Inclusion Criteria For Clinical Trials Research Articles

Development of a Highly Accurate Nomogram for Prediction of the Need for Exploration in Patients With Renal Trauma

To develop and validate a nomogram for predicting the need for renal exploration after renal trauma. From 1995 through 2004, 419 consecutive patients presented to our institution with traumatic renal injury. All were randomly divided into a development (50%, n = 210) and a split sample validation cohort (50%, n = 209). Logistic regression models were used to develop a nomogram for prediction of the need for renal exploration after renal trauma. Internal (200 bootstrap resamples) and 50% split sample validations were performed. Overall, 89 patients (21.2%) underwent renal exploration, from which 60.7% (54 of 89) underwent nephrectomy and 39.3% (35 of 89) underwent renorrhaphy. Nine percent of patients with grade II injury underwent renal exploration, 16% with grade III injuries, 41% with grade IV injuries, and 100% of grade V injuries. The kidney injury scale, the mechanism of injury, the need for transfusion, blood urea nitrogen level, and serum creatinine represented the most informative predictors and were included in the nomogram. The split sample accuracy of the nomogram for prediction of the need for renal exploration was 96.9%. It significantly (p < 0.001) exceeded the accuracy of each of its components including the American Association for the Surgery of Trauma kidney injury scale (87.7%). The nomogram generates highly accurate and reproducible predictions of the probability for renal exploration according to our decision-making. It could help standardize the management of patients with renal trauma (i.e., inclusion criteria for clinical trials) and serves as a proof-of-principle that predictive tools can be applied to the trauma setting. Its use may improve the management of renal trauma patients at institutions with limited trauma experience.

Abstract No. 41: Midterm Survival Following Endovascular Repair of the Thoracic Aorta in the Post-FDA Approval Era

Following FDA approval of the Gore TAG® (W. L. Gore & Associates, Flagstaff, AZ), off-label indications rapidly expanded to include additional thoracic aortic pathologies. The purpose of this study was to examine whether the outcomes with this device changed after the strict anatomical and pathological inclusion and exclusion criteria of FDA-controlled clinical trials no longer governed patient selection for thoracic aortic stent-graft placement.

Upgrading from right ventricular pacing to biventricular pacing in pacemaker patients with chronic heart failure

Cardiac resynchronisation therapy (CRT) is now a recommended treatment in patients with advanced heart failure despite optimal drug treatment, left ventricular systolic dysfunction, enlarged left ventricle, and cardiac dyssynchrony defined...

Differences in Survival Rates for Patients with Hodgkin Lymphoma, Who Were Treated Inside vs. Outside Therapy Optimisation Protocols in Germany.

Introduction: Despite the improvements and knowledge brought by clinical trials to cancer treatment, it remained unclear how beneficial participation in a clinical trial with Therapy Optimisation Protocol (TOP) is for patients (pts) with Hodgkin Lymphoma (HL) in relation to pts treated outside of trials. In the TOPiCS project, trial participants (TOP) were compared with non-trial pts (non-TOP).Methods: In the population-based survey NLL, which aimed to register all incident HL-cases 356 pts were recorded in six counties of northern Germany with a first diagnosis of HL in 1988–1998. Data on staging, therapy, adverse events and survival were collected. The dataset was additionally screened for patients fulfilling inclusion and exclusion criteria for clinical trials of the German Hodgkin Study Group (GHSG). A total of 328 pts were documented of whom 198 pts (60%) met the inclusion criteria of the GHSG. Of these, 125 pts (63%) have not been recruited into GHSG trials (non-TOP pts). They were compared retrospectively with 4963 TOP pts randomised nation-wide between 1988–1998 in the GHSG trials HD4-HD9. Endpoints were Overall Survival (OS) and Progression Free Survival (PFS) which considered progression, relapse and death of any cause as events. Survival analysis was performed using Kaplan-Meier method and log-rank tests. Cox regression analysis was used for multivariable modelling of risk of death or progression and included 118 non-TOP pts and 4958 TOP pts.Results: The demographic parameters were not well balanced between the two groups: TOP pts were younger, had more often advanced stage and diagnosis in the later study generation than the non-TOP pts. The median observation time for OS was 7 yrs for the TOP group and 10 yrs for the non-TOP group. The 5-yrs OS for TOP pts is 89% (95%–CI [88–90]) and for non-TOP 89% (95%-CI [82–94])(p=0.63). The 5-year PFS for TOP pts is 79% (95%–CI [78–80]) and for non-TOP pts 68% (95%–CI [59–76])(p<0.001). According to Cox-regression analysis, 5 parameters were significantly (p<0.01) associated with poor OS and PFS: male sex, older age, advanced stage (according to DHSG classification considering Ann Arbor stage, B-symptoms and risk factors) and earlier study generation. Participation in a TOP-trial did not contribute independently for OS (Hazard Ratio (HR)=1.12, 95%–CI [0.71–1.79]) but contributed independently and positively for PFS (HR=0.66, 95%–CI [0.49–0.89]). The difference is mainly due to a higher number of relapses.Conclusion: For German patients fulfilling inclusion and exclusion criteria for TOP, a participation in therapy optimisation protocols results in a higher PFS, allowing for the influence of other factors, than for patients who were treated outside of TOP-trials. However, no difference was observed in OS.

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Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

Improving Patient Selection for Clinical Acute Stroke Trials

Objective: To optimize patient inclusion criteria for clinical acute stroke trials. Methods: We stratified probabilities of death and complete recovery based on two validated prognostic models using age and the National Institutes of Health Stroke Scale (NIH-SS) at admission. In an independent data set of 1,725 consecutively admitted patients with acute ischemic stroke, computer simulation with various inclusion thresholds was used to calculate the number and percentage of potential treatment responders, i.e. who had not died or spontaneously recovered. Results: Using defined thresholds for recovery and mortality, inclusion and exclusion criteria could be designed to considerably decrease both trial time and study size compared to a fixed inclusion criterion based on the NIH-SS alone. Other thresholds may allow optimization of either trial time or study size. Conclusions: The resulting models provide a validated approach for an efficient study inclusion of potential treatment responders based on the Barthel Index 100 days after ischemic stroke. These techniques provide the opportunity for improved stroke trials in terms of enrollment speed, treatment effect size or both.

Lung Function in Children with Stable, Controlled Asthma: A Critical Look at Inclusion Criteria for Clinical Trials in Childhood Asthma

Lung Function in Children with Stable, Controlled Asthma: A Critical Look at Inclusion Criteria for Clinical Trials in Childhood Asthma

Predicting late anemia in critical illness

IntroductionIdentifying critically ill patients most likely to benefit from pre-emptive therapies will become increasingly important if therapies are to be used safely and cost-effectively. We sought to determine whether a predictive model could be constructed that would serve as a useful decision support tool for the pre-emptive management of intensive care unit (ICU)-related anemia.MethodsOur cohort consisted of all ICU patients (n = 5,170) admitted to a large tertiary-care academic medical center during the period from 1 July 2000 to 30 June 2001. We divided the cohort into development (n = 3,619) and validation (n = 1,551) sets. Using a set of demographic and physiologic variables available within six hours of ICU admission, we developed models to predict patients who either received late transfusion or developed late anemia. We then constructed a point system to quantify, within six hours of ICU admission, the likelihood of developing late anemia.ResultsModels showed good discrimination with receiver operating characteristic curve areas ranging from 0.72 to 0.77, although predicting late transfusion was consistently less accurate than predicting late anemia. A five-item point system predicted likelihood of late anemia as well as existing clinical trial inclusion criteria but resulted in pre-emptive intervention more than two days earlier.ConclusionA rule-based decision support tool using information available within six hours of ICU admission may lead to earlier and more appropriate use of blood-sparing strategies.

Non-enrolment of ovarian cancer patients in clinical trials: reasons and background

Background: Some retrospective analyses have suggested that participation in clinical trials is associated with better outcome. However, it is not clear to what extent selection bias contributes to this observation.Patients and methods: We evaluated the reasons for non-enrolment of ovarian cancer patients in clinical trials. All patients with ovarian cancer not enrolled in clinical studies and treated in 2001 in the participating centres were documented retrospectively and compared with patients enrolled in clinical trials at the same institutions during the same time period.Results: Two hundred and seventy-four patients with advanced ovarian cancer (FIGO stage IIB–IV) were included, of whom 139 (51%) and 135 (49%) patients were enrolled in this study and in prospective clinical trials, respectively. Ninety-four of 274 patients (34%) did not meet the inclusion criteria for clinical trials. Of 180 eligible patients, 28 (16%) refused participation and a further 17 patients (9%) were not recruited although they met the inclusion criteria. The non-study patients were older (66.7 versus 57.2 years; P <0.0001), underwent less radical surgery (hysterectomy, oophorectomy and omentectomy performed: 61.2% versus 80.7%; P = 0.001; rate of lymphadenectomy 30.9% versus 45.2%; P = 0.015) and more frequently had bulky residual disease (residual disease >2 cm: 36.2% versus 20%; P = 0.016). However, 62% of the non-study patients were treated with the same chemotherapy as in the standard arm of the respective clinical studies.Conclusions: Study patients differ substantially from non-study patients, thus hampering generalisation of study results. Our results suggest that at least some inclusion criteria for clinical trials should be modified to increase study participation without compromising safety.

Inclusion Criteria for Clinical Trials in Sepsis: Did the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Definitions of Sepsis Have an Impact?

Over the last 25 years, a growing number of clinical trials have evaluated novel sepsis therapies. To promote uniformity in inclusion criteria for patient enrollment, the American College of Chest Physicians and Society of Critical Care Medicine first published consensus conference definitions for sepsis in 1992.To characterize (1) the utilization of specific criteria for patient enrollment in sepsis clinical trials and (2) the impact that the consensus conference definitions have had on these criteria.We used MEDLINE to identify clinical trials in sepsis from 1976 to 2001. Clinical trials published after the consensus conference (ACC; from 1993 to 2001) were compared with trials published before the consensus conference (BCC; from 1976 to 1992).We identified 176 clinical trials (ACC, 119 trials; BCC, 57 trials). Clinical trials published ACC were more likely to utilize or reference a previously published standard for inclusion criteria (65% vs 11%, respectively; p < 0.001). The consensus conference definitions were the standards used in 69% of these trials. The utilization of specified values for WBC count, temperature (T), heart rate (HR), and respiratory rate (RR) was significantly increased in the ACC group compared to the BCC group, as follows: WBC count, 62% vs 26%, respectively (p < 0.001); T, 89% vs 56%, respectively (p < 0.001); HR, 77% vs 26%, respectively (p < 0.001); and RR, respectively 76% vs 28% (p < 0.001). ACC, clinical trials were less likely to require blood culture positivity (4 of 119 trials [3%] vs 9 of 57 trials [16%], respectively; p < 0.006) and were more likely to incorporate markers of acute organ dysfunction (81 of 119 trials [68%] vs 28 of 57 trials [49%], respectively; p < 0.03) in the inclusion criteria.(1) Since 1992 there has been a significant increase in the utilization of predefined sepsis criteria for patient enrollment in clinical trials, and this increase can be attributed to the existence of consensus conference definitions. (2) Compared to inclusion criteria BCC, inclusion criteria ACC were less reliant on blood culture positivity and were more likely to incorporate markers of organ dysfunction.

Efficacy of bolus and infusional 5-FU in elderly and non-elderly patients with metastatic colorectal cancer - a pooled analysis of clinical trials

8045 Background: Recently published population-based investigations showed elderly patients to be underrepresented in clinical trials and less often treated according the standard therapy, although they benefit to the same extent from adjuvant (radio-) chemotherapy as younger patients. No large series describes the influence of age on efficacy of chemotherapy in metastatic colorectal cancer. Methods: We carried out a retrospective analysis using source data of 3,825 patients who received 5-FU containing treatment in 22 European trials and identified 629 patients with an age of ≥ 70 years. Results: An equal overall survival was observed in elderly patients (10.8 months, 95 % CI 9.7–11.8) and in younger patients (11.3 months, 95 % CI 10.9–11.7, p = .31). Response rate did not differ between the age groups ≥ 70 and < 70 years (20.8 % and 17.6 %, p = .14). Progression free survival was marginally prolonged in elderly patients (5.5 months, 95 % CI 5.2–5.8 and 5.3 months, 95 % CI 5.1–5.5, p = .01). In both age groups, infusional 5-FU resulted in significantly increased response rates, overall survival and progression free survival compared to bolus 5-FU. The Cox- regression analysis showed no influence of age on OS. Conclusions: We conclude that “fit” elderly patients (fulfilling standard inclusion criteria of clinical trials) benefit to the same extent from palliative chemotherapy with 5-FU. Infusional 5-FU is more effective in elderly as in younger patients. Standardized palliative chemotherapy should generally be offered to elderly patients and they should not be excluded from clinical trials. No significant financial relationships to disclose.

Can generic paediatric mortality scores calculated 4 hours after admission be used as inclusion criteria for clinical trials?

IntroductionTwo generic paediatric mortality scoring systems have been validated in the paediatric intensive care unit (PICU). Paediatric RISk of Mortality (PRISM) requires an observation period of 24 hours, and PRISM III measures severity at two time points (at 12 hours and 24 hours) after admission, which represents a limitation for clinical trials that require earlier inclusion. The Paediatric Index of Mortality (PIM) is calculated 1 hour after admission but does not take into account the stabilization period following admission. To avoid these limitations, we chose to conduct assessments 4 hours after PICU admission. The aim of the present study was to validate PRISM, PRISM III and PIM at the time points for which they were developed, and to compare their accuracy in predicting mortality at those times with their accuracy at 4 hours.MethodsAll children admitted from June 1998 to May 2000 in one tertiary PICU were prospectively included. Data were collected to generate scores and predictions using PRISM, PRISM III and PIM.ResultsThere were 802 consecutive admissions with 80 deaths. For the time points for which the scores were developed, observed and predicted mortality rates were significantly different for the three scores (P < 0.01) whereas all exhibited good discrimination (area under the receiver operating characteristic curve ≥0.83). At 4 hours after admission only the PIM had good calibration (P = 0.44), but all three scores exhibited good discrimination (area under the receiver operating characteristic curve ≥0.82).ConclusionsAmong the three scores calculated at 4 hours after admission, all had good discriminatory capacity but only the PIM score was well calibrated. Further studies are required before the PIM score at 4 hours can be used as an inclusion criterion in clinical trials.

A simplified psoriasis area severity index (SPASI) for rating psoriasis severity in clinic patients

The Psoriasis Area and Severity Index (PASI) is the most widely used tool to assess psoriasis disease severity in clinical trials, although it can be exceedingly cumbersome for use in daily clinical practice. Because clinical trials rely on the PASI for inclusion criteria, having a PASI score on a clinic patient may be useful for determining if the patient has a level of disease severity similar to that of patients treated in clinical trials. The purpose of this study is to assess a simplified measure of psoriasis disease severity that is more conducive to use in general dermatology practice, the simplified PASI (SPASI). We evaluate an area-weighted assessment of lesion severity composed of the sum of the average redness, thickness, and scaliness of all the psoriasis lesions multiplied by an estimate of total body surface area involved. The SPASI is mathematically derived from the PASI. The SPASI and PASI are not identical because of the categorical nature of area estimates used in the PASI. We use existing psoriasis-population data regarding the anatomical distribution of psoriasis lesions to create a simulated patient database. Monte Carlo analysis is then performed to determine the relation between the PASI and SPASI. For a sample population with a mean PASI score of 12.8, the mean SPASI was 14.2. Correlation between the PASI and the SPASI was high (r = 0.90). Bland-Altman analysis showed no consistent bias between the PASI and the SPASI. When attempting to identify simulated patients with a PASI score of 12 (an inclusion criterion for many clinical trials for severe psoriasis), SPASI was 97 percent sensitive and 66 percent specific. The SPASI is much less onerous than the PASI, requiring estimation of only four rather than sixteen independent variables. It provides a quick and practical estimate of disease severity similar to the PASI and can be used to communicate that patients have a level of disease severity similar or dissimilar to that of patients studied in clinical trials.

Translating angiogenesis research into the clinic: the challenges ahead.

The field of angiogenesis research has evolved to become one of the most rapidly growing biomedical disciplines. The interest in basic angiogenesis research is sparked by the translational therapeutic potential aimed at developing anti-angiogenesis as a novel therapeutic modality for tumours and a number of non-oncological diseases, such as rheumatoid arthritis, psoriasis, diabetic retinopathy and age-dependent macula degeneration. The molecular determinants of the angiogenic cascade have been characterized in great detail over the last few years. Likewise, intense ongoing efforts are aimed at identifying and validating additional vascular specific determinants that may be exploited as therapeutic targets for pro-angiogenic and anti-angiogenic therapy. At the same time, a large number of angiomodulatory compounds are in various phases of clinical trials. These include the neutralizing vascular endothelial growth factor (VEGF) antibody Avastin, which has successfully passed phase III clinical trials for the combination with chemotherapy in colorectal cancers. In view of the dramatic progress in basic angiogenesis research, surprisingly little is known about the nature of the neovasculature in human tumours. The inclusion and exclusion criteria of clinical trials of anti-angiogenic compounds are devoid of angiogenesis-related parameters and reliable biomarkers to trace the efficacy of an anti-angiogenic intervention are largely missing. Based on a brief review of the biology of the angiogenic cascade, this review provides an overview of the current concepts of the angiogenic vasculature in human tumours and discusses some key unanswered questions in translating angiogenesis research into the clinic.

Role of biologic markers in patient selection and application to disease prevention.

Aromatase inhibitors (AIs) are now under investigation for the treatment of early stage breast cancer and for disease prevention as alternatives to standard treatment with tamoxifen. Currently identified genetic risk factors of breast cancer include BRCA-1/BRCA-2 mutations, ATM mutations, and history of high estrogen levels, as evidenced by plasma analyses and/or dense bones. To date, estrogen receptor (ER) and progesterone receptor (PgR) status has predictive value for determining response to therapy in patients with hormone receptor-positive breast cancer (ER+ and/or PgR+ tumors). Recent studies have shown AIs to be safer and more effective than tamoxifen in postmenopausal women with advanced disease. Some data suggest that letrozole may be a more effective treatment than tamoxifen for patients with ER+ and/or PgR+ early breast cancers expressing ErbB-1 and/or ErbB-2. Changes in cell proliferation markers (e.g., S-phase fraction and Ki67 antigen), plasma lipid levels, and the bone resorption marker C-terminal peptide are biomarkers that have been evaluated for preventive and prognostic value in breast cancer patients and normal volunteers. Results from biomarker screens can be used to define inclusion criteria for clinical trials and eventually to individualize treatment. Gene expression profiling (microarray analysis), i.e., genomic and proteomic studies, will probably advance the discovery of new biomarkers for breast cancer prevention and treatment.

The feasibility of airways hyperresponsiveness as an inclusion criterion for studies on childhood asthma.

The feasibility of moderately severe airway hyperresponsiveness (AH) was examined as an inclusion criterion for clinical trials in asthmatic children. During the baseline period of a long-term clinical trial in asthmatic children, maintenance therapy with fluticasone (200 microg x day(-1)) was stopped for a maximum of 8 weeks and methacholine challenges were performed at 2-week intervals or earlier if the patients' condition deteriorated. Patients were eligible to continue the study if the provocative dose of methacholine causing a 20% fall in forced expired volume in one second (FEV1) (PD20) was <80 microg. Fifty-one per cent of the children did not develop a PD20 < 80 microg after withdrawal of fluticasone. Patients with or without a PD20 <80 microg did not differ in duration of asthma, duration of treatment, or peak flow variation. Patients with a PD20 <80 microg had higher levels of total and specific immunoglobulin-E, and lower levels of FEV1 and mean maximal expiratory flow than patients with a PD20 > or = 80 microg. Forty-four per cent of the patients with a PD20 > or = 80 microg did not have any symptoms during the wash-out period and 39% of these patients remained free from symptoms during one year follow-up. The results of this study suggest that recruiting asthmatic children for clinical trials may be difficult if airways hyperresponsiveness is used as the sole inclusion criterion.

Cost-Minimization and the Number Needed to Treat in Uncomplicated Hypertension

The goal of this study was to compare the direct costs associated with the prescription of thiazide diuretics, β-receptor blockers (β-blockers), angiotensin converting enzyme inhibitors (ACEI), α-receptor blockers (α-blockers), and calcium channel blockers (CCB) for the prevention of stroke, myocardial infarction (MI) and premature death in uncomplicated hypertension. We performed a cost-minimization analysis based on numbers-needed-to-treat (NNT) derived from the metaanalysis of 15 major clinical trials of hypertension treatment, and the average wholesale prices of both the most commonly prescribed and the least expensive drugs in each class. The inclusion criteria for clinical trials were that they be randomized, controlled trials of drug therapy of uncomplicated mild-to-moderate hypertension with stroke, MI, or death as endpoints. The wholesale drug costs and the total direct outpatient treatment costs to prevent a stroke, MI or death among middle-aged and elderly hypertensives were our outcome measures. The estimated wholesale drug acquisition cost to prevent one major event (MI or stroke or death) ranged from $4730 to $346,236 among middle-aged patients, and from $1595 to $116,754 in the elderly; generic diuretic or β-blocker therapy was more economical than treatment with an ACEI, α-blocker, or CCB. The associated 5-year NNT was 86 for middle-aged patients and 29 for elderly patients. Diuretic therapy remained more cost-effective even under the unlikely assumption that the newer drugs were 50% more effective than diuretics at preventing these major events. The costs associated with potassium supplementation did not eliminate the advantage of diuretics. Treatment costs to prevent major hypertensive complications are much lower with diuretics and β-blockers than with ACEI, CCB, or α-blockers, especially in middle-aged patients.

The use of accurate visual acuity measurements in clinical anti-cataract formulation trials.

A standardized visual acuity technique is presented for use in anti-cataract drug trials. Ferris Logmar charts were used in repeatability studies of vision, visual acuity and pinhole visual acuity measurements for twenty normal subjects (mean (+/- SD) age 64 +/- 6.3 years). Visual acuity measurements were shown to be the most repeatable and thought to be the most suitable for monitoring cataract progression. Repeated visual acuity measurements were made on 29 cataractous eyes of 15 subjects (mean (+/- SD) age 67.8 +/- 7.2 years). A Logmar score change of 0.1 (one line) was shown to be a statistically significant change. This value can be used in statistical analyses of drug efficacy. The normal data gives a mean Logmar visual acuity of 1.15 (Snellen equivalent 6/5). This indicates the inadequacy of using 6/6 as a norm value for visual acuity, even for older patients. As the possibility of reversal of cataract theoretically exists in the early stages of cortical and capsular cataracts, patients with small amounts of these types of cataract are ideal patients for anti-cataract formulation trials. The normal visual acuity results indicate that the inclusion criteria for clinical trials can include patients with cataracts with visual acuity as good as 6/6.