Monitoring strategies for clinical intervention studies.

BACKGROUND: Trial monitoring is an important component of good clinical practice to ensure the safety and rights of study participants, confidentiality of personal information, and quality of data. However, the effectiveness of various existing monitoring approaches is unclear. Information to guide the choice of monitoring methods in clinical intervention studies may help trialists, support units, and monitors to effectively adjust their approaches to current knowledge and evidence. OBJECTIVES: To evaluate the advantages and disadvantages of different monitoring strategies (including risk-based strategies and others) for clinical intervention studies examined in prospective comparative studies of monitoring interventions. SEARCH METHODS: We systematically searched CENTRAL, PubMed, and Embase via Ovid for relevant published literature up to March 2021. We searched the online 'Studies within A Trial' (SWAT) repository, grey literature, and trial registries for ongoing or unpublished studies. SELECTION CRITERIA: We included randomized or non-randomized prospective, empirical evaluation studies of different monitoring strategies in one or more clinical intervention studies. We applied no restrictions for language or date of publication. DATA COLLECTION AND ANALYSIS: We extracted data on the evaluated monitoring methods, countries involved, study population, study setting, randomization method, and numbers and proportions in each intervention group. Our primary outcome was critical and major monitoring findings in prospective intervention studies. Monitoring findings were classified according to different error domains (e.g. major eligibility violations) and the primary outcome measure was a composite of these domains. Secondary outcomes were individual error domains, participant recruitment and follow-up, and resource use. If we identified more than one study for a comparison and outcome definitions were similar across identified studies, we quantitatively summarized effects in a meta-analysis using a random-effects model. Otherwise, we qualitatively summarized the results of eligible studies stratified by different comparisons of monitoring strategies. We used the GRADE approach to assess the certainty of the evidence for different groups of comparisons. MAIN RESULTS: We identified eight eligible studies, which we grouped into five comparisons. 1. Risk-based versus extensive on-site monitoring: based on two large studies, we found moderate certainty of evidence for the combined primary outcome of major or critical findings that risk-based monitoring is not inferior to extensive on-site monitoring. Although the risk ratio was close to 'no difference' (1.03 with a 95% confidence interval [CI] of 0.81 to 1.33, below 1.0 in favor of the risk-based strategy), the high imprecision in one study and the small number of eligible studies resulted in a wide CI of the summary estimate. Low certainty of evidence suggested that monitoring strategies with extensive on-site monitoring were associated with considerably higher resource use and costs (up to a factor of 3.4). Data on recruitment or retention of trial participants were not available. 2. Central monitoring with triggered on-site visits versus regular on-site visits: combining the results of two eligible studies yielded low certainty of evidence with a risk ratio of 1.83 (95% CI 0.51 to 6.55) in favor of triggered monitoring intervention. Data on recruitment, retention, and resource use were not available. 3. Central statistical monitoring and local monitoring performed by site staff with annual on-site visits versus central statistical monitoring and local monitoring only: based on one study, there was moderate certainty of evidence that a small number of major and critical findings were missed with the central monitoring approach without on-site visits: 3.8% of participants in the group without on-site visits and 6.4% in the group with on-site visits had a major or critical monitoring finding (odds ratio 1.7, 95% CI 1.1 to 2.7; P = 0.03). The absolute number of monitoring findings was very low, probably because defined major and critical findings were very study specific and central monitoring was present in both intervention groups. Very low certainty of evidence did not suggest a relevant effect on participant retention, and very low certainty evidence indicated an extra cost for on-site visits of USD 2,035,392. There were no data on recruitment. 4. Traditional 100% source data verification (SDV) versus targeted or remote SDV: the two studies assessing targeted and remote SDV reported findings only related to source documents. Compared to the final database obtained using the full SDV monitoring process, only a small proportion of remaining errors on overall data were identified using the targeted SDV process in the MONITORING study (absolute difference 1.47%, 95% CI 1.41% to 1.53%). Targeted SDV was effective in the verification of source documents, but increased the workload on data management. The other included study was a pilot study, which compared traditional on-site SDV versus remote SDV and found little difference in monitoring findings and the ability to locate data values despite marked differences in remote access in two clinical trial networks. There were no data on recruitment or retention. 5. Systematic on-site initiation visit versus on-site initiation visit upon request: very low certainty of evidence suggested no difference in retention and recruitment between the two approaches. There were no data on critical and major findings or on resource use. AUTHORS' CONCLUSIONS: The evidence base is limited in terms of quantity and quality. Ideally, for each of the five identified comparisons, more prospective, comparative monitoring studies nested in clinical trials and measuring effects on all outcomes specified in this review are necessary to draw more reliable conclusions. However, the results suggesting risk-based, targeted, and mainly central monitoring as an efficient strategy are promising. The development of reliable triggers for on-site visits is ongoing; different triggers might be used in different settings. More evidence on risk indicators that identify sites with problems or the prognostic value of triggers is needed to further optimize central monitoring strategies. In particular, approaches with an initial assessment of trial-specific risks that need to be closely monitored centrally during trial conduct with triggered on-site visits should be evaluated in future research.

Repeated Cortisol Awakening Response as Predictor of Antidepressant Treatment Outcome with Duloxetine.

BACKGROUND: Despite considerably extended knowledge about the mechanism of action of antidepressants, physicians would greatly benefit from reliable biological predictors identifying those patients who will respond poorly to a given treatment. The aim of the present study was to assess whether repeated testing of the cortisol awakening response (CAR) between baseline and after 10 days of duloxetine treatment is able to predict antidepressant treatment outcome after 6 weeks of treatment. METHODS: 12 patients with a major depressive episode were treated with duloxetine 90 mg/day for 6 weeks. At baseline and after 10 days of duloxetine treatment, the CAR was assessed, and changes between baseline and day 10 were categorized as improved or unimproved according to the change in cortisol area under the concentration-time curve total concentrations. Depression severity was assessed with the 21-item Hamilton Depression Rating Scale (HDRS-21). RESULTS: Non-remission after 6 weeks of treatment with duloxetine was predicted by an unfavourable saliva cortisol change between baseline and 10 days of duloxetine treatment. Linear regression analysis revealed that patients with a higher decrease in saliva cortisol measures between baseline and 10 days of treatment show a higher decrease in HDRS-21 scores. CONCLUSION: Repeated CAR during early treatment is a putative predictive marker of antidepressant treatment outcome with duloxetine. © 2015 S. Karger AG, Basel.

A minimal model of peptide binding predicts ensemble properties of serum antibodies.

BACKGROUND: The importance of peptide microarrays as a tool for serological diagnostics has strongly increased over the last decade. However, interpretation of the binding signals is still hampered by our limited understanding of the technology. This is in particular true for arrays probed with antibody mixtures of unknown complexity, such as sera. To gain insight into how signals depend on peptide amino acid sequences, we probed random-sequence peptide microarrays with sera of healthy and infected mice. We analyzed the resulting antibody binding profiles with regression methods and formulated a minimal model to explain our findings. RESULTS: Multivariate regression analysis relating peptide sequence to measured signals led to the definition of amino acid-associated weights. Although these weights do not contain information on amino acid position, they predict up to 40-50% of the binding profiles' variation. Mathematical modeling shows that this position-independent ansatz is only adequate for highly diverse random antibody mixtures which are not dominated by a few antibodies. Experimental results suggest that sera from healthy individuals correspond to that case, in contrast to sera of infected ones. CONCLUSIONS: Our results indicate that position-independent amino acid-associated weights predict linear epitope binding of antibody mixtures only if the mixture is random, highly diverse, and contains no dominant antibodies. The discovered ensemble property is an important step towards an understanding of peptide-array serum-antibody binding profiles. It has implications for both serological diagnostics and B cell epitope mapping.

Integrative genome-wide expression profiling identifies three distinct molecular subgroups of renal cell carcinoma with different patient outcome.

BACKGROUND: Renal cell carcinoma (RCC) is characterized by a number of diverse molecular aberrations that differ among individuals. Recent approaches to molecularly classify RCC were based on clinical, pathological as well as on single molecular parameters. As a consequence, gene expression patterns reflecting the sum of genetic aberrations in individual tumors may not have been recognized. In an attempt to uncover such molecular features in RCC, we used a novel, unbiased and integrative approach. METHODS: We integrated gene expression data from 97 primary RCC of different pathologic parameters, 15 RCC metastases as well as 34 cancer cell lines for two-way nonsupervised hierarchical clustering using gene groups suggested by the PANTHER Classification System. We depicted the genomic landscape of the resulted tumor groups by means of Single Nuclear Polymorphism (SNP) technology. Finally, the achieved results were immunohistochemically analyzed using a tissue microarray (TMA) composed of 254 RCC. RESULTS: We found robust, genome wide expression signatures, which split RCC into three distinct molecular subgroups. These groups remained stable even if randomly selected gene sets were clustered. Notably, the pattern obtained from RCC cell lines was clearly distinguishable from that of primary tumors. SNP array analysis demonstrated differing frequencies of chromosomal copy number alterations among RCC subgroups. TMA analysis with group-specific markers showed a prognostic significance of the different groups. CONCLUSION: We propose the existence of characteristic and histologically independent genome-wide expression outputs in RCC with potential biological and clinical relevance.

Biplanar MRI for the assessment of the spinal cord in multiple sclerosis.

OBJECTIVE: To investigate the entire spinal cord (SC) of multiple sclerosis (MS) patients with biplanar MRI and to relate these MRI findings to clinical functional scores. METHODS: Two hundred and two patients (140 women, 62 men 24-74 years, Expanded Disability Status Scale (EDSS) scores 0-7.5) were investigated clinically and with biplanar MRI. Sagittal and axial proton density weighted (PDw) and T2 weighted (T2w) images of the whole SC were obtained employing parallel imaging. Data were analyzed by consensus reading using a standardized reporting scheme. Different combinations of findings were compared to EDSS scores with Spearman's rank correlation coefficient (ρ). RESULTS: The combined analysis of sagittal and axial planes demonstrated slightly differing results in 97/202 (48%) patients. There were 9% additional lesions identified, leading to a higher lesion count in 28% of these patients, but also rejection of equivocal abnormality leading to a lower lesion count in 11% of patients. Considering both sagittal and axial images, SC abnormalities were found in 167/202 (83%) patients. When compared with EDSS scores, the combination of focal lesions, signs of atrophy and diffuse abnormalities showed a moderate correlation (ρ=0.52), that precludes its use for individual patient assessment. CONCLUSION: Biplanar MRI facilitates a comprehensive identification, localization, and grading of pathological SC findings in MS patients. This improves the confidence and utility of SC imaging.

Body composition analysis in patients with acute heart failure: the Scale Heart Failure trial.

AIMS: In this study, we aimed to investigate whether body composition analysis (BCA) derived from bioelectrical impedance vector analysis (BIVA) could be used to monitor the hydration status of patients with acute heart failure (AHF) during intensified diuretic therapy. METHODS AND RESULTS: This observational, single-centre study involved a novel, validated eight-electrode segmental body composition analyser to perform BCA derived from BIVA with an alternating current of 100 µA at frequencies of 5, 7.5, 50, and 75 kHz. The BCA-derived and BIVA-derived parameters were estimated and compared with daily body weight measurements in hospitalized patients with AHF. A total of 867 BCA and BIVA assessments were conducted in 142 patients (56.3% men; age 76.8 ± 10.7 years). Daily changes in total body water (TBW) and extracellular water (ECW) were significantly associated with changes in body weight in 62.2% and 89.1% of all measurements, respectively (range, ±1 kg). Repeated measures correlation coefficients between weight loss and TBW loss resulted with rho 0.43, P < 0.01, confidence interval (CI) [0.36, 0.50] and rho 0.71, P > 0.01, CI [0.67, 0.75] for ECW loss. Between the first and last assessments, the mean weight loss was -2.5 kg, compared with the -2.6 L mean TBW loss and -1.7 L mean ECW loss. BIVA revealed an increase in mean Resistance R and mean Reactance Xc across all frequencies, with the subsequent reduction in body fluid (including corresponding body weight) between the first and last assessments. CONCLUSIONS: Body composition analysis derived from BIVA with a focus on ECW is a promising approach to detect changes in hydration status in patients undergoing intensified diuretic therapy. Defining personalized BIVA reference values using bioelectrical impedance devices is a promising approach to monitor hydration status.

Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial.

BACKGROUND: Cervical artery dissection is a major cause of stroke in young people (aged <50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K antagonists for patients with cervical artery dissection, although some current guidelines-based on available evidence from mostly observational studies-suggest using aspirin. If proven to be non-inferior to vitamin K antagonists, aspirin might be preferable, due to its ease of use and lower cost. We aimed to test the non-inferiority of aspirin to vitamin K antagonists in patients with cervical artery dissection. METHODS: We did a multicentre, randomised, open-label, non-inferiority trial in ten stroke centres across Switzerland, Germany, and Denmark. We randomly assigned (1:1) patients aged older than 18 years who had symptomatic, MRI-verified, cervical artery dissection within 2 weeks before enrolment, to receive either aspirin 300 mg once daily or a vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target international normalised ratio [INR] 2·0-3·0) for 90 days. Randomisation was computer-generated using an interactive web response system, with stratification according to participating site. Independent imaging core laboratory adjudicators were masked to treatment allocation, but investigators, patients, and clinical event adjudicators were aware of treatment allocation. The primary endpoint was a composite of clinical outcomes (stroke, major haemorrhage, or death) and MRI outcomes (new ischaemic or haemorrhagic brain lesions) in the per-protocol population, assessed at 14 days (clinical and MRI outcomes) and 90 days (clinical outcomes only) after commencing treatment. Non-inferiority of aspirin would be shown if the upper limit of the two-sided 95% CI of the absolute risk difference between groups was less than 12% (non-inferiority margin). This trial is registered with ClinicalTrials.gov, NCT02046460. FINDINGS: Between Sept 11, 2013, and Dec 21, 2018, we enrolled 194 patients; 100 (52%) were assigned to the aspirin group and 94 (48%) were assigned to the vitamin K antagonist group. The per-protocol population included 173 patients; 91 (53%) in the aspirin group and 82 (47%) in the vitamin K antagonist group. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI -4 to 21], non-inferiority p=0·55). Thus, non-inferiority of aspirin was not shown. Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischaemic strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial haemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group, and 26 in the vitamin K antagonist group. INTERPRETATION: Our findings did not show that aspirin was non-inferior to vitamin K antagonists in the treatment of cervical artery dissection. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Stroke Funds Basel, University Hospital Basel, University of Basel, Academic Society Basel.

Epitope mapping using randomly generated peptide libraries.

Characterizing the immune response towards a pathogen is of high interest for vaccine development and diagnosis. However, the characterization of disease-related antigen-antibody interactions is of enormous complexity. Here, we present a method comprising binding studies of serum antibody pools to synthetic random peptide libraries, and data analysis of the resulting binding patterns. The analysis can be applied to classify and predict different groups of individuals and to detect the peptides which best discriminate the investigated groups. As an example, the analysis of antibody repertoire binding patterns of different mice strains and of mice infected with helminth parasites is shown. Due to the design of the library and the sophisticated analysis, the method is able to classify and predict the different mice strains and the infection with very high accuracy and with a very small number of peptides, illustrating the potential of random library screenings in determining molecular markers for diagnosis.

Single-dose versus 3-day cotrimoxazole prophylaxis in transurethral resection or greenlight laser vaporisation of the prostate: study protocol for a multicentre randomised placebo controlled non-inferiority trial (CITrUS trial).

BACKGROUND: Transurethral resection of the prostate (TURP) and Greenlight laser vaporisation (GL) of the prostate are frequently performed urological procedures. For TURP, a single-dose antimicrobial prophylaxis (AP) is recommended to reduce postoperative urinary tract infections. So far, no international recommendations for AP have been established for GL. In a survey-based study in Switzerland, Germany and Austria, urologists reported routinely extending AP primarily for 3 days after both interventions. We therefore aim to determine whether single-dose AP with cotrimoxazole is non-inferior to 3-day AP with cotrimoxazole in patients undergoing TURP or GL of the prostate. METHODS/DESIGN: We will conduct an investigator-initiated, multicentre, randomised controlled trial. We plan to assess the non-inferiority of single-dose AP compared to 3-day AP. The primary outcome is the occurrence of clinically diagnosed symptomatic urinary tract infections which are treated with antimicrobial agents within 30 days after randomisation. The vast majority of collected outcomes will be assessed from routinely collected data. The sample size was estimated to be able to show the non-inferiority of single-dose AP compared to 3-day AP with at least 80% power (1 - ß = 0.8) at a significance level of α = 5%, applying a 1:1 randomisation scheme. The non-inferiority margin was determined in order to preserve 70% of the effect of usual care on the primary outcome. For an assumed event rate of 9% in both treatment arms, this resulted in a non-inferiority margin of 4.4% (i.e. 13.4% to 9%). To prove non-inferiority, a total of 1574 patients should be recruited, in order to have 1416 evaluable patients. The study is supported by the Swiss National Science Foundation. DISCUSSION: For AP in TURP and GL, there is a large gap between usual clinical practice and evidence-based guidelines. If single-dose AP proves non-inferior to prolonged AP, our study findings may help to reduce the duration of AP in daily routine-potentially reducing the risk of emerging resistance and complications related to AP. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03633643 . Registered 16 August 2018.

Affinity profiling using the peptide microarray technology: a case study.

Little about the reliability of measurements obtained using synthetic peptide microarrays is known. We report results from a study on the quantitative reliability of microarrays manufactured by robot-supported immobilization of presynthesized peptides for different microarray platforms. Technological precision is assessed for inter- and intra-device readout comparisons. Correlations between measured signals and known dissociation constants using a phenomenological model derived from the mass action law are discussed. Special emphasis is on discussing the pitfalls of high-throughput affinity measurements. We show that the quantitative determination of binding affinities is prone to be biased toward a mean affinity of around 10(-7)M, while the classification of peptides into either "binders" or "nonbinders" provides very high prediction accuracy. The experimental requirements needed to obtain reliable binding affinity predictions are discussed.

Influence of the photocycle and thermocycle on rhythms of plasma thyroxine and plasma and ocular melatonin in late metamorphic stages of the bullfrog tadpole, Rana catesbeiana.

The diel fluctuations in plasma thyroxine (T(4)) and plasma and ocular melatonin entrain to the light/dark (LD) cycle in the bullfrog tadpole, although the phase of the rhythms changes during development. Previous studies on the rhythmicity of these hormones were conducted under various LD cycles, but with a constant temperature, raising the question of the role of the natural thermocycle in determining the phase of the rhythms, and the changes that occur in the hormone levels and rhythms during late metamorphosis. To study this question, tadpoles were acclimated to simulated natural conditions of 14.5L:9.5D with a corresponding thermocycle in which the thermophase was 28 degrees C and the cryophase was 18 degrees C, or to the same thermocycle under constant light (24L). On both photoregimens, the diel fluctuations changed between prometamorphosis and metamorphic climax. However, more statistically significant rhythms, as indicated by the cosinor, occurred on 14.5L:9.5D than on 24L. At climax on the LD cycle, all hormones peaked around the same time in the late scotocryophase, whereas on 24L, plasma T(4) peaked in the thermophase and plasma and ocular melatonin peaks occurred some distance from each other early in the cryophase. The earlier peaks of plasma and ocular melatonin on 24L were due to a transient rise in these hormones at the onset of the cryophase, which was not sustained in the absence of an LD cycle. On 14.5L:9.5D with a corresponding thermocycle, the hormone rhythms had nearly the same phases as was found in previous work on 12L:12D at a constant temperature of 22 degrees C, allowing for minor phase shifting due to the photocycle differences, indicating that in this species laboratory studies on constant temperature give valid results even in the absence of a thermocycle. The findings show that the phases of the hormone rhythms are determined by the LD cycle although the onset of the cryophase, in the absence of a photocycle, may exert some influence on the nighttime rise in melatonin. The developmental rise in plasma T(4), and drop in plasma melatonin, occurred on both 14.5L:9.5D and 24L, indicating, taken together with previous work, that these climactic changes were independent of temperature and light cycling.