General Multistage Gatekeeping Procedures

Dmitrienko, Alex; Tamhane, Ajit C.; Wiens, Brian L.

doi:10.1002/bimj.200710464

Cited by 110 publications

(152 citation statements)

References 24 publications

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“…This corresponds to 280 patients per active treatment arm and 140 for placebo, with an assumed dropout rate of 11%. The type I error rate across all treatment comparisons for change from baseline in HbA 1c at 26 weeks was controlled at 0.025 (one-sided) by tree gatekeeping (10). P values were adjusted so that each could be compared with 0.025 to assess significance while accounting for multiplicity adjustments (11).…”

Section: Statistical Analysesmentioning

confidence: 99%

Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1)

et al. 2014

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OBJECTIVETo compare the efficacy and safety of dulaglutide, a once-weekly GLP-1 receptor agonist, with placebo and exenatide in type 2 diabetic patients. The primary objective was to determine superiority of dulaglutide 1.5 mg versus placebo in HbA 1c change at 26 weeks. RESEARCH DESIGN AND METHODSThis 52-week, multicenter, parallel-arm study (primary end point: 26 weeks) randomized patients (2:2:2:1) to dulaglutide 1.5 mg, dulaglutide 0.75 mg, exenatide 10 mg, or placebo (placebo-controlled period: 26 weeks). Patients were treated with metformin (1,500-3,000 mg) and pioglitazone (30-45 mg). Mean baseline HbA 1c was 8.1% (65 mmol/mol). RESULTSLeast squares mean 6 SE HbA 1c change from baseline to the primary end point was 21.51 6 0.06% (216.5 6 0.7 mmol/mol) for dulaglutide 1.5 mg, 21.30 6 0.06% (214.2 6 0.7 mmol/mol) for dulaglutide 0.75 mg, 20.99 6 0.06% (210.8 6 0.7 mmol/mol) for exenatide, and 20.46 6 0.08% (25.0 6 0.9 mmol/mol) for placebo. Both dulaglutide doses were superior to placebo at 26 weeks (both adjusted one-sided P < 0.001) and exenatide at 26 and 52 weeks (both adjusted one-sided P < 0.001). Greater percentages of patients reached HbA 1c targets with dulaglutide 1.5 mg and 0.75 mg than with placebo and exenatide (all P < 0.001). At 26 and 52 weeks, total hypoglycemia incidence was lower in patients receiving dulaglutide 1.5 mg than in those receiving exenatide; no dulaglutide-treated patients reported severe hypoglycemia. The most common gastrointestinal adverse events for dulaglutide were nausea, vomiting, and diarrhea. Events were mostly mild to moderate and transient. CONCLUSIONSBoth once-weekly dulaglutide doses demonstrated superior glycemic control versus placebo and exenatide with an acceptable tolerability and safety profile.

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Section: Statistical Analysesmentioning

confidence: 99%

Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1)

et al. 2014

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“…A sequential tree gatekeeping strategy was used to control the family-wise type 1 error rate. 8 Simultaneous noninferiority tests of dulaglutide 1.5 mg and 0.75 mg versus placebo were conducted with a multiplicity adjusted 1-sided α of 0.0135. If noninferiority between dulaglutide and placebo was achieved, then superiority testing was performed.…”

Section: Statistical Analysesmentioning

confidence: 99%

Effects of the Once-Weekly Glucagon-Like Peptide-1 Receptor Agonist Dulaglutide on Ambulatory Blood Pressure and Heart Rate in Patients With Type 2 Diabetes Mellitus

et al. 2014

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Abstract-Glucagon-like peptide-1 receptor agonists, used to treat type 2 diabetes mellitus, are associated with small reductions in systolic blood pressure (SBP) and increases in heart rate. However, findings based on clinic measurements do not adequately assess a drug's 24-hour pharmacodynamic profile. The effects of dulaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, on BP and heart rate were investigated using ambulatory BP monitoring. Patients (n=755; 56±10 years; 81% white; 48% women), with type 2 diabetes mellitus, taking ≥1 oral antihyperglycemic medication, with a clinic BP between 90/60 and 140/90 mm Hg were randomized to dulaglutide (1.5 or 0.75 mg) or placebo subcutaneously for 26 weeks. Ambulatory BP monitoring was performed at baseline and at 4, 16, and 26 weeks. The primary end point was change from baseline to week 16 in mean 24-hour SBP, a tree gatekeeping strategy compared the effects of dulaglutide to placebo. Both doses of dulaglutide were noninferior to placebo for changes in 24-hour SBP and diastolic blood pressure, and dulaglutide 1. 5,6 and has been shown to reduce body weight in many subjects. 6 The present study (NCT01149421) investigated the effects of dulaglutide on BP and HR during 26 weeks using 24-hour ambulatory blood pressure monitoring (ABPM) in patients with T2DM. Methods Study DesignThe study was a randomized, double-blind, multicenter, placebo-controlled, 26-week trial designed to evaluate the effects of dulaglutide when compared with placebo on BP and HR in patients with T2DM with or without hypertension and BP<140/90 mm Hg. After a 2-week placebo screening and run-in period, eligible patients were randomly assigned using a computer-generated random sequence to injectable placebo or 1.5 or 0.75 mg of dulaglutide (1:1:1) once weekly for 26 weeks and followed up for an additional 4-week off-therapy. Study visits occurred approximately every 4 weeks through 16 weeks, and then at 26 weeks with interim phone follow-up. Randomization was stratified by site and hypertension status (previous diagnosis and the use of antihypertensive medications or a new diagnosis if SBP≥130 mm Hg or DBP ≥80 mm Hg on ≥2 separate days 7 versus normotensive). PopulationPatients were recruited from 76 centers in Argentina, Brazil, Canada, Czech Republic, Denmark, India, Puerto Rico, and the United States. Men and women ≥18 years of age with T2DM, a glycated hemoglobin A1c ≥7.0% and ≤9.5%, on ≥1 oral antihyperglycemic medication for ≥1 month (≥3 months if taking a thiazolidinedione), body mass index ≥23 kg/m 2 , and a stable body weight (±5% for ≥3 months), were included. Mean seated BP was required to be between >90/60 and <140/90 mm Hg, and patients with hypertension had to be taking ≤3 classes of antihypertensive medications (same regimen, ≥1 month). Exclusion criteria were a recent (<3 months) major cardiovascular event, mean seated HR<60 or >100 bpm, history of tachyarrhythmia, pancreatitis, clinically significant hepatic disease, renal impairment (estimated glomerular filtration r...

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“…In addition, the Dunnett-Bonferroni-based procedure shares some similarities with the multi-stage Dunnett-based procedure introduced in Dmitrienko et al [20]. The multi-stage gatekeeping procedure splits a based on the observed number of accepted hypotheses in the primary family F 1 , and therefore a 0 is unique.…”

Section: Discussionmentioning

confidence: 96%

A Dunnett–Bonferroni‐based parallel gatekeeping procedure for dose–response clinical trials with multiple endpoints

Nuamah

Liu

et al. 2008

Pharmaceutical Statistics

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This paper proposes a Dunnett-Bonferroni-based parallel gatekeeping procedure in a setting of dose-response clinical trials with multiple endpoints. It follows the Dunnett-based parallel gatekeeping strategy of Dmitrienko et al. (Pharm. Stat. 2006; 5:19-28), but differs in the calculation of the critical values. The implementation of the Dunnett-based parallel gatekeeping procedure relies on assumptions difficult to justify in typical clinical trials, namely (a) that the joint distribution of the test statistics from different endpoints can be approximated by a multivariate-t distribution and (b) that the true correlation between multiple endpoints can be well estimated using observed data. The proposed Dunnett-Bonferroni-based parallel gatekeeping procedure relaxes the preceding assumptions by splitting type I error rate among families using the Bonferroni inequality. While it is potentially less powerful than a Dunnett-based procedure when both procedures are applicable, the power loss is very minimal. Our proposed method avoids assumptions that might be challenged by regulatory agencies and does so with virtually no cost. Moreover, in most cases this method is easier to implement compared with the Dunnett-based procedure.

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General Multistage Gatekeeping Procedures

Cited by 110 publications

References 24 publications

Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1)

Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1)

Effects of the Once-Weekly Glucagon-Like Peptide-1 Receptor Agonist Dulaglutide on Ambulatory Blood Pressure and Heart Rate in Patients With Type 2 Diabetes Mellitus

A Dunnett–Bonferroni‐based parallel gatekeeping procedure for dose–response clinical trials with multiple endpoints

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