Use of composite outcomes to assess risk–benefit in clinical trials

2018 ◽  
Vol 15 (4) ◽  
pp. 352-358 ◽  
Author(s):  
Pamela A Shaw
Keyword(s):  
Clinical Success ◽  
Clinical Status ◽  
Data Safety Monitoring Board ◽  
Nuisance Parameters ◽  
Decision Tool ◽  
Test Statistic ◽  
Treatment Groups ◽  
Novel Treatment ◽  
Composite Outcomes ◽  
Net Clinical Benefit

Before a novel treatment can be deemed a clinical success, an assessment of its risk–benefit profile must be made. One of the inherent challenges for this assessment comes from the multiplicity that arises from comparing treatment groups across multiple outcomes. Composite outcomes that summarize a patient’s clinical status, or severity, across a prioritized list of safety and efficacy outcomes have become increasing popular. In this article, we review these approaches and illustrate through examples some of the challenges and complexities of a composite derived from prioritized outcomes, such as the win ratio. These challenges include the difficult tension between the analytical validity that comes from choosing a pre-specified outcome and an evaluation that is responsive to unexpected safety events that arise during the course of a trial. Other challenges include a sensitivity of the resulting test statistic to the underlying censoring distribution and other nuisance parameters. Approaches that resolve some of the difficulties of the analytical challenges associated with prioritized outcomes are then discussed. Ultimately, a composite outcome of net clinical benefit is another decision tool, but one to be used alongside more traditional analyses of efficacy and safety, and with the broader perspective that investigators, the data safety monitoring board, and regulators bring to an evaluation of risk–benefit.

scholarly journals A FLEXIBLE NONPARAMETRIC TEST FOR CONDITIONAL INDEPENDENCE

2015 ◽  
Vol 32 (6) ◽  
pp. 1434-1482 ◽  
Author(s):  
Meng Huang ◽  
Yixiao Sun ◽  
Halbert White
Keyword(s):  
Conditional Independence ◽  
Kernel Smoothing ◽  
Nonparametric Test ◽  
Nuisance Parameters ◽  
Local Power ◽  
Test Statistic ◽  
Conditional Moment ◽  
Finite Samples ◽  
Monte Carlo Experiments ◽  
Logistic Functions

This paper proposes a nonparametric test for conditional independence that is easy to implement, yet powerful in the sense that it is consistent and achieves n−1/2 local power. The test statistic is based on an estimator of the topological “distance” between restricted and unrestricted probability measures corresponding to conditional independence or its absence. The distance is evaluated using a family of Generically Comprehensively Revealing (GCR) functions, such as the exponential or logistic functions, which are indexed by nuisance parameters. The use of GCR functions makes the test able to detect any deviation from the null. We use a kernel smoothing method when estimating the distance. An integrated conditional moment (ICM) test statistic based on these estimates is obtained by integrating out the nuisance parameters. We simulate the critical values using a conditional simulation approach. Monte Carlo experiments show that the test performs well in finite samples. As an application, we test an implication of the key assumption of unconfoundedness in the context of estimating the returns to schooling.

Rehabilitation Protocols After Isolated Meniscal Repair: A Systematic Review

2016 ◽  
Vol 45 (7) ◽  
pp. 1687-1697 ◽  
Author(s):  
Kevin O’Donnell ◽  
Kevin B. Freedman ◽  
Fotios P. Tjoumakaris
Keyword(s):  
Systematic Review ◽  
Range Of Motion ◽  
Significant Variation ◽  
Clinical Success ◽  
Meniscal Repair ◽  
Postoperative Rehabilitation ◽  
Treatment Groups ◽  
Rehabilitation Protocols ◽  
Outcome Scores ◽  
The Ideal

Background: Current postoperative rehabilitation protocols after isolated meniscal repair vary widely. No consensus exists with regard to the optimal amount of weightbearing, range of motion, or speed at which the patient progresses through the rehabilitation phases. Confounding factors including concomitant ligamentous or cartilaginous injuries have made studying isolated meniscal tears problematic. Purpose: To systematically review and evaluate the influence of range of motion and weightbearing status during the postoperative rehabilitation period after isolated meniscal repair on clinical efficacy and outcome scores. Study Design: Systematic review. Methods: A search of PubMed, Scopus, and Cochrane Central Register of Controlled Trials was conducted. The selection criteria for inclusion were English-language in vivo clinical studies reporting on isolated meniscal repairs utilizing an arthroscopically assisted technique that outlined the postoperative rehabilitation protocol and included at least a 2-year follow-up. Titles, abstracts, and articles were reviewed, and data concerning patient demographics, tear type, repair technique, postoperative protocol details, clinical failures, and outcome scores were extracted from the eligible studies. Rehabilitation protocols were divided into “accelerated,” “motion restricted,” “weight restricted,” and “dual restricted” according to the limitations placed on the treatment groups. Results: Fifteen studies, containing 17 different treatment groups, met the inclusion criteria. The 2 accelerated groups, 2 motion-restricted groups, 4 weight-restricted groups, and 9 dual-restricted groups showed similar efficacy in terms of clinical success and postoperative outcome scores. Early range of motion and weightbearing status showed no influence over clinical outcomes. Of the 17 groups, 13 reported a greater than 70% clinical success rate with significant variation in the tear type, fixation technique, and postoperative restrictions. Conclusion: Early range of motion and immediate postoperative weightbearing appear to have no detrimental effect on the chances for clinical success after isolated meniscal repair. Significant variation exists between postoperative protocols, with no current consensus on the ideal parameters for weightbearing and range of motion. Studies reporting outcomes regarding isolated meniscal repair are limited. Future research should include determining the ideal combination of weightbearing and range of motion for specific tear types.

Targeting the cell cycle for cancer therapy in rhabdomyosarcoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10535-10535 ◽  
Author(s):  
Elizabeth Stewart ◽  
Victoria Honnell ◽  
Monica Ocarz ◽  
Kaley Blankenship ◽  
Jason Dapper ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Treatment Strategies ◽  
Heat Shock Protein 90 ◽  
Complete Response ◽  
Phase Iii ◽  
Pharmacokinetic Studies ◽  
Durable Response ◽  
Treatment Groups ◽  
Novel Treatment

10535 Background: Rhabdomyosarcoma (RMS) is an aggressive malignancy of childhood with a poor prognosis in patients with metastatic or recurrent disease. Inhibitors of Wee1 kinase and heat shock protein 90 (HSP90) have in vitro activity in RMS and have emerged as potential novel treatment strategies. We performed a comprehensive preclinical phase III study to compare the Wee1 inhibitor AZD1775 and HSP90 inhibitor ganetespib (GANET) in combination with irinotecan (IRN) and vincristine (VCR). Methods: Orthotopic xenografts (O-PDXs) were created by injecting luciferase labeled RMS cells into the hind-leg muscle of CD-1 nude mice. Pharmacokinetic studies on RMS O-PDXs were performed to determine matched human AUC-guided dosing. A total of 540 O-PDXs derived from 4 high risk RMS patients, 2 alveolar and 2 embryonal, were randomly enrolled into 14 treatment groups. Six courses of blinded placebo-controlled therapy were given on a clinically relevant schedule. Mice were classified as having progressive disease if tumor approached 20% body weight at any time in the study. For mice completing all 6 courses, bioluminescence was used to determine complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Results: The addition of AZD1775 to IRN and VCR demonstrated the most significant response for all 4 O-PDX lines tested; 70% of mice achieved a CR or PR. GANET combined with IRN and VCR had a 54% response (CR + PR) which was not significantly better than IRN plus VCR for most O-PDXs tested. Overall response data for select treatment groups is shown in the table below. Conclusions: Comprehensive preclinical testing using multiple O-PDX models of RMS that represent the clinical spectrum of disease is feasible. Comparison of novel treatment regimens to standard of care at clinically relevant doses is warranted as justification for future clinical trials. Observation to assess durable response following completion of therapy is ongoing to determine if AZD1775 remains a promising treatment strategy. [Table: see text]

scholarly journals Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Liang Chen ◽  
Ellen G. Press ◽  
Brian A. Potoski ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Clinical Success ◽  
Severity Of Illness ◽  
Content Type ◽  
Treatment Groups ◽  
Treatment Regimens ◽  
Carbapenem Resistant ◽  
Underlying Diseases

ABSTRACT There are no data comparing outcomes of patients treated with ceftazidime-avibactam versus comparators for carbapenem-resistant Enterobacteriaceae infections. At our center, ceftazidime-avibactam treatment of carbapenem-resistant Klebsiella pneumoniae bacteremia was associated with higher rates of clinical success (P = 0.006) and survival (P = 0.01) than other regimens. Across treatment groups, there were no differences in underlying diseases, severity of illness, source of bacteremia, or strain characteristics (97% produced K. pneumoniae carbapenemase). Aminoglycoside- and colistin-containing regimens were associated with increased rates of nephrotoxicity (P = 0.002).

scholarly journals Prospective randomized comparison of cefepime and cefotaxime for treatment of bacterial meningitis in infants and children.

1995 ◽  
Vol 39 (4) ◽  
pp. 937-940 ◽  
Author(s):  
X Sáez-Llorens ◽  
E Castaño ◽  
R García ◽  
C Báez ◽  
M Pérez ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Bacterial Meningitis ◽  
Clinical Status ◽  
Infants And Children ◽  
Treatment Groups ◽  
Treatment Regimens ◽  
Duration Of Illness ◽  
Neurologic Sequelae ◽  
History Of ◽  
In Infants And Children

Ninety infants and children were prospectively randomized to receive cefepime (n = 43) or cefotaxime (n = 47) for therapy of bacterial meningitis. The two treatment groups were comparable in terms of age, duration of illness before enrollment, history of seizures, clinical status on admission, and etiology. Six (7%) patients died--two treated with cefepime and four treated with cefotaxime. Clinical response, cerebrospinal fluid sterilization, development of complications, antibiotic toxicity, and hospital stay were similar for the two treatment regimens. Concentrations of cefepime in cerebrospinal fluid varied from 55 to 95 times greater than the maximal MIC required by the causative pathogens. Audiologic and/or neurologic sequelae were found in 16% of the cefepime-treated patients and 15% of the cefotaxime-treated patients examined 2 to 6 months after discharge. We conclude that cefepime is safe and therapeutically equivalent to cefotaxime for management of bacterial meningitis in infants and children.

scholarly journals Adaptive Contrast Test For Dose-Response Studies

2021 ◽  
Author(s):  
Masahiro Kojima
Keyword(s):  
Simulation Study ◽  
Dose Response ◽  
Recommended Dose ◽  
Test Statistic ◽  
Significance Level ◽  
Treatment Groups ◽  
Type 1 Error ◽  
Higher Power ◽  
Sample Data ◽  
Dose Response Study

Abstract Background: A confirmation of dose-response is complicated by the need to adjust for multiplicity. We propose a simple and powerful adaptive contrast test with ordinal constraint contrast coefficients determined by observed responses.Methods: The adaptive contrast test can perform using easily calculated contrast coefficients and existing statistical software. We provide the sample SAS program codes of analysis and calculation of power for the adaptive contrast test. After the adaptive contrast test shows the statistically significant dose-response, we consider to select the best dose-response model from multiple dose-response models. Based on the best model, we identify a recommended dose. We demonstrate the adaptive contrast test for sample data. In addition, we show the calculation of coefficient, test statistic, and recommended dose for the actual study. We perform the simulation study with eleven scenarios to evaluate the performance of the adaptive contrast test.Results: We confirmed the statistically significant dose-response for the sample data and the actual study. In the simulation study, we confirmed that the adaptive contrast test has higher power in most scenarios compared to the conventional method. In addition, we confirmed that the type 1 error rate of the adaptive contrast test was maintained at a significance level when there was no difference between the treatment groups.Conclusions: We conclude that the adaptive contrast test can be applied unproblematically to the dose-response study.

scholarly journals A Randomized Clinical Trial Comparing Eyetronix Flicker Glass and Patching for Treatment of Amblyopia in Children Reveals Similar Improvements in Vision

2021 ◽  
Vol 15 ◽  
Author(s):  
Seung Hyun Min ◽  
Shijia Chen ◽  
Jinling Xu ◽  
Bingzhen Chen ◽  
Hui Chen ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Randomized Clinical Trial ◽  
Contrast Sensitivity ◽  
Primary Outcome ◽  
Secondary Outcome ◽  
Clinical Trial Registration ◽  
Treatment Groups ◽  
Corrected Visual Acuity ◽  
Novel Treatment ◽  
Best Corrected Visual Acuity

PurposeRecently, Eyetronix Flicker Glass (EFG) has been introduced as a novel treatment for amblyopia. It alternatively deprives the visual input of each eye rapidly (e.g., 7 Hz). However, whether it is comparable with standard patching therapy is unclear. In this randomized clinical trial, we evaluate the efficacy of an EFG therapy as treatment for amblyopia in children and compare it to the patching therapy.MethodsWe tested 31 children (aged 4–13 years) with amblyopia. They were assigned into one of the two treatment groups and were treated for 12 weeks. The first group was treated with EFG for 1 h/day (Flicker Group) and the latter with a standard patch (Patching Group) for 2 h/day. We designated changes from baseline in best-corrected visual acuity (BCVA) of the amblyopic eye as our primary outcome. Changes from baseline in other visual outcomes, such as contrast sensitivity, stereopsis, and fusional vergence range were measured as secondary outcome.ResultsBCVA improved significantly at 12 weeks relative to baseline in both the Flicker (0.13 ± 0.11 logMAR; mean ± SD) and Patching Groups (0.21 ± 0.14 logMAR). However, the improvements were not significantly different between groups (p = 0.13). Contrast sensitivity also significantly improved at 3 and 12 cycles/degree between baseline and 12 weeks in both groups (p’s < 0.05). However, stereopsis and fusion range did not improve significantly in both groups.ConclusionAn EFG therapy and patching improved BCVA similarly for children with amblyopia at 12 weeks. Both therapies improved the contrast sensitivity at 3 and 12 cycles per degree (cpd); however, only patching improved the contrast sensitivity at 6 cpd. Both therapies did not benefit binocular visual functions (stereopsis and fusional vergence range). We believe that EFG can be an additional choice for therapy.Clinical Trial Registrationchictr.org number: ChiCTR2000034436.

scholarly journals Phase II Clinical Study of BC-3781, a Pleuromutilin Antibiotic, in Treatment of Patients with Acute Bacterial Skin and Skin Structure Infections

2013 ◽  
Vol 57 (5) ◽  
pp. 2087-2094 ◽  
Author(s):  
W. T. Prince ◽  
Z. Ivezic-Schoenfeld ◽  
C. Lell ◽  
K. J. Tack ◽  
R. Novak ◽  
...  
Keyword(s):  
Clinical Success ◽  
Clinical Success Rate ◽  
Response To Treatment ◽  
Clinical Response Rate ◽  
Success Rates ◽  
Gram Positive ◽  
Content Type ◽  
Skin Structure ◽  
Treatment Groups ◽  
Vancomycin Group

ABSTRACTThis study investigated the potential of the novel systemic pleuromutilin antibiotic BC-3781 to treat patients with an acute bacterial skin and skin structure infection (ABSSSI) caused by a Gram-positive pathogen. Patients were randomized to intravenous BC-3781 100 mg, BC-3781 150 mg, or vancomycin 1 g every 12 h. Response to treatment was assessed daily and at test of cure (TOC). The primary endpoint was the clinical success rate at TOC in the modified intent-to-treat (MITT) and clinically evaluable (CE) analysis populations. Baseline characteristics, including the frequency of methicillin-resistantStaphylococcus aureus(MRSA), were comparable between the different treatment groups. Of 210 patients randomized, 186 (88.6%) patients completed the study. Clinical success at TOC in the CE population occurred in 54 (90.0%) patients in the BC-3781 100-mg group, 48 (88.9%) in the BC-3781 150-mg group, and 47 (92.2%) in the vancomycin group. At day 3, the clinical response rate was similar across the three treatment groups. Six patients discontinued study medication following an adverse event. The incidence rate for drug-related adverse events was lower for patients receiving BC-3781 (34.3% and 39.4% in the 100-mg and 150-mg groups, respectively) than those receiving vancomycin (53.0%). When BC-3781 was used to treat ABSSSIs caused by a Gram-positive pathogen, including MRSA, clinical success rates were comparable to those of the comparator, vancomycin. BC-3781 was generally well tolerated. These results provide the first proof of concept for the systemic use of a pleuromutilin antibiotic for the treatment of ABSSSIs.

Efficacy and Safety of Azithromycin as Monotherapy or Combined with Metronidazole Compared with Two Standard Multidrug Regimens for the Treatment of Acute Pelvic Inflammatory Disease

2003 ◽  
Vol 31 (1) ◽  
pp. 45-54 ◽  
Author(s):  
CD Bevan ◽  
GL Ridgway ◽  
CD Rothermel
Keyword(s):  
Chlamydia Trachomatis ◽  
Pelvic Inflammatory Disease ◽  
Inflammatory Disease ◽  
Clinical Success ◽  
Mycoplasma Hominis ◽  
Efficacy And Safety ◽  
Successful Management ◽  
Once Daily ◽  
Treatment Groups ◽  
Acute Pelvic Inflammatory Disease

The objective of the study was to compare the efficacy of azithromycin, alone or with metronidazole, versus two standard multidrug regimens for the treatment of acute pelvic inflammatory disease (PID). Patients with PID were treated with once-daily intravenous (IV) azithromycin 500 mg for 1 day or 2 days followed by once-daily azithromycin 250 mg orally for a total of 7 days, alone or with three-times-daily metronidazole 400 mg or 500 mg IV then orally for a total of 12–14 days. The comparators were either metronidazole + doxycycline + cefoxitin + probenecid or doxycycline + amoxycillin/clavulanate given at standard recommended doses for up to 21 days. In total, 309 patients were treated for PID. The diagnosis was confirmed laparoscopically in 74.8% of patients. Rates of clinical success for azithromycin, alone (97.1%) or with metronidazole (98.1%), were comparable to those for the comparator regimens (94.6%). Eradication rates for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma hominis and anaerobes were also comparable for each of the treatment groups. Both azithromycin regimens were well tolerated. In conclusion, azithromycin, alone or with metronidazole, provides a shorter, simpler treatment option for the successful management of acute PID.

scholarly journals Efficacy of Omadacycline Versus Moxifloxacin in the Treatment of Community-Acquired Bacterial Pneumonia by Disease Severity: Results From the OPTIC Study

2021 ◽  
Vol 8 (6) ◽  
Author(s):  
Julio Ramirez ◽  
Daniel H Deck ◽  
Paul B Eckburg ◽  
Marla Curran ◽  
Anita F Das ◽  
...  
Keyword(s):  
Disease Severity ◽  
Mortality Risk ◽  
Bacterial Pneumonia ◽  
Clinical Success ◽  
Risk Scores ◽  
Chronic Obstructive ◽  
Success Rates ◽  
Risk Class ◽  
Treatment Groups ◽  
Disease Characteristics

Abstract Background Severity/mortality risk scores and disease characteristics may assist in deciding whether patients with community-acquired bacterial pneumonia (CABP) require outpatient treatment or hospitalization. The phase 3 OPTIC (Omadacycline for Pneumonia Treatment In the Community) study enrolled patients with Pneumonia Outcomes Research Team (PORT) risk class II–IV. Omadacycline demonstrated noninferiority to moxifloxacin in adults with CABP, at early clinical response (ECR) and posttreatment evaluation (PTE). We assessed efficacy of omadacycline versus moxifloxacin in these patients based on disease severity. Methods Patients were randomized 1:1 to receive intravenous (IV) omadacycline (100 mg every 12 hours for 2 doses followed by 100 mg daily [q24h], with optional transition to omadacycline 300 mg orally q24h after 3 days of IV treatment) or moxifloxacin IV 400 mg q24h (with optional transition to 400 mg orally q24h after 3 days of IV treatment). Total treatment duration was 7–14 days. We compared rates of early clinical success (72–120 hours after first dose) and investigator-assessed clinical success at PTE (5–10 days after last dose) in subgroups based (1) on severity/mortality risk scores (PORT, CURB-65, systemic inflammatory response syndrome, quick Sequential [Sepsis-related] Organ Failure Assessment, modified ATS, SMART-COP) and (2) on presence of baseline radiographic characteristics, chronic obstructive pulmonary disease (COPD)/asthma, or bacteremia. Results Altogether, 774 patients (omadacycline, n = 386; moxifloxacin, n = 388) were randomized. Clinical success rates (ECR/PTE) were similar between treatment groups (across all subgroups). Efficacy across treatment groups was similar in patients with baseline radiographic characteristics or COPD/asthma, but moxifloxacin had higher clinical success rates in patients with bacteremia. Conclusions Efficacy of omadacycline was similar to that of moxifloxacin, regardless of disease severity/mortality risk and disease characteristics.

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