Valid Endpoint Research Articles

Microalbuminuria: target for renoprotective therapy PRO.

Drug efficacy is ascertained using clinically meaningful outcomes that directly affect the well-being of patients. However, in studies of chronic kidney disease progression, clinically meaningful outcomes like end-stage renal disease take a long time to occur. The use of surrogate end points/markers as replacement for clinical outcomes is tempting as it may reduce sample size requirements, shorten follow-up time, facilitate trial conduct, and allow the performance of intervention trials in earlier stages of kidney disease to be carried out. We here reviewed recent data supporting the use of microalbuminuria as a valid surrogate end point in clinical trials of chronic kidney disease. We provide data that albuminuria is associated with worse renal prognosis and that pharmacological treatment aimed to reduce albuminuria levels delays the progression of renal disease and the occurrence of clinical outcomes. Furthermore, we review new studies showing that albumin is not only an inert molecule but also directly affects the function of several cell types in the kidney and may have a pathogenic role in renal disease. Accepting microalbuminuria as a surrogate marker for renal outcomes will lead to less resource-consuming hard outcome trials, will accelerate the development of drugs for chronic kidney disease, and enable earlier access of these drugs to individual patients.

Surrogate endpoints for overall survival in advanced non-small-cell lung cancer patients with mutations of the epidermal growth factor receptor gene.

Subsequent therapies confound the ability to discern the effect of first-line chemotherapy on overall survival (OS). We investigated whether progression-free survival (PFS), post-progression survival (PPS) and tumor response were valid surrogate endpoints for OS following first-line chemotherapy in individual patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epidermal growth factor receptor gene mutations. We retrospectively analyzed 35 patients with advanced NSCLC treated with first-line gefitinib. The associations of PFS, PPS and tumor response with OS were analyzed. PPS was found to be strongly correlated with OS, unlike PFS and tumor shrinkage. The factors significantly associated with PPS were performance status (PS) after first-line treatment, best response to second-line treatment and number of regimens used after disease progression. PPS may be a surrogate for OS in this patient population and further therapy after disease progression following first-line chemotherapy may significantly affect OS. However, a larger study is required to validate these results.

Are hemodynamics surrogate end points in pulmonary arterial hypertension?

Although frequently assessed in trials and clinical practice, hemodynamic response to therapy has never been validated as a surrogate end point for clinical events in pulmonary arterial hypertension (PAH). We performed a patient-level pooled analysis of 4 randomized, placebo-controlled trials to determine whether treatment-induced changes in hemodynamic values at 12 weeks accounted for the relationship between treatment assignment and the probability of early clinical events (death, lung transplantation, atrial septostomy, PAH hospitalization, withdrawal for clinical worsening, or escalation in PAH therapy). We included 1119 subjects with PAH. The median (interquartile range) age was 48 years (37-59 years), and 23% were men. A total of 656 patients (59%) received active therapy (101 [15%] iloprost, 118 [18%] sitaxsentan, 204 [31%] sildenafil, and 233 [36%] subcutaneous treprostinil). Active treatment significantly lowered right atrial pressure, mean pulmonary artery pressure, and pulmonary vascular resistance and increased cardiac output and index (P<0.01 for all). Changes in hemodynamic values (except for right atrial pressure and mean pulmonary artery pressure) were significantly associated with the risk of a clinical event (P<0.02 for all). Although active treatment approximately halved the odds of a clinical event compared with placebo (P<0.001), changes in hemodynamics accounted for only 1.2% to 13.9% of the overall treatment effect. Treatment-induced changes in hemodynamics at 12 weeks only partially explain the impact of therapy on the probability of early clinical events in PAH. These findings suggest that resting hemodynamics are not valid surrogate end points for short-term events in PAH clinical trials.

Use of composite endpoints in clinical trials

The success of a confirmatory clinical trial designed to demonstrate the efficacy of a new treatment is highly dependent on the choice of valid primary efficacy endpoint(s). The optimal clinical and statistical situation for the design of such a trial is one that starts with the selection of a single primary efficacy endpoint that completely characterizes the disease under study, admits the most efficient clinical and statistical evaluation of treatment effect, and provides clear and broad interpretation of drug effect. For diseases with multidimensional presentations, however, the selection of such an endpoint may not be possible, and so drug effectiveness is often characterized by the use of composite or multiple efficacy endpoint(s). The use of a composite endpoint with components that are only slightly correlated but not quite dissimilar in their recognized clinical relevance could lead to a more sensitive statistical test and thus, adequately powered trials with smaller sample size. This note discusses the utility of composite endpoints in clinical trials and some of the common approaches for dealing with multiplicity arising from their use.

Early Change in Proteinuria as a Surrogate End Point for Kidney Disease Progression: An Individual Patient Meta-analysis

It is controversial whether proteinuria is a valid surrogate end point for randomized trials in chronic kidney disease. Meta-analysis of individual patient-level data. Individual patient data for 9,008 patients from 32 randomized trials evaluating 5 intervention types. Randomized controlled trials of kidney disease progression until 2007 with measurements of proteinuria both at baseline and during the first year of follow-up, with at least 1 further year of follow-up for the clinical outcome. Early change in proteinuria. Doubling of serum creatinine level, end-stage renal disease, or death. Early decline in proteinuria was associated with lower risk of the clinical outcome (pooled HR, 0.74 per 50% reduction in proteinuria); this association was stronger at higher levels of baseline proteinuria. Pooled estimates for the proportion of treatment effect on the clinical outcome explained by early decline in proteinuria ranged from-7.0% (95%CI,-40.6% to 26.7%) to 43.9% (95%CI, 25.3% to 62.6%) across 5 intervention types. The direction of the pooled treatment effects on early change in proteinuria agreed with the direction of the treatment effect on the clinical outcome for all 5 intervention types, with the magnitudes of the pooled treatment effects on the 2 end points agreeing for 4 of the 5 intervention types. The pooled treatment effects on both end points were simultaneously stronger at higher levels of proteinuria. However, statistical power was insufficient to determine whether differences in treatment effects on the clinical outcome corresponded to differences in treatment effects on proteinuria between individual studies. Limited variety of interventions tested and low statistical power for many chronic kidney disease clinical trials. These results provide new evidence supporting the use of an early reduction in proteinuria as a surrogate end point, but do not provide sufficient evidence to establish its validity in all settings.

Effects of selected metal oxide nanoparticles on Artemia salina larvae: evaluation of mortality and behavioural and biochemical responses

The aim was to investigate the toxicity of selected metal oxide nanoparticles (MO-NPs) on the brine shrimp Artemia salina, by evaluating mortality and behavioural and biochemical responses. Larvae were exposed to tin(IV) oxide (stannic oxide (SnO2)), cerium(IV) oxide (CeO2) and iron(II, III) oxide (Fe3O4) NPs for 48h in seawater, with MO-NP suspensions from 0.01 to 1.0mg/mL. Mortality and behavioural responses (swimming speed alteration) and enzymatic activities of cholinesterase, glutathione-S-transferase and catalase were evaluated. Although the MO-NPs did not induce any mortality of the larvae, they caused changes in behavioural and biochemical responses. Swimming speed significantly decreased in larvae exposed to CeO2 NPs. Cholinesterase and glutathione-S-transferase activities were significantly inhibited in larvae exposed to SnO2 NPs, whereas cholinesterase activity significantly increased after CeO2 NP and Fe3O4 NP exposure. Catalase activity significantly increased in larvae exposed to Fe3O4 NPs. In conclusion, swimming alteration and cholinesterase activity represent valid endpoints for MO-NP exposure, while glutathione-S-transferase and catalase activities appear to be NP-specific.

PCR Proves Valid Surrogate Endpoint

Results from the randomized, phase III NeoALTTO trial, presented at the 2013 San Antonio Breast Cancer Symposium in December, support the idea that pathologic complete response is a valid surrogate endpoint for the effectiveness of long-term neoadjuvant treatment of breast cancer.

The Calcium Supplement Controversy: Now What?

The Calcium Supplement Controversy: Now What?

Towards Restoration of Continuous Nasal Breathing as the Ultimate Treatment Goal in Pediatric Obstructive Sleep Apnea

The interaction between oral-facial structural growth and muscle activity starts early in development and continues through childhood. Chronic oral breathing is an important clinical marker of orofacial muscle dysfunction, which may be associated with palatal growth restriction, nasal obstruction, and/ or a primary disorder of muscular or connective tissue dysfunction. It is easily documented objectively during sleep. Treatment of pediatric obstructive-sleep-apnea (OSA) and sleep-disordered-breathing (SBD) means restoration of continuous nasal breathing during wakefulness and sleep; if nasal breathing is not restored, despite short-term improvements after adenotonsillectomy (T&A), continued use of the oral breathing route may be associated with abnormal impacts on airway growth and possibly blunted neuromuscular responsiveness of airway tissues. Elimination of oral breathing, i.e., restoration of nasal breathing during wake and sleep, may be the only valid end point when treating OSA. Preventive measures in at-risk groups, such as premature infants, and usage of myofunctional therapy as part of the treatment of OSA are proposed to be important approaches to treat appropriately SDB and its multiple co-morbidities.

Individual-level data on the relationships of progression-free survival, post-progression survival, and tumor response with overall survival in patients with advanced non-squamous non-small cell lung cancer

The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with non-small cell lung cancer (NSCLC). We examined whether progression-free survival (PFS), post-progression survival (PPS), or tumor response could be valid surrogate endpoints for OS after first-line chemotherapies in advanced NSCLC by using individual-level data, given the lack of research in this area. Between April 2009 and June 2011, 50 patients with advanced non-squamous NSCLC treated with cisplatin and pemetrexed as first-line chemotherapy were analyzed. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level. Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.89, P < 0.05, R2 = 0.79), PFS was moderately correlated with OS (r = 0.67, P < 0.05, R2 = 0.39), and tumor shrinkage was weakly correlated with OS (r = 0.36, P < 0.05, R2 = 0.14). Performance status at the beginning of second-line treatment, the best response to second-line treatment, and number of regimens used after progression following first-line chemotherapy were significantly associated with PPS (P < 0.05). Analysis of individual-level data suggested that PPS could be used as a surrogate for OS in patients with advanced non-squamous NSCLC with unknown oncogenic driver mutations and therefore limited options for subsequent chemotherapy. Our findings also suggest that subsequent treatment after disease progression following first-line chemotherapy may greatly influence OS. These results should be validated in other larger populations.

Intraoperative magnetic resonance imaging versus standard neuronavigation for the neurosurgical treatment of glioblastoma: A randomized controlled trial.

Background:Although the added value of increasing extent of glioblastoma resection is still debated, multiple technologies can assist neurosurgeons in attempting to achieve this goal. Intraoperative magnetic resonance imaging (iMRI) might be helpful in this context, but to date only one randomized trial exists.Methods:We included 14 adults with a supratentorial tumor suspect for glioblastoma and an indication for gross total resection in this randomized controlled trial of which the interim analysis is presented here. Participants were assigned to either ultra-low-field strength iMRI-guided surgery (0.15 Tesla) or to conventional neuronavigation-guided surgery (cNN). Primary endpoint was residual tumor volume (RTV) percentage. Secondary endpoints were clinical performance, health-related quality of life (HRQOL) and survival.Results:Median RTV in the cNN group is 6.5% with an interquartile range of 2.5-14.75%. Median RTV in the iMRI group is 13% with an interquartile range of 3.75-27.75%. A Mann-Whitney test showed no statistically significant difference between these groups (P =0.28). Median survival in the cNN group is 472 days, with an interquartile range of 244-619 days. Median survival in the iMRI group is 396 days, with an interquartile range of 191-599 days (P =0.81). Clinical performance did not differ either. For HRQOL only descriptive statistics were applied due to a limited sample size.Conclusion:This interim analysis of a randomized trial on iMRI-guided glioblastoma resection compared with cNN-guided glioblastoma resection does not show an advantage with respect to extent of resection, clinical performance, and survival for the iMRI group. Ultra-low-field strength iMRI does not seem to be cost-effective compared with cNN, although the lack of a valid endpoint for neurosurgical studies evaluating extent of glioblastoma resection is a limitation of our study and previous volumetry-based studies on this topic.

OMERACT – Where it came from and what it is trying to do

Please cite this article in press as: Kirwa Rheumatology (2013), http://dx.doi.org/10 0973-3698/$ e see front matter Copyright a http://dx.doi.org/10.1016/j.injr.2013.11.019 Between 1983 and 1988 a series of papers demonstrated that Rheumatologists varied considerably in the way they use clinical measures to make judgements about the efficacy of treatment. Clinicians came tomarkedly different conclusions about individual patient response to treatment when managing rheumatoid arthritis (RA) in routine clinical practice. In clinical studies of RA it had been common to use a selection of traditional measures to define the endpoints of the trials. However, the measures chosen were often unique to a particular study, not comprehensive, insensitive to change, and measured overlapping concepts. In spite of conferences, reviews, and editorials no consensus emerged on the appropriate endpoints to include in RA clinical trials. In this context, an endpoint is any measure that is used in the evaluation of patients with RA. During these activities a methodological framework to select valid endpoints and indices was proposed, but the problems with existing measures were in their validity, their relation with individual patient outcomes, and in their multitude. It became recognised that some measures represent the patho-physiological occurrences that follow from the cause of RA, suchas inflammatoryactivity,whereasoutcomemeasures represent the suffering or loss of health experienced by an

End Points in Lung Cancer Clinical Trials: Are we Ready to Step Away from Overall Survival?

467 ISSN 1758-1966 10.2217/LMT.13.54 © 2013 Future Medicine Ltd Lung Cancer Manage. (2013) 2(6), 467–470 Overall survival (OS), defined as the time from randomization or registration to death from any cause, is the gold standard end point in clinical trials as it is a measure of direct clinical benefit to a patient. OS as an end point is unambiguous and can unequivocally assess the benefit of a new treatment relative to the current standard of care. While improving OS remains the ultimate goal of new cancer therapy, an intermediate end point, such as progression-free survival (PFS), a composite end point defined as time from randomization to disease progression or death, is commonly used to evaluate the treatment effect of new oncologic products studied in randomized controlled trials (RCTs) [1]. Two major reasons to explore alternate end points to OS are: first, the inability to effectively assess crossover effects and subsequent therapies; and second, the requirement of large patient numbers and extended follow-up, making it a ‘long’ end point to assess, thereby delaying the development, approval and access to potentially efficacious drugs. Korn et al. discussed the influence of effective subsequent therapies on OS comparisons in RCTs where either subsequent therapy is equally effective in both arms of the RCT or where control arm patients crossover to experimental therapy upon disease progression [2]. The authors concluded that while improvement in an intermediate end point, such as PFS or disease-free survival (DFS), could be considered as evidence of true clinical benefit in adjuvant settings (i.e., early-stage disease), use of OS as the primary outcome is appropriate in trials where there is no intermediate end point to assess clinical benefit. This brings up the discussion of an intermediate end point versus a surrogate end point. An intermediate end point as defined by Korn et al. is one that directly measures true clinical benefit, whereas a surrogate end point is one that has been validated as an adequate substitute for the true clinical end point [2]. A valid surrogate end point must, therefore, both correlate with and accurately predict the true outcome of interest, for example, the treatment effect observed on the surrogate end point should reliably and precisely predict the treatment effect on the true clinical end point [3,4]. Shi et al. elegantly outline the issues surrounding the validation of surrogate end points [4], and review meta-analytic approaches

S82 Multi-centre prospective comparison of the BTS and ACCP guidelines to determine size in primary spontaneous pneumothorax

Introduction and ObjectivesAttempts to develop standardised guidelines in the management of primary spontaneous pneumothorax (PSP) have been severely hampered by a lack of high quality clinical research. The American College...

PHP184 - Acceptance of Surrogate Endpoints by HTA Agencies in Europe

To compare how different European HTA agencies assess surrogate endpoints to demonstrate efficacy. We identified 8 therapies with surrogate endpoints that were evaluated in the last 6 years by NICE and/or SMC (UK), HAS (France) and G-BA (Germany). The acceptability of the use of surrogate endpoints and any specific comments made by these agencies were analysed. Commonly used surrogate endpoints such as glycated haemoglobin (HbA1c) in diabetes, progression free survival (PFS) in oncology and forced expiratory volume (FEV1) for respiratory diseases have been generally accepted as sufficient evidence to gain reimbursement by HTA agencies. Especially when a surrogate endpoint has been accepted by EMA, it is usually considered a valid outcome measure. Less well-accepted were several surrogate cardiovascular endpoints such as 6 minute walk test, blood pressure and LDL cholesterol. For G-BA it is important that surrogate endpoints have been properly validated and are patient relevant but they did accept endpoints such as sustained virological response (SVR) for hepatitis treatments, FEV1 and body mass index (BMI) based on minor evidence. NICE and SMC also strongly value evidence to demonstrate the correlation between surrogate endpoints and clinical outcomes. Interestingly SMC has recently become more cautious in accepting widely established endpoints such as HbA1c. With regards to the HAS, they often did not comment on the use of surrogate endpoints at all in their published reports. The use of surrogate endpoints in the assessment of clinical benefit is still controversial; however, attempts are made to establish clearer regulations such as the recently published EUnetHTA guidelines regarding surrogate endpoints. In the absence of evidence on final patient-relevant clinical endpoints, several commonly used biomarkers and intermediate endpoints will be considered as valid surrogate endpoints by HTA agencies. Newer, less established surrogate endpoints will be more subject to strict validation requirements.

CHronic use of Amiodarone aGAinSt Implantable cardioverter-defibrillator therapy for primary prevention of death in patients with Chagas cardiomyopathy Study: Rationale and design of a randomized clinical trial

The implantable cardioverter defibrillator (ICD) is better than antiarrhythmic drug therapy for the primary and secondary prevention of all-cause mortality and sudden cardiac death in patients with either coronary artery disease or idiopathic dilated cardiomyopathy. This study aims to assess whether the ICD also has this effect for primary prevention in chronic Chagas cardiomyopathy (CCC). In this randomized (concealed allocation) open-label trial, we aim to enroll up to 1,100 patients with CCC, a Rassi risk score for death prediction of ≥10 points, and at least 1 episode of nonsustained ventricular tachycardia on a 24-hour Holter monitoring. Patients from 28 centers in Brazil will be randomly assigned in a 1:1 ratio to receive an ICD or amiodarone (600 mg/d for 10 days, then 200-400 mg/d until the end of the study). The randomization sequence will be generated by computer, and the members of the committees responsible for end point validation and data analysis will be blinded to study assignment. The primary end point is all-cause death, and enrolment will continue until 256 patients have reached this end point. Key secondary end points include cardiovascular death, sudden cardiac death, hospitalization for heart failure, and quality of life. We expect follow-up to last 3 to 6 years, and data analysis will be done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov number NCT01722942. CHAGASICS is the first large-scale trial to assess the benefit of ICD therapy for the primary prevention of death in patients with CCC and nonsustained ventricular tachycardia, who have a moderate to high risk of death.

Quantitative 3D MRI as a Valid Endpoint for Randomized Clinical Trials in Cartilage Repair and its Correlation with Repair Tissue Collagen Architecture

Standardized quantitative 3D MRI was used in a multicenter clinical trial and demonstrated structural superiority of BST-CarGel® treatment over microfracture with regards to both the quantity and quality of repair cartilage. Such improved repair cartilage structure may predict superior durability and sustained clinical benefit. T2 MRI correlated with both PLM and the degree of lesion filling.

Adapting social neuroscience measures for schizophrenia clinical trials, Part 1: ferrying paradigms across perilous waters.

Social cognitive impairment is prominent in schizophrenia, and it is closely related to functional outcome. Partly for these reasons, it has rapidly become a target for both training and psychopharmacological interventions. However, there is a paucity of reliable and valid social cognitive endpoints that can be used to evaluate treatment response in clinical trials. Also, clinical studies in schizophrenia have benefited rather little from the surge of activity and knowledge in nonclinical social neuroscience. The National Institute of Mental Health-sponsored study, "Social Cognition and Functioning in Schizophrenia" (SCAF), attempted to address this translational challenge by selecting paradigms from social neuroscience that could be adapted for use in schizophrenia. The project also evaluated the psychometric properties and external validity of the tasks to determine their suitability for multisite clinical trials. This first article in the theme section presents the goals, conceptual background, and rationale for the SCAF project.

Statistical issues in the validation of prognostic, predictive, and surrogate biomarkers

Biomarkers have many distinct purposes, and depending on their intended use, the validation process varies substantially. The goal of this article is to provide an introduction to the topic of biomarkers, and then to discuss three specific types of biomarkers, namely, prognostic, predictive, and surrogate. A principle challenge for biomarker validation from a statistical perspective is the issue of multiplicity. In general, the solution to this multiplicity challenge is well known to statisticians: pre-specification and replication. Critical requirements for prognostic marker validation include uniform treatment, complete follow-up, unbiased case selection, and complete ascertainment of the many possible confounders that exist in the context of an observational sample. In the case of predictive biomarker validation, observational data are clearly inadequate and randomized controlled trials are mandatory. Within the context of randomization, strategies for predictive marker validation can be grouped into two categories: retrospective versus prospective validation. The critical validation criteria for a surrogate endpoint is to ensure that if a trial uses a surrogate endpoint, the trial will result in the same inferences as if the trial had observed the true endpoint. The field of surrogate endpoint validation has now moved to the multi-trial or meta-analytic setting as the preferred method. Biomarkers are a highly active research area. For all biomarker developmental and validation studies, the importance of fundamental statistical concepts remains the following: pre-specification of hypotheses, randomization, and replication. Further statistical methodology research in this area is clearly needed as we move forward.

Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052)

BackgroundThis was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free survival rate at 18weeks (PFSR-18)1 as primary end-point. MethodsChemotherapy-naïve patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75mg/m2 on day 1 and bortezomib 1.3mg/m2 on days 1, 4, 8, 11 every 3weeks. The primary end-point validation utilised the landmark method. ResultsBetween 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42–64%). The overall survival (OS) was 13.5months (95% CI 10.5–15) with 56% (95% CI 44–66%) alive at 1year. The median PFS was 5.1months (95% CI 3.3–6.5) and the response rate was 28.4% (95% CI 18.9–39.5%).The most frequent grade 3–4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74days) due to acute pneumonitis and cardiac arrest.End-point validation showed that patients with no progression/progression at 18weeks had median OS of 16.9/11.9months, respectively. Hazard ratio was 0.46 (CI 0.32–0.67), logrank test and C-index were 0.007 and 0.60. ConclusionThe 50% PFSR-18 for CB was contained within the 80% CI for (42–64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival.