Testing strategies in multi-dose experiments including active control

Bauer, Péter; Röhmel, Joachim; Maurer, Willi; Hothorn, Ludwig A.

doi:10.1002/(sici)1097-0258(19980930)17:18<2133::aid-sim901>3.0.co;2-2

Cited by 157 publications

(99 citation statements)

References 2 publications

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“…Patients who discontinued the randomized study medication for whatever reason were censored at the time of discontinuation as defined in the analysis plan prior to data analysis. A sequentially ordered testing strategy was a priori defined such that the primary safety endpoint (NODAT or IFG) was tested first and as the result was statistically significant, the primary efficacy endpoint was also tested in a confirmative way without further adjustment of the significance level (25,26). The primary safety analysis was based on a superiority null hypothesis and the primary efficacy analysis on a noninferiority null hypothesis whereby CsA-ME was to be inferred noninferior to tacrolimus if the upper limit of the 95% confidence interval for the difference observed was less than the noninferiority margin of 10%.…”

Section: Discussionmentioning

confidence: 99%

Results of an International, Randomized Trial Comparing Glucose Metabolism Disorders and Outcome with Cyclosporine Versus Tacrolimus

Vincenti

Friman

Scheuermann

et al. 2007

American Journal of Transplantation

551

353

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Clinical trials registry: ClinicalTrials.gov Trial identifier number: NCT00171496DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C 2 Monitoring Versus Tacrolimus) was a 6-month, open-label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novo renal transplant patients were randomized to cyclosporine microemulsion (CsA-ME, using C 2 monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent-to-treat population comprised 682 patients (336 CsA-ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new-onset diabetes after transplant (NO-DAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA-ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy-proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA-ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft-Gault) was 63.6 ± 20.7 mL/min/1.73 m 2 in the CsA-ME cohort and 65.9 ± 23.1 mL/min/1.73 m 2 with tacrolimus (p = 0.285); mean serum creatinine was 139 ± 58 and 133 ± 57 lmol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post-transplant is significantly lower with CsA-ME than with tacrolimus without a significant difference in short-term outcome.

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Section: Discussionmentioning

confidence: 99%

Results of an International, Randomized Trial Comparing Glucose Metabolism Disorders and Outcome with Cyclosporine Versus Tacrolimus

Vincenti

Friman

Scheuermann

et al. 2007

American Journal of Transplantation

551

353

View full text Add to dashboard Cite

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“…The significance of the differences in the mean RTV between the treated and control groups on day 15 was analyzed using the Aspin-Welch two-tailed t-test. The combinational effect of targeted agents on the antitumor activity was analyzed according to a closed testing procedure using the Aspin-Welch two-tailed t-test (25) and EXSAS, ver. 7.11 (Arm Systex Co., Ltd., Osaka, Japan).…”

Section: Real-time Reverse Transcription (Rt)-polymerase Chain Reactimentioning

confidence: 99%

Combination therapy using oral S-1 and targeted agents against human tumor xenografts in nude mice

Nukatsuka

Saitô

Nakagawa

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. In this study, combination therapies using the oral fluoropyrimidine tegafur-gimeracil-oteracil (S-1) with several targeted agents or antibodies, were evaluated. First, the effects of tyrosine kinase inhibitors (erlotinib hydrochloride, sorafenib tosilate and sunitinib malate) against human nonsmall cell lung cancer (NSCLC), breast cancer and colorectal cancer were evaluated in vivo. The effects of the combination of S-1 and targeted antibodies (bevacizumab and cetuximab) against human colorectal cancers was also evaluated in vivo. S-1 and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, showed a significant inhibition of growth in human NSCLC (Lu-99 and PC-9 cell lines). The antitumor activity of the combination of S-1 and erlotinib against Lu-99 and PC-9 cancer cell lines was significantly superior to either monotherapy (P<0.05). Combination therapy using the multi-tyrosine kinase inhibitors, sorafenib or sunitinib, with S-1 against breast cancer (MX-1 cell line) and NSCLC (NCI-H460 cell line) was significantly superior to either monotherapy (P<0.01). The combination of the anti-vascular endothelial growth factor antibody bevacizumab or the anti-EGFR antibody, cetuximab, with S-1 against human colorectal cancer [Col-1, KM20C (bevacizumab) and DLD-1 (cetuximab) cell lines] and a 5-fluorouracil (5-FU)-resistant cell line (KM12C/5-FU) was significantly superior to either monotherapy (p<0.01). In particular, the growth of the Col-1 cells was completely inhibited by the combination of S-1 and bevacizumab. No toxic mortalities and no significant difference in the body weight changes of the animals treated with S-1 combined with the targeted agents or with the monotherapies were observed; therefore, the treatments appeared to be well-tolerated. Our preclinical findings indicate that the combination therapies of S-1 and targeted agents are promising treatment options. IntroductionNew targeted agents, i.e., targeted antibodies and tyrosine kinase inhibitors, have been developed and used clinically against various cancers (colorectal, lung, kidney and breast cancer, etc.). As the antitumor activity of these agents originates from anti-angiogenesis or the inhibition of growth signals, and thus differs from that of traditional chemotherapeutic agents, these targeted agents reportedly enhance antitumor activity when used in combination with chemotherapy by means of their different mechanisms (1-5).Tegafur-gimeracil-oteracil (S-1), an oral fluoropyrimidine, is composed of 1 M tegafur [a masked form of 5-fluorouracil (5-FU)], 0.4 M 5-chloro-2, 4-dihydroxypyrimidine [gimeracil, a potent inhibitor of the 5-FU degradation enzyme dihydropyrimidine dehydrogenase (DPD) in the liver and tumor tissues] and 1 M potassium oxonate (oteracil, which mainly inhibits the phosphorylation of 5-FU in the gastrointestinal tract) (7). S-1 has been clinically shown to be effective against various human cancers (8) and to have a potent antitumor efficacy, with a low gastrointestinal toxicity, against var...

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“…Bauer et al, 1998). This order can be a natural one in the sense that testing a hypothesis is only of interest if another hypothesis has been rejected, or the order is given by some expectations that it is easier to reject certain hypotheses than other ones.…”

Section: :3 a Priori Ordered Hypothesesmentioning

confidence: 99%