% CI, 0.66-0.85]; P < .001), with similar reduction in adjudicated end points, (379 patients [4.1%] vs 496 patients [5.4%]; HR, 0.76 [95% CI, 0.66-0.86]; P < .001). Likewise, effects on ischemic end points were highly concordant (κ statistic = 0.94 [95% CI, 0.93-0.95] for the primary composite end point). Unlike with adjudicated outcomes, there was a significant reduction in the primary end point with rivaroxaban monotherapy vs aspirin monotherapy using investigator-reported events (477 patients [5.2%] vs 542 patients [5.9%]; HR, 0.88 [95% CI, 0.78-0.99]; P = .04) compared with adjudicated events (448 patients [4.9%] vs 496 patients [5.4%]; HR, 0.90 [95% CI, 0.79-1.03]; P = .12). This secondary analysis of the COMPASS trial found that whether assessed by blinded site investigators or adjudicators, dual pathway inhibition significantly reduced CV events among patients with stable atherosclerotic disease compared with aspirin plus placebo. These findings suggest that using investigator-reported events in blinded clinical trials may be a more efficient alternative to adjudication. ClinicalTrials.gov Identifier: NCT01776424.

Abstract 11004: Investigator-Reported versus Adjudicated Clinical Events for Worsening Heart Failure

Introduction: Clinical event committee (CEC) adjudication is the gold standard for event reporting in clinical trials. In some instances, investigator-reported events may be an appropriate substitute to reduce operational complexity and costs of heart failure (HF) trials, but the level of agreement between CEC and trial investigators for defining worsening HF (WHF) events is not well described. Methods: The ASCEND-HF trial compared nesiritide vs. placebo among patients hospitalized for HF, regardless of ejection fraction, and adjudicated endpoints through 30-day follow-up. This post-hoc analysis included patients with death or rehospitalization within 30 days. Concordance between the CEC and site investigators for WHF death and rehospitalization was measured using simple kappa (ĸ) statistics. Factors independently associated with discordance were identified using a backward selection model. Results: Over 30-day follow-up, there were 105 investigator-reported WHF deaths and 154 CEC-classified WHF deaths (p&lt;0.001), with a modest level of agreement (ĸ 0.59) ( Figure 1A ). For 30-day WHF rehospitalization, there were 355 events reported by investigators and 426 classified by CEC, with high levels of agreement (ĸ 0.77). Older age was independently associated with higher likelihood of CEC-investigator discordance for WHF death (OR 1.16 [1.01-1.33] per 5-year increase). For WHF rehospitalization, older age (OR 0.91 [0.84-0.98] per 5-year increase) and higher systolic blood pressure (OR 0.82 [0.71-0.94] per 10 mmHg increase) were associated with lower likelihood of discordance. Agreement for WHF endpoints varied by geographic region ( Figure 1B ). Conclusions: CEC and trial investigators had modest rates of agreement for characterizing WHF death and high rates of agreement for WHF rehospitalization. Multiple patient factors were associated with CEC-investigator discordance and levels of agreement for WHF endpoints varied across geographic regions.

PARADISE-MI – event rates and treatment effect of sacubitril/valsartan v ramipril by the presence or absence of transient pulmonary congestion and/or LVEF less or greater than 40

Abstract Background/Introduction Sacubitril/valsartan was compared to ramipril in patients with acute myocardial infarction in the PARADISE-MI trial. In the whole trial population sacubitril/valsartan did not reduce the composite primary outcome of CV death or incident heart failure compared to ramipril. Whether or not event rates and/or treatment effects vary in patients with different baseline characteristics is unknown. Purpose To investigate a) event rates b) the treatment effect of sacubitril/valsartan compared to ramipril and c) safety by the presence or absence of transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40%. Methods PARADISE-MI was a double-blind, randomised clinical trial that compared sacubitril/valsartan to ramipril in 5661 patients with an acute myocardial infarction with either LVEF ≤40% and/or transient pulmonary congestion. 3 groups were investigated: 1) LVEF ≤40% with pulmonary congestion (n=2012) and 2) LVEF ≤40% without pulmonary congestion (n=2596) and 3) LVEF not ≤40% with pulmonary congestion (n=1044). Results Patients with pulmonary congestion (with and without LVEF ≤40%) were more likely to have had a prior MI, prior CABG or PCI, had more atrial fibrillation and were more often treated with mineralocorticoid receptor antagonists and diuretics than patients with no pulmonary congestion and LVEF ≤40%. Patients with LVEF ≤40% and pulmonary congestion had more than twice the rate of the primary composite outcome compared to those with LVEF ≤40% without pulmonary congestion: 10.2 (95% CI 9.2–11.3) vs. 4.8 (4.3–5.5) events per 100 patient-years, respectively). Patients with pulmonary congestion and LVEF not ≤40% had an intermediate event rate (6.6, 5.5–7.9, events per 100 patient-years). A similar pattern of event rates was seen for the components of the primary outcome and for all secondary outcomes whether Clinical Events Committee or investigator-reported events were analysed. The treatment effect of sacubitril/ valsartan versus ramipril did not vary between the 3 congestion/ LVEF subgroups. The safety of sacubitril/valsartan compared to ramipril did not vary between congestion/LVEF subgroups. Conclusion Patients with pulmonary congestion with or without LVEF ≤40% had higher rates of primary and all secondary outcomes than those without pulmonary congestion and LVEF ≤40%. The treatment effect, and safety, of sacubitril/valsartan compared to ramipril was consistent in patients with or without pulmonary congestion and with or without LVEF ≤40%. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis

Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT

BackgroundREDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE. ObjectivesThe purpose of this study was to determine the effects of IPE on investigator-reported events. MethodsPotential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance. ResultsThere was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints. ConclusionsIPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361)

Causes of Cardiovascular Hospitalization and Death in Patients With Transthyretin Amyloid Cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT. Clinical trial registration ClinicalTrials.gov: NCT01994889.

Abstract 15091: Significant Reductions in Both Adjudicated and Investigator-Reported Ischemic Events in REDUCE-IT

Introduction: REDUCE-IT was an event-driven trial that randomized 8,179 statin-treated patients with controlled LDL-C and moderately elevated triglycerides to icosapent ethyl (IPE) 4g daily or placebo, with a median of 4.9 years of follow-up. There was a significant reduction in the prespecified adjudicated rates of the primary endpoint (cardiovascular [CV] death, non-fatal myocardial infarction [MI], non-fatal stroke, coronary revascularization, and unstable angina requiring hospitalization) and of the key secondary endpoint (CV death, MI, stroke), as well as in all the primary endpoint components. We sought to determine the effect of IPE on investigator-reported events. Methods: The Clinical Endpoint Committee (CEC) blindly adjudicated investigator-reported events according to a prespecified charter. Medical records and reports were also reviewed to assess for clinical events not reported by investigators. An endpoint management team compiled and electronically provided event packets to the CEC via an adjudication database. The CEC Chair provided final adjudication if the two primary adjudicators could not reach consensus. Results: IPE significantly reduced the rate of the primary endpoint (hazard ratio 0.74, p=0.0000000002) and the key secondary endpoint (hazard ratio 0.75, p=0.000007) as reported by the site investigators, with consistent benefits in each component of the primary endpoint (Table). There was a high degree of concordance between investigator-reported and adjudicated endpoints. Conclusions: Icosapent ethyl significantly reduced multiple types of ischemic events, both by independent, blinded adjudication as well as by investigator-reported assessment. These results underscore the robustness of the benefits of icosapent ethyl seen in REDUCE-IT.

Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial

Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. We quantified the agreement rates in the STABILITY trial on 15,828 patients with stable coronary heart disease. Investigators were instructed to report all potential events. Each reported event was reviewed independently by 2 reviewers according to prespecified processes and prespecified end point definitions. Concordance between reported and adjudicated cardiovascular (CV) events was evaluated, as well as event classification influence on final study results. In total, CEC reviewed 7,096 events: 1,064 deaths (696 CV deaths), 958 myocardial infarctions (MI), 433 strokes, 182 transient ischemic attacks, 2,052 coronary revascularizations, 1,407 hospitalizations for unstable angina, and 967 hospitalizations for heart failure. In total, 71.8% events were confirmed by CEC. Concordance was high (>80%) for cause of death and nonfatal MI and lower for hospitalization for unstable angina (25%) and heart failure (50%). For the primary outcome (composite of CV death, MI, and stroke), investigators reported 2,086 events with 82.5% confirmed by CEC. The STABILITY trial treatment effect of darapladib versus placebo on the primary outcome was consistent using investigator-reported events (hazard ratio 0.96 [95% CI 0.87-1.06]) or adjudicated events (hazard ratio 0.94 [95% CI 0.85-1.03]). The primary outcome results of the STABILITY trial were consistent whether using investigator-reported or CEC-adjudicated events. The proportion of investigator-reported events confirmed by CEC varied by type of event. These results should help improve event identification in clinical trials to optimize ascertainment and adjudication.

Management of Infusion-Related Reactions Following Daratumumab Monotherapy in Patients with at Least 3 Lines of Prior Therapy or Double Refractory Multiple Myeloma (MM): 54767414MMY2002 (Sirius)

Introduction: Daratumumab (DARA), a human anti-CD38 IgG1κ monoclonal antibody, showed single agent activity in a phase 1/2 study of patients (pts) with relapsed or refractory (r/r) MM (Lokhorst HM. J Clin Oncol. 2014; 32(suppl): 8513). In this study infusion-related reactions (IRRs) were generally mild. The occurrence of serious adverse events (AEs) was rare with DARA monotherapy. Similar efficacy and safety findings were reported in a preliminary analysis of an ongoing phase 2 study (NCT01985126) of DARA monotherapy in MM pts who had received ≥3 prior lines of therapy, including a PI and IMiD, or were double refractory to a PI and IMiD (Lonial S. J Clin Oncol. 2015; 33(suppl): LBA8512). This analysis examined IRR incidence and management in this phase 2 study in r/r MM.Methods: This open-label, 2-part, international, multicenter, phase 2 study was conducted to determine the optimal DARA dose and schedule. Thirty-four pts were randomized in part 1 to DARA 8 mg/kg q4w or DARA 16 mg/kg qw for 8 weeks, then q2w for 16 weeks, and q4w thereafter. An additional 25 pts were subsequently enrolled in part 1 into the 16-mg/kg cohort based on a pre-specified interim analysis. An additional 65 pts were then enrolled in the 16-mg/kg DARA group in part 2. IRRs were broadly defined to include investigator-reported events such as cough, hypersensitivity reactions, and cytokine release syndrome. To manage IRRs, pts received pre-infusion medication: methylprednisolone 100 mg (or equivalent) intravenously for the first 2 infusions and 60 mg thereafter; paracetamol (acetaminophen) 650-1000 mg orally; and diphenhydramine 25-50 mg (or equivalent). Corticosteroid post-infusion medication (20 mg methylprednisone or equivalent) was given on the 2 days following DARA infusions to prevent delayed IRRs. DARA infusion was initiated in 1,000 mL at 50 mL/hr. In the absence of IRRs/hypersensitivity, the rate increased hourly at 50-mL/hr intervals to 200 mL/hr. Second and subsequent infusions (in 500 mL) began at 50 and 100 mL/hr, respectively, and escalated to 200 mL/hr. Upon onset of IRRs, infusions were temporarily interrupted or slowed.Results: Data from the DARA 16 mg/kg (n = 106) and 8 mg/kg (n = 18) treatment groups are presented. All pts received pre-infusion medication as prescribed, consisting of analgesics (100%), antihistamines (100%), and corticosteroids (100%). All pts received post-infusion corticosteroids except 3 pts in the 16 mg/kg group. IRRs occurred in 43% and 44% of pts in the 16 mg/kg and 8 mg/kg groups, respectively. Among pts receiving 16 mg/kg (8 mg/kg), 87% (82%) of IRRs were during the first infusion; 4% (19%) and 9% (0%) of IRRs occurred during the second and all subsequent infusions, respectively. The median (range) time to onset for IRRs was 90 (1-514) minutes after the start of infusion, and the median duration of infusion was 7.0 (2-24), 4.2 (2-9), and 3.4 (1-7) hours during the first, second, and all subsequent infusions, respectively. The most frequently reported IRRs appear in Table 1. Most IRRs were grade 1 or 2. Few pts reported grade 3 IRRs, which included bronchospasm (n = 2 at 16 mg/kg), and hypertension, anemia, and dyspnea (n = 1 each at 16 mg/kg), and chills and cytokine release syndrome (both in 1 pt at 8 mg/kg), and hypertension (n = 1 at 8 mg/kg). Infusion rates were decreased for 10% and 17% of pts in the 16 mg/kg and 8 mg/kg groups, respectively. Grade 4 IRRs were not reported, and no IRRs led to treatment discontinuation. Three pts were unable to finish an infusion due to an IRR but received subsequent DARA infusions; the remaining pts who experienced an IRR continued full-dose therapy with supportive treatment. Cytokine changes (IL-6, TNFα, IFNγ, and IL-1β) from baseline to 4 hours after the first DARA infusion were variable, but did not correlate with clinical response or IRRs.Conclusions: DARA-related IRRs were manageable with temporary slowing or stopping of infusion. No pt discontinued treatment due to an IRR. IRRs were most likely to occur during the first or second infusion, were predominantly of grade 1 or 2 severity, and did not recur at a higher grade with subsequent infusions. These results highlight the favorable safety profile of DARA in r/r MM pts.Table 1IRRs Reported in >2 Pts16 mg/kg8 mg/kgAdverse Event, n (%)Any GradeAny GradeCongestion13 (12.3)1 (5.6)Chills6 (5.7)5 (27.8)Cough6 (5.7)3 (16.7)Throat irritation7 (6.6)0Dyspnea6 (5.7)1 (5.6)Vomiting6 (5.7)1 (5.6)Nausea5 (4.7)0Bronchospasm4 (3.8)0 DisclosuresVoorhees:Celgene, GlxoSmithKline, and Oncopeptides: Research Funding; Array Biopharma, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Millennium/Takeda and Novartis: Honoraria. Weiss:Janssen and Onclave: Research Funding; Janssen and Millennium: Consultancy. Usmani:Celgene Corporation: Consultancy, Honoraria; Janssen: Research Funding; Onyx: Consultancy, Honoraria, Research Funding. Feng:Janssen: Employment. Uhlar:Janssen: Employment. Khan:Janssen: Employment. Ahmadi:Janssen: Employment. Lonial:Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events

BackgroundThe cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM).MethodsPre-specified patient-level pooled analysis of all available double-blind, randomized, controlled trials, ≥12 weeks’ duration (19 trials, 9459 subjects) of linagliptin versus placebo/active treatment. Primary end point: composite of prospectively adjudicated CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina (4P-MACE). Hospitalization for congestive heart failure (CHF) was also evaluated; adjudication of CHF was introduced during the phase 3 program (8 trials; 3314 subjects). 4P-MACE was assessed in placebo-controlled trials (subgroup of 18 trials; 7746 subjects). Investigator-reported events suggestive of CHF from 24 placebo-controlled trials (including trials <12 weeks’ duration, 8778 subjects) were also analyzed.Results5847 patients received linagliptin (5 mg: 5687, 10 mg: 160) and 3612 comparator (glimepiride: 775, voglibose: 162, placebo: 2675); cumulative exposure, 4421.3 and 3254.7 patient-years, respectively. 4P-MACE incidence rates: 13.4 per 1000 patient-years, linagliptin (60 events), 18.9, total comparators (62 events); overall hazard ratio (HR), 0.78 (95% confidence interval [CI], 0.55–1.12). HR for adjudicated hospitalization for CHF (n = 21): 1.04 (0.43–2.47). For placebo-controlled trials, 4P-MACE incidence rates: 14.9 per 1000 patient-years, linagliptin (43 events), 16.4, total comparators (29 events); overall HR, 1.09 (95% CI, 0.68–1.75). Occurrence of investigator-reported events suggestive of CHF was low for linagliptin- (26 events, 0.5%; serious: 16 events, 0.3%) and placebo-treated (8 events, 0.2%; serious: 6 events, 0.2%) patients.ConclusionsLinagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

Acceptance rate of clinical study endpoints and adequacy of source documentation: experience from clinical study endpoint review in NEAT001/ANRS143.

Introduction NEAT001/ANRS143 was an open-label, randomized, non-inferiority study comparing raltegravir+darunavir/r(RGV+DRV/r) vs. tenofovir/emtricitabine+darunavir/r (TDF/FTC+DRV/r) in HIV-infected antiretroviral naïve adults. Primary efficacy outcome was a composite of virological and clinical events by week 96.Materials and Methods Clinical trial units collected and translated supporting documentation (SD) related to the investigator-reported events. A coordinator checked events and SD for consistency and completeness. The Endpoint Review Committee (ERC) determined if clinical events met pre-defined diagnostic criteria in categories “confirmed” or “probable”. The ERC of 12 experienced, independent clinicians served in groups of three conducting individual reviews in writing, blinded to treatment arm. Differences of opinion were adjudicated in a second review by direct dialogue between reviewers. “Confirmed” events required adequate SD like laboratory, radiographic or pathology diagnostic reports. “Probable” events were typically based on clinical criteria.ResultsOf the 164 serious and 3,964 adverse events reported in the study, 133 qualified for endpoint review, for a total of 153 adjudications:Sixty of 111 per protocol endpoints were confirmed (n=53) or probable (n=7), which equals an acceptance rate of 54%. In two confirmed cases, SD was partly adequate and evaluation uncertain. Of 51 rejected events, 13 had insufficient SD, two were recurrent events. The rate of rejected events was comparable between treatments with 41% rejected events in the RGV+DRV/r arm compared to 52% in the TDF/FTC+DRV/r arm. The IRIS acceptance rate was low (3 of 18), demonstrating the difference in perception of IRIS in daily patient management and the stricter protocol definition.ConclusionsBlinded endpoint review prevented unacceptably high false positive event rates documenting that real-time ascertainment of clinical endpoints is crucial for appropriateness of the overall results. Non-confirmed events jeopardize the statistical power in this and probably all kinds of clinical studies. The rejection rate was not indicative of poor study conduct – on the contrary over-reporting prevented missing events, which would have adversely impacted the trial. Adequacy of SD and investigator training on possible differences in event criteria in daily pragmatic clinical management compared to protocol defined criteria is essential.

Effects of the Endpoint Adjudication Process on the Results of a Randomised Controlled Trial: The ADVANCE Trial

BackgroundEndpoint adjudication committees (EPAC) are widely used in clinical trials. The aim of the present analysis is to assess the effects of the endpoint adjudication process on the main findings of the ADVANCE trial (Trial registration: ClinicalTrials.gov NCT00145925).Methods and FindingsThe ADVANCE trial was a multicentre, 2×2 factorial randomised controlled trial of blood pressure lowering and intensive blood glucose control in 11140 patients with type 2 diabetes. Primary outcomes were major macrovascular (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) and microvascular (new or worsening nephropathy and retinopathy) events. Suspected primary outcomes were initially reported by the investigators at the 215 sites with subsequent adjudication by the EPAC. The EPAC also adjudicated upon potential events identified directly by ongoing screening of all reported events. Over a median follow-up of 5 years, the site investigators reported one or more primary outcomes among 2443 participants. After adjudication these events were confirmed for 2077 (85%) with 48 further events added through the EPAC-led database screening process. The estimated relative risk reductions (95% confidence intervals) in the primary outcome for the blood pressure lowering comparison were 8% (−1 to 15%) based on the investigator-reported events and 9% (0 to 17%) based on the EPAC-based events (P for homogeneity = 0.70). The corresponding findings for the glucose comparison were 8% (1 to 15%) and 10% (2% to 18%) (P for homogeneity = 0.60). The effect estimates were also highly comparable when studied separately for macrovascular events and microvascular events for both comparisons (all P for homogeneity>0.6).ConclusionsThe endpoint adjudication process had no discernible impact on the main findings in ADVANCE. These data highlight the need for careful consideration of the likely impact of an EPAC on the findings and conclusions of clinical trials prior to their establishment.

Under-reporting of cardiovascular events in the rofecoxib Alzheimer disease studies

In September 2004, rofecoxib (Vioxx) was removed from the market after it was found to produce a near doubling of cardiovascular thrombotic (CVT) events in a placebo-controlled study. Its manufacturer stated that this was the first clear evidence of such risk and criticized previous analyses of earlier CVT risk for focusing on investigator-reported events. We studied contemporaneously adjudicated CVT events to assess the information on cardiovascular risk available while the drug was in widespread use. Using an intention-to-treat analysis of adjudicated CVT deaths, we analyzed detailed patient-level data collected during 3 randomized placebo-controlled trials of rofecoxib versus placebo that had been designed to define the drug's possible role in the prevention or treatment of Alzheimer disease. All trials had been completed by April 2003. In the 3 studies combined, the data indicated that rofecoxib more than tripled the risk of confirmed CVT death (risk ratio = 3.57 [1.48-9.72], P = .004). This finding reached the P < .05 level of significance by June 2001. Intention-to-treat analysis of placebo-controlled studies of rofecoxib for Alzheimer disease demonstrated that the drug produced a significant increase in confirmed CVT deaths nearly 40 months before it was removed from the market. By contrast, published analyses of these trials were restricted to on-treatment analyses (ending 14 days after cessation of treatment) that did not reveal this risk. Intention-to-treat analyses of clinical trial data can reveal important information about potential drug risks and should be performed routinely and reported in a timely manner.

Risk of serious upper gastrointestinal and cardiovascular thromboembolic complications with meloxicam

Purpose To assess the risk of serious gastrointestinal and thromboembolic complications with approved doses of meloxicam. Methods We pooled data from clinical trials of meloxicam at doses of 7.5 or 15 mg/d. A blinded gastrointestinal adjudication committee used prespecified criteria to identify gastric or duodenal perforation, gastric outlet obstruction, or hemodynamically important upper gastrointestinal bleeding. For analysis of thromboembolic complications, investigator-reported events were analyzed without adjudication. Results We analyzed data from 24,196 patients from 28 trials, most of whom had been followed for up to 60 days. Of these patients, 13,118 received meloxicam (10,158 received a daily dose of 7.5 mg and 2960 received 15 mg), 5283 were treated with diclofenac 100 mg, 181 received diclofenac 150 mg, 5371 were treated with piroxicam 20 mg, and 243 received naproxen 500 mg twice daily. Patients who received 7.5 mg of meloxicam daily had a 0.03% risk of serious upper gastrointestinal events, which was significantly lower than the risk in those who received diclofenac, naproxen, or piroxicam ( P <0.02). With the 15 mg daily dose of meloxicam, this risk was significantly different only when compared with piroxicam ( P = 0.03). The risk of thromboembolic events in patients treated with meloxicam at either dose was lower than with diclofenac, but similar to that observed with piroxicam and naproxen. Conclusion This pooled analysis of 24,196 patients demonstrates that meloxicam has a favorable gastrointestinal and thromboembolic safety profile. However, only a small number of patients were followed for more than 60 days, and meaningful comparisons were not possible in this subgroup.

The gastrointestinal safety of the COX-2 selective inhibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events

Objective Etoricoxib is a selective cyclooxygenase inhibitor that in clinical studies has improved the signs and symptoms of osteoarthritis and rheumatoid arthritis and reduced the potential for GI injury. The incidence of endoscopically detected ulcers and of clinically important upper GI events (perforations, ulcers, and bleeding episodes) was compared in patients taking etoricoxib or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Methods Upper GI endoscopy was performed at intervals over 12 wk in 680 patients taking etoricoxib 120 mg once daily, ibuprofen 800 mg three times daily, or placebo in a randomized, parallel-group, double-blind study. Survival analysis was used to analyze time-to-event data for the incidence of gastric or duodenal ulcers (≥3 mm and ≥5 mm), and the log rank test was used to compare the cumulative incidence between treatment groups. A combined analysis of upper GI events in all 10 Phase II/III clinical trials of etoricoxib (60, 90, or 120 mg) versus nonselective NSAIDs (naproxen, ibuprofen, or diclofenac) for osteoarthritis, rheumatoid arthritis, and chronic low back pain was conducted. Investigators reported potential events for adjudication by an external, blinded committee, using prespecified criteria to confirm events. All events that occurred during active treatment periods (maximum 792 days) or within 14 days of stopping treatment were included in the analysis. Time to first event was evaluated using survival analysis; the Kaplan–Meier method was used to determine the cumulative incidence, and relative risk was estimated with the Cox proportional hazards model. Results In the endoscopy study, the cumulative incidence of ulcers ≥3 mm at 12 wk in the ibuprofen group (17%) was significantly higher than in the etoricoxib group (8.1%, p < 0.001); similar results were seen for ulcers ≥5 mm. In the placebo group, the rate of ulcers ≥3 mm was 1.86%. Of 3142 patients treated with once-daily etoricoxib and 1828 patients treated with a nonselective NSAID (ibuprofen, naproxen, or diclofenac), 82 patients with investigator-reported upper GI events (71 confirmed) were eligible for the combined analysis. For etoricoxib versus NSAIDs, the rate per 100 patient-yr for confirmed events was 1.16 versus 3.05 (relative risk = 0.44, 95% CI = 0.27–0.72, p < 0.001), whereas that for investigator-reported events was 1.35 versus 3.42 (relative risk = 0.47, 95% CI = 0.30–0.74, p = 0.001). Results were driven primarily by studies with naproxen as the comparator. Conclusions The incidence of endoscopically detected ulcers was significantly lower with etoricoxib 120 mg than with ibuprofen 2400 mg. Treatment with etoricoxib reduced the incidence of investigator-reported and confirmed adverse upper GI events by approximately 50% compared with treatment with nonselective NSAIDs.