Assessing non‐inferiority of a new treatment in a three‐arm clinical trial including a placebo

Pigeot, Iris; Schäfer, Juliane; Röhmel, Joachim; Hauschke, Dieter

doi:10.1002/sim.1450

Cited by 128 publications

(235 citation statements)

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“…(12) It was assumed that the placebo-adjusted effect for both treatment groups was 1.56% and that the placebo-adjusted effect for the oral rsCT tablets must be at least 0.5 times the placebo-adjusted effect for the ssCT nasal spray for the study to demonstrate the non-inferiority of the oral rsCT tablets to the ssCT nasal spray. Thus we wished to have 95% confidence that the oral tablets were not less than one-half as effective as nasal spray.…”

Section: Discussionmentioning

confidence: 99%

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: The oral calcitonin in postmenopausal osteoporosis (ORACAL) trial

Binkley

Bolognese²,

Sidorowicz-Bialynicka³

et al. 2012

Journal of Bone and Mineral Research

130

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The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active-and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (!1000 mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean AE SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% AE 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% AE 2.9%) or placebo (0.5% AE 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis. ß

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Section: Discussionmentioning

confidence: 99%

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: The oral calcitonin in postmenopausal osteoporosis (ORACAL) trial

Binkley

Bolognese²,

Sidorowicz-Bialynicka³

et al. 2012

Journal of Bone and Mineral Research

130

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“…for the standardized difference). Pigeot et al (2003) or Tang & Tang (2004) investigated trials where the noninferiority margin δ 1 for a new treatment compared to a standard treatment is specified as a fraction of the true difference between the standard treatment and placebo. This setting can also be treated with help of the LR test -both asymptotically and exact.…”

Section: Discussionmentioning

confidence: 99%

“…See e.g. Wiens & Iglewicz (1999) and Tang & Tang (2004) for an account of methods for the assessment of noninferiority with binary data, or Pigeot, Schäfer, Röhmel & Hauschke (2003) for the case of normal responses.…”

Section: Introductionmentioning

confidence: 99%

Testing noninferiority in three‐armed clinical trials based on likelihood ratio statistics

et al. 2007

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Clinical noninferiority trials with three (or more) groups recently have received much attention, e.g. due to the fact that regulatory agencies often require that a placebo group has to be evaluated in addition to a new experimental drug and an active control. We discuss the likelihood ratio tests for binary endpoints and various noninferiority hypotheses. We find that, depending on the particular hypothesis, either the LR test reduces asymptotically to the intersection union test, or to a test which follows asymptotically a mixture of generalized χ 2 -distributions. The performance of this asymptotic is investigated and an exact modification is given. It is shown that this test considerably outperforms multiple testing methods with respect to power, such as the Bonferroni adjustment. The methods are illustrated with a cancer study where antiemetic agents were compared. Finally, we discuss the extension of the results to other settings, such as normal endpoints.

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“…[11][12] The approach illustrated here considers having the outcome variables that are normally distributed with common but unknown variances and that higher values correspond to better efficacy. The statistical procedure follows the one proposed in earlier study, 12 that is testing superiority of reference against placebo in the first place, and then followed with testing non-inferiority of experimental treatment against the reference, provided that superiority can be established in the first stage. The hypothesis formulation in the second stage is given as follows:…”

Section: 20 Statistical Design For Three-arm Non-inferiority Trialsmentioning

confidence: 99%

“…Note that Equation (2) is slightly different from the previous study, 12 since it considers expressing the sample sizes in experimental and reference groups as proportions of those in the placebo group. Thus, the total sample size, N for a clinical study is given as:…”

Section: 20 Statistical Design For Three-arm Non-inferiority Trialsmentioning

confidence: 99%

Determination of the Required Sample Size with Assurance for Three-Arm Non-Inferiority Trials

2013

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The concept of assurance in the two-arm non-inferiority trials has been explored, expressing the noninferiority margin as a clinically meaningful treatment difference. This short paper focuses on developing an assurance formula in the three-arm non-inferiority trial, based on the ratio of means. The discussion starts with the simple case of known variances and then extends to the case of unknown but equal variances. To avoid complicated integration, assurance for the latter case was studied using Bayesian Clinical Trial Simulation (BCTS). The findings indicate that assurance allows the experimenter to formally take into account the uncertainty surrounding the parameter estimates by using the prior distributions. Furthermore, BCTS can be easily implemented to find the required sample size without having to resort to complex integration.Keywords: Assurance; power; non-inferiority trial; three-arm design; BCTS AbstrakKajian kaedah jaminan di dalam ujian tidak-inferior dua-kumpulan telah pun dibuat dengan mewakilkan margin tidak-inferior sebagai perbezaan rawatan yang bermakna (dalam konteks klinikal). Fokus kertas ini pula adalah terhadap pembentukan formula jaminan di dalam ujian tidak-inferior tiga-kumpulan, yang mewakilkan margin tidak-inferior sebagai nisbah min. Perbincangan dimulakan dengan kes asas di mana varians populasi dianggap diketahui dan dilanjutkan pada kes varians populasi tidak diketahui. Oleh kerana kes yang kedua ini melibatkan kamiran kompleks, kaedah jaminan telah diaplikasikan dengan bantuan Bayesian Clinical Trial Simulation (BCTS). Hasil kajian mendapati bahawa kaedah jaminan membolehkan penyelidik mengambil kira secara formal ketidakpastian berkenaan anggaran parameter yang terlibat di dalam pencarian saiz sample, iaitu dengan mewakilkan ketidakpastian tersebut menggunakan taburan prior yang bersesuaian. Selain itu, BCTS boleh diaplikasikan dengan mudah untuk mencari saiz sampel yang diperlukan tanpa perlu menyelesaikan masalah kamiran yang kompleks.Kata kunci: Jaminan; kuasa; ujian tidak-inferior; rekabentuk 3-kumpulan, BCTS

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Assessing non‐inferiority of a new treatment in a three‐arm clinical trial including a placebo

Cited by 128 publications

References 10 publications

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: The oral calcitonin in postmenopausal osteoporosis (ORACAL) trial

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: The oral calcitonin in postmenopausal osteoporosis (ORACAL) trial

Testing noninferiority in three‐armed clinical trials based on likelihood ratio statistics

Determination of the Required Sample Size with Assurance for Three-Arm Non-Inferiority Trials

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