Clinical Trial Criteria Research Articles

Tradeoff-based optimization criteria in clinical trials with multiple objectives and adaptive designs

ABSTRACTThe article discusses clinical trial optimization problems in the context of mid- to late-stage drug development. Using the Clinical Scenario Evaluation approach, main objectives of clinical trial optimization are formulated, including selection of clinically relevant optimization criteria, identification of sets of optimal and nearly optimal values of the parameters of interest, and sensitivity assessments. The paper focuses on a class of optimization criteria arising in clinical trials with several competing goals, termed tradeoff-based optimization criteria, and discusses key considerations in constructing and applying tradeoff-based criteria. The clinical trial optimization framework considered in the paper is illustrated using two case studies based on a clinical trial with multiple objectives and a two-stage clinical trial which utilizes adaptive decision rules.

Predictive factors associated with success and failure for Calmare (Scrambler) therapy: a multicenter analysis.

Calmare (Scrambler) therapy is a novel therapeutic modality that purports to provide pain relief by "scrambling" afferent pain signals and replacing them with "non-pain" information through conventional lines of neural transmission. The goal of this study is to identify which factors are associated with treatment outcome for Calmare therapy. Data were garnered from 3 medical centers on 147 patients with various pain conditions who underwent a minimum of either 3 Calmare therapies on consecutive days or 5 therapies overall. A successful outcome was predefined as ≥50% pain relief on a 0 to 10 numerical rating scale that persisted for longer than 1 month after the last treatment. Variables evaluated for their association with outcome included age, sex, study site, baseline pain score, etiology, type of pain, diagnosis, treatment compliance, coexisting psychopathology, opioid use, antidepressant use, and membrane stabilizer use. Overall, the success rate was 38.1%. Variables found to be associated with a positive outcome in multivariate logistic regression included the presence of neuropathic (OR=24.78; 95% CI, 2.47-248.97; P=0.006) or mixed (OR=10.52; 95% CI, 1.09-101.28; P=0.042) pain, and treatment at either Walter Reed (OR=6.87; 95% CI, 1.60-29.51; P=0.010) or Seoul National University (OR=12.29; 95% CI, 1.73-87.43; P=0.012). Factors that correlated with treatment failure were disease (OR=0.04; 95% CI, 0.002-0.59; P=0.020) or traumatic/surgical etiologies (OR=0.05; 95% CI, 0.005-0.56; P=0.015) and antidepressant use (OR=0.47; 95% CI, 0.18-1.02; P=0.056). A neuropathic or mixed neuropathic-nociceptive pain condition was associated with a positive treatment outcome. Investigators should consider these findings when developing selection criteria in clinical trials designed to determine the efficacy of Calmare therapy.

Does Age Influence Cardiac Resynchronization Therapy Use and Outcome?

ObjectivesThis study sought to describe the use of CRT-D and its association with survival for older patients. BackgroundMany patients who receive cardiac resynchronization therapy with defibrillator (CRT-D) in practice are older than those included in clinical trials. MethodsWe identified patients undergoing ICD implantation in the National Cardiovascular Disease Registry (NCDR) ICD registry from 2006 to 2009, who also met clinical trial criteria for CRT, including left ventricular ejection fraction (LVEF) ≤35%, QRS ≥120 ms, and New York Heart Association (NYHA) functional class III or IV. NCDR registry data were linked to the social security death index to determine the primary outcome of time to death from any cause. We identified 70,854 patients from 1,187 facilities who met prior trial criteria for CRT-D. The mean age of the 58,147 patients receiving CRT-D was 69.4 years with 6.4% of patients age 85 or older. CRT use was 80% or higher among candidates in all age groups. Follow-up was available for 42,285 patients age ≥65 years at 12 months. ResultsReceipt of CRT-D was associated with better survival at 1 year (82.1% vs. 77.1%, respectively) and 4 years (54.0% vs. 46.2% , respectively) than in those receiving only an ICD (p < 0.001). The CRT association with improved survival was not different for different age groups (p = 0.86 for interaction). ConclusionsMore than 80% of older patients undergoing ICD implantation who were candidates for a CRT-D received the combined device. Mortality in older patients undergoing ICD implantation was high but was lower for those receiving CRT-D.

Comparison and evaluation of lupus nephritis response criteria in lupus activity indices and clinical trials

Comparison and evaluation of lupus nephritis response criteria in lupus activity indices and clinical trials

Patterns of relapse and growth kinetics of surgery- and radiation-refractory meningiomas.

Patients with surgery- and radiation-refractory meningiomas have a poor outcome. Due to our lack of knowledge concerning multi-recurrent meningioma natural history, their clinical course is poorly defined. This retrospective study aims at defining patterns of relapse in order to help in the definition of response criteria in future clinical trials. We performed a retrospective review of surgery- and radiotherapy-refractory meningioma cases with interpretable radiological follow-up treated in our department. Tumor volumes were measured on 3D T1 Gadolinium volumetric sequences using a semi-automated algorithm for tumor segmentation. Twenty nine patients with multi-treated meningioma (11 WHO Grade II, 5 de novo WHO Grade III and 13 transformed WHO Grade III), were evaluated. Median PFS was 16 months for patients with Grade II meningiomas. In patients with Grade III meningiomas, the de novo subgroup had a median PFS of 4 months compared with 7 months in patients with malignant transformation. Volumetric analysis of tumor growth concerned 95 tumor nodules in 50 relapses. The mean growth rate of tumor nodules was 10.4 cm(3)/year (95% CI 7.3-14.8 cm(3)/year). Three patterns of tumor growth were described: "classical" for 9 (31%) patients, "local multi-nodular" for 6 (21%) patients and "multi-nodular metastatic" for the last 14 (48%) patients. Considering all tumor nodules, median time to tumor progression (TTP) was 3.7 months. Progressing tumors represent the most frequent histological subgroup of surgery and radiation-refractory meningiomas while tumors with multi-nodular metastatic dissemination are the prominent radiological pattern of progression.

Assessment of Enrollment Criteria in Clinical Trials for Drug Resistant Epilepsy (S31.006)

Assessment of Enrollment Criteria in Clinical Trials for Drug Resistant Epilepsy (S31.006)

Intravenous thrombolysis for acute stroke: current standards and future directions.

Intravenous thrombolysis with the recombinant tissue plasminogen activator alteplase is the standard of care for patients with acute ischaemic stroke presenting within 4.5h of symptom onset. The odds of independent survival decline steeply with longer time to treatment delivery, reflecting progressive ischaemic damage to the brain. Standards accordingly emphasise optimisation of patient pathways to minimise treatment delays. Observational data and international clinical guidelines support the safety and efficacy of alteplase in many patient groups currently excluded from treatment (e.g. seizure at onset, concomitant diabetes and previous stroke) on the basis of historical clinical trial criteria. Future evolution of thrombolysis will optimise dosing, apply advanced imaging to extend treatment to groups currently excluded and investigate novel drugs, and adjunctive drug and device therapies. To date, trials of novel therapeutic approaches that have been applied at later time points have failed to demonstrate benefit, suggesting that the future gains are likely to arise from applications within current time windows.

OC-014: Molecular screening for cancer treatment optimization in head and neck cancer (MOSCATO 01)

OC-014: Molecular screening for cancer treatment optimization in head and neck cancer (MOSCATO 01)

Maintenance chemotherapy in advanced NSCLC: a population-based assessment of eligibility.

Maintenance chemotherapy has been incorporated into treatment paradigms for advanced NSCLC. Eligibility criteria include stable disease/partial response and PS 0-1 after a first line platinum doublet. In practice, maintenance can be difficult to deliver due to patient factors and preferences. We propose to examine the proportion of patients eligible for maintenance and factors associated with the delivery of subsequent lines of chemotherapy. The BC Cancer Agency provides care to a population of 4.5 million. A retrospective review was conducted of all referred Stage IIIB/IV patients in 2009 who received first line systemic therapy. Baseline characteristics, PS and response after first line and subsequent systemic therapy details were recorded. Patients were deemed potentially maintenance eligible or not based on clinical trial criteria; however maintenance therapy was not delivered to these patients as it was not yet available. 330 patients were identified; 98 were potentially maintenance eligible. The reason for maintenance ineligibility in n = 232; no upfront doublet (n = 41), PS ≥ 2 (n = 38), progressive disease (PD) (n = 53), PS ≥ 2 and PD (n = 62), PS ≥ 2 and unknown response (n = 35), PD and unknown PS (n = 3). Further chemotherapy (2nd line or beyond) was administered in maintenance eligible 68% vs ineligible 56%. Reasons for no further chemotherapy were predominantly decline in PS and brain metastasis. Median OS: 7 m for 1st line only versus 16.8m for ≥ 2 nd line (p < 0.001). In our population based study, 30% of advanced NSCLC patients were eligible to receive maintenance chemotherapy based on the clinical trial criteria. Despite a good initial PS and disease control only 68% of maintenance eligible patients received subsequent therapy. A clear survival benefit was seen with ≥ 2 nd line treatment. Maintenance therapy or initiation of early second line therapy should be considered for advanced NSCLC patients to improve survival outcomes.

Indikation zur endoprothetischen Versorgung des Kniegelenks – ein Evidence Mapping

Joint replacement surgery is one of the most often performed routine procedures for the treatment of knee osteoarthritis in Germany. Currently, there is no consensus on indication criteria for total knee arthroplasty (TKA). The topic indication for TKA was processed using six guiding questions concerning: 1) Common practice in determining the indication for TKA; 2) Inclusion criteria in clinical trials; 3) Treatment goals/goal criteria; 4) Predictors for goal attainment; 5) Economic aspects of determining a TKA indication; 6) Guidelines of the "Working Group of Scientific Medical Societies" (AWMF) in other areas. The evidence mapping was conducted by systematically searching Medline via Ovid, the Cochrane Library, through hand searching national guidelines and selected journals as well as the AWMF guideline portal. 1) In Germany there is currently no consented guideline regarding indications for TKA surgery. 2) Indication criteria for clinical trials are: diagnosed osteoarthritis of the knee, limitations of age and BMI. The most common criteria for exclusion include rheumatoid/inflammatory arthritis, secondary diagnoses and allergies. 3) As yet, no international initiatives have been identified which, by involving all relevant stakeholders, have reached consensus regarding the indication criteria for TKA. 4) A variety of predictors were identified with effects on individual treatment goals acting in different directions. 5) Very few studies were identified concerning economic aspects of determining TKA indication. 6) Comparable AWMF guidelines are currently not available. The findings of this study suggest that specific systematic reviews are needed to explore the following questions: What are the treatment goals of a TKA intervention? For whom are these relevant? And how are they measured? Continuous analyses are recommended in the field of predictors for a positive TKA outcome.

Self-Reported Memory Complaints: A Comparison of Demented and Unimpaired Outcomes.

Subjective memory complaints are common in aged persons, indicating an increased, but incompletely understood, risk for dementia. To compare cognitive trajectories and autopsy results of individuals with subjective complaints after stratifying by whether a subsequent clinical dementia occurred. Observational study. University of Kentucky cohort with yearly longitudinal assessments and eventual autopsies. Among 516 patients who were cognitively intact and depression-free at enrollment, 296 declared a memory complaint during follow-up. Among those who came to autopsy, 118 died but never developed dementia, while 36 died following dementia diagnosis. Cognitive domain trajectories were compared using linear mixed models adjusted for age, gender, years of education and APOE status. Neuropathological findings were compared cross-sectionally after adjustment for age at death. While the groups had comparable cognitive test scores at enrollment and the time of the first declaration of a complaint, the group with subsequent dementia development had steeper slopes of decline in episodic memory and naming but not fluency or sequencing. Autopsies showed the dementia group had more severe Alzheimer pathology and a higher proportion of subjects with hippocampal sclerosis of aging and arteriolosclerosis, whereas the non-demented group had a higher proportion expressing primary age related tauopathy (PART). While memory complaints are common among the elderly, not all individuals progress to dementia. This study indicates that biomarkers are needed to predict whether a complaint will lead to dementia if this is used as enrollment criteria in future clinical trials.

Current experience in testing mitochondrial nutrients in disorders featuring oxidative stress and mitochondrial dysfunction: rational design of chemoprevention trials.

An extensive number of pathologies are associated with mitochondrial dysfunction (MDF) and oxidative stress (OS). Thus, mitochondrial cofactors termed “mitochondrial nutrients” (MN), such as α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and l-carnitine (CARN) (or its derivatives) have been tested in a number of clinical trials, and this review is focused on the use of MN-based clinical trials. The papers reporting on MN-based clinical trials were retrieved in MedLine up to July 2014, and evaluated for the following endpoints: (a) treated diseases; (b) dosages, number of enrolled patients and duration of treatment; (c) trial success for each MN or MN combinations as reported by authors. The reports satisfying the above endpoints included total numbers of trials and frequencies of randomized, controlled studies, i.e., 81 trials testing ALA, 107 reports testing CoQ10, and 74 reports testing CARN, while only 7 reports were retrieved testing double MN associations, while no report was found testing a triple MN combination. A total of 28 reports tested MN associations with “classical” antioxidants, such as antioxidant nutrients or drugs. Combinations of MN showed better outcomes than individual MN, suggesting forthcoming clinical studies. The criteria in study design and monitoring MN-based clinical trials are discussed.

602P - Rebecca: a Large Cohort Study of Regorafenib (Reg) in the Real-Life Setting in Patients (Pts) Previously Treated for Metastatic Colorectal Cancer (Mcrc)

ABSTRACT Aim: REG is a multi-kinase inhibitor with survival benefits in pts with pretreated mCRC, as demonstrated in the phase III CORRECT study. As a result, REG has been made available for medical practice use in the US, and in the EU. However, prescribing conditions in the real-life setting are known to be less stringent than selection criteria in clinical trials. The REgorafeniB in mEtastatic Colorectal cancer: a French Compassionate progrAm (REBECCA) is an ambispective cohort study designed to elucidate safety and effectiveness outcomes associated with REG as used in clinical practice for mCRC refractory to all available therapies. Methods: Pts were identified from the database of the French ATU (Temporary Authorization for Use), approved by the French Health Authorities to provide early access to innovative, not yet approved medicinal products such as REG. Baseline patient and tumor characteristics, REG dosing and dose-intensity, REG-related adverse events, pre- and post REG treatments, predictors of events, and effectiveness data (PFS, OS) were collected from pts who agreed, and whom physicians accepted to collaborate to the REBECCA study which had OS estimate as a primary objective. Results: 1178 pts met the ATU criteria, of whom 1119 started on REG. 681/1178 (58%) were male. Median age was 64 years (range 25-92). ECOG PS was 0 (31%), 1 (59%), and ≥ 2 (10%). Median time since diagnosis of the metastatic disease was 2.7 years. KRAS mutation was documented in 604/1178 (51%) of pts. Metastases were predominantly located in the liver (76%) and lungs (62%). The starting dose of REG was 160 mg/day in 89.7% of pts. Of the 1178 pts who met the ATU criteria, 787 pts treated by 283 physicians were included in the REBECCA study. Analyses in these patients are in progress. Conclusions: Apart from a baseline PS > 1 in 10% of the pts, the patterns of pts included in the ATU seem to be comparable to those of pts included in the phase III CORRECT study. REBECCA, which is the largest cohort study of REG in mCRC pts ever reported, will provide valuable insights in the therapeutic benefit of this new compound in the real-life setting. Full results of this study will be presented at the meeting. Disclosure: A. Adenis: Bayer (advisory board, research funding). All other authors have declared no conflicts of interest.

Alternative Views On Setting Clinical Trial Futility Criteria

A feature increasingly utilized in clinical trial practice is to allow a study to stop early when it seems unlikely to achieve its primary efficacy objectives. This is commonly referred to as stopping for futility, and can be motivated by ethical and financial considerations. A number of methods for addressing futility have been described in the literature, including rules based upon conditional power, predictive probability, beta spending functions, and others. We consider futility stopping from the point of view of quantifying and providing an objective sensible balance between risks of incorrect decisions (e.g., stopping trials which should continue, and continuing trials which should stop), and discuss how specific considerations within a trial can lead to choice of a sensible scheme. This approach is not specific to any particular scales in the literature such as those just mentioned, and we describe interrelationships among criteria expressed on different scales. As futility may be evaluated multiple times in a long-term trial and the amount of information available at scheduled interim analyses may be difficult to predict in advance, we present a specific optimality criterion and discuss which of the familiar scales tend to produce schemes simple to describe and implement, and with better behavior across different timepoints at which futility might be evaluated.

Disease-specific guidelines for reporting adverse events for peripheral vascular medical devices

Disease-specific guidelines for reporting adverse events for peripheral vascular medical devices

Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer.

Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices.

Definition of improvement in juvenile idiopathic arthritis using the Juvenile Arthritis Disease Activity Score

The aim of this study was to define improvement thresholds for the Juvenile Arthritis Disease Activity Score (JADAS). Physicians' and parents' judgements on treatment efficacy, the ACR paediatric response measure (PedACR) and JADAS were extracted from BIKER. Patients were categorized by baseline classes in the 10-joint JADAS (JADAS10) as low (5 to <15), moderate (15 to <25) and high (25 to ≤40). Cut-offs for defining improvement following treatment with biologics or MTX were chosen by calculating the interquartile ranges (IQRs) of the judgement groups and considering the accuracy, sensitivity and specificity of the resulting model. Differences in the change of JADAS10 by JIA category were also analysed by analysis of variance (ANOVA). Sensitivity, specificity and accuracy were calculated. A total of 1315 treatment courses were analysed. The ANOVA of the JIA categories showed no significant differences of the mean JADAS10 in all baseline classes and IQRs also showed good overall limits. Therefore all JIA categories were combined for a collective cut-off. Analysis by baseline class revealed clear cut-off points. Improvement could be defined by the minimal decrease in the JADAS10 in baseline class low by 4 (41%), moderate by 10 (53%) and high by 17 (57%). The model shows values for accuracy from 75.6 to 85.5% and comparable values for sensitivity and specificity. Improvement after 3 months can be defined efficiently by the decrease of the JADAS10, depending on the baseline JADAS10 score, which specifies low, moderate or high disease activity. Our model demonstrates clear cut-off values. The JADAS10 may be used in addition to ACR criteria in clinical trials. Also, since the JADAS10 can easily be calculated at each patient visit, it also can be used for clinical decisions.

Direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism.

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism (PE), is a serious complication of cancer and its treatment. Patients with cancer have 4- to 7-fold higher risk of developing VTE than those without cancer [1]. Cancer patients with concurrent VTE have approximately 12% risk of bleeding during anticoagulation therapy and up to 25% annual risk of recurrent VTE [1]. The occurrence of VTE may also cause a delay or discontinuation of anti-cancer treatments, including chemotherapy and surgery [2]. Therefore, development of VTE in cancer patients has been associated with an increased risk of death [1]. In general, patients with VTE require anticoagulation therapy to prevent thrombus extension and death, which was largely associated with fatal PE, and to prevent recurrence in the long-term [2]. Traditionally, warfarin has been a common treatment strategy for patients with VTE; the use of warfarin in cancer patients, however, might be limited by complications of cancer and its treatment, including drug reactions, malnutrition, and the frequent need for dose adjustment [3]. As a result, low-molecular-weight-heparin (LMWH) was introduced as a suitable alternative anticoagulant because of few drug interactions and lack of requirement for routine laboratory monitoring; thus, it has been actively investigated in the treatment of cancer-associated VTE. A decade ago, the results of the phase III CLOT trial, which compared initial and maintenance therapy with dalteparin to warfarin therapy after initial dalteparin treatment in patients with cancer-associated VTE, were reported [4]. In this study, long-term dalteparin therapy was significantly associated with lower rates of 6-month cumulative incidence of recurrent VTE (9% vs. 17%) [4]. Since this study, LMWH has been the standard of care for initial and long-term therapy of patients with cancer-associated VTE. However, LMWH for long-term therapy requires a daily subcutaneous injection for cancer patients with VTE, which makes them feel uncomfortable. Thus, unmet needs are still present in the management of cancer-associated VTE.

The American College of Rheumatology and the Systemic Lupus International Collaborating Clinics Classification criteria for systemic lupus erythematosus in two multiethnic cohorts: a commentary

The authors offer some comments on the advantages and possible drawbacks of using the SLICC criteria in longitudinal observational studies and clinical trials after applying and comparing them to the ACR criteria in two multinational, multiethnic lupus cohorts.

Remission of Generalized Anxiety Disorder after 6 Months of Open-Label Treatment with Venlafaxine XR

Background: Remission has become one of the leading outcome criteria in clinical trials. Data collected by this research group assessed the rate of remission after 6 months of treatment of generalized anxiety disorder (GAD) with venlafaxine XR, to search for predictors of remission and to define how early on in treatment later remission can be predicted. Method: Two hundred sixty-eight patients with a GAD diagnosis enrolled into an open-label 6-month-treatment trial with venlafaxine XR (75-225 mg/day). Remission was defined by a Hamilton anxiety scale total score ≤7. Logistic regression approaches were used to find out how early on in treatment later remission could be predicted, as well as to determine predictors of remission. In addition, adverse events were also followed over time. Results: While the total enrolled patient sample (n = 268) had a remission rate of 53%, 6-month completers (n = 159) had a remission rate of 79%. The only statistically significant predictor of remission, independent of baseline anxiety and depression levels, was a low Eysenck neuroticism score. The remission status outcome could best be predicted after 8 weeks of treatment when a CGI-I score of 1 or 2 predicted later remission with 78% accuracy and later nonremission with 91% accuracy. The incidence of adverse events decreased over the 6-month period, with sexual adverse events decreasing the least. Conclusion: The only significant predictor of remission was a low score on the Eysenck neuroticism scale. The earliest reliable prediction of later remission, based on improvement, could be made after 8 weeks of treatment with 91% accuracy.