Primary Outcome In Clinical Trials Research Articles

The New Freezing of Gait Questionnaire: Unsuitable as an Outcome in Clinical Trials?

Freezing of gait (FOG) is a common gait deficit in Parkinson's disease. The New Freezing of Gait Questionnaire (NFOG-Q) is a widely used and valid tool to quantify freezing of gait severity. However, its test-retest reliability and minimal detectable change remain unknown. To determine the test-retest reliability and responsiveness of the NFOG-Q. Two groups of freezers, involved in 2 previous rehabilitation trials, completed the NFOG-Q at 2 time points (T1 and T2), separated by a 6-week control period without active intervention. Sample 1 (N = 57) was measured in ON and sample 2 (N = 14) in OFF. We calculated various reliability statistics for the NFOG-Q scores between T1 and T2 as well as correlation coefficients with clinical descriptors to explain the variability between time points. In sample 1 the NFOG-Q showed modest reliability (intraclass correlation coefficient = 0.68 [0.52-0.80]) without differences between T1 and T2. However, a minimal detectable change of 9.95 (7.90-12.27) points emerged for the total score (range 28 points, relative minimal detectable change of 35.5%). Sample 2 showed largely similar results. We found no associations between cognitive-related or disease severity-related outcomes and variability in NFOG-Q scores. We conclude that the NFOG-Q is insufficiently reliable or responsive to detect small effect sizes, as changes need to go beyond 35% to surpass measurement error. Therefore, we warrant caution in using the NFOG-Q as a primary outcome in clinical trials. These results emphasize the need for robust and objective freezing of gait outcome measures.

Skin improvement is a surrogate for favourable changes in other organ systems in early diffuse cutaneous systemic sclerosis.

Skin improvement in diffuse cutaneous SSc (dcSSc), measured with modified Rodnan skin score (mRSS), is frequently used as a primary outcome in clinical trials, but it is uncertain whether mRSS changes reflect changes in other organ systems. This aim of this study was to explore if skin changes in early dcSSc over 1 and 2 years are associated with changes in severity of other organ involvement. Canadian Scleroderma Research Group database patients with dcSSc, disease duration of ≤5 years, no evidence of initial end-stage organ damage and/or significant comorbidity who had 1 year (n = 154) and 2 years (n = 128) of follow-up data were included. mRSS changes of 25% and/or ≥5 points were considered significant. Organ involvement was assessed by Medsger Disease Severity Score and Canadian Scleroderma Research Group definitions using bivariate, chi-square, ANOVA, adjusted regression and longitudinal mixed effect model analyses. Improvement in mRSS was found in 41% of patients at 1 year and in 50% at 2 years. Improved patients showed less forced vital capacity decline (P = 0.012) and less frequent new cardiac involvement (P = 0.02) over 1 year, as well as better lung (by both Disease Severity Score, P = 0.006, and Δforced vital capacity%, P = 0.026), peripheral vascular (P = 0.006) and joint/tendon (P = 0.002) involvement over 2 years. mRSS worsening was consistently linked to less favourable lung outcomes at both 1- and 2-year follow-up visits, and more severe gastrointestinal disease at 2 years. Changes in lung function in early dcSSc closely parallel skin changes. mRSS improvement reflects better prognosis for visceral disease and may be a reliable outcome measure in clinical trials.

Anatomic measures as primary outcomes in clinical trials

Anatomic measures as primary outcomes in clinical trials

Time to get rid of the Investigator's Global Assessment as the primary outcome for clinical trials in atopic dermatitis?

Time to get rid of the Investigator's Global Assessment as the primary outcome for clinical trials in atopic dermatitis?

Meta-analysis of patient-reported outcomes after laparoscopic versus open inguinal hernia repair

Inguinal hernia repair is a common low-risk intervention. Patient-reported outcomes (PROs) are being used increasingly as primary outcomes in clinical trials. The aim of this study was to review and meta-analyse the PROs in RCTs comparing laparoscopic versus open inguinal hernia repair techniques in adult patients. A systematic review and meta-analysis was carried out in accordance with PRISMA guidelines. Only RCTs in peer-reviewed journals were considered. PubMed, Ovid Embase, Scopus and the Cochrane Library were searched. In addition, four trial registries were searched. The search interval was between 1 January 1998 and 1 May 2018. Identified publications were reviewed independently by two authors. The review was registered in the PROSPERO database (CRD42018099552). Bias was assessed using the Cochrane Collaboration risk-of-bias tool. Some 7192 records were identified, from which 58 unique RCTs were selected. Laparoscopic hernia repair was associated with significantly less postoperative pain in three intervals: from 2 weeks to within 6 months after surgery (risk ratio (RR) 0·74, 95 per cent c.i. 0·62 to 0·88), 6 months to 1 year (RR 0·74, 0·59 to 0·93) and 1 year onwards (RR 0·62, 0·47 to 0·82). Paraesthesia (RR 0·27, 0·18 to 0·40) and patient-reported satisfaction (RR 0·91, 0·85 to 0·98) were also significantly better in the laparoscopic repair group. The data and analysis reported in this study reflect the most up-to-date evidence available for the surgeon to counsel patients. It was constrained by heterogeneity of reporting for several outcomes.

Assessment and Impact of Cognitive Impairment in Multiple Sclerosis: An Overview.

Cognitive impairment affects 40–60% of patients with multiple sclerosis. It may be present early in the course of the disease and has an impact on a patient’s employability, social interactions, and quality of life. In the last three decades, an increasing interest in diagnosis and management of cognitive impairment has arisen. Neuropsychological assessment and neuroimaging studies focusing on cognitive impairment are now being incorporated as primary outcomes in clinical trials. However, there are still key uncertainties concerning the underlying mechanisms of damage, neural basis, sensitivity and validity of neuropsychological tests, and efficacy of pharmacological and non-pharmacological interventions. The present article aimed to present an overview of the assessment, neural correlates, and impact of cognitive impairment in multiple sclerosis.

Evidence supporting wound care end points relevant to clinical practice and patients' lives. Part 2. Literature survey.

Patients with wounds bear significant clinical, personal, and economic burdens yet complete wound healing is the only United States Food and Drug Administration (FDA) recognized primary clinical trial end point. The overall goal of this project is to work with FDA to expand the list of acceptable primary end points, recognizing that new and innovative treatments, devices, and drugs may not have complete healing as the focus. Part 1 of the project surveyed 628 wound care experts who identified and content-validated 15 end points most relevant to clinical practice and benefitting patients' lives as primary outcomes in clinical trials. Part 2 is focused on critical appraisal of the evidence in the wound care literature supporting FDA criteria to qualify these 15 end points as primary end points in clinical trials. Further research involved systematic review of the literature regarding the most promising end points. Forty volunteer, interdisciplinary, wound healing experts in fields related to the end points compiled evidence from systematic MEDLINE searches and society databases supporting the FDA criteria of reliability, clinical construct validity, capacity to detect concurrent or longitudinal change, and responder analysis. The search revealed 485 references involving over 462,000 subjects supporting FDA-required parameters for all 15 end points More than 50 references supported FDA-required parameters qualifying the following outcomes for use in clinical trials supporting interventions for FDA clearance: Pain reduction, Physical function and ambulation, Infection reduction, Time to heal, and Percent wound area reduction in 4-8 weeks. Among these, only Time to heal is currently recognized by the FDA as a primary wound outcome in clinical trials. These results suggest that wound science is already serving patients and professionals by improving these content-validated outcomes that merit regulatory consideration.

The Satisfaction with Communication in Everyday Speaking Situations (SCESS) scale: An overarching outcome measure of treatment effect

PurposeThe Consolidated Standards of Reporting Trials (CONSORT) statement strongly suggests one primary outcome for clinical trials, yet the outcomes of stuttering treatments span numerous behavioral and psychosocial domains. That presents a roadblock to eventual meta-analysis of clinical trials for adults who stutter. MethodWe propose a simple and convenient outcome measure for clinical trials of stuttering treatment for adults that spans whatever behavioral and psychosocial factors might impel clients to seek treatment: a nine-point scale of Satisfaction with Communication in Everyday Speaking Situations (SCESS). The scale consists of one question which is simple, brief, easy to administer, cost-free, and translatable into many languages. The present report develops the SCESS scale by determining its reliability, content validity, and construct validity. ResultsReliability, content validity, and construct validity of the SCESS were confirmed with statistically significant and substantive correlations with speech-related and anxiety-related measures. However, the SCESS did not correlate well with percentage syllables stuttered. Three behavioral and psychosocial measures had the highest correlation with the SCESS: total Overall Assessment of the Speaker’s Experience of Stuttering, self-reported stuttering severity, and Unhelpful Thoughts and Beliefs about Stuttering. ConclusionThe SCESS measure has potential to be applied as an overarching clinical trial outcome measure of stuttering treatment effect. This study provides some preliminary evidence for including it as a primary or secondary outcome in clinical trials of adult stuttering treatments. However, further studies are needed to establish the SCESS responsiveness to different stuttering treatments.

Pharmacotherapy of Adult Patient with Chronic Urticaria Associated with Gastritis

Chronic urticaria is a challenge both for the patient and the physician. It may seem as a trivial disease, but significantly undermines the patients' quality of life. Due to the constant or constantly relapsing tormenting itch and changes in the appearance, it has a negative impact on the social life and mental state of the patients that limit their working lives. The aim of treatment is to achieve complete symptom relief. However, it can take quite a long time to achieve complete remission. Treating the cause is the most desirable option, but it is, unfortunately, not applicable in the majority of patients, in which urticaria is idiopathic. In all cases, unless contraindicated, symptomatic relief should be offered while searching for the underlying cause. Symptomatic treatment is currently the most frequent form of management. Health related quality of life is increasingly being recognized as a primary outcome in clinical trials, population studies and public health. In treatment the patient's well-being should be a central focus as CU can persist over an extended duration from six weeks to over twenty years.

Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community.

Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient-centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient-centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature-based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty-two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory evaluation.

Disease-modifying Antirheumatic Drugs (DMARD) and Combination Therapy of Conventional DMARD in Patients with Spondyloarthritis and Psoriatic Arthritis with Axial Involvement.

Treatment with nonsteroidal antiinflammatory drugs (NSAID) is the recommended first-line therapy in patients with axial spondyloarthritis (axSpA); and for those patients who have persistently active disease, the introduction of tumor necrosis factor-α (TNF-α) inhibitors is indicated. Conventional nonbiological disease-modifying antirheumatic drugs (DMARD), although effective and used in clinical practice for peripheral arthritis, are not recommended. Few studies have been conducted with the aim of evaluating the effect of conventional DMARD, either alone or in combination, in axSpA. As for psoriatic arthritis (PsA), DMARD are widely used, but few trials are available about their effects on axial involvement, which is not often assessed as a primary outcome in clinical trials. In rheumatoid arthritis, combination therapy of 2 or more conventional DMARD appears to confer better response than methotrexate monotherapy, and may even be a viable alternative to TNF-α inhibitors. In peripheral PsA, combination therapy can be used after treatment failure with 1 DMARD, but few studies have been conducted. However, available evidence for the combination of conventional DMARD indicates a lack of any significant benefit on axial symptoms; thus this treatment approach does not represent an effective alternative to anti-TNF-α therapy.

Carotid Artery Intima-Media Thickness Measurements in the Youth: Reproducibility and Technical Considerations

Carotid artery intima-media thickness (CIMT), a marker of atherosclerosis, is increased in youth at risk for future cardiovascular disease. Some pediatric studies have used CIMT as a primary outcome in clinical trials, yet data are limited on the standardization of methodology in children. The goal of this study was to evaluate reproducibility of CIMT measurements using two different measurement techniques. Carotid artery ultrasound studies of children and adolescents obtained as a component of a research study in Kawasaki syndrome were retrospectively analyzed. The CIMTs of both common carotid arteries (CCAs) were measured by one of two sonographers at the time in the cardiac cycle when resolution subjectively was determined to be optimal (Opt-CIMT). These sonographers blindly remeasured a random sample of studies of their own and each other's, using the same method. Another observer made CIMT measurements using exclusively frames on the R wave (R-CIMT). A fourth observer independently measured a random sample of studies twice with the R-CIMT method. Carotid artery images from 184 subjects (mean age, 14.7 ± 2.2 years) were analyzed. The intraclass correlation coefficient for interobserver variability was 0.86 (95% confidence interval [CI], 0.69-0.94) compared with 0.85 (95% CI, 0.65-0.93) for the right and 0.86 (95% CI, 0.67-0.94) versus 0.95 (95% CI, 0.87-0.98) for the left CCA for Opt-CIMT and R-CIMT, respectively. R-CIMT was significantly thicker than Opt-CIMT (right CCA, 0.439 ± 0.030 vs 0.428 ± 0.024 mm, P < .001; left CCA, 0.446 ± 0.030 vs 0.434 ± 0.025 mm, P < .001). Pediatric CIMT measurements have excellent reproducibility when the same methodology is applied but vary significantly throughout the cardiac cycle. This report highlights the need to standardize CIMT measurements in the youth and supports the use of electrocardiographic timing, as recommended in adults, in pediatric longitudinal studies.

SAT0219 Shear-Wave Elastography: A New Imaging Method for Evaluating Scleroderma Skin

BackgroundSkin involvement is of major clinical and prognostic relevance in systemic sclerosis (SSc) and is often the primary outcome in clinical trials in SSc. Nevertheless, a fully validated, objective and...

OP0228 Optical coherence tomography validation: A new quantitative imaging biomarker for affected skin in scleroderma

BackgroundSkin involvement in systemic sclerosis (SSc) is often primary outcome in clinical trials but it is still orphan of a quantitative imaging technique. Optical Coherence Tomography (OCT) is an emerging...

Virtual skin biopsy by optical coherence tomography: the first quantitative imaging biomarker for scleroderma

BackgroundSkin involvement is of major prognostic value in systemic sclerosis (SSc) and often the primary outcome in clinical trials. Nevertheless, an objective, validated biomarker of skin fibrosis is lacking. Optical...

Visual acuity in children with low grade gliomas of the visual pathway: implications for patient care and clinical research

Low grade gliomas affecting the visual pathway, commonly referred to as optic pathway gliomas (OPGs), have a relatively high survival rate but can cause significant vision loss. While previous treatment outcomes for tumors of the central nervous system have focused primarily on changes in tumor size or patient survival, more recently preservation of vision has also become a primary objective when treating these tumors. Visual acuity (VA) is the most testable and reliable visual parameter in young children with OPGs. Unfortunately, standardized VA assessments have neither been employed to make treatment decisions nor used as primary outcomes in clinical trials. The lack of a standardized VA assessment has also hindered the ability to interpret and compare results between studies. It is essential that all members of the multidisciplinary care team (i.e., pediatric neuro-oncologist, neurologist, neurosurgeon, and ophthalmologist) can accurately interpret VA results and properly use them to guide management decisions. Specifically, determining what constitutes a significant change in VA and the factors that may influence these results should be incorporated into collective team recommendations. This review describes the VA assessment in children with OPGs and proposes a standardized VA testing protocol for future pediatric OPG clinical treatment trials.

Incidence of pressure ulcers as primary outcomes in clinical trials: A comment on

Special support surfaces are indispensable measures for essure ulcer prevention in high risk patients. Since merous products and systems are on the market, it may metimes be difficult to find out which ones work best. stematic reviews evaluating and summarizing the levant clinical data in the literature provide excellent pport for practitioners who are expected to make idence-based decisions, such as in regard to purchase protective equipment for a patient population or escription of a support surface for an individual. With eir high-quality systematic review and meta-analysis, cInnes et al. (2012) made a valuable contribution to our idence-based knowledge in pressure ulcer prevention. sults from over 50 different studies were collected, refully evaluated and analyzed using state-of-the-art ethodological standards. However, a typical limitation of ch meta-analyses is that information which is inherent the individual studies, is somehow lost when ‘‘avering’’ the many trials together. It is this loss of sometimes portant information which may later on cause problems our general understanding of whether and how the vestigated interventions might have worked. One major and still not fully resolved problem in essure ulcer research is the definition of what pressure cers really are. Conceptual difficulties persist around aetiology, pathogenesis and clinical appearance (e.g. Beeckman et al., 2009; Campbell and Parish, 2010; Kottner et al., 2009). These difficulties are very well reflected in the constantly changing pressure ulcer classifications. In 1975, Shea proposed, what soon became one of the first formal pressure ulcer classification systems, five pressure ulcer categories including so called ‘‘Closed Pressure Sores’’ under intact skin. Among others, Shea described category 1 pressure ulcers as ‘‘. . . a thickening and distortion of all tissue layers between the surface and the underlying bone’’ (p. 91). This definition of category 1 pressure ulcers and the ‘‘Closed Pressure Sore’’ category indicate that Shea regarded the origin of pressure-related tissue breakdown somewhere in all the tissue layers that could potentially be affected by the mechanical loading, including the dermis, subcutaneous fat and muscles. These ideas correspond to very early experimental results (e.g. Groth, 1942) but they are also very well accepted today (e.g. Bouten et al., 2003; Gefen, 2007). The development of pressure ulcers under intact skin is sometimes called bottom-up or inside-out process, in which damage first appears in skeletal muscle tissue directly under a weight-bearing bony prominence or in adipose tissue in vicinity of such a bony prominence (Fig. 1). There is a ‘‘middle-model’’ as well (Sharp and McLaws, 2005), which describes the onset of cell death and tissue damage anywhere in the skin or deeper tissues (Fig. 2). Importantly, both theories share the concept that sustained mechanical loads, which are manifested by compressive, tensile and shear deformations in all the soft tissue layers around a weight-bearing bony prominence, are primarily being responsible for the clinical outcome of a deep tissue injury (Bouten et al., 2003). On the other hand, nearly all the subsequently proposed pressure ulcer classification systems seemed to be based on a kind of top-down or outside-in mechanism. The (implicit) assumption of these models is that tissue R T I C L E I N F O

Quality of life in advanced non-small cell lung cancer patients receiving palliative chemotherapy: A meta-analysis of randomized controlled trials

For advanced non-small cell lung cancer (NSCLC) patients, the only treatment option is palliative therapy, with the aim of prolonging overall survival and improving disease-related symptoms and quality of life (QOL). However, to date, the effect of palliative care on QOL has not yet been thoroughly examined, and there has been no meta-analysis of previous studies reporting QOL outcomes following palliative care. We consider that it is important to evaluate not only survival and/or response rates, but also QOL in patients with advanced NSCLC receiving palliative chemotherapy. The aim of the present study was to obtain useful information for the selection of suitable chemotherapy regimens for advanced NSCLC patients, taking into consideration QOL, and to demonstrate the importance of QOL assessments during treatment. We performed a meta-analysis of QOL outcomes following treatments that compared carboplatin- to cisplatin-based chemotherapy. Trials were eligible for analysis if they had compared carboplatin- to cisplatin-based chemotherapy in advanced NSCLC patients who had not received prior chemotherapy, and if these studies reported QOL data. In the six trials eligible for analysis, 2,405 patients were randomized to receive cisplatin-based or carboplatin-based chemotherapy. The patients who received carboplatin-based chemotherapy had higher global QOL and less severe symptoms than those who received cisplatin-based chemotherapy. The survival rate, which was the primary outcome in clinical trials, and the response rate did not differ significantly between the two treatment groups. It is important to evaluate QOL in addition to the survival and response rates for advanced NSCLC, particularly when the treatment is palliative.

Asthma outcome measures

Asthma is a common chronic disease with underlying inflammation of the airway. Advances in science have led to increased understanding of the heterogeneous nature of asthma and its complex mechanisms. Traditionally, asthma-practice guidelines have focused on optimizing lung function and the US FDA has required increases in lung function and reduction of exacerbation as primary outcomes in clinical trials of new asthma therapeutics. Improved lung function is a critical indicator of bronchodilator therapy, but the importance of long-term asthma control while maintained on controller medication is increasingly emphasized. The NIH asthma guidelines suggest the use of patient-reported outcomes, including health-related quality-of-life measures, to assess asthma control. Clinical practices and research studies concerning asthma can benefit from harmonizing the major outcome measures so that comparisons across studies can be made. In this article, we review common asthma outcome measures with a focus on recent efforts to harmonize outcomes for therapeutic clinical trials in asthma.

Incomplete and inconsistent reporting of maternal and fetal outcomes in infertility treatment trials

Pregnancy outcomes and adverse outcomes in infertility trials are reported to varying extents; for example, 35% of clinical trials reported no information on pregnancy loss, only 43% reported adverse events during the preconception treatment period, and only 7% reported any serious adverse events. Incomplete reporting limits the value of these studies in counseling patients on the risk-benefit ratio of treatment to themselves and their infants.