scholarly journals Two-Stage Single-Arm Trials Are Rarely Analyzed Effectively or Reported Adequately

2021 ◽  
pp. 1813-1820
Author(s):  
Michael J. Grayling ◽  
Adrian P. Mander
Keyword(s):  
Final Stage ◽  
Interim Analysis ◽  
Primary Outcome ◽  
Point Estimate ◽  
Two Stage ◽  
Stage Design ◽  
Patient Subgroup ◽  
Future Studies ◽  
Point Estimates ◽  
Outcome Trial

PURPOSE Two-stage single-arm designs have historically been the most common design used in phase II oncology. They remain a mainstay today, particularly for trials in rare subgroups. Consequently, it is imperative such studies be designed, analyzed, and reported effectively. We comprehensively review such trials to examine whether this is the case. METHODS Oncology trials that used Simon's two-stage design over a 5-year period were identified and reviewed. They were evaluated for whether they reported sufficient design (eg, required sample size) and analysis (eg, CI) details. Articles that did not adjust their inference for the incorporation of an interim analysis were also reanalyzed. RESULTS Four-hundred twenty-five articles were included. Of these, just 47.5% provided the five components that ensure design reproducibility. Only 1.2% and 2.1% reported an adjusted point estimate or CI, respectively. Just 55.3% provided the final stage rejection bound, indicating many trials did not test a hypothesis for their primary outcome. Trial reanalyses suggested reported point estimates underestimated treatment effects and reported CIs were too narrow. CONCLUSION Key design details of two-stage single-arm trials are often unreported. Their inference is rarely performed such as to remove bias introduced by the interim analysis. These findings are particular alarming when considered against the growing trend in which nonrandomized trials make up a large proportion of all evidence on a treatment's effectiveness in a rare biomarker-defined patient subgroup. Future studies must improve the way they are analyzed and reported.

scholarly journals Exact confidence limits for the response rate in two-stage designs with over- or under-enrollment in the second stage

2016 ◽  
Vol 27 (4) ◽  
pp. 1045-1055 ◽  
Author(s):  
Guogen Shan
Keyword(s):  
Study Design ◽  
Response Rate ◽  
Sample Space ◽  
P Value ◽  
Two Stage ◽  
Stage Design ◽  
Second Stage ◽  
Point Estimates ◽  
Exact Confidence Intervals ◽  
Early Phase Clinical Trials

Simon’s two-stage design has been widely used in early phase clinical trials to assess the activity of a new investigated treatment. In practice, the actual sample sizes do not always follow the study design precisely, especially in the second stage. When over- or under-enrollment occurs in a study, the original critical values for the study design are no longer valid for making proper statistical inference in a clinical trial. The hypothesis for such studies is always one-sided, and the null hypothesis is rejected when only a few responses are observed. Therefore, a one-sided lower interval is suitable to test the hypothesis. The commonly used approaches for confidence interval construction are based on asymptotic approaches. These approaches generally do not guarantee the coverage probability. For this reason, Clopper-Pearson approach can be used to compute exact confidence intervals. This approach has to be used in conjunction with a method to order the sample space. The frequently used method is based on point estimates for the response rate, but this ordering has too many ties which lead to conservativeness of the exact intervals. We propose developing exact one-sided intervals based on the p-value to order the sample space. The proposed approach outperforms the existing asymptotic and exact approaches. Therefore, it is recommended for use in practice.

A phase II study investigating biological effects of maintenance usage of hydroxychloroquine on Par-4 levels in patients with resected tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3085-3085
Author(s):  
Peng Wang ◽  
Ravshan Burikhanov ◽  
Heidi Weiss ◽  
Rani Jayswal ◽  
Susanne M. Arnold ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Disease Progression ◽  
Phase Ii ◽  
Interim Analysis ◽  
Phase Ii Study ◽  
Biological Effects ◽  
Fold Increase ◽  
Two Stage ◽  
Stage Design

3085 Background: Hydroxychloroquine (HCQ) is an inducer of the tumor suppressor Par-4 (prostate apoptosis response-4) secretion from normal cells. Secreted Par-4 causes paracrine apoptosis of tumor cells in mice. Established dosing of HCQ 200 mg bid induces Par-4 secretion but not the autophagy-inhibition marker p62 and correlates with apoptosis induction in patients' tumors. Methods: This is a single-arm, single institute phase II study to characterize the biological effects of 3-months of HCQ at fixed-dose (200 mg p.o. twice a day) on plasma Par-4 levels in adults with resected solid tumors. The primary endpoint is proportion of patients who will exhibit a two-fold increase in Par-4 levels from baseline compared to 3 months of follow-up. 12-month progression free survival (PFS) is one of the secondary endpoints. A Simon's two-stage design was used to test the null hypothesis that the proportion of patients exhibiting a two-fold increase in Par-4 is equal to 50% compared to 70% using a one-sided alternative. These hypothesized assumptions are based on a small pilot human data and from a phase I clinical trial on a small number of patients (n = 9). The first stage of interim analysis will be performed after a total of 15 patients have been accrued. If there are eight or fewer responses occurred, the study will be stopped. Otherwise, 28 additional patients will be accrued for a total of 43 subjects. Results: A total of 19 patients were enrolled in the trial. Per protocol, the interim analysis and stopping boundary is based on the first 15 patients. A total of 4 out of 15 patients (26.7%) 95% CI: 8% - 55% exhibited a >2-fold increase in Par-4 levels at 3 months. This did not surpass the stopping bound for futility and thus indicates stopping of patient accrual based on the assumptions used for the Simon's two-stage design. 7 out of 19 patients (36.8%) 95% CI: 16% - 62% who exhibited at least a 2-fold increase at either 2 or 3 months of follow-up, 50% (95% CI: 26% - 74%) and 56% (95% CI: 31% -79%) exhibited a 1.5-fold and 1.25-fold increase respectively. To date, 10/19 patients finished 12-month follow-up, 4/19 and 5/19 finished 6-month and 3-month follow up respectively. 2 of 12 patients with less than 2-fold increase of Par-4 developed disease progression. None of 7 patients with 2-fold increase of Par-4 showed disease progression. Conclusions: Despite that the study was terminated prematurely, to our knowledge this is the first study in human to identify dynamic changes of serum Par-4 while on long-term of usage of HCQ. We also demonstrate trend of PFS benefit especially for subjects having 2-fold increase of Par-4 induction. Identification of tumors more Par-4 sensitive and predictive biomarkers of Par-4 induction are necessary to continue our investigation. Clinical trial information: NCT02232243.

Tubular electrostatic precipitators of two-stage design

1981 ◽  
Vol 6 (1-6) ◽  
pp. 239-244 ◽  
Author(s):  
Harish S. Surati ◽  
Michael R. Beltran ◽  
Isaac Raigorodsky
Keyword(s):  
Two Stage ◽  
Stage Design ◽  
Electrostatic Precipitators ◽  
Two Stage Design

Iron Oxidation and Jarosite Precipitation in a Continuous Two-Stage 70°C Archaeal Bioreactor

2015 ◽  
Vol 1130 ◽  
pp. 230-233
Author(s):  
Anna H. Kaksonen ◽  
Christina Morris ◽  
Jason Wylie ◽  
Jian Li ◽  
Kayley Usher ◽  
...  
Keyword(s):  
Iron Oxidation ◽  
Volume Index ◽  
Redox Potentials ◽  
Continuous Stirred Tank Reactor ◽  
Two Stage ◽  
Dominant Form ◽  
Stage Design ◽  
Hydrometallurgical Processing ◽  
Co Precipitation ◽  
Cstr System

This study is the first demonstration of a continuous culture bio-catalysed iron oxidation and jarosite precipitation reactor using thermophilic archea, for use in hydrometallurgical process flow sheets. A two-stage continuous stirred tank reactor (CSTR) system comprised of two CSTRs, each with its own settler, was operated for biological iron oxidation and precipitation at 70°C. The two-stage design was to allow the growth of microorganisms that prefer various redox regimes. The bioreactors were inoculated with a mixed culture of extreme thermophilic iron oxidisers from genera Acidianus, Metallosphaera and Sulfolobus. The influent (pH 1.5) contained (g L-1) 15 Fe2+, 1.5 Cu, 1.5 Ni (all as sulfates), nutrients and trace elements. At a hydraulic retention time (HRT) of 6-7 h in each CSTR, the overall iron oxidation rate was 1.0±0.1 g L-1 h-1 and percent 97±2%. The pH values were 1.38±0.16 and 1.57±0.05, and redox potentials (Ag/AgCl reference) were474±47 mV and 575±1 mV, in CSTR1 and CSTR2, respectively. The percentages of influent Fe, Cu and Ni removed as precipitates from settlers were 52%, 0.46% and 0.03%, respectively. The precipitates were comprised of jarosite (100%), potassium jarosite being the dominant form (38-51%), followed by hydronium (30-35%), ammonium (13-18%) and sodium jarosites (6-9%). The precipitates had a sludge volume index of 5.8-19 mL g-1, indicating good settling properties facilitating easy removal through settling. The simultaneous and instantaneous addition of contaminants (g L-1: 2.0 Al, 0.05 As, 0.05 F, 0.2 Co, 5.0 Mg and 0.4 Mn), potentially contained in hydrometallurgical processing streams, into the influent decreased the iron oxidation (50% overall oxidation with HRT of 26-29 h in each CSTR) and jarosite content in precipitates (85-87%). In conclusion, the two-stage high-temperature CSTR system allowed iron oxidation and precipitation of the oxidised iron in the form of well settling jarosite with only minor loss of Cu and Ni via co-precipitation. However, the bioreactor performance was hampered by the introduction of other transition metals, fluoride and arsenic.

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